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Ferrari, Anna C., Yu-Hui Chen, Gary R. Hudes, Michael Anthony Carducci, Emmanuel S. Antonarakis, Noah M. Hahn, Yu-Ning Wong e Robert S. DiPaola. "E2809: Androgen receptor (AR) modulation by bicalutamide (Bic) and MK-2206 (MK) in men with rising PSA at high-risk of progression after local prostate cancer (PC) treatment." Journal of Clinical Oncology 34, n.º 2_suppl (10 de janeiro de 2016): 9. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.9.
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9 Background: Men with PSA recurrence and fast PSA doubling time (PSADT) are at high risk of progression. While castration effectively decreases PSA and delays metastases, it compromises heath and quality of life without clear survival benefit. E2809 tested whether blocking Akt with MK alone or together with the AR using Bic, would be more effective than Bic alone to suppress AR activity without castration. Methods: 108 PSA-recurrent N0 M0, non-castrate PC patients (pts) with PSADT<12 months (mo) and PSA>2ng/mL; were randomized 1:1 to 11, 4-week (wk) treatment (tx) cycles (cy), up to18cy: arms (A) cy1-3, observation, cy 4-11, Bic 50 mg daily; (B) cy1-3 MK 200 mg once wk orally, cy 4-11 MK+Bic. Endpoints: Primary: proportion of pts with PSA <0.2 by cy11 (90% power to detect 45% vs. 20% using 0.1 level one-sided Fisher’s exact test); Secondary, PSA decline: ≥85%; nadir levels before and after Bic. Toxicity (Tox). Results: 54 pts/arm. Baseline characteristics (median (m) or %, A/B): age, 66/67 years; Gl>7 81/81%; >T2b 98/86%; prostatectomy, 81/75%; radiation, 30/31%; previous castration, 43/46%; testosterone, 302/333 ng/dL; PS 0, 94/93%; mPSA 5.1/6.1ng/dL; PSADT<9 mo, 87/81%, <3 mo 24/37%; Tox. Grade(G)/n: G4: A, 0; B, 2 (embolism, hyperglycemia). G3: A, 1(LFTs); B, 32, 60% (rash 20, hyperglycemia 5, low lymphs, 5; hypertension, 4). At 23.9 mo follow-up, 1 death B. Tx . A: 4 no tx; 14 (26%) started Bic early; 9 (16.7%) stopped <11cy without SAE’s; 41 (76%) completed 11cy, 23 (43%) 18cy. B: 7 (13%) started Bic early; 21 (39%) stopped <11cy due to AE’s in 14 (66%) cases; 32 (59%) completed 11cy, 14 (26%) 18cy. PSA<0.2 at 44wks (cy11): A, 6 (11.1%); B, 8 (14.8%), p=0.39. Among evaluable pts, PSA ≤0.2 occurred only after Bic: A: 10/49 pts (20.4%); B: 16/45 pts (35.6%), p=0.08. Conclusions: Overall, by intent to treat analysis at 44 wks, MK alone had no effect on PSA, nor did it increase response to Bic by any set criteria. High MK discontinuation due to rash before cy11 may have blunted the significance of a higher proportion of evaluable pts on MK+Bic achieving PSA ≤0.2ng/ml compared to Bic alone. Clinical trial information: 01251861.
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Romero, Samuel, Juan Montoro, Jaime Sanz, Marta Guinot, Empar Mayordomo, Rafael López, Isabel Beneyto et al. "Comparative Study of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation Versus Hematopoietic Stem Cell Transplantation". Blood 126, n.º 23 (3 de dezembro de 2015): 4358. http://dx.doi.org/10.1182/blood.v126.23.4358.4358.
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Abstract Introduction. Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of both solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT). However, differences in clinical and biological characteristics between the two procedures are not well established. Methods. We retrospectively evaluated 84 consecutive patients diagnosed of PTLD at a single institution between 1993 and 2014. Results. Sixty-three cases occurred after SOT (25 hepatic, 20 renal, 10 cardiac, 9 pulmonary and 1 double-leg transplant) and 21 after HSCT (18 unrelated donor, 16 umbilical cord blood, 2 haploidentical and 2 HLA-identical sibling). There was a male predominance (73% in SOT and 62% in HSCT). Median age at transplant was 53 years (range, 11-76) in SOT and 43 years (range, 18-59) in HSCT (p=0.03). EBV serostatus before transplant was positive in 78% and 92% for SOT and HSCT recipients, respectively. Table 1 summarizes clinical and biological characteristics at diagnostic of PTLD. Briefly, HSCT patients had 89% of B symptoms compared to 60% in the SOT group (p<0.001). WaldeyerÕs ring, spleen and liver involvement was 25%, 45% and 45%, respectively, in the HSCT group; and 5% (p=0.03), 17% (p=0.03) and 13% (p=0.007), respectively, in the SOT group. There was a higher Ann Arbor stage in the HSCT group compare to the SOT group (p<0,05). Time from transplant to PTLD was 4 months (range, 1-27) and 60 months (range, 3-246) for HSCT and SOT group, respectively. Table 1. Clinical and biological characteristics at diagnostic of PTLD SOT HSCT p - value Time from transplant to PTLD (months), median (range) 60 (3 - 246) 4 (1- 27) <0.0001 Early onset, n (%) 14 (22) 19 (90.5) Late onset, n (%) 28 (44) 2 (9.5) Very late onset, n (%) 20 (32) 0 (0) B symptoms, n (%) 33 (60) 16 (89) <0.001 Nodal involvement, n (%) 33 (59) 12 (67) 0.75 WaldeyerÕs ring 3 (5) 5 (25) 0.03 Spleen 10 (17) 9 (45) 0.03 Extranodal involvement, n (%) 35 (58) 16 (80) 0.1 Bone marrow 8 (14) 6 (30) 0.2 Central nervous system 4 (7) 5 (25) 0.07 Liver 8 (13) 9 (45) 0.007 Gastrointestinal 13 (22) 2 (10) 0,4 Lung 7 (12) 1 (5) 0,7 Kidney 6 (10) 1 (5) 0,8 LDH (U/L), median (range) 568 (201 - 2415) 702 (328 - 1515) 0.24 ECOG 1 0-1 41 (87) 8 (89) 2-4 6 (13) 1 (11) Ann Arbor stage <0.05 I 12 (21.4) 1 (4.8) II 8 (14.3) 3 (14.3) III 8 (14.3) 0 (0) IV 28 (50.0) 17 (81.0) WHO classification, n (%) 0.2 Early lesion 0 (0) 0 (0) Polymorphic 7 (12.3) 4 (20) Monomorphic B 45 (79) 16 (80) DLBCL 36 (63.2) 16 (80) Others 9 (15.8) 0 (0) Monomorphic T/NK 3 (5.3) (0) Monomorphic E. Hodgkin 2 (3.5) (0) ND 6 (9.5) 1 (5) CD20+, n (%) 42 (86) 13 (68) 0.2 Most patients (95%) had received calcineurine inhibitors with other immunosuppressive agents. PTLD treatment was different between both groups (p=0.0001); in the SOT group, 22% received rituximab as monotherapy and 63% chemotherapy, as compared with 62% and 19% in the HSCT group, respectively. In SOT, 42 (70%) patients died at a median of 208 days (range, 0-4178) while in HSCT 19 (91%) patients died at a median of 26 days (range, 0-485) (p=0.002). Overall survival at 4 years was 35% for SOT and 7% for HSCT (p<0.0001). Most deaths were directly related to PTLD. Conclusions. PTLD after HSCT appears to be a different entity because of the earlier appearance after transplant, a more aggressive clinical presentation (B symptoms, nodal and extranodal involvement, higher Ann Arbor staging system) and a poorer survival outcome compared with PTLD after SOT. Disclosures No relevant conflicts of interest to declare.
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Yan, Xiao J., Daniel Kalenscher, Erin Boyle, Sophia Yancopoulos, Rajendra N. Damle, Aarti Damle, Houman Khalili et al. "Gene Set Enrichment Analysis of Ki-67high CLL Clones Suggests Complex Interactions of B-Cell Receptor Signaling and Normal Cell Interactions in the Disease". Blood 118, n.º 21 (18 de novembro de 2011): 2833. http://dx.doi.org/10.1182/blood.v118.21.2833.2833.
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Abstract Abstract 2833 Introduction: In chronic lymphocytic leukemia (CLL), clonally expanded CD5+ B lymphocytes eventually overwhelm healthy immune cells, hindering normal immune function. To determine mechanisms fueling this expansion, gene expression data were gathered by microarray analysis of cells from CLL patients. Samples were grouped based on Ki-67 expression, an indicator of proliferation. To determine mechanisms correlating with B-cell proliferation and impacting on CLL B-cell biology, microarray profiles were compared using Gene Set Enrichment Analysis (GSEA) [Subramanian A, et al. PNAS 2005]. Methods: Samples were analyzed for intracellular expression of Ki-67 by flow cytometry and divided into 2 groups based on Ki-67 expression (cutoff at 5%). RNA was then purified from CD5+CD19+ CLL cells and gene expression microarray assays were performed using Illumina HumanHT12 beadchips. GSEA was carried out using a library of signatures by Dr. Louis Staudt [Shaffer AL, et al. Immunol Rev 2006] containing 305 gene sets encompassing 13, 564 genes biased towards hematopoietic signatures. Results: Of 61 cases, 14 were Ki-67high and 47 were Ki-67low. When time-to-first-treatment (TTFT) was compared between the groups, Ki67high patients had significantly shorter TTFT (2.76 yrs) compared to Ki-67low patients (23.46 yrs; P<0.0001). By GSEA, we determined 255/285 gene sets were upregulated in the Ki-67high group with 50 gene sets significantly enriched at a false discovery rate (FDR) <25%. For the Ki-67low group, 30/285 gene sets were upregulated with only one significant at FDR <25%. IGHV unmutated CLL (U-CLL) was enriched in only one gene set, termed CLLUNMUT-1, while mutated CLL (M-CLL) was only enriched in CLLMUT-1. CD38high and CD38low subsets were similarly enriched in these two gene sets, with 4 additional gene sets in the CD38high group, including MYD88UP-4 and IFN-2. Of the 50 significantly enriched gene sets in the Ki-67high group, 17 relate to signaling pathways, 16 to cellular differentiation, 6 to cellular processes, 4 to transcription factor targets, and the remaining 7 relate to cancer. Of these, the percentage of the signaling component is up 13% from its representation in the original Staudt library. The top 5 gene sets enriched in the Ki-67high group are: upregulated U-CLL compared to M-CLL (CLLUNMUT-1), myeloid tissue compared to other tissues (MYELOID-1), T cell cytokine induced proliferation (TCYTUP-8), BCR crosslinking CLL B cells (CLLBCRUP-1) and BDCA4+ dendritic cells compared to other hematopoietic cells (DC-1). The total number of genes enriched in these 50 sets is 769, with 217 genes shared in two or more gene sets. Twenty genes were enriched in the CLL BCR signature, CLLBCRUP-1 [Herishanu Y, et al. Blood 2011]. Of these, WARS, IRF4, MX1, OAS1, and NAMPT are also enriched in the T cell cytokine induced and T cell activation signatures. Only one gene set was enriched in the Ki-67low group, CLLMUT-1, upregulated in M-CLL compared to U-CLL. CD274 (PD-L1) was consistently elevated in the Ki-67low group in all the patients, irrespective of IGHV mutation status. Discussion: The observed GSEA profiles in Ki-67high patients correlated with gene signatures biased towards BCR signaling, signal transduction, and hematopoietic cancer, consistent with the Ki-67high group containing more (recently) proliferating cells influenced at least in part by BCR signaling. The profiles also suggest that additional cells (T lymphocytes and dendritic cells) may be involved. It is notable these gene sets were not observed for CLL patients subgrouped by IGHV mutation status or by CD38, and that these other subsets did not show as pronounced a distinction by GSEA profiling. Disclosures: No relevant conflicts of interest to declare.
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Amisha, Fnu, Sunilkumar Kakadia e Akash Mukherjee. "Clinical Outcome of Refractory Lymphoma Patients with Non Response to Chimeric Antigen Receptor T Cell Therapy". Blood 138, Supplement 1 (5 de novembro de 2021): 4823. http://dx.doi.org/10.1182/blood-2021-154356.
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Abstract Background Chimeric antigen receptor T cell (CART) therapy has remarkably improved the outcome of patients (pts) with relapsed refractory B cell non-Hodgkin lymphoma. Anti-CD19 directed CART therapy have shown to yield durable remission in 40%-50% of patients with relapsed refractory (r/r) diffuse large B cell lymphoma (Neelapu et al. NEJM 2017; NCT 02348216). However, pts who had disease progression post CART therapy (non-responders) have poor outcomes. There is paucity of information regarding negative predictors for disease progression and outcome of non-responders post CART therapy. Methods We conducted a single center retrospective study of 11 patients with relapsed refractory large B cell lymphoma who underwent treatment with CART in our institution from December 2019 to June 2021 and further studied the baseline characteristics, and clinical outcome of 8 pts who were non responders to CART therapy. Results All patients received low dose fludarabine cyclophosphamide based lymphodepleting conditioning regimen followed by anti-CD19 directed CART cells using CD28 as costimulatory domain with a target dose of 2 x 10 6 cells /kilogram of body weight. Baseline characteristics as shown in [Table 1]. Median age at CART therapy was 61 years (range 49-71). Median ECOG score at CART therapy was 1. All patients had chemo refractory disease at time of CART therapy with 9 patients having refractory diffuse large B cell lymphoma and 2 patients had transformed large B cell lymphoma. Genomic studies showed high risk disease in 4 patients with double hit lymphoma, 3 patients with complex cytogenetics with one having 17 p deletion and 2 patients with double expressors of c-myc and bcl2. Only 5 patients had available Ki-67 score > 80%. All patients had stage III-IV disease at the time of CART therapy. Seven pts had extra nodal disease and one patient had CNS involvement. Median R-IPI score at time of CART therapy was 3 (range 2-4). Median LDH, serum ferritin and serum CRP at the time of CART therapy was 388 (range 136-1489); 831 (range 116.9-1503); and 28.1 (range 7.4-226) respectively. Median number of prior therapies were 3 (range 2-9). One patient had prior autologous stem cell transplant. Median absolute lymphocyte count (ALC) and platelet count at CART therapy was 0.01/ul (range 0.01-2.5) and 89 x 10 3/ul (range 10-385) respectively. Median time from last salvage chemotherapy to CART therapy was 62 days (range 28-492). Total six pts had cytokine release syndrome (CRS) with median time for CRS onset was 3.5 days (range 1-8) with all of them having grade 1-2 CRS. Total seven pts had neurotoxicity with median time for onset was 5 days (range 1-41) post CART with 4 pts having > grade 3 immune effector cell associated neurotoxicity syndrome (ICANS). Overall, six and seven pts received tociluzumab and steroids respectively for treatment of CART related CRS and ICANS. Day 30 PET/CT scan showed three responders (2CR,1PR) and eight non responder patients with disease progression. Non responder pts to CART, when compared with responders had higher value of median LDH (438 vs 300; p = 0.92); median CRP (29 vs 13; p = 0.497) ; higher extra nodal involvement ( 6 pts vs one), median R-IPI score at the time of CART ( 4 vs 3), median number of prior therapies (4 vs 3), and median time from last salvage therapy to CART ( 73 days vs 50 days ; p = 0.91). No difference in baseline ALC count and platelet count was noted between the two groups. Compared to responders, non-responder pts had lower incidence of CRS (100% vs 37.5%) and ICANS (100% vs 50%). Post CART therapy, non-responder pts were treated with Nivolumab based immunotherapy in 5 pts, Ipilimumab based therapy in 1 pt, Selinexor in 1 patient and Polatuzumab based therapy in 2 pts. Median progression free survival and overall survival of non-responders was only 30.5 days and 94 days respectively. 5 out of 8 non responder pts died (4 due to disease progression and 1 due to sepsis). All three responder pts were alive and disease free at the end of study. Median follow up of our study was 108 days (range 32- 561). Conclusions Despite smaller sample size, our study showed dismal outcome of pts who don't respond to CART therapy, showing an unmet need for better salvage therapies in such pts. Refractory lymphoma pts with extra nodal disease involvement, higher LDH and CRP at the time of CART therapy could be negative predictors for response. Further prospective studies with larger sample size required to further validate these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Zahid, Anza, Prema P. Peethambaram, Carrie A. Thompson, Minetta C. Liu, Kathryn Jean Ruddy, Sushil s. Luis, Malcolm s. Anastasius et al. "Descriptive evaluation of frequent patient referrals to our cardio-oncology clinic: The Mayo experience." Journal of Clinical Oncology 38, n.º 15_suppl (20 de maio de 2020): e14018-e14018. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14018.
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e14018 Background: Cancer survival rates are improving. Therefore, management of cardiovascular complications has now become a crucial clinical concern. Cardio-oncology is the sub-specialty that assists in the overall management of cancer patients in a multi-disciplinary manner. Mayo Clinic cardio-oncology practice was initiated to work closely with our oncology colleagues for early detection of cardiovascular complications in response to cancer-therapy. Majority of the patients visit our cardio-oncology clinic once, we thought it is important to study the group of patients that visited frequently due to cardiovascular complications. Aim: To evaluate the most common cardiovascular complication in patients with 2 or more visits to our cardio-oncology clinic. Methods: From 2012-2017, there were > 2500 patients visits to our clinic, with 24 patients having 2 or more visits. Data including patients’ demographics, ethnicity, chemotherapeutic medications, primary cancer type, cardiovascular risk factors, echocardiography and clinical outcomes were collected. Cardiotoxicity was defined as the decrease in left ventricular ejection fraction (LVEF) of > 10% to a value of < 53%. Heart failure was diagnosed based on Framingham’s criteria or by a cardiologist. Results: There were 19 women (80%) and 5 men (20%). Median age at the time of diagnosis was 56 years [19-76]. The most common malignancy was breast cancer (70%), followed by B-cell lymphoma (12%) and acute myeloid leukemia (8%). Thirty percent had > 2 risk factors for cardiovascular disease. 75% of the patients had an LVEF of < 53, of these 67% developed heart failure with 58% preserved and 42% reduced ejection fraction. Those with heart failure had received a mean anthracycline dose of 305 ± 91.8mg/m2. With initiation of ACEI, B-Blockers, and diuretics (GDMT) 79% showed recovery of LVEF to ≥53 during the follow up. Conclusions: In our experience, most patients who were seen at least twice in the cardio-oncology clinic for heart failure had received a dose of > 300mg/m2 anthracycline. With GDMT over 75% of the patients recovered. Care in the cardio-oncology clinic plays a key role in optimizing these clinical outcomes.
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Davids, Matthew Steven, Andrew Warwick Roberts, John Francis Seymour, William G. Wierda, Soham D. Puvvada, Lori A. Gressick, Debbie Alter et al. "Venetoclax (VEN) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL)." Journal of Clinical Oncology 35, n.º 15_suppl (20 de maio de 2017): e19041-e19041. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19041.
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e19041 Background: VEN is a selective orally bioavailable BCL-2 inhibitor. The dose-escalation Phase 1 study of VEN in 106 patients (pts) with relapsed/refractory NHL reported an ORR of 44%. Most pts had diffuse large B-cell/follicular lymphoma; we report on updated results in pts with less common NHL subtypes. Methods: VEN was administered and continued until progressive disease (PD)/unacceptable toxicity, in dose cohorts ranging from 300–1200 mg. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and response by 2007 Cheson IWG response criteria, utilizing CT scans beginning at wk 6. Results: 35 of 106 pts had mantle cell lymphoma (MCL, n=28), marginal zone lymphoma (MZL, n=3) or Waldenström macroglobulinemia (WM, n=4). Most common all grade treatment emergent AEs were nausea (51%), diarrhea (49%) and fatigue (34%); grade 3/4 AEs in >10% of pts were neutropenia and anemia (17% each). Laboratory TLS was reported in a single pt (bulky MCL). MCL pts (median age: 72 years) had received a median of 3 (1–7) prior treatments (tx). Median time from start of prior tx to start of VEN was 13 mo (2–148) and time on VEN was 11 mo (0.2–42). ORR was 75%, 6 pts (21%) achieved CR and remain on study (DORs: 25–40 mo). One pt with a PR proceeded to elective allogeneic stem cell transplant and remained disease free at last protocol defined follow-up (24 mo after coming off study). Median PFS was 11 mo and DOR was 15 mo. MZL pts (median age: 63 years) had received a median of 4 (2–6) prior tx. Time from start of prior tx to start of VEN was 8, 14, 73 mo and time on VEN was 5, 1, 35 mo. One pt (6 prior tx) received VEN for <1 mo due to progressive cytopenias; 1 pt (4 prior tx) achieved a PR with VEN at wk 6 but had PD at wk 16; 1 pt (2 prior tx) achieved PR at wk 6 and is the only pt to remain on study (DOR:32 mo). WM pts (median age: 67 years) had a median of 4 (3–5) prior tx. Time from start of prior tx to start of VEN was 5, 18, 33, 67 mo and time on VEN was 42, 17, 54, 20 mo. All pts achieved PR (at wks 6 [n=2], 16 and 36), with DORs of 11, 12, 38 and 50+ mo (latter is ongoing and remains on study). Conclusions: VEN monotherapy has a tolerable safety profile in MCL, MZL and WM pts. ORR were high and most responses durable; median PFS and DOR suggest significant activity in MCL pts. Further investigation of VEN in each disease is indicated. Clinical trial information: NCT01328626.
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Moccia, Moccia A., Jane Donaldson, Mukesh Chhanabhai, Paul Hoskins, Richard Klasa, Kerry J. Savage, Tamara Shenkier et al. "The International Prognostic Factor Project Score (IPS) in Advanced Stage Hodgkin Lymphoma Has Limited Utility in Patients Treated in the Modern Era." Blood 114, n.º 22 (20 de novembro de 2009): 1554. http://dx.doi.org/10.1182/blood.v114.22.1554.1554.
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Abstract Abstract 1554 Poster Board I-577 Introduction The International Prognostic Factor Project Score (IPS) is the most widely utilized risk stratification index for Hodgkin lymphoma (HL) (Hasenclever, N Engl J Med, 1998). Based on patients treated before 1992, it incorporates 7 adverse risk features (male gender, age ≥45 y, stage IV, hemoglobin <105 g/L, WBC ≥15 × 109/L, lymphocyte count <0.6 × 109/L or <8% of differential, albumin <40 g/L) and predicts for a 5-year freedom-from progression (FFP) ranging from 42-84%.The IPS has not been validated in a more recently treated population, where more accurate pathologic diagnosis, routine use of growth factors and enhanced supportive care may have improved outcomes compared with historic results. Methods This retrospective population-based analysis used the British Columbia Cancer Agency Lymphoid Cancer Database to identify all patients ages 15-65 y diagnosed from January 1st,1990 to June 30th, 2008 with advanced stage HL (stage III/IV, or stage I/II with B symptoms or bulky disease ≥10 cm), who were treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or an ABVD-equivalent regimen and had complete information including all IPS variables. Primary endpoint was FFP, defined as the interval from diagnosis to first progression or relapse or death due to treatment toxicity; deaths from unrelated causes were censored. Results 579 patients were identified. Median age was 29 y (range 15-65); 11 (2%) stage I, 239 (41%) stage II, 202 (35%) stage III and 127 (22%) stage IV; 245 (42.3%) had bulky disease; and 359 (62%) had B symptoms. Histologies included: 455 (79%) nodular sclerosing, 35 (6%) mixed cellularity, 7 (1%) lymphocyte-rich, 11 (2%) lymphocyte depleted, 13 (2%) nodular lymphocyte predominant, 58 (10%) HL NOS. 161 (28%) patients received IFRT with primary treatment. Adverse prognostic factors were present as follows: 119 (21%) age≥45, 375 (65%) albumin <40 g/L, 88 (15%) WBC ≥15 × 109/L, 116 (20%) hemoglobin <105 g/L, 57 (10%) lymphocyte count <0.6 × 109/L or <8%, 302 (52%) male, 127(22%) stage IV. Only 37 (6.4%) patients had a prognostic score ≥5. With a median follow-up of 73 months (range, 1-222), 512 (88.4%) patients were alive and 67 (11.6%) had died (39 with HL, 7 due to toxicity and 21 from unrelated causes). Five year FFP and overall survival (OS) were 79% and 91%, respectively. The IPS was prognostic for both FFP (p=.0035) and OS (p<.0001), with 5-y FFP ranging from 66% to 86% and 5-y OS ranging from 74% to 98% (Table 1). In univariate analysis only stage IV (p=.003) and hemoglobin (P=.001) were prognostic for FFP. Albumin (p=.054), age (p=.082) and WBC (p=.094) were borderline significant, but gender (p=.329) and lymphocyte count (P=.496) appeared to have a weaker prognostic value for FFP. Only stage IV (HR=1.63, CI 1.10-2.40, p=.014) and hemoglobin (HR=1.73, CI 1.17-2.57, p=.006) were prognostic for FFP in a multivariate Cox regression. Conclusion The IPS remains prognostic for patients with advanced stage HL treated in a more modern era. However, it does not identify risk groups with sufficiently good or poor outcome to justify deviation from standard therapy. Identification of truly low or high risk populations will require supplementation with molecular markers and/or the use of early PET scanning. Caution should be used when comparing results from current clinical trials to historic controls, since more recent outcomes with standard therapy are clearly superior to those previously reported. Disclosures No relevant conflicts of interest to declare.
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Issa, Ghayas C., Hagop M. Kantarjian, C. Cameron Yin, Koji Sasaki, Guillermo Garcia-Manero, Courtney DiNardo, Koichi Takahashi et al. "Prognostic Implications of Pre-Treatment Hypodiploidy and Complex Cytogenetics in Adult Patients with Acute Lymphocytic Leukemia (ALL) Treated with Hyper-CVAD". Blood 126, n.º 23 (3 de dezembro de 2015): 4874. http://dx.doi.org/10.1182/blood.v126.23.4874.4874.
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Abstract Background Pretreatment cytogenetic analysis is frequently used to predict response and outcome in hematologic malignancies. Hypodiploidy is associated with a poor prognosis in childhood ALL. Similarly, complex cytogenetics is a known adverse prognostic factor in myeloid malignancies. The impact of hypodiploidy and complex cytogenetics has not been extensively assessed in adult patients with ALL. To address this issue, we have conducted a retrospective analysis of all adult patients with ALL treated with frontline Hyper-CVAD based regimens at our institution. Methods We reviewed 332 adult patients treated between May 2000 and March 2015. Patients with Philadelphia-positive ALL and those with t(4;11) were excluded. Hyodiploidy was defined as 45 or less chromosomes. Hyperdiploidy was defined as 47 and more chromosomes. Complex karyotype was defined as having 5 or more chromosomal abnormalities (Moorman et al., Blood 2007). We analyzed the clinical outcomes based on the cytogenetic risk groups. Chi-square test was performed to evaluate differences in response rates. Survival was calculated using Kaplan-Meier estimates and compared using the log-rank test. Results Patient characteristics, responses to therapy, and outcomes are summarized in Table 1. Thirty-five patients (10%) were hypodiploid, 67 (20%) were hyperdiploid, and 71 (21%) had a complex karyotype. With a median follow-up of 28 months (range 0.5 - 176 months), the median survival was 61, 69, and 45 months for patients with diploid, hypodiploid, and hyperdiploid cytogenetics respectively. The 3-year survival rates were 63%, 59% and 53%, respectively (p=0.18). Similarly, having a complex karyotype did not affect survival when compared to diploid cytogenetics with a median survival of 58 and 61 months respectively. The 3-year survival rates were 63% and 59%, respectively (p=0.27). Conclusion Unlike what has been described in childhood ALL, the prognosis of adult ALL patients with a hypodiploid or complex karyotype treated with Hyper-CVAD based regimens is similar to patients with a diploid karyotype. This could be attributed to a different biology of the disease or could be related to the treatment given in this population. The use of genomics combined with cytogenetic analysis could perhaps constitute a better predictive biomarker. Table 1. Characteristics (n total=332) Diploid (n=147) Hypodiploid(n=35) Hyperdiploid(n=67) Complex (n=71) Median age, y (range) 44 (16-83) 58 (20-80) 54 (18-85) 58 (18-85) Sex no. (M/F) (182/150) 95/52 14/21 34/33 39/32 WBC, median x 109/L(range) 3.85 (0.4-216) 3.6 (0.7-420) 3.9 (0.6 -134) 3 (0.5-87) Hg, median g/L (range) 9.3 (3.5-16) 8.9 (4-11.9) 9.2 (4.5-14) 9.2 (5-14) Platelets, median x 109/L (range) 64 (1-626) 32 (7-233) 36 (7-271) 32 (7-233) Creatinine, median mg/dL (range) 0.9 (0.3-4) 0.8 (0.45-1.5) 0.8 (0.5-2.3) 0.8 (0.4-2.3) Bilirubin, median mg/dL (range) 0.5 (0-8) 0.6 (0.2-5.6) 0.5 (0.2-11) 0.5 (0.2-5.4) LDH, median IU/L (range) 839 (268-32029) 1460 (172-6408) 1177 (345-8953) 1241 (172-8953) Blasts in BM, median % (range) 78 (0-99) 88 (60-98) 83 (26-100) 84(26-97) Blasts in PB, median % (range) 12 (0-99) 36 (0-92) 26 (0-96) 26(0-100) B-ALL (n=282) n 120 33 63 65 T-ALL (n=50) n 27 2 4 6 Complete response (%) 92 88 88 88 3-year survival rate (%) 63 59 53 56 Disclosures DiNardo: Novartis: Research Funding. Cortes:Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.
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Rabaglio, Manuela, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel et al. "Abstract P4-01-25: Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer". Cancer Research 83, n.º 5_Supplement (1 de março de 2023): P4–01–25—P4–01–25. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-01-25.
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Abstract Background: The SAKK 22/99 is a phase III randomized clinical trial launched by the Swiss Group for Clinical Cancer Research and the European Institute of Oncology in Milan in 99 for women with HER2-positive advanced breast cancer (ABC). 175 patients were randomized 1:1 from Sept 99 to Jan 2013 to receive first-line trastuzumab (T) alone followed at disease progression by the combination with chemo (Arm A) vs the upfront combination of T and chemo (Arm B). The results were published in 2017 (O. Pagani et al Ann Onc 28: 305–312, 2017). The outcome was similar for sequential T-chemo or upfront combination The patients’ treatment and FU continued until March 2022 and we now report the safety data after 135.2 months of median FU. Patients and methods: at the time of study termination 1 patient with SD was still receiving T alone in the study and T was continued after trial closure. The safety analyses include 86 pts allocated to arm A and 88 to arm B. 1 pt did not receive any trial treatment and was excluded from this analyses. 19 of the 86 patients in arm A stopped trial treatment after T alone, 67 continued with T+ chemo. Baseline characteristics were well balanced and are summarized in Table 1. Treatment The T loading dose of 4 mg/kg/iv was followed by 2 mg/kg/iv weekly. In the 1st-line population (84) chemo was weekly paclitaxel (90 mg/m2/iv-3/4 weeks). After amendment 1 chemo was at investigator’s choice (taxanes, vinorelbine, platin) according to label indications and could be stopped after 24 weeks (6–8 cycles) in responding patients or after unacceptable toxicity. Results: 7 patients in arm A (8%) and 11 in arm B (13%) stopped trial treatment due to toxicities (Fisher’s exact test, p=0.46). 3 of the 7 patients in arm A stopped under T alone and 4 under T+chemo (all paclitaxel weekly) Treatment durations of these 7 and 11 patients were 7.7 months (range 0.5 – 49) in arm A and 5.5 months (range 0.6 – 31 months) in arm B, respectively. Cardiovascular toxicities: The most common toxicities were thromboembolic events, blood pressure disorders and arrhythmia. 6 patients (7%) in arm A and 10 (11%) in arm B had cardiac events (Fisher’s exact test, p=0.43). G1-3 toxicities occurred in 2 (2%), 2 (2%) and 2 (2%) patients of arm A and in 5 (7%), 2 (2%) and 3 (3%) of arm B. We observed no grade 4 events. Split by treatment phase in arm A, G1-3 toxicities were seen in in 1 (1%), 2 (2%) and 1 (1%) patient under T alone (N=86) and in 1 (1%), 0 (0%) and 2 (3%) under T+chemo (N=67). LVEF-decline: 78 patients in arm A and 74 in arm B had sequential LVEF measurements. A decline ≥ 10% was found in 35 patients (45%) in arm A and in 20 (27%) in arm B (Fisher’s exact test, p=0.028). Among the 35 patients in arm A, 12 had the decline under T alone, 14 under T+chemo, and 9 under both T alone and T+chemo. A decline ≥ 20% was found in 10 patients (13%) in arm A and in 3 (4%) in arm B (Fisher’s exact test, p=0.08). Among the 10 patients in arm A, 7 had the decline under T alone, 3 under T+chemo. Sensory neuropathy 43 patients (50%) in arm A and 48 (54%) in arm B had neuropathy (Fisher’s exact test, p=0.65). G1-3 toxicity in arm A was developed by 26 (30%), 11 (13%) and 6 (7%) patients, respectively; in arm B 30 (34%), 12 (14%) and 6 (7%). No grades 4 events occurred. Conclusion: After more than 11 years of follow-up, no relevant toxicities were found in these patients receiving T for ABC. In particular, the incidence and grade of cardiac toxicity was low. The decline in LVEF was numerically higher in the arm A and in particular in the T alone group, but was not clinically relevant. Our data potentially suggest that T+chemo followed by T maintenance could have less cardiotoxicity than T followed by T+chemo. The possible causes for the difference in LVEF decline between the two arms are unclear, but could be related to treatment duration. The women in Arm A shows a trend to longer therapy: Median treatment duration (months) in Arm A was 7.92 (0.46 - 135.98) vs 6.62 (0.56 - 71.28) in Arm B. This long-term analysis confirms the favorable safety and good tolerability of the reported regimes. Table 2: Treatment duration Citation Format: Manuela Rabaglio, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Stefan Aebi, Marcus Vetter, Beat Thuerlimann, Roger von Moos, Khalil Zaman, Olivia Pagani. Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-25.
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Квітіньйо Макарена Мартінез, Соріано Федеріко Ґонзало, Яйченко Вірджинія, Стіб Бренда e Барейро Хуан Пабло. "Predictors of Picture Naming and Picture Categorization in Spanish". East European Journal of Psycholinguistics 6, n.º 1 (30 de junho de 2019): 6–18. http://dx.doi.org/10.29038/eejpl.2019.6.1.cui.
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The aim of this paper was to identify which psycholinguistic variables are better predictors of performance for healthy participants in a picture naming task and in a picture categorization task. A correlation analysis and a Path analysis were carried out. The correlation analysis showed that naming accuracy and naming latency are significant and positively correlated with lexical frequency and conceptual familiarity variables, whereas they are negatively correlated with H index. Reaction times in the categorization task were negatively correlated with lexical frequency and conceptual familiarity variables and positively correlated with visual complexity variable. The Path analysis showed that subjective lexical frequency and H index are the better predictors for picture naming task. In picture categorization task, for reaction times, the better predictor variables were subjective lexical frequency, conceptual familiarity and visual complexity. These findings are discussed considering previous works on the field.
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Lykova, Inna, Ralph Rowe, Glenn Poirier, Henrik Friis e Kate Helwig. "Mckelveyite group minerals – Part 2: Alicewilsonite-(YCe), Na2Sr2YCe(CO3)6 ⋅ 3H2O, a new species". European Journal of Mineralogy 35, n.º 1 (28 de fevereiro de 2023): 143–55. http://dx.doi.org/10.5194/ejm-35-143-2023.
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Abstract. The new mckelveyite group mineral alicewilsonite-(YCe), ideally Na2Sr2YCe(CO3)6 ⋅ 3H2O, was found at Mont Saint-Hilaire, Quebec, Canada, and subsequently at the Saint-Amable sill, Quebec, Canada, and the Khibiny Massif, Kola Peninsula, Russia. Alicewilsonite-(YCe) crystals are commonly hemimorphic pseudotrigonal and pseudohexagonal and show barrel-shaped, saucer-shaped, spindle-shaped, cone-shaped, columnar, tabular, and platy habits. They are usually up to 2–3 mm in size with some larger crystals reaching 2–3 cm. The crystals often form stacked or parallel growth aggregates and rosettes. Alicewilsonite-(YCe) colour varies from pale yellow to yellow, lemon yellow, green yellow, orange-yellow, pale green to green, pale grey to grey, green grey, beige, and colourless. The streak is white; the lustre is vitreous. The cleavage is fair to indistinct, parallel to (001). The Mohs hardness is 3. Dcalc is 3.37 g cm−3. Alicewilsonite-(YCe) is optically biaxial (+), with α=1.554(3), β=1.558(3), γ=1.644(2), 2V (calc.) = 26∘, 2V (meas.) = 20(3)∘ (589 nm). The IR spectrum is reported. The composition (wt %, average of six analyses) is Na2O 7.42, CaO 0.72, SrO 21.49, BaO 1.41, Y2O3 8.52, La2O3 5.93, Ce2O3 9.52, Pr2O3 0.59, Nd2O3 1.75, Sm2O3 0.46, Gd2O3 0.83, Dy2O3 1.65, Ho2O3 0.34, Er2O3 1.21, Yb2O3 0.64, CO2 29.33, H2O 6.13, total 97.94. The empirical formula of the holotype calculated on the basis of six cations is Na2.11Ca0.11Sr1.83Ba0.08Y0.67(Ce0.51La0.32Pr0.03Nd0.09Sm0.02Gd0.04 Dy0.08Ho0.02Er0.06Yb0.03)Σ1.20(CO3)5.88 (H2O)3.00. The mineral is triclinic, P1, a=9.0036(6) Å, b=9.0175(6) Å, c=6.7712(5) Å, α=102.724(2)∘, β=116.398(2)∘, γ=60.003(2)∘, V=426.46(5) Å3, and Z=1. The strongest reflections of the powder X-ray diffraction pattern [d,Å(I)(hkl)] are 6.07(31)(001), 4.372(100)(120, 2‾1‾1, 11‾0), 4.037(25)(1‾11, 1‾2‾1, 210), 3.201(25)(121, 2‾1‾2, 11‾1), 2.831(67)(1‾12, 1‾2‾2, 211, 1‾21, 21‾0), 2.601(39)(030, 3‾3‾1,3‾01), 2.236(24)(2‾4‾1, 2‾21, 4‾2‾1). 2.019(23)(003, 2‾22, 2‾4‾2‾, 420). 1.9742(24)(032, 3‾03, 3‾3‾3, 331, 03‾2, 301). The crystal structure, solved and refined from single-crystal X-ray diffraction data (R1=0.055), is of the weloganite type.
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Varettoni, Marzia, Luca Arcaini, Silvia Zibellini, Emanuela Boveri, Sara Rattotti, Roberta Riboni, Alessandro Corso et al. "Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Patients with Waldenström Macroglobulinemia, IgM-Monoclonal Gammopathy of Undetermined Significance or Other Mature B-Cell Neoplasms." Blood 120, n.º 21 (16 de novembro de 2012): 2667. http://dx.doi.org/10.1182/blood.v120.21.2667.2667.
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Abstract Abstract 2667 Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic lymphoma associated with a monoclonal component of IgM type in the serum. WM is often preceded by an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The cumulative probability of progression of IgM-MGUS to WM or to other lymphoproliferative disorders is approximately 1.5% per year. Other mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and B-cell chronic lymphoproliferative disorders (B-CLPD) can carry an IgM monoclonal component and should therefore be considered in differential diagnosis with WM. In a study based on parallel sequencing of the whole genome of lymphoplasmacytic cells and paired normal tissue from WM patients, Treon et al (Blood. 2011;118:Abstract 300) have identified a highly recurrent somatic mutation with oncogenic activity in the myeloid differentiation primary response (MYD88) gene, leading to a change from leucine to proline at position 265 of the aminoacid sequence [MYD88 (L265P)]. Targeted Sanger resequencing showed MYD88 (L265P) in 90% of WM patients, but only in a minority of patients with IgM-MGUS or other mature B-cell neoplasms such as SMZL. We developed an allele-specific PCR for the MYD88 (L265P) mutation, and studied 58 patients with WM, 77 with IgM-MGUS, 84 with splenic marginal zone lymphoma (SMZL) and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). DNA was obtained from bone marrow cells (n=204) and peripheral blood (n=67). The aims of this study were: i) to assess the prevalence of the mutation in WM, IgM-MGUS, SMZL, and B-CLPD; ii) to analyze the relationship between MYD88 (L265P) mutation and clinical phenotype; iii) to evaluate the impact of the mutation on the risk of progression from IgM-MGUS WM or other lymphoproliferative disorders. The MYD88 (L265P) mutation was detected in 58/58 (100%) patients with WM, either asymptomatic (n=39) or symptomatic (n=18), and in 36/77 (47%) patients with IgM-MGUS. In addition, it was detected in 5/84 (6%) patients with SMZL and in 3/52 (6%) with B-CLPD; of these MYD88 (L265P)-positive subjects, 4 SMZL and 2 B-CLPD patients carried a serum IgM monoclonal component, while the remaining B-CLPD patient carried a double (IgM and IgG) monoclonal component. Compared with IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) had significantly higher levels of IgM (P<.0001), lower levels of IgG (P=.04) and IgA (P=.04), and higher incidence of Bence-Jones proteinuria at diagnosis (P=.002). During the follow-up, 9 patients with IgM-MGUS progressed to WM (7 cases) or to marginal zone lymphoma (2 cases). Using a case-control approach, the risk of evolution of patients with MYD88 (L265P) was significantly higher as compared to that of patients with wild-type MYD88 sequence (OR 4.7, 95% confidence interval 0.8–48.7, P=.047). In conclusion, the findings of this study indicate that: i) the allele-specific PCR we developed is able to detect the MYD88 (L265P) mutation in all patients with WM and in nearly half the patients with IgM-MGUS, and therefore represents a useful diagnostic tool; ii) MYD88 (L265P) is an uncommon molecular lesion in SMZL and in B-CLPD, but is associated with an IgM monoclonal component in the few positive patients, suggesting that some cases of B-CLPD might be included in the spectrum of WM; iii) in IgM-MGUS, the mutation is associated with greater disease burden and higher risk of disease progression, and therefore represents a useful prognostic marker. Disclosures: No relevant conflicts of interest to declare.
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Castillo, Jorge, Brady Beltran, Jaime Collins, Jose L. Diez-Martin, Francisco Hernandez-Ilizaliturri, Steven M. Horwitz e Julie M. Vose. "Clinicopathologic Characteristics of HIV-Associated Peripheral T-Cell Lymphoma." Blood 114, n.º 22 (20 de novembro de 2009): 3924. http://dx.doi.org/10.1182/blood.v114.22.3924.3924.
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Abstract Abstract 3924 Poster Board III-860 Introduction The incidence of lymphomas is increased in HIV-infected individuals. Most of the cases are B-cell subtypes of non-Hodgkin lymphoma. Although the incidence of mature or peripheral T-cell lymphomas (PTCL) seems to be increased in HIV-positive cases, clinicopathological data is lacking. The objective of this study is to describe the characteristics of non-cutaneous PTCL in HIV-infected individuals and identify potential prognostic factors. Methods Institutions within and outside of the United States were invited to submit original data on cases of HIV-associated PTCL. Data on each case included country of origin, age, sex, ethnicity, CD4 count, use of highly active antiretroviral therapy (HAART), B symptoms, lymphoma subtype according to the WHO classification of lymphoid neoplasms, expression of ALK, EBV and Ki-67, T-cell gene rearrangement, number of extranodal sites, bone marrow involvement, clinical stage, performance status, lactate dehydrogenase (LDH) levels, frontline therapy, response, use of stem cell transplantation (HSCT), final outcome, survival in months and cause of death; these will be presented using descriptive statistics. Univariate analyses were performed using Kaplan-Meier survival estimates compared using the log-rank test. Cox proportional-hazard regression test was used for the multivariate analysis. P-values of less than 0.05 were considered significant. Results Thus far, data on 24 cases have been obtained from 7 institutions. From these cases, 13 (54%) are from South America, 5 (21%) from Europe, 3 (12.5%) from North America and 3 (12.5%) from Asia. Thirteen cases (54%) are Hispanic, 5 (21%) are Caucasian, 3 (12.5%) are Black and 3 (12.5%) are Asian. Median age is 39 years (range 26 to 58 years) and the male-to-female ratio is 7:1. Sixteen cases (70%) presented with B symptoms. Median CD4 count is 129 cells/mm3 (range 4 to 305 cells/mm3). Twelve cases (63%) reported use of HAART. Fourteen cases (58%) are PTCL, unspecified (PTCLU), 4 cases (17%) anaplastic large cell lymphoma (ALCL), 4 cases (17%) of NK/T-cell lymphoma (NKTCL) and 2 cases (8%) angioimmunoblastic lymphoma (AITL). All ALCL cases were ALK-negative; EBV was expressed in 50% of NKTCL cases but in none of the AITL cases. Four of 15 cases (27%) had involvement of more than 2 extranodal sites, 3 of 11 cases (27%) had bone marrow involvement, 19 of 24 cases (79%) presented with advanced stage, 5 of 12 cases (42%) had an elevated LDH level and 8 of 24 cases (33%) had a performance status higher than 2. Thirteen of 24 cases (54%) were treated with chemotherapy alone from which 8 cases (62%) received CHOP therapy; six of 24 cases (25%) did not receive any therapy. Nine of 14 cases (65%) responded to therapy (29% CR and 36% PR); 35% of cases did not respond to therapy. Five cases of 14 (36%) underwent HSCT; 4 cases (29%) in the frontline and 1 case (7%) in the salvage setting. At the time of this report, 63% of cases have died; 53% due to infectious complications and 40% due to lymphoma progression. The median survival for the group was 10 months. The median survival for treated (n=19) and untreated cases (n=5) were 10.5 and 1 month, respectively (p=0.005). Conclusions HIV-associated PTCL tends to affect younger men with CD4 counts of less than 200 cells/mm3. PTCLU is the most common subtype reported in HIV-infected individuals. HIV-associated ALCL cases do not appear to express ALK. The survival of treated HIV-associated PTCL cases is short at 10.5 months despite a 65% initial response to therapy. Accumulation of data continues. Disclosures: No relevant conflicts of interest to declare.
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Yilmaz, Musa, Hagop M. Kantarjian, Jorge Cortes, Guillermo Garcia-Manero, Jad Chahoud, Farhad Ravandi, Koji Sasaki et al. "Results of Intensive Chemotherapy in 434 Adult Patients (pts) with Philadelphia-Negative Acute Lymphoblastic Leukemia (ALL): Predictive Prognostic Model for Survival". Blood 126, n.º 23 (3 de dezembro de 2015): 3722. http://dx.doi.org/10.1182/blood.v126.23.3722.3722.
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Abstract Introduction: Older age, poor performance status, diminished organ function and adverse genetic features are poor prognostic factors in treatment of ALL. Our goal is to develop prognostic models predicting complete response (CR), death in CR, 2-month mortality and survival in adult pts with ALL, which would be used to assist pts and oncologists to establish expectations with intensive chemotherapy. Methods: A total of 434 pts with ALL treated with intensive chemotherapy between 2000 and 2015 were analyzed. Frontline treatments included hyperCVAD alone (n=152) or in combination with rituximab (n=156) [Thomas D, et.al, JCO 2010], or ofatumumab (n=34), and Augmented-BFM (n=92) [Rytting ME, et al Cancer 2014]. Following clinical features were analyzed; age, gender, diagnosis (B or T-ALL), performance status (Zubrod), prior malignancy, prior chemotherapy, white blood cell count, platelet count, hemoglobin level, peripheral blood (PB) blast, bone marrow (BM) blast, mixed lineage leukemia (MLL) gene rearrangements, albumin level, total bilirubin level, estimated glomerular filtration rate (GFR by the Modification of Diet in Renal Disease Study equation) and chemotherapy type. Univariate and multivariate analyses of clinical features associated with CR, death in CR, 2-month mortality and survival were performed. Results: Pts characteristics are summarized in Table 1. The overall CR rate, death in CR rate, 2-month mortality rate, 1-year and 5-year survival rates were 94%, 15%, 8%, 80%, and 47%, respectively. In multivariate analysis, we identified prognostic factors associated with CR, death in CR, 2-month mortality, and survival (Table 2). Age > 40 years, performance status ≥ 2, total bilirubin >1 mg/dL, GFR < 60 mL/min/1.73m2, albumin < 3.5 g/dL, WBC > 50 x109/L and presence of MLL gene rearrangements were identified as independent adverse prognostic features for overall survival (OS). Because all predictive features identified had similar statistical impact, patients were divided into four different risk categories: 1) low (no adverse feature) 92 pts (21%), 2) intermediate-1 (1 adverse feature) 138 pts (32%), 3) intermediate-2 (2 adverse features) 111 pts (26%), and 4) high (≥ 3 adverse features) 93 pts (21%). Median OS survival was not reached in low and intermediate-1 categories, and it was 40 and 15 months for intermediate-2 and high risk categories respectively (p<0.001). The 5-year survival rates were 65%, 57%, 42%, and 22%, respectively (Figure 1). Conclusion: Prognostic model predicting survival in adult ALL pts were developed based on standard readily available baseline clinical features, which may assist in therapeutic and investigational decisions. This prognostic model is based on retrospective analysis, and further validation is needed in independent study groups. Table 1. Characteristics of the Study Group (n=434) Parameter Category No. (%) Age > 40 years old yes 207 (48) no 227 (52) Sex female 198 (46) male 236 (54) Diagnosis Pre-B 419 (97) Pre-T 15 (3) Prior Malignancy yes 46 (11) no 388 (89) Prior Chemotherapy yes 31 (7) no 403 (93) Prior Radiotherapy yes 21 (5) no 413 (95) Performance Status ≥ 2 yes 69 (16) no 365 (84) MLL Gene Rearrangement yes 34 (8) no 400 (92) WBC, x109/L ≤ 50 389 (90) > 50 45 (10) Platelet, x109/L < 100 93 (21) ≥ 100 341 (79) Hg, gr/dl < 8 144 (33) ≥ 8 290 (67) PB Blast yes 337 (78) no 97 (22) BM Blast, % ≥ 50 388 (89) <50 46 (11) Albumin, gr/dl < 3.5 213 (49) ≥ 3.5 221 (51) Total Bilirubin, mg/dl > 1 53 (12) ≤ 1 381 (88) GFR, ml/min/1.73m2 < 60 45 (10) ≥ 60 389 (90) Chemotherapy HCVAD 152 (35) HCVAD + Rituximab 156 (36) HCVAD + Ofatumumab 34 (8) AUG-BFM 92 (21) Table 2. Multivariate Analysis of Adverse Factors Associated with the Clinical Outcomes Outcome Factor p O.R. C.I. Death in CR Age > 40 years old 0.004 3.0 1.4-6.3 2-Month Mortality Total Bilirubin > 1 mg/dl 0.018 3.0 1.2-6.0 Albumin < 3.5 gr/dl 0.023 2.6 1.1-6.0 GFR < 60 ml/min/1.73m2 0.009 3.2 1.3-7.6 Complete Response GFR < 60 ml/min/1.73m2 0.001 0.2 0.1-0.5 Overall Survival Age > 40 years old 0.002 0.6 0.5-0.8 Performance Status ≥ 2 <0.001 0.5 0.4-0.7 Total Bilirubin > 1 mg/dl 0.029 0.7 0.4-0.9 GFR < 60 ml/min/1.73m2 0.003 0.6 0.4-0.8 Albumin < 3.5 gr/dl 0.045 0.8 0.6-0.9 WBC > 50 x109/L 0.030 0.6 0.4-0.9 MLL Gene Rearrangement 0.032 0.6 0.4-0.9 Figure 1. Overall Survival by Risk Categories Figure 1. Overall Survival by Risk Categories Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.
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Scheid, Christof, Pieter Sonneveld, Ingo Schmidt-Wolf, Bronno van der Holt, Thomas Hielscher, Laila el Jarari, Uta Bertsch et al. "Influence of Renal Function on Outcome of VAD or Bortezomib, Doxorubicin, Dexamethasone (PAD) Induction Treatment Followed by High-Dose Melphalan (HDM): A Subgroup Analysis From the HOVON-65/GMMG-HD4 Randomized Phase III Trial for Newly Diagnosed Multiple Myeloma". Blood 116, n.º 21 (19 de novembro de 2010): 2396. http://dx.doi.org/10.1182/blood.v116.21.2396.2396.
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Abstract Abstract 2396 Introduction: Renal impairment is a frequent complication in patients with multiple myeloma (MM) and is correlated with an inferior prognosis. Bortezomib can be applied independently of renal function and has been shown to improve response and overall survival in patients with relapsed MM. We wanted to investigate the role of renal impairment in the context of a large randomized study comparing a bortezomib-containing induction regimen (PAD) with standard VAD followed by HDM and maintenance with either thalidomide or bortezomib. Methods: Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as bortezomib 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, 17–20). Patients received one (HOVON) or two (GMMG) cycles of high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T): 50 mg daily (arm A) or bortezomib (B): 1.3 mg/m2, 2-weekly (arm B) for 2 years. As of July 2010 data from the first consecutively enrolled 626 patients of the HOVON-65/GMMG-HD4 trial have been analyzed. 613 patients have been evaluable (n=305 in arm A and n=308 in arm B, respectively). For this analysis patients were grouped according to renal function at baseline with creatinine < 2 mg/dl (177 μ mol/l, n=553), 2–5 mg/dl (177-442 μ mol/l, n=46) or > 5 mg/dl (> 442 μ mol/l, n=13). Frequencies were compared by logistic regression, survival data by Cox PH regression. The analysis was intention-to-treat, with PFS censored for patients treated with allo-SCT (n=46). Results: Data are summarized in tables 1 –3. Response rates tended to be lower on patients with renal impairment. The overall response rate (at least PR) after HDM in the VAD arm for patients with a creatinine of 2–5 mg/dl was 48% compared to 83% with creatinine < 2 mg/dl. However in the PAD arm the response rate was 84% vs. 89% respectively (Table 1). Progression-free survival (PFS) was significantly influenced by renal function, with 24 months rates of 64%, 50% or 31% for the 3 groups (p=0.006). In patients with creatinine < 2 mg/dl 2yr PFS was 61% (VAD) vs. 67% (PAD), while it was markedly different for creatinine of 2–5 mg/dl: 78% in the PAD arm vs. 30% in the VAD arm (p=0.002) (Table 2.). Overall survival at 24 months was 86% for patients with creatinine < 2 mg/dl in both arms. With a creatinine of 2–5 mg/dl it was similar with PAD (89%) but significantly inferior with VAD (44%, p<0.001)(Table 3). Discussion: Experience in patients with relapsed MM suggests those with an impaired renal function may in particular benefit from a bortezomib-containing therapy-regimen. In this subgroup analysis of a large randomized study testing bortezomib both in the induction and maintenance-treatment before and after HDM in newly diagnosed MM we could show that patients with elevated creatinine (2-5 mg/dl) have a markedly inferior response, progression-free and overall survival when receiving VAD and thalidomide-maintenance, while the treatment results in the bortezomib-containing arm were similar to those in patients with creatinine < 2 mg/dl. We conclude that combining HDM with a bortezomib-containing induction- and maintenance regimen is able to overcome the negative prognostic impact of an impaired renal function in patients with newly diagnosed MM. The HOVON-65/GMMG-HD4-trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to perform this trial by Novartis, AMGEN, Chugai and Roche. Disclosures: Scheid: Ortho Biotech: Honoraria. Off Label Use: Bortezomib in newly diagnosed myeloma. Sonneveld: Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees. Schmidt-Wolf: Janssen Cilag:; Celgene: Membership on an entity's Board of Directors or advisory committees. van de Velde: Johnson & Johnson: Employment. Duehrsen: Ortho Biotech: Honoraria. Delforge: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Weisel: Ortho Biotech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Goldschmidt: Ortho Biotech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding.
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Schönland, Stefan, Ute Hegenbart, Christoph Kimmich, Katarina Lisenko, Dirk Hose, Hartmut Goldschmidt, Anna Jauch, Anthony D. Ho e Michael Hundemer. "Detection and Characterization of Plasma Cell and B Cell Clones in Patients with Systemic Light Chain Amyloidosis Using Flow Cytometry". Blood 124, n.º 21 (6 de dezembro de 2014): 2068. http://dx.doi.org/10.1182/blood.v124.21.2068.2068.
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Abstract Introduction: AL amyloidosis is a rare and life-threatening protein-deposition disorder caused by a small B cell (mostly plasma cell) clone which produces amyloidogenic light chains. The goal of therapy is to target this clone and halt the uncontrolled release of free light chain, which might subsequently lead to improvement of organ function. In routine diagnostic some of these B cell clones are missed as they might be extremely small. However, specific treatment can only be applied if the clone is well characterized. Hardly any data on the characteristics of these cells using flow cytometry have been reported. (e.g. Paiva et al., Blood 2011). Study design: We performed a retrospective analysis of consecutive patients who were referred to our amyloidosis center (March to July 2014) and have been thoroughly studied (immunhistology of amyloid, free light chain assay, immunofixation, bone marrow diagnostic: cytology, flow cytometry and interphase-FISH cytogenetics (iFISH)). Patients and Methods: Twenty-two patients were included (all untreated, 21 AL patients, one pt with monoclonal gammopathy of renal significance (MGRS)). Plasma cells were detected by their co-expression of CD38 and CD138 antigens. Differentiation between malignant and normal plasma cells was achieved by analysis of aberrant CD45 and CD19 expressions and proof of intracellular light chain restriction (see Figure 1). To evaluate potential targets for an antibody-based immunotherapy, we stained CD20, CD22, CD30, CD52 and CS-1 on these plasma cells. Overall, positivity was defined as >20% expression of the antigen. iFISH was done after CD138 selection as previously described (Bochtler et al., Blood 2011). Results: Main characteristics and results are shown in Table 1. Median dFLC was 304 mg/l, three patients had a dFLC of less than 50 mg/l. Median plasma cell count in cytology was 10%, 3 patients had less than 5%. Median plasma cell count by flow was 3.8%, three patients had less than 1%. Correlation between dFLC, plasma cell count in cytology and flow was low (FLC vs. flow: spearman=0.25, p=0.26; FLC vs. cytology: spearman=0.49, p=0.02; flow vs. cytology, spearman=0.36, p=0.1). Detection of the amyloidogenic clone by flow was possible in all but one patient (95%). In this patient we were not able to show a light chain restriction although we detected a relevant aberrant plasma cell clone (CD45low, CD19low). In one patient we found a B cell lymphoma as underlying disease for MGRS type IgG lambda (CD19+, CD20+, lambda+, CD5-, CD22+, FMC7-, CD23-, CD25+, CD103-, CD38+ typical for marginal zone lymphoma). In all 21 patients the light chain restriction demonstrated by flow was confirmed by immunofixation, FLC, and immunohistology of the amyloid. All patients analyzed for the expression of CS-1 were positive. 25% were also positive for CD20 and none was positive for CD22, CD30 and CD52. Detection of the plasma cell clone by iFISH was possible in all 21 patients (see Table 1). Conclusion: Flow cytometric analysis of the bone marrow is a very sensitive method to detect and characterize the amyloidogenic clone in AL amyloidosis. B cell lymphomas can easily be distinguished from pure plasma cell clones. Secondly, flow provides useful information to specify immune-chemotherapy in AL amyloidosis and related disorders. Table 1: Patients (n=22) Characteristics and Results Age in yrs (median / range) 67 (41 – 77) Sex: female / male 9 / 13 Type of light chain: kappa / lambda 4 / 18 Median dFLC in mg/l (range) 304 (22 - 6621) Median % of plasma cells in BM cytology (range) 10 (0 – 68) Underlying disease leading to AL amyloidosis“MG” / MM III / B-NHL 20 / 1 / 1 Median % of PC by flow (range) 3.8 (0.2 - 34) Detection of the amyloidogenic clone by flow 21 / 22 Flow analysis of clonal plasma cells (% of pts)CD20+ / CD22+ / CD30+ / CD52+ / CD56+ / CS-1+ 25 / 0 / 0 / 0 / 75 / 100 Detection of a clone by iFISH 21/21 % of pts with t(11;14) / Gain of 1q21 / Hyperdiploidy / High-risk cytogenetic (del 17p13, t(4;14)) 52 / 10 / 14 / 10 Figure 1: Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Figure 1:. Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Disclosures Schönland: Janssen: Honoraria; Celgene: Honoraria. Hegenbart:Janssen: Honoraria; Celgene: Honoraria. Hose:Novartis: Research Funding. Hundemer:Celgene: Honoraria, Research Funding.
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Saxton, Claire, Kirstin Fearnley, Maria B. Gonzalo e Cynthia Schwartz. "Abstract P3-17-01: Metastatic breast cancer caregiver participation in a psychoeducational cancer support program: Results from the frankly speaking about cancer: Metastatic breast cancer evidence-based educational workshops". Cancer Research 82, n.º 4_Supplement (15 de fevereiro de 2022): P3–17–01—P3–17–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-17-01.
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Abstract Background: Education about metastatic breast cancer can help caregivers by providing tools to deal with the psychosocial effects of the disease. This analysis explores metastatic breast cancer caregivers’ experiences related to participation in Cancer Support Community’s national evidence-based educational program, Frankly Speaking About Cancer: Metastatic Breast Cancer. This comprehensive psychosocial education program, created for people diagnosed with metastatic breast cancer and their caregivers, provides information about current treatments, side-effect management, and social and emotional challenges of an advanced breast cancer diagnosis. Methods: Caregivers who attended 67 workshops across the country between 2014 and 2019 completed program evaluations and provided self-reported data on factors including pre- and post-workshop knowledge, workshop satisfaction, confidence levels, and intentions for patient-provider communication post-workshop. In total, 305 caregivers of patients with metastatic breast cancer attending in-person Frankly Speaking About Cancer: Metastatic Breast Cancer workshops nationwide completed a survey assessing their experiences and learnings as a result of the educational workshops. Descriptive analyses and pre-and post-workshop comparisons were conducted to assess workshop outcomes. Results: Caregivers were predominantly White (79%) and female (75%) and averaged 64.2 years old (s.d.=12.5). 75% strongly identified as caregivers and 69% were strongly involved in coordinating the patient’s care (rated a ‘4’ or ‘5’ on a 5-point scale for both). Most participants in the caregiving capacity (87%) reported experiencing emotional distress due to their loved one’s cancer. The workshop was well-received, with 92% recommending the workshop to others facing similar issues. Most caregivers (77%) reported gaining a “high or very high” level of knowledge about metastatic breast cancer, which was a significant increase compared with pre-workshop levels (42%; χ²= 13.4, p <.05). Caregivers were likely to report that they gained confidence to participate in treatment decision-making with their loved one’s health care team (79%) and to ask questions about side effects of metastatic breast cancer and its treatment (82%) as a result of participating in the workshop. Lastly, 92% of caregivers reported that because of the workshops, they felt better prepared to emotionally cope with their metastatic breast cancer caregiving experience. Discussion: Results suggest that comprehensive information and supportive services are highly relevant in meeting the psychosocial needs of cancer caregivers. Increased understanding of informational and emotional support service utilization can inform provision of services and programs addressing the emotional and informational needs of caregivers. Citation Format: Claire Saxton, Kirstin Fearnley, Maria B. Gonzalo, Cynthia Schwartz. Metastatic breast cancer caregiver participation in a psychoeducational cancer support program: Results from the frankly speaking about cancer: Metastatic breast cancer evidence-based educational workshops [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-17-01.
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Andreica, I., I. Roman, X. Baraliakos, U. Kiltz e J. Braun. "AB1188 SARS-CoV-2 VACCINATION WILLINGNESS AND PREDICTORS IN PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES (CIRD) AND WITHOUT CIRD". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1709.1–1709. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5261.
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BackgroundRecent surveys in chronic inflammatory rheumatic diseases (CIRD) showed a high degree of vaccine hesitancy. Current knowledge about patients’ attitudes towards vaccination against SARS-CoV-2 is limited.ObjectivesTo assess the willingness of CIRD patients to be vaccinated against SARS-CoV-2 and to identify influencing factors compared to non-CIRD patients.MethodsIn this cross-sectional study, two cohorts of consecutively in parallel recruited patients with and without CIRD presenting to our tertiary hospital answered questions of a structured interview to assess vaccination willingness to SARS-CoV-2, experience with SARS-CoV2 in their environment and their personal history of infections and vaccinations. Vaccination willingness was assessed by a numerical rating scale (0: fully disagree; 10: fully agree). Arbitrarily defined cut-offs were used to define definite (score ≥7) and probable willingness (scores of 5 or 6) to be vaccinated. Statistical analyses were performed with appropriate tests such as Kendall-tau b.ResultsA total of 514 CIRD and 100 non-CIRD patients, mean age 54.7±12.8 and 55.6±9.8 years, were included. Definite and probable willingness to be vaccinated against SARS-CoV-2 was declared by 79.6% and 90.7% vs. 76.0% and 85.0% of CIRD and non-CIRD patients, respectively. Only 60% of CIRD patients believed that the vaccines against SARS-CoV-2 were safe, and 42% indicated to be afraid of side effects. Vaccination willingness correlated significantly with the degree of education, age, identification with a risk group for COVID-19 disease, hypertension, and the degree of information about preventable diseases. There was no correlation with the history of infections or with immunosuppressive therapy.ConclusionAlthough our results show a high willingness for vaccination against SARS-CoV-2 in both groups, there was quite some uncertainty regarding the safety and efficacy of the vaccines. Since major influencing factors were education and information about SARS-CoV-2 and COVID-19, patient education should be immediately improved.Table 1.Patient demographics, disease characteristics and infection historyCIRD patientsNon-CIRD patientsMissing values of CIRD and non-CIRD patients No. (%)Group differences p-valueAge (years), mean (SD)54.7 ± 12.855.6 ± 9.800Women, No. (%)315 (61.3)83 (83)00Body mass index (BMI, kg/m2), mean (SD)27.9 ± 5.930.4 ± 7.800CIRD, No. (%)192 (37.3)0Rheumatoid arthritis134 (26)Axial spondyloarthritis72 (14)Psoriatic arthritis116 (22.6) Connective tissue disease/vasculitisDisease duration (years), mean (SD)9.8 ± 8.94.0 ± 6.500Therapy, No. (%)316 (61.5)0 bDMARDs147 (28.6) csDMARDs33 (6.4) tsDMARDs18 (3.5) no DMARDsHistory of a positive SARS-CoV-2 PCR test No. (%)22 (4.3)5 (5.0)3 (0,6)5 (5)0.79History of recurrent infection No. (%)54 (10.5)16 (16.0)1 (0.2)00.12History of severe infection No. (%)23 (4.5)13 (13.0)3 (0.6)00.004Educational level, No. (%)9 (9.3)35 (6.8)3 (3)0.13 low (< 8 years)50 (10.4)67 (69.1) moderate (8 to 12 years)275 (57.4)21 (21.6) high (> 12 years)154 (32.2)BMI body mass index, SD standard deviation, no number, DMRD Disease Modifying Anti-Rheumatic Drugs, b biological, ts targeted synthetic, cs conventional syntheticFigure 1.Vaccination willingness of CIRD patientsAcknowledgementsWe wish to thank all persons who participated in the current study.Furthermore, we thank Dr. Styliani Tsiami, Tanja Kobylinski and the clinical departments for assisting with recruitment of participants.Disclosure of InterestsNone declared
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Seymour, John F., Chan Yoon Cheah, Ricardo Parrondo, Meghan C. Thompson, Don A. Stevens, Masa Lasica, Michael L. Wang et al. "First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)". Blood 142, Supplement 1 (28 de novembro de 2023): 4401. http://dx.doi.org/10.1182/blood-2023-180109.
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Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.
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Call, Justin, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu e Robert Wesolowski. "Abstract PO2-04-13: TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY". Cancer Research 84, n.º 9_Supplement (2 de maio de 2024): PO2–04–13—PO2–04–13. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-04-13.
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Abstract Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex inhibition at the spindle assembly checkpoint and is required for chromosome alignment and error correction. TTK inhibition results in premature mitosis exiting with unattached chromosomes potentially leading to aneuploidy and cell death. High TTK tumor levels correlate with worse prognosis and contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK, inhibits the growth of a variety of human cancer-derived cell lines. A first-in-human phase 1 study of CFI-402257 (NCT02792465) demonstrated a tolerable safety profile when enrolled as a monotherapy in solid tumors, and in combination with fulvestrant in hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer1. The dose for expansion was 168 mg, dose limiting toxicity was dose-dependent neutropenia which was manageable and reversible. Investigator-confirmed partial responses (cPR) were observed in 5 pts (8%) with 32 (50.8%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors (N=25), there were 4 cPR’s with a median duration of response of 223 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors for dose confirmation then focus on advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: In TWT-203 study, safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients (pts) with advanced solid tumors (Part A) or in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response. Results: At data cutoff of 11 May 2023, 14 pts were enrolled. All received monotherapy treatment. Median treatment duration was 2.1 months (range, 0.2-7.3+). Median age was 67 years (57-76). Median number of prior regimens was 3.5 (2-12). Tumor types enrolled were colorectal (n=6, 43%), breast (3, 21%), and endometrial, hepatocellular, leiomyosarcoma, pancreatic, and sarcoma (1 each, 7%). 4 dose levels, from 126 to 252 mg, were studied. Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. Disease control rate (CR, PR, or SD ≥ 6 weeks from baseline) was 54.5% (6 pts/11): all achieved SD. 3 of the 6 pts remain on study. Conclusion: CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence. 1. John Hilton et al. Cancer Res 2023;83(5 Suppl): P6-10-13. Citation Format: Justin Call, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu, Robert Wesolowski. TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-13.
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Baliakas, Panagiotis, Theodoros Moysiadis, Anastasia Hadzidimitriou, Aliki Xochelli, Mattias Mattsson, Lesley-Ann Sutton, Eva Minga et al. "Tailored Approaches for Refined Prognostication in Chronic Lymphocytic Leukemia Patients with Mutated Versus Unmutated Immunoglobulin Receptors". Blood 128, n.º 22 (2 de dezembro de 2016): 3199. http://dx.doi.org/10.1182/blood.v128.22.3199.3199.
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Abstract The classification of CLL patients according to the somatic hypermutation status (SHM) of the immunoglobulin heavy variable (IGHV) genes, namely mutated (M-CLL) versus unmutated (U-CLL), reflects fundamental differences in disease biology and clinical course. Realizing this, here we followed a compartmentalized approach and addressed the issue of prognostication separately for M-CLL and U-CLL. In a multi-institutional cohort of 2366 patients [M-CLL, n=1364 (58%); U-CLL, n=1002 (42%)] consolidated within ERIC, the European Initiative in CLL, we assessed the clinical impact of 'traditional' (age and clinical stage at the time of diagnosis, gender, CD38 expression, FISH detected abnormalities included in the Döhner hierarchical model of cytogenetic aberrations), and novel prognosticators (recurrent mutations within the TP53, SF3B1, NOTCH1, MYD88, and BIRC3 genes; IGHV gene usage; membership in stereotyped subsets) within M-CLL and U-CLL. Our statistical approach was based both on Cox regression models and recursive partitioning algorithms; internal validation was performed via bootstrapping procedures. Given the retrospective nature of our study, time-to-first-treatment (TTFT) was the primary endpoint. As expected, M-CLL exhibited significantly longer TTFT compared to U-CLL [median TTFT: not yet reached (M-CLL) vs 1.9 years (95% CI: 0.01-12.3 years, U-CLL), p<0.0001]. Advanced clinical stages (Binet B-C) were associated with shorter TTFT in both M-CLL and U-CLL; a significantly worse outcome was also identified for Binet C versus Binet B cases (p<0.0001). Binet A patients received our special focus, representing 90% and 67% of M-CLL and U-CLL studied cases, respectively. Amongst Binet A M-CLL cases, TP53 aberrations [TP53abs, deletions of chromosome 17p, del(17p) and/or TP53 mutations], stereotyped subset #2 membership and trisomy 12 were identified as equally adverse prognostic indicators [median TTFT: 5.5 (95% CI: 0.2-12.8), 4 (95% CI: 0.6-6.8) and 7.3 (95% CI: 0.7-13.4) years, respectively; p-value: non-significant when applying the log-rank test for all paired comparisons); of note, TP53abs were mutually exclusive with the other two features. Amongst Binet A U-CLL cases, TP53abs, SF3B1 mutations and deletion of chromosome 11q [del(11q)] had an overall similar adverse impact [median TTFT for TP53abs, SF3B1 mutations and del(11q): 1.8 (95% CI: 0.01-4.4), 2 (95% CI: 0.01-7.7) and 2.1 (95% CI: 0.01-8.1) years, respectively, p-value: non-significant when applying the log-rank test for all paired comparisons]. Within the remaining Binet A U-CLL cases [i.e. those lacking TP53abs and/or SF3B1 mutations and/or del(11q)], the only parameter associated with shorter TTFT was male gender (median TTFT: 3.5 years, 95% CI: 0.5-8.1 years). Based on these findings, we developed two prognostic indices for assessing TTFT tailored specifically to M-CLL and U-CLL, respectively. Within M-CLL (Figure 1A), 4 subgroups were identified: (i) very high risk: Binet C with identical 5- and 10-year treatment-probability (TP) of 92%; (ii) high risk: Binet B, 5y-TP and 10y-TP: 64% and 84%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or +12 or subset #2 membership, 5y-TP and 10y-TP: 40% and 55%, respectively; and (iv) low risk: Binet A nonTP53abs/+12/subset#2, 5y-TP and 10y-TP: 12% and 25%, respectively. Within U-CLL (Figure 1B), 5 subgroups were identified: (i) very high risk: Binet C with 5- and 10-year TP of 100%; (ii) high risk: Binet B, identical 5y-TP and 10y-TP: 90% and 100%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or SF3B1 mutations or del(11q), 5y-TP and 10y-TP: 78% and 98%, respectively; (v) low risk: Binet A, male nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 65% and 85%, respectively and (iv) very low risk: Binet A, female nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 45% and 65%, respectively. In conclusion, we identified clinicobiological parameters with distinct prognostic implications for M-CLL and U-CLL. These parameters were used in order to develop prognostic indices tailored to SHM status that were found capable of distinguishing subgroups with markedly different outcomes. We argue that such a compartmentalized approach may supersede previous attempts, thus overcoming the pronounced heterogeneity of CLL and optimizing prognostication. PB and TM contributed equally as first authors Figure 1 Figure 1. Disclosures Rosenquist: Gilead Sciences: Speakers Bureau.
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George III, Qiuhong Zhao, Timothy Voorhees, Nathan Denlinger, Narendranath Epperla, Audrey M. Sigmund, Gabriela Sanchez-Petitto et al. "Association between post-CART terminal complement complex (TCC) levels and clinically significant immune effector cell–associated neurotoxicity syndrome (ICANS)." Journal of Clinical Oncology 42, n.º 16_suppl (1 de junho de 2024): 7036. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.7036.
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7036 Background: The cornerstone of ICANS pathogenesis is endothelial dysfunction leading to blood-brain barrier disruption driven by inflammatory cytokines. Endothelial dysfunction is often associated with complement activation as in thrombotic microangiopathy, but the association between complement and ICANS has not yet been investigated. Herein, we describe the association between TCC levels (sC5b-9) and ICANS after CART. Methods: We retrospectively included 42 patients (pts) with B-cell non-Hodgkin lymphoma treated with axi-cel or brexu-cel from 03/2022 - 09/2023 at Ohio State University who had had sC5b-9 levels available pre-lymphodepletion (pre-LD), pre-CART and post-CART infusion. sC5b-9 levels were measured once in each of the timepoints: pre-LD (between D-7 and D-4), pre-CART (between D-3 and D0) and post-CART (between D2 and D8). We defined clinically significant ICANS as peak grade ≥2 (G≥2). Median and interquartile range (IQR) were used to describe the biomarkers levels, and Wilcoxon-rank sum test was used to compare values between groups. Results: Median age was 64 years (26-76), 30 (71%) pts had large B-cell lymphoma and 6 (14%) had untransformed follicular lymphoma who received axi-cel (36, 86%), and 6 (14%) had mantle cell lymphoma who received brexu-cel. Following CART, cytokine-release syndrome (CRS) peak grade was 2 and 1 in 16 (38%) and 22 (52%) of the pts, respectively, and 4 pts (10%) had no CRS. The ICANS peak grade was 4, 3, 2 and 1 in 4 (10%), 2 (5%), 6 (14%) and 6 (14%) of the pts, respectively, and 24 (57%) of the pts had no ICANS. The median time from CART to ICANS peak was 6 days (2-12). Tocilizumab and steroids were used in 28 (67%) and 20 (48%) of the pts, respectively. We compared sC5b-9 levels pre-LD, pre-CART and post-CART between pts that had ICANS peak G≥2 (N = 12) vs. grade 1 or did not have ICANS (G0-1, N = 30). We found that the post-CART sC5b-9 levels were significantly higher among pts who had ICANS G≥2 [median (IQR) 254 (129) vs. 183 (82) ng/mL, p = 0.013]. There was no statistical difference in the levels pre-LD and pre-CART between pts who had ICANS G≥2 vs. G0-1, median (IQR) 176 (103) vs. 159 (94) ng/mL, p = 0.37, and 152 (64) vs. 143 (69) ng/mL, p = 0.89, respectively. We also compared levels of other biomarkers associated with tumor burden, inflammation, and endothelial dysfunction at the same time points sC5b-9 was measured between pts with ICANS G≥2 vs. G0-1 and there were no statistically significant differences: median (IQR) pre-LD LDH 171 (73) vs. 180 (115) U/L, p =0.54, post-CART ferritin 262 (546) vs. 297 (333) ng/mL, p = 0.92 and post-CART fibrinogen 302 (221) vs. 405 (146) mg/dL, p = 0.29. Conclusions: Our findings support an association between post-CART sC5b-9 levels and clinically significant ICANS warranting further investigation of the role of complement in the ICANS pathogenesis and as a therapeutic target.
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Farooq, Umar, Matthew J. Maurer, Stephen M. Ansell, Tasha Lin, Grzegorz S. Nowakowski, Luis Porrata, David J. Inwards et al. "Treatment Patterns and Outcomes of DLBCL after Failure of Front-Line Immunochemotherapy". Blood 126, n.º 23 (3 de dezembro de 2015): 2683. http://dx.doi.org/10.1182/blood.v126.23.2683.2683.
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Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). However, up to 40% of patients will relapse or require retreatment of DLBCL and outcomes are poor in this setting. Here we examine the incidence, treatment patterns and outcomes of relapsed DLBCL in the R-CHOP era. Methods: Patients were prospectively enrolled in the University of Iowa / Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma or PTLD were excluded. All relapse and re-treatments were verified by medical record review. Response to front-line therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Unplanned consolidative radiation (RT) without biopsy proven disease after achieving PR from IC (N=21) was not classified as a relapse. Results: 1039 patients with newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 577 patients (56%) were male. 647 patients (63%) had stage III/IV disease and IPI at diagnosis was 0-1 in 350 patients (34%), 2 in 305 patients (29%), 3 in 250 patients (24%) and 4-5 in 134 patients (13%). At a median follow-up of 59 months (range 1-148), 258 patients had relapse or retreatment of DLBCL of which 184 (71%) died. Incidence of relapse was 21.7% (95% CI: 19.3%-24.4%) at 2 years and 25.5% (95% CI: 22.9%-28.5%) at 5 years. In addition, the incidence of lymphoma related death without documented relapse or retreatment was 4.7% (95% CI: 3.6%-6.2%) at 2 years. At first relapse, 174 patients (67% of relapsed) received platinum based salvage therapy with 90 (52%) subsequently proceeding to autologous stem cell transplant (ASCT). 22 patients received CNS directed systemic therapy at relapse with 9 (41%) proceeding to transplant, and 43 received non-platinum-based salvage systemic therapy with 7 proceeding to transplant (17%), 15 patients received RT only as 2nd line therapy, and 4 were untreated. At a median follow-up of 56 months (range 6-121) post-transplant, 39 of 107 patients who underwent transplant remain in remission with a 2-year post-transplant progression-free survival of 45% (95% CI 37%-56%). Response to front-line IC was predictive of post-relapse outcome. Survival post-relapse was superior in the 162 patients with responsive disease (CR or PR) at the end of front-line IC (median OS 21.0 months) compared to the 88 patients who had stable or progressive disease (median OS 6.8 months, HR = 2.33, 95% CI: 1.73-3.14 p<0.0001). Transient response in midst of front-line IC was similar to no response. Patients achieving a CR or PR to front-line IC were more likely to proceed to ASCT at relapse (55%) compared to patients with either SD or PD at the end of front-line IC (25% and 17% respectively, p<0.0001). Other factors associated with poor survival at first relapse were relapse within 12 months of diagnosis (HR = 2.24, 95% CI: 1.57-3.18, p<0.0001), IPI at diagnosis of 3-5 (HR=1.51, 95% CI: 1.13-2.03, p=0.0058), and age > 60 (HR =1.51, 95% CI: 1.12-2.03, p=0.0064). There was no difference in survival at first relapse by cell of origin (HR = 1.13, 95% CI: 0.74-1.72, p=0.59). Conclusions: Most patients undergo therapy after relapsed/refractory DLBCL but only one-third receive ASCT. Outcomes following all treatments for relapsed/refractory DLBCL remain poor. Factors associated with adverse outcomes include refractory to front-line therapy, early relapse, baseline IPI and advanced age. These outcomes provide relevant historical control for the many novel agents being tested in this unmet need. Figure 1. Figure 1. Disclosures Farooq: Kite Pharma: Research Funding. Maurer:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding.
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Retiere, Christelle, Catherine Willem, Thierry Guillaume, Henri Vié, Laetitia Gautrot-Rolland, Emmanuel Scotet, Xavier Saulquin et al. "Post-Transplant Cyclophosphamide (PTCY) Vs Anti-Thymoglobulin (ATG) As Part of the Gvhd Prophylaxis for Fludarabine/Clofarabine/Busulfan Reduced Intensity Conditioning (RIC) in Allogeneic Stem Cell Transplantation (allo-SCT): Influence on Early Immune Reconstitution". Blood 126, n.º 23 (3 de dezembro de 2015): 1955. http://dx.doi.org/10.1182/blood.v126.23.1955.1955.
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Abstract Introduction: The influence of PTCY on early immune reconstitution after allo-SCT has been poorly studied so far, especially in comparison to standard use of ATG as GVHD prophylaxis. Patients and Methods: A prospective study was conducted at the CHU of Nantes with the aim to compare early immune recovery between patients receiving PTCY or ATG as GVHD prophylaxis after a RIC allo-SCT. Secondary objectives were to study the impact of 1 vs 2 days of PTCY (CY1 vs CY2) or ATG (A1 vs A2), and of fludarabine (Flu) vs clofarabine (Clo) as part of the RIC regimen. As such, 3 RIC regimens were considered in both groups: FluCY2 (Baltimore regimen, Luznic, BBMT 2008), FluCY1, CloCY2 (where Clo replaces Flu), on one hand, and FluB2A2, CloB2A2, CloB2A1 (Chevallier, Haematologica, 2014), on the other hand. FluCY2 and FluB2A2 are currently standard of care RIC regimens for patients with haplo-identical and matched donors, respectively. Five patients had to be included in each RIC subgroup, depending on the type of disease and donor (/): FB2A2 (lymphoid/matched); FluCY2 (lymphoid/haplo); CloB2A2 or CloB2A1 (myeloid/matched); CloCY2 (myeloid/haplo), FluCY1 (myeloid or lymphoid/matched). The source of graft was peripheral blood stem cells for all cases. Blood samples were collected before starting the conditioning regimen then 3 times per week from day +0 until day+30, and at days +60 and +90. The following cell subsets were studied: a/b and g/d CD3+, CD8+ and regulatory (Tregs) T cells, B and NK cells and monocytes. The median percentage (%) compared to total lymphocytes was considered for all lymphocytes subsets between days 0-30. Thereafter, median absolute numbers (AN)/mm3 were considered for samples collected at days +30, +60 and +90. The study was approved by the IRB of the CHU of Nantes and all patients provided informed consent. Results: Between August 2014 and May 2015, thirty patients were included, including 15 in both groups and 5 in each RIC subgroups. Median age was 61 years. There were more patients with active disease at transplant (47% vs 7%) and more haplo-identical donors (67% vs 0%) in the PTCY group. All patients engrafted and were alive at day +90. However, 1 PTCY patient with T-ALL relapsed before day+100. Within the first month post-transplant, PTCY group had a significantly higher median % of a/b T cells (69.1 vs 18.9, p<0.0001) and Tregs (3.46 vs 0.45, p<0.0001) while ATG group had higher median % of NK (23 vs 2.57, p<0.0001) and B-cells (0.88 vs 0.43, p=0.0002). Between day+30 and day+90, ATG group had significant higher median counts of a/b T cells at days +60 (1316 vs 79.6, p=0.0001) and +90 (795.8 vs 151.6, p=0.03); g/d T cells at day+60 (27.6 vs 1.26, p=0.002); CD8 T cells at day+60 (735 vs 29.6, p=0.008); NK cells at day+30 (203.7 vs 89, p=0.04) and monocytes at days +30 (455.5 vs 221.7, p=0.009) and +60 (832.5 vs 247.2, p=0.004). Compared to the standard FluCY2 regimen, although not significant, FluCY1 was associated with higher median %, between days 0-30 of g/d T cells (2.32 vs 0.8) and higher median AN of g/d T cells at days +30 (9.2 vs 1.02) and +60 (9.22 vs 1.05), of B cells at days +30 (0.4 vs 0.14) and +60 (1.6 vs 0.39) and of NK cells at day+30 (213.9 vs 82.7). Compared to the standard FB2A2 regimen, although not always significant, CloB2A1 was associated with higher median % between days 0-30 of Tregs (0.97 vs 0.25, p=0.002) and higher median AN of g/d T cells at day+30 (6.8 vs 2), B cells at days +30 (2.35 vs 0) and +60 (43.7 vs 0.19), NK cells at day +30 (288 vs 62.1) and Tregs at days +30 (4.3 vs 0.2), +60 (8.8 vs 1.14) and +90 (8.96 vs 3.45). Compared to the standard FB2A2 regimen, although not always significant, CloB2A2 was associated with higher median % between days 0-30 of a/b T cells (28.87 vs 3.78, p=0.01) and B cells (0.76 vs 0.5, p=0.02) and higher median AN of a/b T cells at days +30 (324.3 vs 125.8) and +90 (1594 vs 604.3), of g/d T cells at day +30 (7.35 vs 2), of CD8 + T cells at days +30 (209.7 vs 38.9) and +90 (1211.7 vs 504.6), of B cells at day +30 ( 1.41 vs 0), of NK cells at days +30 (303 vs 62.1), +60 (514.5 vs 225.7) and +90 (647 vs 102.8, p=0.03) and of monocytes at days +30 (688.9 vs 257.4, p=0.03) and +90 (2157.4 vs 611.2). Conclusion: Strong differences exist in term of early immune recovery when using PTCY or ATG as part of the GHVD prophylaxis for RIC allo-SCT. Dose or drug modifications within the standard RIC regimen in both groups may be envisaged to favor some cell population recoveries after allo-SCT in order to increase outcome in patients. Disclosures No relevant conflicts of interest to declare.
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Song, Alexander, Ron Ng, John Heller, Robin Petro, Ralph D’Agostino, Thomas Lycan e Mercedes Porosnicu. "251 Factors evaluated as predictors of exceptional response to PD-1 inhibitors in patients with head and neck squamous cell cancer". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembro de 2020): A272. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0251.
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BackgroundImmunotherapy has recently emerged as an alternative to traditional chemotherapy in the management of recurrent or metastatic head and neck squamous cell cancer (HNSCC). PD-1 inhibitors were approved for HNSCC in 2016 with ORR of 13–18% and CR of 4%.1, 2 Current research focuses on identifying predictors of response for better patient selection. We present HNSCC patients with exceptional response to PD-1 inhibitors in an attempt to highlight biomarkers that correlated with their remarkable response.MethodsWe analyzed all cases of HNSCC treated with single agent PD-1 inhibitors in the last 4 years at Wake Forest Comprehensive Cancer Center. To identify exceptional responders, we followed the NIH Initiative definition: complete response to drug(s), where complete response is seen in less than 10% of patients receiving similar treatment or partial response lasting at least 6 months, where such response is seen in less than 10% of patients receiving similar treatment. We aimed to test all patients for PD-L1 expression, tumor genomics by Foundation Medicine platform and mutated circulating tumor DNA via Guardant 360 platform.ResultsBased on the above criteria, 11 patients were identified as exceptional responders, 9 of whom had metastatic spread to lung, liver or bones. 7 patients were treated for more than one year, and all achieved CR. 3 patients were treated for less than one year, and all achieved major PR with possible CR to be confirmed with next scans. One patient with metastatic HNSCC achieved CR after just 3 administrations of PD-1 inhibitor and has been in CR for 3.5 years. 9 patients were tested for PD-L1 before starting immunotherapy, and all presented levels above 5% by TPS and above 10% by CPS. Interestingly, three patients older than 75 had the highest PD-L1: 75% by TPS and 100% by CPS in two patients. TMB was found moderate or high in all 8 patients tested before starting immunotherapy. TP53 was found mutated both in tumor and in blood in all but 2 of the 10 tested patients, one of whom is the only HPV positive patient in our series. MSI was stable in all patients.ConclusionsThere are limited reports in the literature of exceptional responders to immunotherapy, particularly among HNSCC patients. High PD-L1 expression, moderate or high TMB and presence of mutated TP53 in both tumor and blood were present in almost all patients, recommending for further investigations as possible predictors of exceptional response to PD-1 inhibitors.Ethics ApprovalThe study was approved by Wake Forest University Institution’s Ethics Board, approval number IRB00056249.ReferencesT.Y. Seiwert, B. Burtness, R. Mehra, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17(7):pp. 956–965.Ferris RL, Blumenschein GJr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67. 10.1056/NEJMoa1602252
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Swic, Sebastian J., Alexander G. T. MacPhail, Chinmay B. Dalal, Steven J. T. Huang, Alina S. Gerrie, Thomas J. Nevill, Heather J. Sutherland et al. "Prognostic Factors and Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Vs. Non-Transplant Chronic Lymphocytic Leukemia (CLL) Patients: A Comparative Analysis with the Leukemia/BMT Program of British Columbia (BC) and the BC Provincial CLL Database". Blood 124, n.º 21 (6 de dezembro de 2014): 2549. http://dx.doi.org/10.1182/blood.v124.21.2549.2549.
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Abstract Background: Chronic Lymphocytic Leukemia (CLL) patients (pts) have significant (sig) heterogeneity; survival ranges from decades to <5 years (yrs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is promising treatment (tx) for high-risk pts. Ideally, predictive (pred) tools would allow clinicians to recognize such pts early, permitting transplant performance to maximize benefit and minimize procedure associated risk. Factors with significant (sig) pred capacity are not, however, entirely clarified. Moreover, limited studies compare CLL pts who have/have not received HSCT in terms of differences (diff) in characteristics (char) at diagnosis (dx), population (pop) composition and outcomes. This study evaluates pred factors for outcomes post allo-HSCT, and compares dx char between (bn) tx CLL pts who did /did not receive HSCT by evaluating a large pop-based CLL cohort (n= 1044) from the BC Provincial CLL Database (BCPCD). Methods: 102 CLL pts (71M, 31F) had consecutive allo-HSCT (01-91 to 03-13, L/BMT Program of BC). Median (med) age (range) at dx:HSCT was 50 (26-65):57 (32-68) yrs; med interval dx to HSCT 5.8 yrs (0.5 to 29). Most pts (78, 76%) received non-ablative therapy; (n=61 [60%] reduced-intensity fludarabine /busulfan [flu/bu] based [RIC], n=17 [17%] non-myeloablative flu-cyclophosphamide based [NMA]); 24 pts had myeloablative (MA) conditioning (CON). Donor status was 50% unrelated (UD) (51UD:51RD); 73M, 28 F. Results: With median (med) follow up (FU) (range) post allo-HSCT of 2 yrs (0.5-18); post dx of 9 yrs (1-38), 67 (50%) pts survive. 70 (69%) achieved CR post-HSCT a med of 187 (28-1274) days (d). 27 had CLL PROG a med of 339 (25-4367) d; 18 of 27 (67%) survive a med of 3 (0.5-18) yrs post HSCT. Factors pred OS post HSCT (KM p=; UVA HR=) (p<0.05) were: pre-HSCT FISH deletion 17p (del 17p) (0.005; 2.9), Dohner rank (0.02), HSCT specific comorbidity index (CoI) >3 vs. 0-2 (0.04; 2.5), HLA mismatched (MM) donor (0.03;2.3), pre-HSCT tx with alemtuzumab (alem) (0.005;3.0), CON (MA vs NMA or RIC) (0.046; 3.0), acute (A) graft vs host disease (GVHD) grade (g) 3-4 vs 0-2. (<0.001; 4.5), dn chim <90% (0.001; 5.2), abn FISH not clear post-HSCT (0.009; 2.6), yr of HSCT (pre- vs post-2010) (0.03; 3.13) and lack of CR post HSCT (<0.001; 10.5).The following sig pred for (OR; p=): >90% dn chim: no B symptoms at dx (2.5; 0.004), CON (RIC vs. NMA, (2.6; 0.006); clear FISH abn post-HSCT: CR post-HSCT (4.6; 0.004); CR post-HSCT: B symptoms at dx (0.4; 0.02), <=1 FISH abn (1.7; 0.045), rituximab (R) pre-HSCT (2.5; 0.001), clear FISH abn (2.5; 0.01), flu sensitivity (S) pre-HSCT (1.8; 0.03), S to last tx pre-HSCT (1.7; 0.03), CON (MA vs. RIC or NMA) (3.2; <0.001); PROG: Richter’s transformation ( Rich trans) pre-HSCT (3.5; 0.008), graft failure (3.3; 0.008), CoI >3 vs. 0-2 (6.9; 0.006), no R pre-HSCT (6.7; 0.01), CON (MA vs. NMA or RIC), (0.2; 0.03); NRM: pre-HSCT alem (2.7; 0.03), CoI >3 vs. 0-2 (2.7; 0.049), HLA MM (2.8; 0.01), CON (MA vs. rest) (3.0; 0.007), AGVHD g 3-4 vs. 0-2 (5.9; <0.001), FISH abn not clear (2.6; 0.04), and no CR (6.5; <0.001). Comparison bn allo-HSCT and BCPCD CLL pts showed sig diff at dx for Dohner FISH rank: more del 17p (23% vs.11%) and 11q (23% vs. 9%) in allo-HSCT pts (n=84 with pre-HSCT FISH); less +12 (13% vs. 17%), del 13q (24% vs.41%) or normal (22% vs 18%), p<0.001 than non-HSCT pts (n=952); Age at dx (med, range) was lower in HSCT (50, 26-65) vs non (62, 25-96), p<0.001; lymphocyte (lymph) count higher (14, 1-300 vs.11, 1-662, p=0.03), tx-free survival (TFS) from dx to 1st tx shorter at 0.75 (0-9.3) vs. 2.86 (0-20.6) yrs. Rich trans was more frequent in HSCT pts (8%) vs. non (3%), p=0.015.OS was sig better for HSCT pts (n=103) (med 17.6, SE 4.5, CI 95% 8.8-26) compared to non (n=494) (med 14.4, SE 1.1, CI 95% 12.1-16.6) (p=0.03). Conclusion: CLL allo-HSCT pts have sig diff than non including higher lymph at dx, shorter time to 1st tx, and higher risk FISH abn. 17p del remains high-risk with allo-HSCT. Pre-HSCT R increased post HSCT CR. Strategies to optimize post-HSCT CR and dn chim are important; these milestones are crucial to best outcome. PROG post-HSCT does not confer worse OS; rescue strategies are successful and deserve further study. Comparison of this large allo HSCT and pop-based BPCDB cohort indicate improved OS for allo-HSCT tx CLL pts vs. other, with a survival plateau. This data indicates early recognition of high-risk CLL patients for HSCT is likely to yield best long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
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Donato, Eva Ma, Rafa Andreu, Aurelio Lopez, Ana Vicente, Ana Carral, Isidro Jarque, M. Angeles Ruiz et al. "A Retrospective Population-Based Study of a Series of 307 Treatment-naïve Patients with Chronic Lymphocytic Leukemia (CLL): Study of the Clinical Features and Efficacy of First-Line Therapy". Blood 116, n.º 21 (19 de novembro de 2010): 2452. http://dx.doi.org/10.1182/blood.v116.21.2452.2452.
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Abstract Abstract 2452 Background. Clinical trials have shown an improved response rate and progression free survival (PFS) among the different treatment options used in the last two decades, specially with rituximab in combination with fludarabine and cyclophosphamide. We wished to analyze, in an unselected community based population, the clinical characteristics and efficacy of first line therapy with several treatment options used throughout a ten-year period. Patients and methods. We included 307 patients diagnosed of CLL and requiring first-line treatment between January 2000 and September 2009. Patients were treated at 20 hospitals placed in the Community of Valencia and Murcia and received first-line therapy according to the clinical guidelines of each hospital. PFS was calculated from date of first treatment to date of progression/relapse. We performed a descriptive analysis of clinical and biological features. The survival curves were built with Kaplan-Meier method and compared with the log rank test. Multivariate analysis for response and PFS were performed by logistic and Cox regression methods respectively, using the statistical package SPSS (v15). Results. Median age at treatment was 67 years (range 28–94) with 58% (n=179) men. 39% (120/305) were in Binet A, 38% (117) in Binet B and 22% (68) in Binet C. 27% (84) were Rai III-IV. B symptoms were present in 25% (77) and fever was a rare symptom 3%. Patients were asymptomatic in 59% (181) of the cases with ECOG performance status 0–1 in 83% (256). Splenomegaly was present in 41% (127) and hepatomegaly only in 8% (24). 42% of the patients (129) had at least three lymph-node areas affected with bulky disease (diameter higher than >5cm) in 10% (32). Median haemoglobin level was 126gr/L (46–169), lymphocyte count 49 x109/L (0,5–613) with lymphocyte doubling time (LDT) <12 months in 43%. LDH was elevated in 34% (95/284) and b2-microglobulin levels in 61% (154/251). CD38 expression was positive in 42% (107/255) and ZAP-70 in 75% (91/122). The overall incidence of trysomy 12, 13q, 11q23 and 17p deletions detected by FISH were 17%, 15%, 12% and 5% respectively. Median follow-up was 33.5 months (0.6–156). First line treatment schedules and treatment response in every group are detailed in table 1. Patients receiving rituximab (group 3–4, n=73) achieved a significant higher response rate (CR or PR) than patients without rituximab (93% vs 61%). The main clinical variables with prognosis significance in the univariate analysis for PFS were: lymphocyte count (p=0,026, HR 1.002, CI95% (1.000–1.004)); haemoglobin level (p=0,02, HR 0.890, CI95% (0.826–0.958); b2-microglobulin (p=0,002, HR 1.372, CI95% (1.125–1.672)); bulky mass (p=0,055, HR 1.656, CI95% (0.989–2.775)); CD38 expression (p=0,045, HR 1.005, CI95% (1.000–1.011)); p53 deletion (p=0,014, HR 2,231, CI95% (1,180–4,217)) and 11q23 deletion (p=0,03, HR 2,138, CI95% (1,290–3,542)). The median PFS for patients in the different groups were: G1:26.9 months (22.4–31.3), G2 45.5 months (32.7–58.4), G3: not reached, G4: 20.5 months (29.6–47.3), p < 0.0001. In the multivariate analysis the variables with independent prognostic significance for PFS were: lymphocyte count (p=0.003, HR 1.004, CI 95% (1.001 −1.007)), 17deletion (p=0.01, HR 2.7 CI95% (1.273–5.73)), 11q deletion (p=0.006, HR 2.193 CI95% (1.248–3.852)) and treatment received (G1 as reference): G2 (p=0.005, HR 0.464, CI95% (0.271–0.794)), G3 (p < 0.001, HR 0.179, CI95% (0.083–0.386)), G4 (p=0.223, HR 0.289, CI95% (0.039–2.130)). Conclusion. In this community based population, treatment with rituximab containing regimens results in a higher global and complete response rate and a longer PFS compared with alquilating agents and purine analogs. Fludarabine containing-schedules also achieved a significant higher response rate than alquilating agents. Rituximab in combination with purine analogs provide the better quality of response. These results confirm the data provided by clinical trials and support their use as front-line treatment. Disclosures: Terol: ROCHE: Consultancy.
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Aljawai, Yosra, Serena McDiarmid, Joseph Cappuccio, Federico Campigotto, Steven Peter Treon, Edie A. Weller, Brenda M. Birmann e Irene M. Ghobrial. "A Case-Control Epidemiological Study Of Waldenstrom Macroglobulinemia". Blood 122, n.º 21 (15 de novembro de 2013): 1713. http://dx.doi.org/10.1182/blood.v122.21.1713.1713.
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Abstract Introduction Waldenstrom Macroglobulinemia (WM) is a distinct lymphoplasmacytic disorder characterized by bone marrow (BM) infiltration and IgM secretion. The etiology remains unknown, but a role for genetic and immune-related factors in the pathogenesis is suspected. To date, few etiologic studies have focused specifically on WM. Therefore, we initiated a large case-control study of WM to evaluate a comprehensive panel of potential risk factors. Here we describe the study design and report initial findings in the enrolled WM patients. Methods Patients are recruited into the study through the WM clinic at the Dana-Farber Cancer Institute, WM meetings or web-based invitations through the International Waldenstrom Macroglobulinemia Foundation (IMWF) website. For each patient, two controls are invited to participate: a family member of the patient, and an acquaintance of similar age and neighborhood of residence to the patient. Enrollment targets are for 1000 patients and an equal number of family members and non-family controls. From the WM patients we collect data on clinical presentation at diagnosis and from follow up of disease progression, as well as diagnostic tumor tissue and other biospecimens. Both patients with LPL/WM and controls completed a self-administered questionnaire that includes items related to personal characteristics, socioeconomic background, medical history, medication use and several lifestyle and environmental factors. Results We identified and invited 1144 WM patients. 396 WM patients and 83 family members of these patients completed the epidemiology survey. Of the 396 patients who completed the survey, 348 were diagnosed with LPL/WM and 48 with MGUS. The median age of patients at diagnosis was 67 years (range, 24-92 years). One patient was younger than 40 years of age, and 14 (4%) were younger than 50 years. 245 (62%) patients were males. Most patients self-reported Caucasian race (N=305, 77%), whereas others were of Ashkenazi Jewish (45, 11%), mixed (30, 8%), or other (16, 4%) racial backgrounds. Almost half (N=193, 49%) have completed graduate or professional school, and another 180 (45%) have completed some college education or a college degree; only seven patients (5%) have only a high school education or less, and education level is missing for 1%.” With regard to personal medical history, the WM patients most frequently reported a history of osteoporosis/osteopenia (20%), followed by that of lymph node enlargement (13%), thyroid disorder (11%), other autoimmune disease (10%), infectious mononucleosis (8%), hemolytic anemia (6%), renal insufficiency (5%), venous thrombosis and strokes (4%), inflammatory bowel disease (ulcerative colitis/Crohn's disease) (4%), diabetes mellitus (4%), and rheumatoid arthritis (3%). The WM patients reported a family history of several cancers in relatives: breast cancer (27%), prostate cancer (16%), colon cancer (14%), uterine cancer (14%) and lung cancer (17%). The most common hematological malignancies observed in relatives included leukemia (8%), WM (5%), other Non-Hodgkin’s lymphomas (5%), Hodgkin’s lymphoma (3%), and myeloma. The 396 patients also self-reported a history of exposure of at least eight hours per week for more than a year to some chemicals, including asbestos (11%), benzene and pesticides (9%), herbicides, fertilizers and gasoline or other solvents (7%), petroleum products, engine exhaust, and acrylic and oil based paints (6%). Five percent or less of the patients reported prior exposure to Agent White, Agent Orange, and Metals. Further patient and control recruitment is ongoing, as are preliminary statistical comparisons of the case and control patient populations to evaluate potential risk factors for the WM. Conclusion These preliminary descriptive data from the first case-control study to focus explicitly on WM confirm prior observations of familial history of B-cell lymphoproliferative disorders in patients with WM and suggest early success at collecting self-reported information on other potential risk factors in the patient population. By collecting and rigorously analyzing diverse risk factor data from both patients and controls, this study is likely to contribute important insights on the etiology of this rare and understudied lymphoma. Such knowledge is urgently needed to permit the development of strategies for WM prevention. Disclosures: Treon: Millennium: Consultancy. Ghobrial:BMS: Advisory board Other, Research Funding; ONYX: Advisory board, Advisory board Other; NOXXON: Research Funding; Sanofi: Research Funding.
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Murillo, Ilda, Marcio M. Andrade, Anel Montes, Jose M. Grasa e Pilar Giraldo. "Are IgM Hevylite® Immunoglobulin Heavy Chain/Light Chain Analysis a Useful Tool to Differentiate IgM MGUS From Waldenström Macroglobulinemia?" Blood 120, n.º 21 (16 de novembro de 2012): 5097. http://dx.doi.org/10.1182/blood.v120.21.5097.5097.
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Abstract Abstract 5097 Background: Monoclonal IgM is the biomarker that characterize to Waldenstrom's macroglobulinemia (WM), a rare low grade B-cell lymphoma derived of the lymphoplasmacytic cell, even serum IgM component also is presented in MGUS. Recently new determinations of heavy chain/light chain immunoglobulins pairs (HLC) have been developed as biomarkers to apply to every day clinical practice. The diagnostic and prognostic potential of these biomarkers is under investigation. The aim of this study is to present our experience in the use of free light chain assay (sFLC) and HLC as biomarkers at diagnostic in order to discriminate between MGUS and WM, and to evaluate their potential prognostic value during disease course. Patients and Methods: A total of 43 patients (pts) were detected as having a serum monoclonal IgM in the Hematology Department of MSUH. Pts were classified as MGUS or WM according to the morphological, immunophenotype characteristics of lymphoplasmacitic bone marrow cells and CT-scan data. Pts were examined every 3–6 months following our clinical protocol in order to detect progression or transformation. Serum samples were collected prior and during treatment and were kept frozen at −70°C since collection and incorporate to our regional Biobank. Analysis of IgM were performed with the sFLC, (Freelite® test, the Binding Site, Birmingham, UK) and the HLC (Hevylite® immunoassay the Binding Site). Freelite® test is a nephelometric measurement of kappa and lambda light chains that circulate not bound to immunoglobulin heavy chain. Hevylite® immunoassay is based on specific polyclonal antibodies that recognize epitopes spanning the junction of the heavy and light chains of the individual immunoglobulin isotypes, it measures specifically IgMkappa and IgMlambda, separately. A normal range of IgM Hevylite assay was produced from normal (blood donor) sera, median (CI 95%) were: IgMkappa, 0. 634 g/L (0. 29–1. 82); IgMlambda, 0. 42g/L (0. 17–0. 94); HLC ratio (HLCR), 1. 6 (0. 95–2. 3). For ease of comparison IgM HLCR was expressed as the involved monoclonal immunoglobulin (iHLC)/uninvolved polyclonal immunoglobulin (uHLC). Results: The study included a series of 25 WM, 18 IgM-MGUS (included 2 IgM-cryoglobulinemia), 36 at diagnosis and 7 at relapse/refractory. The median age was 67. 1 years (13–85); IgM HLCR was 114. 68 (1. 02 – 353) in WM symptomatic, 71. 55 (1. 02 – 286. 43) in WM asymptomatic and 9. 5 (0. 45 – 50. 74) in IgM MGUS (p=0. 003). HLCR was higher in WM patients requiring treatment (n=13) at diagnosis than in pts (n=30) not requiring treatment (113 v 15. 77 p=0. 019) and also HLCR was significantly higher at relapse/refractory (n=9) than in pts (n=34) not relapse (113 v 17. 17 p=0. 012) uHLC was significantly higher in IgM-MGUS than WM to IgMkappa (n=28) and IgMlambda (n=15) iHLC: 0. 37 g/L (0. 11–1. 25) v 0. 1 g/L (0. 02–4. 03), p=0. 022; and 0. 69 g/L (0. 08–4. 09) v 0. 32 g/L (0. 22–0. 63), p=0. 05 respectively. sFLC level was 64 mg/L (10. 88–993) in WM and 31. 7 mg/L (6. 08–141) in IgM MGUS (p=0. 05). sFLC level was higher in WM requiring treatment at diagnosis than in pts not requiring treatment (73. 7 v 36. 85 p=0. 039). sFLC level was not significative in relapse/refractory (p=0. 168), it was not separate between WM asymptomatic and WM symptomatic (p=0. 092). There was a good correlation between HLCR and sFLC ratio (r=0. 3, p=0. 044) but not with sFLC level, HLCR, sFLC level and sFLC ratio did not predict for overall survival (OS) and progression free survival (PFS) in our study. Mean estimated OS was 78. 3 months (95% CI: 53. 67–102. 94) and PFS 69. 7 months (95% CI: 47. 28–92. 13). Conclusion: It seems that HLCR and sFLC could be good biomarkers to differentiate between IgM-MGUS and WM at diagnostic. High levels of HLC and sFLC were also seen in pts requiring treatment. HLCR discriminates WM symptomatic/asymptomatic and progressing pts uHLC levels were significantly higher in IgM-MGUS than WM pts showing that IgM-MGUS have a more robust immune system. Further studies are needed to evaluate their prognostic value. This work has been partially sponsored by a grant from FEHHA Disclosures: No relevant conflicts of interest to declare.
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Narayanan, Bhagavathi A., Cronstein Bruce, Mediero Aranzazu, e Amitabha Mazumder. "Differential Activity of Brain Derived Neurotrophic Factor (BDNF) and RANKL in Promoting Osteoclast Activity in Multiple Myeloma Patients with or without Bone Disease". Blood 124, n.º 21 (6 de dezembro de 2014): 2058. http://dx.doi.org/10.1182/blood.v124.21.2058.2058.
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Abstract Purpose: Brain derived neurotrophic factor (BDNF) which plays an important role in the development of neuronal cells, has a high affinity receptor TrkB and expressed in malignant plasma cells and osteoblasts.Recent reports onage related changes in human serum levels of BDNF drew our attention to further investigate whether soluble BDNF from myeloma cells contributes for the bone related osteolytic activities in MM patients. To answer this question, we analyzed samples from three group of MM patients; (a) bone related early stage, (b) late stage and (c) non-bone related early stage MM (n=10 each). Sample description and assays: Samples were obtained from patients who had given written informed consent and approved by the Institutional Review Board of NYU School of Medicineandserum samples of healthy volunteers were used for control. Multiplex luminex assay was performed to examine serum samples in triplicate (100 μl each) to measure the following analytes: BDNF, RANKL, NGF, FGF, IL-6, MIP-1α, VEGF, DKK1, OPG, and TGF-β. Immuno-profiling was performed using Luminex x-MAP technology (Luminex Corp, Austen Tx) or with Milliplex multi-analyte panels from EMD Millipore (Billerica, MA). Primary plasma cell culture supernatants were also analyzed for BDNF, NGF, FGF, IL-6, MIP-1α, OPG, RANKL and TGF-β. Data collected on a Luminex 200 instrument was further analyzed using xPONENT 3.1 software (Luminex) with 5-parameter logistic curve fitting. All standard curves generated had R2 values calculated at or close to 1 and percent recovery was between 80-120%. Results: More than 90% (9/10)of the serum samples from non-bone related and/or early stage MM patients showed an elevated level of BDNF (1135±7pg/ml) vs. control (217±7pg/ml, >5 fold) in comparison to that in bone related MM (870±12pg/ml). However, the nerve growth factor (NGF) level in the serum was found to be at a minimum detectable level of 30±3pg/ml in non-bone related MM. We observed elevated level of RANKL (305±9pg/ml, >6 fold compared to the control) in late stage bone related MM in contrast to a lesser amount in non-bone related disease (58±2pg/ml). As expected, our findings indicated a decrease in osteoprotegerin (150±9 and 115±11pg/ml) in the serum samples of early and bone related MM respectively. Although several factors were identified to be the cause for an elevated serum BDNF, in this study we asked the question of whether hypoxic conditions could influence the secretion of BDNF in MM cells. To answer this, primary plasma cells from human and mouse were exposed to hypoxia (1% oxygen level) for 24 h and the soluble BDNF measured. We found >2 fold increase in BDNF under hypoxic conditions (1530±2pg/ml) associated with an increase in RANKL (534±9pg/ml) and TGF-β (1300±23pg/ml) in non-bone related human MM. We found an increase in (>67%) differentiating preosteoclasts that are positive for TRAP activity in the presence of an exogenous source of BDNF. This effect was significantly blocked by a neutralizing BDNF antibody and/or RANKL inhibitor. Conclusion: In summary, our data provide evidence for a role of BDNF in MM patients who are presented with non-bone related MM and a risk for progressive MM. Additional experiments conducted to dissect a clear mechanism reveal a potential synergy between BDNF, TrkB and RANKL in promoting osteoclast activities. Overall, our findings provide evidence on the role for BDNF and RANKL that could synergistically interact with proinflammatory cytokines in promoting preosteoclast differentiation at early stages of MM that is not involving the bone. Disclosures No relevant conflicts of interest to declare.
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Ionescu, Filip, Nwabundo Anusim, Eva Ma, Lihua Qu, Leann Blankenship, Michael Stender e Ishmael Jaiyesimi. "Inferior Vena Cava Filter Retrieval Trends: A Single Center Experience". Blood 134, Supplement_1 (13 de novembro de 2019): 4690. http://dx.doi.org/10.1182/blood-2019-129366.
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Background: Inferior vena cava (IVC) filters are indicated in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) who either have contraindications to or have failed anticoagulation (AC). Given rising concerns about their safety and efficacy, the FDA has issued a communication urging clinicians to remove filters (optimally, within 90 days post-implantation). According to national data retrieval rates remain low. Our study aimed to assess IVC filter retrieval rates and factors that influence retrieval. Methods: This is a single center, retrospective cohort study of patients who had IVC filter placement between December 2015 and December 2018. Subjects were identified using procedural codes for IVC filter insertion; data regarding demographics, comorbidities, retrieval, IVC filter-related complications and subsequent thromboembolic events were obtained by direct chart review. Survival analyses and a Cox regression model were performed using JMP statistical software. Results: Over 3 years, 494 patients with IVC filters were identified; 305 (62%) were retrievable. The average age at placement was 69±16 years; 249 (50%) were men and 332 (67%) were Caucasian. After excluding patients who died or were lost to follow-up within 30 days of placement or were discharged to hospice from the index admission, 258 patients with retrievable filters remained (54 retrieved). Indications for IVC filter placement were PE ± DVT 90 (35%), proximal DVT 159 (62%) and prophylactic 9 (3%). Forty two percent of patients (109) were restarted on AC at discharge, while an additional 18% (total 155) received AC at some point thereafter. The rate of retrieval was 8% at 90 days, 23% at 1 year and 28% at 2 years (Figure A). The proportional hazards model identified resumption of AC at any time (HR 3.11, 95%CI 1.6-6.8, p=0.0006) as the strongest predictor of retrieval; AC at discharge was not predictive. Advanced age at placement (HR 0.97 per unit change, 0.96-0.99, p=0.004) and active malignancy (HR 0.5, 95%CI 0.24-0.98, p=0.04) were associated with a lower likelihood of retrieval. The initial thrombotic event, the reversibility of the contraindication to AC, the placing service, sex, ethnicity and other comorbid conditions did not have an impact on retrieval. Kaplan-Meier analysis revealed that subjects who ever resumed AC had significantly higher rates of retrieval at 90 days (11% vs 3.4%) and at 1 year (33% vs 9.7%, log-rank p=0.0003, Figure B) when compared to those who did not. Only four patients experienced IVC filter-related complications (2 filter thrombosis, 1 IVC penetration, 1 device tilting); all occurred 2 or more years after placement. Recurrent thromboembolic events occurred in 50 patients (5 PE, 48 proximal DVT) with no significant difference in frequency between subjects with retrieved and non-retrieved filters; one PE and one DVT occurred at 1 month and 1 week respectively after retrieval. Conclusion: Despite efforts to increase awareness of IVC filter-associated complications, the unweighted retrieval rate remained below the nationally reported average of 30%. Persistent risk factors for thrombosis such as active malignancy or increasing age and poor prognosis may play a role in the decision to defer retrieval. In our study, resumption of AC proved a powerful predictor of retrieval, with rates approaching expected values in this population. Active surveillance for resolution of contraindications to AC post-IVC filter placement is crucial in increasing retrieval rates. Figure Disclosures No relevant conflicts of interest to declare.
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Wang, Wenrui. "The Ways that Digital Technologies Inform Visitor's Engagement with Cultural Heritage Sites: Informal Learning in the Digital Era". GATR Global Journal of Business Social Sciences Review 10, n.º 4 (30 de dezembro de 2022): 237–48. http://dx.doi.org/10.35609/gjbssr.2022.10.4(3).
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Museum objects and Instagram: agency and communication in digital engagement. Continuum, 32(2), 137–150. 8. Callanan, M. A., & Oakes, L. M. (1992). Preschoolers’ questions and parents’ explanations: Causal thinking in everyday activity. Cognitive Development, 7(2), 213–233. 9. Callanan, M., Cervantes, C., & Loomis, M. (2011). Informal learning. Wiley Interdisciplinary Reviews: Cognitive Science, 2(6), 646–655. 10. Cameron, F. (2003). Digital Futures I: Museum collections, digital technologies, and the cultural construction of knowledge. Curator: The Museum Journal, 46(3), 325–340. 11. Cokley, J., Gilbert, L., Jovic, L., & Hanrick, P. (2016). Growth of ‘Long Tail’in Australian journalism supports new engaging approach to audiences. Continuum, 30(1), 58–74. 12. Cole, M., & Consortium, D. L. (2006). The fifth dimension: An after-school program built on diversity. Russell Sage Foundation. 13. European Commission. (2015). i-Treasures: intangible cultural heritage of the past available through advanced modern technologies. 14. Fitts, S., & McClure, G. (2015). Building Social Capital in Hightown: The Role of Confianza in L atina Immigrants’ Social Networks in the New South. Anthropology & Education Quarterly, 46(3), 295–311. 15. Francesca, P. (2017). Final Report on User Requirements: Identification and Analysis. 16. Gade, R. (2009). Event Culture - The Museum and Its Staging (Kopenhagen, 6-7 Nov 09). 17. Gibbert, M., Ruigrok, W., & Wicki, B. (2008). What passes as a rigorous case study? Strategic Management Journal, 29(13), 1465–1474. 18. Gillard, P. (2002). Cruising through history wired. Museums and the Web 2002. 19. Goodwin, M. H. (1990). He-said-she-said: Talk as social organization among black children (Vol. 618). Indiana University Press. 20. Hamma, K. (2004). The role of museums in online teaching, learning, and research. First Monday. 21. Henchman, M. (2000). Bringing the object to the viewer: Multimedia techniques for the scientific study of art. 22. Herrgott, C. (2016). Cantu in paghjella: Patrimoine Culturel Immatériel et nouvelles technologies dans le projet I-Treasures. Port Acadie: Revue Interdisciplinaire En Études Acadiennes/Port Acadie: An Interdisciplinary Review in Acadian Studies, 30, 91–113. 23. Howell, R., & Chilcott, M. (2013). A sense of place: re-purposing and impacting historical research evidence through digital heritage and interpretation practice. International Journal of Intangible Heritage, 8, 165–177. 24. King, L., Stark, J. F., & Cooke, P. (2016). Experiencing the digital world: The cultural value of digital engagement with heritage. Heritage & Society, 9(1), 76–101. 25. Lomb, N. (2009). Dip circle used to study the earth’s magnetic field at Parramatta Observatory. 26. Majors, Y. J. (2015). Shoptalk: Lessons in teaching from an African American hair salon. Teachers College Press. 27. Marty, P. F. (2008). Museum websites and museum visitors: digital museum resources and their use. Museum Management and Curatorship, 23(1), 81–99. 28. Moqtaderi, H. (2019). Citizen curators: Crowdsourcing to bridge the academic/public divide. University Museums and Collections Journal, 11(2), 204–210. 29. Müller, K. (2013). Museums and virtuality. In Museums in a digital age (pp. 295–305). Routledge. 30. Nasir, N. S., Rosebery, A. S., Warren, B., & Lee, C. D. (2006). Learning as a cultural process: Achieving equity through diversity. 31. O’Brien, H. L., & Toms, E. G. (2008). What is user engagement? A conceptual framework for defining user engagement with technology. Journal of the American Society for Information Science and Technology, 59(6), 938–955. 32. O’Neill, R. (2017). The Rise of the Citizen Curator: Participation as Curation on the Web. University of Hull. 33. Opie, I., & Opie, P. (2000). The lore and language of schoolchildren. New York Review of Books. 34. Pallud, J. (2017). Impact of interactive technologies on stimulating learning experiences in a museum. Information & Management, 54(4), 465–478. 35. Pallud, J., & Straub, D. W. (2014). Effective website design for experience-influenced environments: The case of high culture museums. Information & Management, 51(3), 359–373. 36. Pozzi, F. (2017). Final Report on User Requirements: Identification and Analysis. Unpublished I-Treasures Project Report. 37. Proctor, N. (2010). Digital: Museum as platform, curator as champion, in the age of social media. Curator: The Museum Journal, 53(1), 35. 38. Rogoff, B., Callanan, M., Gutiérrez, K. D., & Erickson, F. (2016). The organization of informal learning. Review of Research in Education, 40(1), 356–401. 39. Schugurensky, D. (2000). The forms of informal learning: Towards a conceptualization of the field. 40. Scribner, S., & Cole, M. (1973). 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Kumar, Priya, Todd E. Defor, Claudio Brunstein, Juliet Barker, John E. Wagner, Daniel J. Weisdorf, Jeffrey S. Miller et al. "Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Treatment of Acute Lymphocytic Leukemia (ALL) in 126 Adults: Impact of Donor Source on Leukemia Free Survival (LFS)." Blood 106, n.º 11 (16 de novembro de 2005): 2064. http://dx.doi.org/10.1182/blood.v106.11.2064.2064.
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Abstract White blood cell (WBC) count and specific cytogenetic abnormalities at diagnosis, patient age and disease status at HSCT have previously been identified as risk factors associated with LFS in patients with ALL. As the use of umbilical cord blood (UCB) is relatively new, particularly for adults, we sought to evaluate the relative impact of donor source. In this single center study, 126 adults aged 18–61 (median 31) years (yrs) underwent myeloablative conditioning (cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy based regimen in 92%) followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 85, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14 and HLA 0–2 (A, B, DRB1) mismatched UCB in 12. At the time of HSCT, 64 patients were in CR1, 51 in CR2, and 11 patients in ≥ CR3; 20 pts had T-lineage disease; 38 pts (30%) had either t(9;22)(n=28), t(4;11) or t(1,19) (n=10) with the remainder (70%) having normal cytogenetics. WBC ≥ 30 x 109/l at diagnosis was documented in 50%. Demographics, disease characteristics at initial diagnosis and transplant variables were similar in all 4 groups except: year of transplant after 1996 and use of growth factor for all UCB recipients. Outcomes by donor source: MRD URD:M URD:MM UCB P N 85 15 14 12 Median follow up in yrs 9.3 3.5 7.2 1.2 OS 1 yr % (95% CI) 41 (31–52) 33 (9–57) 14 (0–33) 75 (51–100) 0.02 LFS 1 yr % (95% CI) 35 (25–45) 27 (4–49) 14 (0–33) 67 (40–93) 0.03 Relapse 1 yr % (95% CI) 21 (12–30) 20 (0–40) 0 8 (0–23) 0.22 TRM 1 yr % (95% CI) 44 (33–55) 53 (27–79) 86 (57–100) 25 (1–49) <0.01 As a consequence of low TRM, OS and LFS were superior after UCB transplants. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS: use of URD:M (RR 3.8, 95% CI 1.1–13.8, p= 0.04) and URD:MM (RR 4.9, 95% CI, 1.3–19.1, p= 0.02), ≥ CR3 at HSCT (RR 3.0, 95% CI, 1.1–8.8, p= 0.04), WBC >30 x 109/l (RR 2.4, 95% CI, 1.4–4.1, p<0.01), cytomegalovirus (CMV) seropositive recipient and donor (RR 4.0, 95% CI, 2.0–7.9, p<0.01), and ≥ 2 induction regimens to achieve initial CR (RR 2.7, 95% CI, 1.2–5.9, p= 0.01). Patients who developed grade II–IV acute graft versus host disease (GVHD) had significantly lower mortality rates (RR 0.4, 95% CI, 0.2–0.7, p<0.01). There was no impact on OS by year of transplant or use of growth factor. Variables associated with poor LFS were identical to those for OS, and GVHD was again associated with improved LFS. These results support the use of UCB as an alternative stem cell source for adults with ALL with results comparable to outcomes observed with MRDs. In addition, GVHD is associated with improved LFS suggesting a significant graft versus leukemia effect with all donor graft sources.
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Morel, J., L. Dagna, B. Joven-Ibáñez, T. Holzkaemper, C. El Baou, L. Unger, A. Semeraro, N. Gullick e T. Treuer. "AB0899 A 24-month Prospective Psoriatic Arthritis Observational Study of Persistence of Treatment (PRO-SPIRIT) - Interim Analysis of Baseline Characteristics". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1578.1–1578. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1984.
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BackgroundIxekizumab (ixe), a highly selective interleukin (IL)-17A monoclonal antibody, has been approved for treatment of psoriatic arthritis (PsA). However, there is limited real-world evidence (RWE) available for ixe. PRO-SPIRIT is the first large-sample prospective observational study to provide RWE for ixe in patients (pts) with PsA.ObjectivesPRO-SPIRIT’s primary objective is to describe treatment persistence at 24 months (M) among pts with PsA who initiate or switch to a new biologic Disease Modifying Arthritis Rheumatic Drugs (bDMARDs) or targeted synthetic (tsDMARDs), including ixe. This abstract describes the interim baseline (BL) characteristics.MethodsPRO-SPIRIT is a prospective observational study, conducted in FR, ES, IT, DE, UK, and CA, enrolling adults with PsA (≥6M) to be initiated or switched to a new b/tsDMARD, locally approved for PsA. Treatment groups include ixe, secukinumab, IL-12/IL-23 inhibitors (i) (ustekinumab) or IL-23i (guselkumab), tumour necrosis factor (TNFi) (adalimumab, etanercept, infliximab or biosimilar), Janus kinase (JAKi) (tofacitinib or upadacitinib). Pt demographic, disease activity and therapy characteristics are collected at BL; clinical and patient-reported outcomes measures are collected at BL and at a routine post-BL visit. BL descriptive statistics are reported.ResultsFrom December 2019 until this interim data cut (June 2021), a total of 477 pts (305 female; mean age 52) were enrolled. Mean age ranged from 48 (IL-12/23i and IL-23i) to 55 (JAKi), with a majority of female pts in each group (Table 1). Pts in the IL-12/23i and IL-23i and TNFi groups showed the shortest time since PsA diagnosis (5.2±4.5; 6.5±7.9), while pts in the JAKi group showed the longest time (10.6±9.4). The lowest proportion of pts with a prior b/tsDMARDs use was observed in the TNFi group (31%), the highest in the IL-12/23i and IL-23i group (71%). Pts in the ixe and IL-12/23i and IL-23i groups were more likely to be on monotherapy. Tender Joint Count (9.1-11.3) and Swollen Joint Count (3.3-5.8) were comparable across groups, with the highest values in the ixe and JAKi groups, respectively. Pt proportion with enthesitis and dactylitis was higher in the ixe, secukinumab and JAKi groups. Percentage of Body Surface Area affected by psoriasis was higher in the ixe, secukinumab and IL-12/23i and IL-23i groups. Pt proportion with nail psoriasis was higher in the ixe and secukinumab groups. Physician’s Global Assessment Visual Analog Scale (VAS), Patient’s Global Assessment VAS and Patient’s Assessment of Joint Pain VAS reflected a high burden of illness.Table 1.Baseline characteristicsbDMARDstsDMARDsIxekizumabSecukinumabIL-12/23 and IL-23 inhibitorsTNF inhibitorsJAK InhibitorsN=137N=46N=24N=211N=40Age52.8±12.252.8±13.147.6±13.450.3±11.755.3±9.9Female, n (%)86 (62.8)31 (67.4)16 (66.7)135 (64.0)25 (62.5)Years since diagnosis8.4±7.57.6±8.05.2±4.56.5±7.910.6±9.4Prior b/tsDMARD, n (%)87 (63.5)27 (58.7)17 (70.8)66 (31.3)26 (65.0)Concomitant csDMARD, n (%)47 (34.3)19 (41.3)5 (20.8)108 (51.2)19 (47.5)Tender Joint Count11.3±10.29.1±10.89.1±9.310.9±10.611.1±8.8Swollen Joint Count5.7±6.63.3±3.83.4±6.44.8±5.65.8±6.6Body Surface Area % affected by psoriasis6.1±10.57.6±14.27.0±9.74.6±11.02.2±3.1Presence of enthesitis, n (%)58 (42.3)16 (34.8)4 (16.7)67 (31.8)16 (40.0)Presence of dactylitis, n (%)33 (24.1)10 (21.7)3 (12.5)26 (12.3)10 (25.0)Presence of nail psoriasis, n (%)57 (41.6)20 (43.5)7 (29.2)71 (33.6)11 (27.5)Physician’s Global assessment VAS62.6±18.159.5±20.555.7±24.661.7±18.063.0±20.5Patient’s Global Assessment VAS60.5±20.456.8±25.156.2±25.757.5±22.955.4±22.5Patient’s Assessment of Joint Pain VAS62.7±21.358.4±27.155.7±28.359.4±22.957.5±24.0Mean±SD, unless otherwise statedConclusionThe reported BL characteristics offer preliminary information about which pts initiate or switch to a b/tsDMARD in a real life-setting. Future disclosures (at 12 and 24M) will provide RWE regarding persistence, effectiveness, and health care resource use of available treatments for PsA, which will help pts and physicians to make better informed treatment decisions.Disclosure of InterestsJacques Morel Speakers bureau: Abbvie, Amgen, Biogen, Biogen, Bristol Myer Squib, Fresenius, Galapagos, Eli Lilly and Company, Médac, Novartis, Sandoz, Sanofi, Consultant of: Abbvie, Galapagos, Eli Lilly and Company, Médac, Novartis, Glaxo Smith Kline, Grant/research support from: Bristol Myer Squib, Biogen, Eli Lilly and Company, Novartis, Pfizer, Lorenzo Dagna Speakers bureau: Abbvie, Amgen, BMS, Eli Lilly and Company, Galapagos, GSK, Pfizer, Sobi, Consultant of: Abbvie, Amgen, Astra Zeneca, Biogen, BMS, Celltrion, Eli Lilly and Company, Galapagos, GSK, Janssen, Kiniksa, Pfizer, Roche, Sobi, Sanofi, Beatriz Joven-Ibáñez Speakers bureau: Eli Lilly and Company, Grant/research support from: (institutional grant) Eli Lilly and Company, Thorsten Holzkaemper Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Celine El Baou Consultant of: Eli Lilly and Company, Leonore Unger Speakers bureau: Eli Lilly and Company, Angelo Semeraro: None declared, Nicola Gullick Speakers bureau: AbbVie, Celgene, Janssen, Eli Lilly and Company, Novartis, UCB, Consultant of: AbbVie, Janssen, Eli Lilly and Company, Novartis, UCB, Grant/research support from: (institutional grants) Eli Lilly and Company, AbbVie, Astra Zeneca, Izana, Novartis, Tamas Treuer Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company
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Dewi, Melina Surya, e Yufiarti. "Play-based Learning Activities for Creativity in Children's Dance Movements". JPUD - Jurnal Pendidikan Usia Dini 15, n.º 1 (30 de abril de 2021): 101–20. http://dx.doi.org/10.21009/jpud.151.06.
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Play-based learning activities are important programs throughout the world of children's education. Through play, children learn creatively and constructively. This study aims to solve the problem of creativity in early-childhood dance movements with the hope that there will be an increase in aspects of fluency, flexibility and elaboration through play activities related to educational dance. This action research uses an action research method which is carried out in three cycles. The subjects in this study were 19 children aged 5-6 years in Kindergarten in Central Jakarta. Data collection was carried out through observation, interviews, field notes, video documentation and photos. The findings show every child's creativity in dance movements can be improved through playing activities. Increased creativity in dance movements occurs in the aspects of fluency, flexibility, and elaboration. Another important finding, there is an increase in the optimal ability of dance creativity in the third cycle of this action research. The implication from this research is that play activities suitable for learning creative dance in early childhood must be designed as a program that emphasizes aspects of fluency, flexibility, and elaboration.
Keywords: Early Childhood, Creativity in dance movements, Play based learning activities
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Cortivo, Liliane Dal, Mathilde Bahuaud, Marie Noelle Lacassagne, Vincent Monchois, Cecile Ducasse e Marina Cavazzana-Calvo. "Anti CMV Immunotherapy with Donor Antigen Specific Lymphocytes Selected with GMP HLA Class 1 Tetramer Reagents." Blood 114, n.º 22 (20 de novembro de 2009): 4492. http://dx.doi.org/10.1182/blood.v114.22.4492.4492.
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Abstract Abstract 4492 Patients undergoing allogeneic haematopoietic stem cell transplants frequently develop infections that are responsible for a high rate of morbidity and mortality during first 6 months post transplantation. The occurrence of CMV infection might reach 70% to 80% of transplanted patients; this rate is increased in HSC transplantations conditioned by in vivo and/or in vitro immunosuppressive treatment. Prophylactic treatment of CMV infection by ganciclovir or foscarnet, though proven to be efficient, faces complications such as myelotoxicity, nephrotoxicity and/or the development of virus resistance. The control of CMV reactivation is achieved in healthy individuals by CD4 +and CD8 +T lymphocytes specifically directed against CMV. After allograft, it has been demonstrated that restoration of anti-CMV immune responses is efficient but all the more delayed when conditioning is heavier. Furthermore, it has been demonstrated that the transfer of donor T lymphocytes specifically directed against CMV was able to prevent and even more to control viral reactivation. Several strategies have been described to generate anti-CMV CD8+ cytotoxic T lymphocytes (CTL) in vitro, by using as antigen-presenting cells (APCs) CMV-infected fibroblasts (Walter, NEJM 1995, 333: 1038), or EBV-transformed B cells retrovirally transduced to express CMV pp65 protein (Sun, Blood 1999, 94: 3242). However, the length of process and the presence of potentially dangerous viral particles in these trials limit their clinical utilisation. Recent progresses in technology resulting from the HLA tetramer technique have enabled to develop direct and fast enrichments of anti-CMV CTL sufficient to inject one or several doses of these lymphocytes (Cobbod abstract 155, ASH 2004). In order to reach the regulatory requirements for ancillary products to be used in an anti CMV immunotherapy protocol, a tetramer selection system and its associated production process compatible with cGMP has been developed. The developed manufacturing process (Protein Expert) is based on: - the E. coli production of the different components, HLA201 heavy chain and β2 microglobulin as well as streptavidin, the chemical synthesis of the pp65 peptide; - the production and biotinylation of the monomers-the production of the tetramers using recombinant streptavidin covalently linked to magnetic beads (Miltenyi Biotec ®) compatible with clinical applications. Seven immunomagnetical selections on MS column of HLA A2-pp65 positive tetramer cells from healthy blood donors were performed with these GMP reagents. Respective means of CD8 tetramer +cells in starting and selected fractions were 2.5 %(+/-3.1) and 99 %(+/-0.6). Expt Start Selected CD8 tetramer+ cells (%) CD8 tetramer+ cells (10e5)) CD3 + cells (%) CD8 tetramer+ cells (%) CD8 tetramer+ cells (10e5) CD8 tetramer+ cells yield (%)) 1 0,54 1,31 89 99 1,73 117 2 8,45 7,46 99 99 12,2 162 3 0,32 0,57 93 99 0,64 105 4 0,39 1,37 91 99 1,68 112 5 3,35 8,59 98 99,5 5,84 67 6 4,47 2,7 98 98 2,4 86 7 0,14 0,2 79 99,8 0,29 116 Mean 2,5 3,2 92,4 99,0 3,5 109,3 SD 3,1 3,4 7,1 0,6 4,2 29,6 Starting and selected cells were restimulated with CMV or irrelevant peptide and evaluated for interferon gamma secretion (respectively 5.4%+/5.2 and 71.8%+/-14.7) and CD107a expression (6.1%+/-2.9 and 56.2%+/-32.7). The GMP reagents used for selection demonstrated a very good efficacy for enrichment of HLA A2-pp65 positive tetramer CD8 cells with high purity and yield. Selected cells were shown to be antigen specific and cytotoxic. This procedure scaled up on Clinimacs device could provide in a very short time, sufficient CD8 tetramer positive cells for very selective adoptive immunotherapy after stem cells transplant. Disclosures: No relevant conflicts of interest to declare.
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Sehn, Laurie H., Angela Giovanna Congiu, Dominic J. Culligan, Mercedes Gironella, Dok Hyun Yoon, Michinori Ogura, Andras Rosta et al. "No Added Benefit of Eight Versus Six Cycles of CHOP When Combined with Rituximab in Previously Untreated Diffuse Large B-Cell Lymphoma Patients: Results from the International Phase III GOYA Study". Blood 132, Supplement 1 (29 de novembro de 2018): 783. http://dx.doi.org/10.1182/blood-2018-99-116845.
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Abstract Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus 6-8 cycles of CHOP (R-CHOP). While the RICOVER trial (Pfreundschuh et al. Lancet Oncol 2008) showed no benefit of 6 versus 8 cycles of R-CHOP administered at 2-weekly intervals, this has not been assessed with the standard 3-weekly regimen, and many centers continue to administer 8 cycles. GOYA (NCT01287741) was an open-label, randomized, Phase III study of the efficacy and safety of R-CHOP versus obinutuzumab (GA101; G) plus CHOP in previously untreated pts with DLBCL. The current exploratory analysis compared investigator (INV)-assessed progression-free survival (PFS) and overall survival (OS) in pts receiving 6 or 8 cycles of CHOP in combination with 8 cycles of R in GOYA. Methods: Eligible pts were aged ≥18 years with histologically documented, CD20-positive DLBCL and ≥1 bi-dimensionally measurable lesion, ECOG PS 0-2, IPI score ≥2, and adequate hematologic function. Low-risk pts with IPI score 1 not due to age alone or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts who were randomized to R-CHOP received 8 cycles of R (375mg/m2) in combination with 6 (CHOP6) or 8 (CHOP8) cycles of CHOP. Centers elected upfront to administer either 6 or 8 CHOP cycles to all pts enrolled at that site. Efficacy was evaluated in all pts who were randomized to R-CHOP (intent-to-treat population; data cut-off: January 31, 2018). Safety was assessed in all pts who completed the 6th treatment cycle and received R in the 7th cycle (CHOP6 safety population: no additional CHOP cycles; CHOP8 safety population: at least 7 or 8 CHOP cycles received). Only AEs starting during or after the 7th cycle were considered. Statistical analyses included Kaplan-Meier estimates and Cox-regression, with and without propensity score adjustment to correct for baseline imbalances. Results: Results are reported for 712 pts who were randomized to R-CHOP (CHOP6, n=526; CHOP8, n=186; safety population: CHOP6, n=461; CHOP8, n=144). In the CHOP6 group, 55% were male and median age was 62 years (range 54-70). In CHOP8, 49% were male and median age was 60 years (range 47-67). Baseline characteristics were broadly comparable across treatment groups, except for geographic region (CHOP6 vs CHOP8: Asia, 32% vs 49%, respectively; Eastern Europe, 10% vs 24%; Western Europe, 36% vs 13%; North America, 18% vs 8%; other, 4% vs 5%). In CHOP6, 89% completed 6 cycles of R-CHOP, while in CHOP8, 76% completed 8 cycles. Three-year INV-assessed PFS rates were comparable between groups: 68.7% in CHOP6 versus 66.8% in CHOP8 (HR 0.92; 95% CI: 0.69, 1.23; Figure 1a). Three-year OS rates appeared higher in the CHOP6 group (83.2% vs 76.2% in CHOP8; HR 0.65; 95% CI: 0.46, 0.91; Figure 1b). PFS and OS comparisons were unchanged after propensity score adjustment for the prespecified baseline characteristics, including age, gender, disease stage, geographic region, IPI score, extranodal sites, body surface area, bulky disease, LDH, and COO (PFS: HR 0.96, 95% CI: 0.70, 1.32; OS: HR 0.66, 95% CI: 0.45, 0.97). Interim treatment response (by CT) did not influence these findings. Model-based subgroup analysis according to baseline pt characteristics did not identify any pt subgroups benefitting from 8 versus 6 cycles of CHOP (Figure 1c). Incidence of grade 3-5 adverse events (AEs) was lower in the CHOP6 group than in the CHOP8 group (17.8% vs 38.9%, respectively); cardiac AEs (all grade: 2.4% vs 6.3%; grade 3-5: 1.3% vs 3.5%) and infections (all grade: 10.6% vs 23.6%) were also less common. In support of these findings, similar results were achieved after repeating the same efficacy analysis in pts who received 6 or 8 cycles of CHOP in combination with 8 cycles of obinutuzumab. Conclusions: In this exploratory analysis of 712 previously untreated DLBCL pts in GOYA, in which the number of CHOP cycles was selected upfront by each site, no additional PFS benefit was observed with 8 cycles of R-CHOP compared with 6 cycles of R-CHOP plus 2 cycles of R, even after adjusting for baseline differences, including COO and IPI. Slow response, assessed by interim CT, did not influence these findings. Furthermore, incidence of grade 3-5 AEs (including cardiac) and any grade infections was markedly higher in pts receiving 8 cycles of CHOP versus 6 cycles. These results suggest that rituximab with 6 cycles of 3-weekly CHOP should be considered standard of care. Disclosures Sehn: Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Culligan:JAZZ: Honoraria; Celgene: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; Abbvie: Other: Support to attend conferences; Pfizer: Honoraria; Merck Sharp & Dohme (MSD): Honoraria. Ogura:Cellgene: Honoraria; Celltrion: Research Funding; Takeda: Honoraria; SymBio: Research Funding. Launonen:Roche: Employment, Other: Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sellam:Roche: Employment. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Vitolo:Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau. Martelli:Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees.
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Burns, David, Katherine Clesham, Joanna Haughton, Michelle Lannon, Hayder Hussein, Jennifer Marsh, Martin Rowe et al. "Outcomes With Rituximab Monotherapy Versus R-CHOP In Post-Transplant Lymphoproliferative Disease Arising After Solid Organ Transplant: A Multicentre UK Study". Blood 122, n.º 21 (15 de novembro de 2013): 3043. http://dx.doi.org/10.1182/blood.v122.21.3043.3043.
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Abstract Post-transplant lymphoproliferative disease (PTLD) remains an important complication of solid organ transplantation. For B-cell PTLD, current first line therapies are Rituximab monotherapy (R-Mono) or R-CHOP. However, optimal selection of initial treatment is challenging due to concerns about the relative efficacy and toxicity of these modalities, and because of uncertainty about the prognostic value of baseline factors. This retrospective study identified 72 biopsy-proven cases of PTLD, diagnosed between 2000 and 2012, from 4 UK centres. These included 34 liver, 32 renal and 6 cardiothoracic transplant recipients. The median age at histological diagnosis was 47 years (range 16 - 72 years) and 68% were male. The median time from transplant to diagnosis of PTLD was 93 months (range 2 – 302 months), with 83% of cases occurring after 1 year. Tumour histology included 14 polymorphic and 49 monomorphic lesions (including 34 diffuse large B-cell, 5 plasmablastic, 4 Hodgkin and 1 T-cell lymphomas) whilst in 9 cases the PTLD subtype was unspecified. EBV-association was noted in 39/72 (54%) and this was significantly related to disease presenting within a year of transplant (X2 p=0.004). Initial therapy was R-Mono in 16/72 (22%) and R-CHOP in 34/72 (47%). Selection of R-CHOP versus R-Mono was significantly associated with stage ≥3 disease (odds ratio [OR] 6.7, p=0.01), onset more than 1 year after transplant (OR 7.3, p=0.03), lack of EBV association (OR 0.1, p=0.002) and monomorphic versus polymorphic histology (OR 14.0, p=0.004). In a multivariate logistic model, advanced stage (OR 11.0, p=0.06) and monomorphic histology (OR 8.5, p=0.03) retained significance. Of patients who received R-Mono, 15/16 (94%) completed at least 4 infusions, with no treatment-related deaths. Of these, 4 patients subsequently received R-CHOP for consolidation of response (2 patients) or for relapsed / refractory disease (2 patients). Of those who received R-CHOP as initial therapy, 23/34 (68%) completed at least 6 cycles, with 4 treatment-related deaths. The overall response rate to R-Mono was 81% (10 CR [complete remission], 3 PR [partial remission] and 3 NR [no remission]), similar to that of R-CHOP at 74% (19 CR, 6 PR, 5 NR and 4 undetermined; X2 p=0.67). With a median follow-up of 38 months, survival outcomes for R-Mono and R-CHOP were 2 year Event-Free Survival of 62% and 54% (p=0.77), 2 year Progression-Free Survival of 67% and 58% (p=0.48) and 2 year Overall Survival (OS) of 74% and 59% (p=0.52; Figure 1A) respectively. Amongst all study patients, significant baseline predictors of (inferior) OS were age ≥50 years (HR 2.9, p=0.006), stage ≥2 disease (HR 4.9, p=0.003), ECOG performance status ≥2 (HR 2.1, p=0.05), and elevated LDH (HR 2.2, p=0.08 borderline significance). Extra-nodal disease, histology, EBV-association and time from transplant were not predictive. In multivariate analysis, age>50 (HR 3.2, p=0.01) and advanced stage (HR 4.0, p=0.02) retained significance. Importantly, amongst those treated with R-Mono or R-CHOP, response to initial therapy was highly predictive of OS (overall response, HR 0.2, p<0.0001; complete response, HR 0.1, p<0.0001). Applying a 4 point modified prognostic index comprised of age>50, stage ≥2 disease, ECOG performance status ≥2 and elevated LDH, patients treated with R-Mono or R-CHOP with low risk disease (<2 points) had significantly improved survival compared to those with high risk disease (≥2 points), with 2 year OS of 90% versus 43% (p=0.001, Figure 1B). Notably, comparison of outcomes for R-Mono versus R-CHOP within high risk or low risk groups revealed no significant differences in survival. However, there was a trend towards inferior response amongst patients with high risk disease treated with R-Mono compared to R-CHOP (CR rate 1/6 [17%] versus 9/16 [56%]; X2 p=0.16), which was not observed for low risk disease. We report outcomes for R-Mono versus R-CHOP as initial therapy for PTLD arising after adult solid organ transplantation. Whilst R-CHOP is associated with greater toxicity, R-Mono may deliver inferior response rates in patients with high risk disease. Survival outcomes were not significantly different between therapies. Importantly, using a modified prognostic index we identify a subset of patients with high risk disease who exhibit very poor outcome, irrespective of initial treatment, for whom novel therapeutic strategies are urgently required. Disclosures: Chaganti: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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Abaza, Yasmin, Hagop M. Kantarjian, Gautam Borthakur, Guillermo Garcia-Manero, Naval Daver, Farhad Ravandi, Srdan Verstovsek et al. "An Open-Label, Phase I Study of Dasatinib in Combination with Decitabine in Patients (Pts) with Accelerated or Blastic Phase Chronic Myeloid Leukemia (CML)". Blood 128, n.º 22 (2 de dezembro de 2016): 5433. http://dx.doi.org/10.1182/blood.v128.22.5433.5433.
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Abstract Background: Current treatment for advanced phase CML remains unsatisfactory. Dasatinib induces major cytogenetic response (MCyR) in 31% and 37% of pts with imatinib-resistant or -intolerant accelerated (AP) and blast phase (BP), respectively (Cortes 2007). Hypermethylation is associated with disease progression in CML. In pts with imatinib-refractory CML-AP and CML-BP, low dose decitabine induced MCyR in 12% and 17% of pts, respectively, with similar rates achieved combining decitabine with imatinib (Issa 2005, Oki 2007). The reported synergy between imatinib and decitabine depends upon residual sensitivity to imatinib (La Rosee 2004). We investigated whether improved responses might be achieved through synergy between dasatinib, a 2nd generation tyrosine kinase inhibitors (TKI) and decitabine. Methods: Pts age 18 years or older with CML-AP, CML-BP, or Philadelphia chromosome (+) acute myeloid leukemia (Ph+AML) were enrolled regardless of previous TKI therapy. Pts were assigned to 2 schedules on a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD; primary objective). The starting schedule was decitabine 10mg/m2 daily for 10 days and dasatinib 100 mg daily (schedule A), and decitabine 20mg/m2 daily for 10 days with dasatinib 100 mg (schedule B). The next dose level (target dose) was decitabine 10mg/m2 daily for 10 days (schedule A) or 20 mg/m2 daily for 10 days (schedule B) with dasatinib 140 mg daily. Secondary objectives are to determine the rate of overall hematologic response (OHR) (2 cycles required to be evaluable for response), response duration (RD), overall survival (OS), and toxicity profile. OHR includes complete hematologic response (CHR), no evidence of leukemia (NEL), and minor hematologic response (MiHR). CHR is defined as normal WBC, no blasts or promyelocytes in peripheral blood (PB), ANC ≥1x109/L, platelets >100 x109/L, PB basophils < 5%, ≤ 5% blasts in bone marrow (BM), and no extra-medullary disease. NEL is the same criteria as CHR except for platelets between ≥ 20 x109/L and <100x109/L or ANC between ≥ 0.5x109/L and < 1x109/L. MiHR is defined as <15% blasts in PB and BM, <30% blasts + promyelocytes in BM and PB, <20% basophils in PB, and no extra-medullary disease. Once MTD or target dose (if MTD not exceeded) determined for both arms subsequent pts are to be randomized to the two schedules. Results: A total of 23 pts were enrolled (4 AP, 16 BP, 3 Ph+AML); 21 were evaluable for response. The remaining 2 pts were not evaluable for response since they did not complete 2 cycles of therapy as defined in the protocol, due to drug toxicity (n=1; cardiac arrest due to myocardial infarction) or insurance issues (n=1). Patient characteristics are shown in Table 1. Sixteen pts received prior TKI therapy with a median of 2 TKI per pt (range, 1-4). Three pts had a kinase domain mutation (V299L, E255K, and 1 pt with both L298V and T315I); one other patient had a 162 bp deletion. No dose-limiting toxicity (DLT) was observed at the starting dose level for either schedule. One DLT (among 6 pts) was observed at the target dose level of each schedule (1A: grade 3 heart failure; 1B: grade 4 cardiac arrest), therefore the target dose was considered the dose to be further explored in phase 2 for each arm. Pts received a median of 2 treatment cycles (range 1-11) and 3 pts are still receiving study therapy. Fourteen (67%) pts achieved OHR (7 CHR, 3NEL, 4 MiHR). A MCyR was achieved by 38% (8/21). Median duration of OHR was 3.5 months (95% CI: 2- 4.9). Median OS was 12 months (95% CI: 2.9- 21.3). A total of 11 pts (48%) died: 10 due to disease progression and 1 pt died in complete molecular response from SCT complications. Three pts have ongoing responses, 2 pts with major molecular response (MMR) and one with NEL, with the combination therapy for 5+, 7+, and 3+ cycles, respectively. Six pts received SCT of which 4 pts remain alive 39, 27, 4, and 0.2 months post-SCT; they had achieved CHR, MCyR, MMR, and CHR, respectively with DAC + dasatinib prior to SCT. Grade 3-4 nonhematological toxicity was reported in 17 (74%) pts, most frequent toxicities being infections (26%), bleeding (17%), and acute renal failure (13%). Conclusion: The combination of decitabine plus dasatinib is well tolerated and active in pts with advanced phase CML. Phase 2 portion of this study is in progress to determine the efficacy of this combination and difference in outcome by treatment schedule. Disclosures Daver: Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Ariad: Research Funding; BMS: Research Funding. Burger:Pharmacyclics: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.
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Pieri, Lisa, Giada Rotunno, Francesca Gesullo, Tiziana Fanelli, Giuditta Corbizi Fattori, Annalisa Pacilli, Federica Scarfì et al. "Prognotic Impact of Mutations in Systemic Mastocytosis". Blood 128, n.º 22 (2 de dezembro de 2016): 1953. http://dx.doi.org/10.1182/blood.v128.22.1953.1953.
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Abstract Introduction: Systemic mastocytosis (SM) is an heterogeneous myeloproliferative neoplasm characterized by uncontrolled growth of cKIT mutated clonal mast cells, with clinical manifestations ranging from indolent forms (ISM) with only skin lesions and/or anaphylactic shock to smouldering SM (SSM) with evidence of organ involvement to aggressive forms (ASM) with extensive organ damage. SM with an associated hematological neoplasm (SM-AHN) is a subtype with adverse prognosis possibly related to the associated neoplasm rather than SM. Recent data indicate that mutations in genes associated to myeloid malignancies correlate with survival and disease progression but information are still scanty and not completely concordant, and mutations apparently did not correlate with disease manifestations; furthermore, most patients analyzed were SM-AHN, therefore the contribution of mutations associated with the non-mast cell clone could not be ascertained clearly. The aim of this study was to address the prognostic relevance of mutations at diagnosis in a series of 70 pts with SM, excluding SM-AHD. Methods: There were 58 ISM, 4 SSM, 7 ASM and 1 mast cell leukemia (MCL) pts. cKITD816V mutation was assessed by RTQ-PCR. Mutations in myeloid-neoplasm associated genes were assessed by next generation sequencing (NGS) with Ion Torrent PGM platform; analyzed genes included ASXL1, CBL, cKIT, ETNK1, EZH2, IDH1, IDH2, SRSF2, RUNX1, TET2. We also evaluated the cKITD816V variant allele frequency (VAF) by NGS. Kruskal-Wallis test and Chi-squared test were used for analysis of continuous and categorical variables, respectively. Cox regression model was used for survival analysis; variables included were WHO subgroup, cKITD816V >2% VAF, mutations in additional genes, age at diagnosis >60 years, serum tryptase >200 ng/mL, alkaline phosphatase and white blood cells greater than upper normal limit. We did not considered as single entities the features included in B and/or C findings. Results: Median age at diagnosis was 45 years (y)(range 17-76) for ISM, 67 y (53-74) for SSM, 73 (41-81) for ASM (p<0.001). At last follow up (median 2 years, range 0.2-14) 2 pts with ASM evolved to acute myeloid leukemia (AML, 2.8% of all series, 28% of ASM), 1 ISM pts developed organ damage and shifted to ASM; 4 pts died (4/70, 5.7%). Skin involvement was found in 80.6% of pts, 31.3% had history of anaphylaxis and 27.8% osteoporosis. Median serum tryptase levels were 28.7 ng/mL (range 3-192) for ISM, 190 (60-591) for SSM, 64 (23-300) for ASM and 2000 in MCL. All but 3 pts (2 ISM, 1 ASM) were cKITD816V mutated by RT-PCR in bone marrow aspirate (BM) or peripheral blood (PB) (in pts with punctio sicca). 54/67 (80%) had a cKITD816V mutation detectable in PB, underlying that even with high sensitivity methods PB cannot replace BM analysis for diagnosis. Median VAF was 0.34% (range 0.03-38.4) in ISM, 17.2% (0.3-45) in SSM, 26.7% (0.9-81.7) in ASM and 71.7% in MCL. Pts with at least 1 additional mutation were 6.9% (4/54) ISM, 50% (2/4) SSM and 57% (4/7) ASM(p<0.001). Five pts (7%), 4 ASM (57%) and 1 MCL, had more than 1 additional mutations (p<0.001). TET2 was the most frequent mutated gene, in 9/70 cases (12.9%), followed by ASXL1 and SRSF2 in 2 pts (2.9% each) and EZH2, IDH2, CBL and RUNX1 in 1 pts each (1.4%). No mutation was found in IDH1 and ETNK1. No recurrent mutation types were found. All pts with more than one additional mutations other than cKITD816V carried a TET2 mutation combined with ASXL1 and SRSF2 mutation in two cases each and CBL in one case. One pt had a third additional EZH2 mutation. Karyotype was normal in all the 58 pts evaluated, including 5 ASM and 3 SSM. In univariate analysis the following parameters were associated with shorter survival: one or more additional mutations (HR 19.2, CI 2-185, p<0.001), TET2 mutation (HR 28, CI 2.9-271, p=0.004) (mutations in other single genes were not evaluated due to low number of cases) and ASM variant (HR 5.3, CI 1.7-16.1, p=0.003). Pts older than 60 y at diagnosis had higher frequency of additional mutations (35% versus 8% in pts <60 y, p=0.005) and of cKITD816V VAF >2% (68.8% versus 8.3%, P<0.001). None of the analyzed molecular features correlated with anaphylaxis, osteoporosis or skin involvement. Conclusions: With the limitations due the small number of events recorded in this series, these data suggest that knowledge of molecular asset in pts with SM might provide prognostically relevant information. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau.
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M, Luis Villela, Ana Ramirez-Ibarguen, Brady E. Beltrán, Victoria Otero, Denisse A. Castro, Myrna Candelaria, Fernando Pérez-Jacobo et al. "Assessment of Different Biological Variables (Serum Albumin, β-2-Microglobulin, Lymphocyte/Monocyte ratio, Neutrophil/Lymphocyte ratio, Platelet/Lymphocyte ratio) in a Retrospective Cohort of 525 Diffuse Large B-Cell Lymphomas As Predictor Factor(s) for Overall Survival". Blood 134, Supplement_1 (13 de novembro de 2019): 1613. http://dx.doi.org/10.1182/blood-2019-123841.
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Introduction. Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas (NHL). The use of chemoimmunotherapy (R-CHOP) in DLBCL has improved Overall Survival (OS). However, there are among 45-55% of patients who will die due to relapse, progression (refractoriness) or toxicity to treatment. Genomic classifications are difficult to use in clinical practice, especially in lain America, due to the need of trained personnel and cost. So, we continue using the International Prognostic Index (IPI) and its variations (e.g. revised-IPI, NCCN-IPI) for prognostic purposes. However, other biological variables have been reported to be prognostic, such as serum beta-2-microglobulin (B2M), lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), platelets/lymphocyte ratio (PLR) and serum albumin (SA). These factors have been associated with burden of disease, inflammation and nutritional status. Aim. Therefore, we performed a retrospective analysis of the databases of two Latin American groups to determine which biological variable is the most powerful factor prognostic of OS. Methods. A total of 1,250 patients were analyzed from two databases [(Grupo de Estudio para el Linfoma Mexicano (GELMEX) and the Grupo de Estudio para el Linfoma Latino Americano (GELL)], where 525 patients met the following inclusion criteria: DLBCL diagnosis by immunochemistry; complete data on absolute lymphocyte, absolute monocyte, absolute neutrophil and absolute platelet count, serum B2M and SA; and complete data on traditional variables for calculating risk groups for IPI, NCCN-IPI & R-IPI. The LMR, NLR and PLR was obtained. We evaluated the AUC of the biological variables and the differences among each one of them (including cut-off). Kaplan-Meier curves (KMC) were estimated and subsequently, the inference of OS was evaluated by Hazard Ratio (HR) Cox-regression in univariate/multivariate analyses by forward model. All variables with p<0.05 were considered independent variable for the multivariate analysis. Outcomes: Clinical characteristics of the cohort (n=525) were as follows: median follow-up time was 32 months (range: 0.2-132), 52% were male, 60% had more than 60 y/o (≥75 y/o, 21%), one third (32%) had a bad performance status (ECOG ≥2), 63% had advanced stage (III-IV), 49% had high serum lactate dehydrogenase (LDH; ratio 1.1-2.9, 41%; ratio ≥3, 8%), 21% had ≥2 extranodal sites involved (28%, NCCN-specific sites) and 43% had bulky disease. SA had the best AUC comparing with other variables (see figure 1). 5-y OS rates by SA (>3.2 mg/dL vs. ≤3.2 mg/dL) were 72% vs 34% (Log Rank p<0.0001), by B2M (<4 µg/dl vs. ≥4 µg/dL) were 68% vs. 45% (p<0.0001), by LMR (≥2.2 vs. <2.2) were 67% vs. 47% (p<0.0001), by NLR (<4 vs. ≥4) were 70% vs. 52% (p<0.0001) and by PLR (<475 vs. ≥475) were 65% vs. 44% (p<0.0001). In the univariate Cox regression analysis, SA ≤3.2 mg/dL was associated with HR 3.41 (CI95% 2.47-4.64), B2M ≥4 µg/dL with HR 2.13 (CI95% 1.57-2.88), LMR <2.2 with HR 2.11 (CI95% 1.56-2.87), NLR ≥4 with HR 1.92 (CI95% 1.45-2.55), and PLR ≥475 with HR 2.17 (CI95% 1.52-3.1)]. The multivariate Cox regression analyses (Forward model) showed that SA ≤3.2 mg/dL, B2M ≥4 µg/dL and high NLR ≥4 retained their prognostic value for worse OS (HR 2.87, CI95% 2.1-3.90; p=<0.0001; HR 1.40, CI95 1.02-1.94; p=0.036; and HR 1.43, CI95% 1.06-1.92; p=0.01, respectively). SA ≤3.2 mg/dL was the only independent factor associated with worse OS when adjusted by IPI (HR 2.53, CI95% 1.75-3.67; p<0.0001), NCCN-IPI (HR 2.51, CI95%1.81-3.5; p<0.0001) and R-IPI (HR 3.12, CI95%2.34-4.16; p<0.0001). Conclusion: Low SA emerges as an easy-to-use, important biological factor prognostic of worse survival, independent of the IPI, R-IPI and NCCN-IPI scores, in Latin American patients with DLBCL treated with chemoimmunotherapy. Figure 1 Disclosures M: Roche-Mexico: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Merck-Sharp-Dome: Speakers Bureau. Ramirez-Ibarguen:Roche-Mexico: Consultancy, Speakers Bureau. Peña:Novartis: Other: Congress inscription and flights; Tecnofarma: Other: Congress inscription and flights; Roche: Other: Congress inscription and flights; Biotoscana: Other: Congress inscription and flights; Janssen: Other: Congress inscription and flights; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paredes:Tecnofarma: Honoraria. Gomez-Almaguer:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Abello:Takeda: Other: Participation in advisory board meeting. Tena:Roche-Mexico: Employment. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding.
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Fix, Samantha, Marie-Andrée Forget, Donastas Sakellariou-Thompson, Yunfei Wang, Ana Lucía Dominguez, Rafet Basar, Christopher Reyes et al. "172 Overcoming immunosuppressive TGF-β signaling in human ovarian cancer-derived tumor infiltrating lymphocytes via non-viral CRISPR engineering". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembro de 2021): A183—A184. http://dx.doi.org/10.1136/jitc-2021-sitc2021.172.
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BackgroundOur ongoing clinical trial for the treatment of melanoma with TGF-β-resistant tumor-infiltrating lymphocytes (TIL) [TGF-β dominant negative receptor 2 (TGFβDNR2) transduced-TIL] has yielded long-term responses in checkpoint refractory patients (NCT01955460). Building on this success, we sought to extend the impact of TGF-β–resistant TIL therapy to additional cancers while optimizing a non-viral alternative to transduction with a TGFβDNR2. Ovarian cancer (OvCa), which is characterized by an abundance of TGF-β, a dysfunctional immune infiltrate, and a paucity of novel treatment options, is an ideal candidate for TGF-β–resistant TIL therapy. Here, we present an optimized and clinically-scalable method for CRISPR/Cas9-mediated deletion of the TGF-β receptor (TGFBR2) in OvCa TIL.MethodsOvCa TIL were generated from tumor fragments1 and subjected to CRISPR-mediated knockout of TGFBR2 before going through a rapid expansion protocol. Resistance of TGFBR2-knockout TIL to TGF-β signaling was evaluated via quantification of downstream SMAD-2/-3 phosphorylation, global transcriptional changes upon TGF-β exposure, and cytokine release following TCR stimulation in the presence of TGF-β. The impact of CRISPR modification on TIL expansion and TCR clonal diversity was evaluated. Finally, the risk of off-target CRISPR activity throughout the genome was evaluated using Target Enriched GUIDE-seq (TEG-seq)2 followed by next generation sequencing (NGS) validation of putative off-target sites.ResultsUsing five TGFBR2-directed guide RNAs (gRNAs), we achieved gene disruption efficiencies ranging from 48%–90%, which correlated inversely with the degree of SMAD phosphorylation after TGF-β exposure (r=-0.9440, p=0.0158, n=4 donors) (figure 1A-C). TGF-β exposure induced a strong transcriptional response in wild-type TIL but had little to no effect on TGFBR2-knockout TIL (figure 2). TGFBR2-knockout TIL functioned well in the presence of exogenous TGF-β as evidenced by equally strong secretion of pro-inflammatory cytokines in the presence and absence of TGF-β (figure 3). CRISPR-modification did not hamper the ex vivo expansion efficiency nor the TCR clonal diversity of expanded OvCa TIL (figure 4). Using TEG-seq, we identified ≤5 low-probability off-target sites for gRNA-#3 and gRNA-#4, each of which were attributed to background sequencing artifacts upon further validation by NGS of specific amplicons (figure 5).Abstract 172 Figure 1(A) Genomic-level TGFBR2 knockout efficiency using 5 different gRNAs as evidenced by NGS of specific amplicons (n=1 TIL donor). (B) SMAD-2 and SMAD-3 phosphorylation in TGFBR2 knockout TIL vs. control TIL after 30 min exposure to TGF-β1. The left panel shows representative histograms of phospho-SMAD staining, and the right panel shows quantification of cells positive for phospho-SMAD-2/-3 after TGF-β exposure (n=4 TIL donors). The statistical significance of each experimental condition compared to the non-transfected control is shown. (C) Inverse correlation of TGFBR2 knockout efficiency and TGF-β-mediated SMAD phosphorylation.Abstract 172 Figure 2Top 100 differentially expressed genes in non-transfected (WT) TIL exposed to TGF-β. TGFBR2 knockout (KO) TIL display minimal gene expression changes upon TGF-β exposure (n=3 technical replicates).Abstract 172 Figure 3TIL were collected after 14 days of expansion and re-stimulated with 300 ng/mL plate-bound anti-CD3 in the presence of 3000 IU/mL IL2 and 10 ng/mL human TGF-β1 or vehicle. Cell culture supernatant was collected after 72 hrs of stimulation and assayed for the presence of 10 proinflammatory cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α). For TIL with intact TGFBR2 (non-transfected and Cas9 mock transfected TIL), the production of many pro-inflammatory cytokines decreased significantly in the presence of TGF-β. Conversely, TGFBR2 knockout TIL (generated using gRNA #3 or gRNA #4) retain cytokine secretion in the presence of TGF-β. IL-12p70 was below the limit of detection in this assay and is therefore not presented.Abstract 172 Figure 4(A) Control and CRISPR-modified OvCa TIL expand with equal efficiency during a 14-day rapid expansion protocol. Fold expansions ranging from 1000× - 3000× were observed across 4 independent patient samples. (B) The TCR clonal diversity of TIL after 14-day expansion was assessed by TCRB sequencing. Productive Simpson Clonality was equivalent in CRISPR-modified TIL compared to control TIL samples.Abstract 172 Figure 5TEG-seq revealed 3 putative off-target sites for gRNA #3 and 5 putative off-target sites for gRNA #4. The aligned sequences show similarities and differences between the gRNA sequence and the reference genome site. Dots represent exact matches in the reference genome compared to the gRNA sequence. Dashes represent missing bases, lower-case letters represent extra bases, and upper-case letters represent a base mismatch. Validation by NGS of specific amplicons confirmed the presence of TEG-seq Tag integration and large indels at the on-target cleavage sites for gRNA #3 and #4, indicating successful Cas9 editing and Tag integration in our experiment. NGS validation revealed that all putative low probability off-target sites were background artifacts as evidenced by the lack of Tag identification and lack of large indels.ConclusionsCRISPR/Cas9-mediated knockout of TGFBR2 is feasible and efficient in patient-derived OvCa TIL using clinically-scalable methods that yield little to no evidence of off-target activity. This study lays the groundwork for clinical translation of CRISPR-modified, TGF-β-resistant TIL for OvCa treatment, which will not only provide a novel immunotherapy for OvCa patients but also a platform for engineering more potent TIL therapies in general.ReferencesSakellariou-Thompson D, Forget MA, Hinchcliff E, Celestino J, Hwu P, Jazaeri AA, et al. Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy. Cancer Immunology, Immunotherapy: CII 2019;68(11):1747–57.Tang PZ, Ding B, Peng L, Mozhayskiy V, Potter J, Chesnut JD. TEG-seq: an ion torrent-adapted NGS workflow for in cellulo mapping of CRISPR specificity. Bio Techniques 2018;65(5):259–67.Ethics ApprovalAll procedures performed were in accordance with the 1975 Helsinki declaration. Ethical approval and tissue from surgical resections used to expand TIL were both obtained under protocols (PA16-0912 and LAB02-188) approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. Written informed consent was obtained from all individual participants included in the study for their specimens and data to be used in research and for publication.
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Corcione, Silvia, Cecilia Grosso, Ernesta Audisio, Jessica Cusato, Miriam Antonucci, Alessandro Busca, Benedetto Bruno, Annamaria Gulla, Antonio d'Avolio e francesco Giuseppe de Rosa. "Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship". Blood 142, Supplement 1 (28 de novembro de 2023): 5849. http://dx.doi.org/10.1182/blood-2023-190034.
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DISCUSSION INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2]. ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated . MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023. Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission. Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change. RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease. Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI. There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825.Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.
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Bishton, Mark, Pier Luigi Zinzani, Scott Marshall, Veronica Conteh, Alicia Rodríguez Fernández, SooKyoung Kim e Young Nam Lee. "Rapid Infusion with CT-P10 in Patients with Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukaemia: Interim Six Month Follow-up from a European Non-Interventional Post-Authorisation Safety Study". Blood 134, Supplement_1 (13 de novembro de 2019): 4135. http://dx.doi.org/10.1182/blood-2019-121957.
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Background: In February 2017, CT-P10 became the first rituximab biosimilar to be approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). More recently, CT-P10 was approved in the US for NHL. Although the recommended rituximab administration protocol is a slow initial infusion rate with gradual up-titration, rapid infusion protocols are used widely in patients with no serious complications from their first infusion. There are limited data on the safety of rapidly infused CT-P10. Aims: To evaluate the safety and effectiveness of rapidly infused CT-P10 in patients with NHL or CLL in a real world clinical setting over a 6 month follow up period. Methods: This non-interventional post-authorisation safety study is in progress in the United Kingdom (UK), Spain, France and Italy. It involves collection of data from the medical records of consenting adult patients with NHL or CLL who received rapidly-infused CT-P10 (total infusion time ≤90 minutes) during routine clinical practice. The index date (day 1) is the date of the first rapid CT-P10 infusion. Safety and effectiveness data have been collected over a 6 month observation period from the index date (or to death, if sooner). Early results from this study have been previously presented and showed the index IRR rate (the primary outcome) to be 8% (Bishton, 2019). Updated interim results with full 6 month follow-up are now available for 112 patients and are reported here, based on a data cut on 19 June 2019. Results: This interim analysis includes patients enrolled from the UK, Italy and Spain. Ninety four patients (84%) have NHL (68 [61%] diffuse large B-cell lymphoma [DLBCL], 26 [23%] follicular lymphoma [FL]) and 18 (16%) have CLL. Other patient characteristics at index date: 74 (66%) male; median age 67 years (interquartile range [IQR] 58.0-74.0); median disease duration 0.2 years (IQR 0.1-0.4); 20 (18%) patients with prior treatment recorded (n=111); Ann Arbor stage for NHL at index (n=58): I (n=7, 12%), II (n=7, 12%), III (n=8, 14%), IV (n=35, 60%) or other (n=1, 2%; recorded as '1E'); Binet stage for CLL at index (n=11): A (n=5, 45%), B (n=4, 36%) or C (n=2, 18%). Patients had between 1 and 4 CT-P10 infusions prior to the index date, with first infusions given over a median of 4 hours (IQR 3.5-4.1 hours). Median CT-P10 dose at index was 375 mg/m2 (IQR 375.0-375.0 mg/m2) and a median of 5 infusions per patient (IQR 3.8-6.0) were given over 6 months. A total of 512 CT-P10 infusions were given over the 6 month observation period across all 112 patients. Of 19 (17%) patients who experienced one or more IRRs over the observation period (including index IRRs), 9 patients had one, 5 had two and 5 had three or more IRRs. Thirty six IRRs were reported in total and are listed in Table 1 by grade. Ninety six (86%) patients experienced an adverse event (AE) and 31 (28%) experienced a serious AE (SAE) over the observation period. At 6 months post-index, 95 (85%) patients had discontinued first line CT-P10 due to planned completion of their treatment course, 7 (6%) had discontinued due to AEs, 1 (1%) due to disease progression and 5 (4%) due to other reasons (reason for discontinuation not known for 1 patient [1%]), with treatment ongoing for 3 patients (3%). Best responses to CT-P10 during the observation period (as documented by the local investigator) were complete response (n=83, 74%), partial response (n=24, 21%), stable disease (n=3, 3%) and progressive disease (n=2, 2%). Summary/conclusions: In this multi-country study of patients treated with rapidly-infused CT-P10 in a real world setting, a high proportion of patients achieved complete or partial responses over 6 months follow-up. The results also suggest that CT-P10 is generally well-tolerated, with 36 (predominantly mild) IRRs recorded over a total of 512 infusions, and the majority of patients discontinuing CT-P10 due to planned completion of treatment. Disclosures Bishton: Takeda: Other: Travel support, Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Celltrion: Employment. Nam Lee:Celltrion: Employment. OffLabel Disclosure: CT-P10 is a rituximab biosimilar, approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). In Europe, the recommended administration protocol is a slow initial infusion rate with gradual up-titration. However, rapid infusion protocols are used routinely in many countries for second and subsequent infusions in patients with no serious complications from their first infusion. There are limited data on the safety of rapid infusion of CT-P10 so this non-interventional study aims to address this gap and reflect practice in the real world. Rapid infusion is on-label in the United States.
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Novi Sekar Sari, Ririn Tri Ratnasari, Ismah Osman e Ega Rusanti. "Materialism and Environmental Knowledge as a Mediator for Relationships between Religiosity and Ethical Consumption". Jurnal Ekonomi Syariah Teori dan Terapan 10, n.º 5 (30 de setembro de 2023): 467–81. http://dx.doi.org/10.20473/vol10iss20235pp467-481.
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ABSTRACTOn a global and regional scale, Indonesia has one of the least environmentally sustainable economies in the Asia-Pacific region. Consumption is one of the key factors contributing to environmental degradation. By using materialism and environmental knowledge as mediators, this study aimed to understand how religiosity affects ethical consumption. This research used quantitative methods with structural equation modeling (SEM) analysis techniques based on partial least squares (PLS). The data came from a questionnaire distributed online. 153 valid questionnaires were selected for analysis. All respondents came from Indonesia, were adults (from 18 years old), and were Muslims. Findings show that religiosity influences ethical consumption, materialism, and environmental knowledge. This research also reveals that materialism and environmental knowledge influence ethical consumption, as well as the mediating effect of materialism and environmental knowledge on the influence between religiosity and ethical consumption. So, all hypotheses from this research can be accepted. These findings contribute theoretically to explaining the relationship between religiosity, materialism, environmental knowledge, and ethical consumption. Thus, this findings contribute to the field of Islamic economics. Practically, the findings of this research can help marketers formulate communication strategies that take into account the level of religiosity of consumers in Indonesia. Marketers must avoid unethical practices to encourage ethical consumption.Keywords: Religiosity, ethical consumption, materialism, environmental knowledge ABSTRAKPada skala global dan regional, Indonesia merupakan salah satu negara dengan perekonomian paling tidak ramah lingkungan di kawasan Asia-Pasifik. Konsumsi merupakan salah satu faktor utama yang berkontribusi terhadap degradasi lingkungan. Dengan menggunakan materialisme dan enviromental knowledge sebagai mediator, penelitian ini berupaya memahami bagaimana religiosity mempengaruhi ethical consumption. Penelitian ini menggunakan metode kuantitatif dengan teknik analisis Structural Equation Model (SEM) berbasis Partial Least Square (PLS). Data berasal dari kuesioner yang disebarkan online. 153 kuesioner yang valid dipilih untuk analisis. Seluruh responden berasal dari Indonesia, dewasa (mulai 18 tahun) dan beragama Islam. Temuan menunjukkan bahwa religiosity berpengaruh terhadap ethical consumption, materialism, dan environmental knowledge. Selain itu juga diketahui bahwa materialism dan environmental knowledge berpengaruh ethical consumption, serta adanya efek mediasi dari materialism dan environmental knowledge pada pengaruh antara religiosity dan ethical consumption. Sehingga, semua hipotesis penelitian ini dapat diterima. 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MacMillan, Margaret L., Marie Robin, Andrew C. Harris, Todd E. Defor, Paul J. Martin, Amin Alousi, Vincent T. Ho et al. "A Refined Clinical Risk Score at Onset of Treatment for Acute Gvhd That Predicts Response to Initial Therapy, Survival and Transplant-Related Mortality". Blood 124, n.º 21 (6 de dezembro de 2014): 188. http://dx.doi.org/10.1182/blood.v124.21.188.188.
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Abstract Corticosteroids are the standard initial therapy for acute graft-versus-host disease (aGVHD) but are effective in only half of the cases. Methods to identify patients who are unlikely to respond to conventional initial therapy and who warrant alternative, more effective initial therapy are needed. The Minnesota (MN) group recently defined high-risk (HR)-aGVHD at onset by a novel acute GVHD risk score (Br J Haem 157(6):732,2012). Patients with HR-aGVHD were less likely to respond to steroid therapy and had a 2-fold increased risk of treatment-related (non-relapse) mortality (TRM) compared to patients with standard-risk (SR)-aGVHD. To validate this novel aGVHD risk score, we examined a larger group of patients who received steroids as initial systemic therapy for aGVHD. A database of 1723 patients was created from 5 cohorts; the previously reported patients from Minnesota (n=864), Hopital Saint Louis, Paris (n=184), the University of Michigan (n=307) and the Blood and Marrow Clinical Trials Network studies 0302 (n=155), and 0802 (n=213). Using multiple regression analyses, we identified poorly responsive, HR-aGVHD by the number of involved organs and severity of aGVHD at onset observed in this cohort as outlined in Table 1. The overall response [(complete response/partial response (CR/PR)] rate 28 days after initiation of steroid therapy for aGVHD was lower in the 269 patients with HR-aGVHD than in the 1454 patients with SR-aGVHD [44% (95% CI 38-50%) vs. 68% (95% CI 66-70%), p<0.001. Similarly, the 6-month incidence of TRM was twice as high in patients with HR-aGVHD as in those with SR-aGVHD [44% (95% CI 38-50%) vs. 22% (95% CI 20-24%), p<0.001, Figure 1]. Finally, survival at 6 months after the onset of steroid treatment was lower in patients with HR-aGVHD than in those with SR-aGVHD [52% (95% CI 46-58%) vs 71% (95% CI 69-73%), p<0.001]. In multiple regression analysis, the probability of CR/PR at day 28 in patients with HR-aGVHD was lower than in those with SR-aGVHD [Odds ratio (OR) 0.3, 95% CI 0.2-0.4, p<0.001]. Donor type was the only other factor associated with response. Patients who received a graft from an HLA-matched (OR 0.7, 95% CI 0.6-0.9, p=0.01) or mismatched (OR 0.3, 95% CI 0.2-0.5 p<0.001) unrelated donor (URD) were less likely to respond than those who received either a related donor graft or an umbilical cord blood graft. Patients with HR-aGVHD had a 2-fold increase in risk of mortality (RR, 2.1, 95% CI, 1.7-2.6, p<0.001) and a 2.5-fold increased risk of TRM (RR 2.5, 95% CI, 2.0-3.2 p<0.001) compared to patients with SR-aGVHD. Risks of mortality and TRM were also significantly higher in older patients, recipients of HLA-matched or mismatched URD grafts and in those with onset of aGVHD treatment within 28 days after HCT. This refined definition of aGVHD risk is a better predictor of response, survival and TRM than the CIBMTR or MN grading systems (Table 2). Patients with HR-aGVHD warrant more targeted upfront therapy. A future prospective study to examine the aGVHD score and biomarkers in the same aGVHD population would help further refine the predictive ability of each and determine how or whether a combination of clinical score and biomarker levels could even better identify HR-aGVHD. Table 1 GVHD Risk Definition by Organ Number* and Stage GVHD Risk Score One Organ (n) Two Organs (n) Three Organs (n) Standard Risk N=1454 84% Stage 1-3 Skin (901) Stage 1-2 GI (279) Stage 1-3 Skin plus Stage 1 GI (223) Stage 1-3 Skin plus Stage 1-4 Liver (51) High Risk** N=269 16% Stage 4 Skin (13) Stage 3-4 GI (74) Stage 1-4 Liver (25) Stage 1-3 Skin plus Stage 2 GI (54) Stage 1-2 Lower GI plus Stage 1-3 Liver (12) Stage 3-4 GI plus Stage 1-3 Skin (45) Stage 3-4 GI plus Stage 1-4 Liver (10) Stage 1-3 Skin plus Stage 1-2 GI plus Stage 1-3 Liver (23) Stage 1-3 Skin plus Stage 3-4 GI plus Stage 1-4 Liver (13) Abstract 188. Table 2 Outcomes Based on Published GVHD Grading Systems GVHD Grading System Severity N CR/PR at day 28 P 6 month survival (95% CI) P 6 month TRM (95% CI) P CIBMTR A-B C-D 930 793 626 (67%) 485 (61%) 0.008 660 (71%) 515 (65%) 0.008 213 (23%) 228 (29%) 0.006 MN I-II III-IV 1379 344 938 (68%) 173 (50%) <0.001 984 (71%) 192 (56%) <0.001 304 (22%) 137 (40%) <0.001 GVHD Risk Score SR HR 1454 269 993 (68%) 118 (44%) <0.001 1039 (71%) 137 (53%) <0.001 326 (22%) 115 (42%) <0.001 * UGI plus Lower GI considered as one organ disease Figure 1 Cumulative incidence of transplant related mortality at 6 months after initiation of steroid therapy by risk group Figure 1. Cumulative incidence of transplant related mortality at 6 months after initiation of steroid therapy by risk group Disclosures Levine: University of Michigan: Patents & Royalties.
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Wang, Michael, Javier Munoz, Andre H. Goy, Frederick L. Locke, Caron A. Jacobson, Brian T. Hill, John M. Timmerman et al. "One-Year Follow-up of ZUMA-2, the Multicenter, Registrational Study of KTE-X19 in Patients with Relapsed/Refractory Mantle Cell Lymphoma". Blood 136, Supplement 1 (5 de novembro de 2020): 20–22. http://dx.doi.org/10.1182/blood-2020-136382.
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Background: KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is currently being evaluated in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who received 1 - 5 prior therapies (including a Bruton tyrosine kinase inhibitor) in the Phase 2, registrational, multicenter ZUMA-2 study. With a median follow-up of 12.3 months, we previously reported an objective response rate (ORR) of 93% (67% complete response [CR] rate) with KTE-X19 treatment in the 60 efficacy-evaluable patients in ZUMA-2 (Wang et al. N Engl J Med. 2020;382:1331). Here, we present an updated analysis of efficacy, safety, and pharmacology for all patients with a minimum follow-up of 1 year. Methods: Eligible patients with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19 (2 × 106 CAR T cells/kg; Wang et al. N Engl J Med. 2020;382:1331). The primary endpoint was ORR (CR + partial response) as assessed by an Independent Review Committee according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014;32:3059). Efficacy data are reported for the 60 treated patients with ≥ 1 year of follow-up; safety data are presented for all 68 treated patients. Results: As of December 31, 2019, the median follow-up was 17.5 months (range, 12.3 - 37.6). The ORR was 92% (95% CI, 81.6 - 97.2), with a CR rate of 67% (95% CI, 53.3 - 78.3). Of all efficacy-evaluable patients, 48% had ongoing responses at the data cutoff. Medians were not reached for duration of response, progression-free survival (PFS), or overall survival; 15-month estimates were 58.6% (95% CI, 42.5 - 71.7), 59.2% (95% CI, 44.6 - 71.2), or 76.0% (95% CI, 62.8 - 85.1), respectively. In patients who achieved a CR, the median PFS was not reached (15-month rate, 75.1% [95% CI, 56.8 - 86.5]); in those who achieved a partial response, the median PFS was 3.1 months (95% CI, 2.3 - 5.2). Median PFS was 1.1 months (95% CI, 0.9 - 3.0) in nonresponding patients. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6 - 37.6); 39.3% of these patients remain in remission with no further therapy. Common grade ≥ 3 adverse events were neutropenia (85%), thrombocytopenia (53%), anemia (53%), and infections (34%). Grade ≥ 3 cytopenias were reported in 60% of patients ≥ 30 days post-infusion. Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al. [Blood. 2014;124:188]) occurred in 15% of patients; 59% received tocilizumab for management of CRS. Grade ≥ 3 neurologic events (NEs) were reported in 31% of patients, and 38% received steroids for NE management. All CRS events and most NEs (37/43) resolved, as previously reported. There were no Grade 5 CRS events or NEs, and no new Grade 5 events occurred with additional follow-up. As previously reported, there were 2 cases of Grade 2 cytomegalovirus infection, 1 case each of Grade ≥ 3 hypogammaglobulinemia and Grade ≥ 3 tumor lysis syndrome, and no cases of Epstein-Barr virus-associated lymphoproliferation, replication-competent retrovirus, hemophagocytic lymphohistiocytosis, or KTE-X19-related secondary cancers. Median peak CAR T cell levels and median area under the curve (Days 0 - 28) were 98.9 cells/µL (range, 0.2 - 2565.8) and 1394.9 cells/µL (range, 3.8 - 27,700) in patients with ongoing responses at 12 months, 202.6 cells/µL (range, 1.6 - 2589.5) and 2312.3 cells/µL (range, 19.0 - 27,200) in patients who were relapsed at 12 months, and 0.4 cells/µL (range, 0.2 - 95.9) and 5.5 cells/µL (range, 1.8 - 1089.1) in nonresponders. Of the 57 efficacy-evaluable patients with data available, 84% had B cells detectable by flow cytometry at baseline. Of those in ongoing responses at 12 months, 10 of 26 patients (38%) with evaluable samples had B cells detectable at 3 months, and 10 of 18 (56%) had detectable B cells at 12 months; gene-marked CAR T cells were no longer detectable at 12 months in 5 of 28 evaluable patients (17%). Conclusions: The ZUMA-2 study continues to demonstrate substantial and durable clinical benefit of KTE-X19 therapy with manageable safety in patients with R/R MCL. Within this patient population, which lacks curative treatment options, most patients achieved durable CR, and no new safety signals were reported. Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL. Disclosures Wang: Verastem: Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Targeted Oncology: Honoraria; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Guidepoint Global: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; InnoCare: Consultancy; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria. Munoz:Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Innovent: Consultancy; Fosunkite: Consultancy; Beigene: Consultancy, Speakers Bureau; Alexion: Consultancy; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Millenium: Research Funding. Goy:MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Xcenda: Consultancy; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity Verastem: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment. Locke:Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options. Hill:Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Timmerman:Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Merck: Research Funding; Valor: Research Funding; Genmab: Current equity holder in publicly-traded company. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Flinn:Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Agios: Research Funding; ArQule: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Great Point Partners: Consultancy; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; Nurix Therapeutics: Consultancy; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Curio Science: Consultancy. McSweeney:Fred Hutchinson: Patents & Royalties; Colorado Blood Cancer Institute: Current Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Miltenyi Biotec: Research Funding. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy. Kersten:Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Research Funding; Roche: Research Funding; Takeda: Research Funding; Miltenyi: Consultancy, Honoraria, Other: travel support. Milpied:Celgene: Other: Travel support; Gilead Sciences: Other: consultancy or advisory role; Janssen: Honoraria; Sandoz: Honoraria, Other: consultancy or advisory role; Astellas: Honoraria; Roche: Honoraria, Other: Travel support. Fung:Takeda: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Houot:Janssen: Honoraria; Gilead: Other: Personal fees; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Beitinjaneh:Jazz: Other: speaker's bureau; Kite, a Gilead Company: Honoraria, Other: consulting or advisory role, speaker's bureau, ; ATARA: Research Funding; Gilead: Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Murugappan:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kloos:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Reagan:Curis: Consultancy; Seattle Genetics: Research Funding; Kite, a Gilead Company: Consultancy.
48
Warmansyah, Jhoni, Elis Komalasari, Eliza Febriani, Gusmiati e Amalina. "Factors Affecting Teacher Readiness for Online Learning (TROL) in Early Childhood Education: TISE and TPACK". JPUD - Jurnal Pendidikan Usia Dini 16, n.º 1 (30 de abril de 2022): 32–51. http://dx.doi.org/10.21009/jpud.161.03.
Texto completo da fonteResumo:
This study aims to find empirical information about the effect of Technological Pedagogical Content Knowledge (TPACK), and Technology Integration Self Efficacy (TISE) on Teacher Readiness for Online Learning (TROL). This study uses a quantitative survey method with path analysis techniques. This study measures the readiness of kindergarten teachers in distance learning in Tanah Datar Regency, West Sumatra Province, Indonesia with a sampling technique using simple random sampling involving 105 teachers. Empirical findings reveal that; 1) there is a direct positive effect of Technology Integration Self Efficacy on Teacher Readiness for Online Learning; 2) there is a direct positive effect of PACK on Teacher Readiness for Online Learning; 3) there is a direct positive effect of Technology Integration Self Efficacy on TPACK. If want to improve teacher readiness for online learning, Technological Pedagogical Content Knowledge (TPACK) must be improved by paying attention to Technology Integration Self Efficacy (TISE).
Keywords: TROL, TPACK, TISE, Early Childhood Education
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Kohls-Santos, Pricila, e Marília Costa Morosini. "Trilha para internacionalização em casa: Brasil-Colômbia em espaços não formais (Trail to internationalization at home: Brazil-Colombia in non-formal spaces)". Revista Eletrônica de Educação 15 (30 de novembro de 2021): e4884048. http://dx.doi.org/10.14244/198271994884.
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e4884048One of the impacts of the pandemic caused by Covid-19 is the decrease in internationalization via academic mobility and the need to consolidate other forms of internationalization, such as “internationalization at home” – IaH. In this context, this article discusses an internationalization experience between Brazil and Colombia, with the aim of offering subsidies to the concept of internationalization at home. To reach the proposed objective, qualitative research was carried out, through a case study, in the discipline of Education in Non-Formal Spaces, in a community university. The experience took place in March and April 2019 and was supported by Meet software from Google's Classroom package. The methodology adopted was embodied in a Trail for Internationalization at Home, through the proposition of four stages: Knowledge and evaluation of the proposal; Brazil-Colombia joint planning; Virtual experience; and Evaluation of experience. As results of the investigation, challenges are pointed out, such as the consolidation of an online and/or hybrid teaching culture in on-site courses, the possibility of expanding internationalization actions through technology; in addition, the contribution that the perspective of internationalization at home can make possible the improvement of the quality of higher education, especially considering South-South internationalization, deserves to be highlighted.ResumoUm dos impactos da pandemia ocasionada pela Covid-19 é a diminuição da internacionalização via mobilidade acadêmica e a necessidade da consolidação de outras formas de internacionalização, como “internacionalização em casa” – IaH. Neste bojo, o presente artigo discute uma experiência de internacionalização entre Brasil e Colômbia, com o fito de oferecer subsídios à concepção de internacionalização em casa. Para o alcance do objetivo proposto, foi realizada uma pesquisa qualitativa, por meio de estudo de caso, na disciplina de Educação em Espaços não Formais, em uma universidade comunitária. A experiência ocorreu nos meses de março e abril de 2019 e teve como suporte o aplicativo Meet do pacote Classroom da Google. A metodologia se consubstanciou numa Trilha para a Internacionalização em Casa, mediante a proposição de quatro etapas: Conhecimento e avaliação da proposta; Planejamento conjunto Brasil-Colômbia; Vivência virtual; e Avaliação da experiência. Como resultados da investigação, são apontados desafios, tais como a consolidação de uma cultura de ensino online e/ou híbrido nos cursos presenciais, a possibilidade de ampliação das ações de internacionalização por intermédio da tecnologia; outrossim, merece destaque a contribuição de que a perspectiva da internacionalização em casa pode possibilitar o aprimoramento da qualidade da educação superior, considerando principalmente a internacionalização Sul-Sul.ResumenUno de los impactos de la pandemia provocada por Covid-19 es la disminución de la internacionalización a través de la movilidad académica y la necesidad de consolidar otras formas de internacionalización, como la “internacionalización en casa” - IaH. En este contexto, este artículo analiza una experiencia de internacionalización entre Brasil y Colombia, con el objetivo de ofrecer subsidios al concepto de internacionalización en casa. Para alcanzar el objetivo propuesto, se realizó una investigación cualitativa, a través de un estudio de caso, en la disciplina de Educación en Espacios No Formales, en una universidad comunitaria. La experiencia tuvo lugar en marzo y abril de 2019 y fue respaldada por el software Meet del paquete Classroom de Google. La metodología adoptada se plasmó en un Camino de Internacionalización en el Hogar, a través de la propuesta de cuatro etapas: Conocimiento y evaluación de la propuesta; Planificación conjunta Brasil-Colombia; Experiencia virtual; y Evaluación de la experiencia. Como resultados de la investigación se señalan desafíos como la consolidación de una cultura docente online y/o híbrida en los cursos presenciales, la posibilidad de ampliar las acciones de internacionalización a través de la tecnología; Además, merece destacarse el aporte que la perspectiva de internacionalización en casa puede hacer posible la mejora de la calidad de la educación superior, especialmente considerando la internacionalización Sur-Sur.Palavras-chave: Educação superior, Internacionalização em casa, Educação em espaços não formais, Global Sul.Keywords: Higher education, Internationalization at home, Education in non-formal spaces, Global South.Palabras claves: Educación superior, Internacionalización en casa, Educación en espacios no formales, Sur global.ReferencesALMEIDA, Joana; ROBSON, Sue; MOROSINI, Marília Costa; BARANZELI, Caroline. Understanding internationalization at home: from perspectives the global north and south. European Educational Research Journal. 1-18. V.18, issue 2, 2019.ALTBACH, Philip. Why higher education is not a global commodity. The Chronicle of Higher Education. USA, v. 47, may, 2001.ALTBACH, Philip; DE WIT, Hans. O impacto do coronavírus no ensino superior. Nexo. Merida. 2020. Disponível em: https://educacion.nexos.com.mx/?p=2221. Acesso em: 24 fev. 2020.ALTBACH, Philip; KNIGHT, Jane. The Internationalization of Higher Education: Motivations and Realities. Journal of Studies in International Education, Los Angeles, n. 3/4, p. 290-305, 2007.BEELEN, Jos. Implementing internationalisation at home. European Association for International Education (EAIE), 2012.BEELEN, Jos; JONES, Elspeth. Redefining internationalization at home. In: CURAJ, A.; PRICOPIE, L. M. R.; SCOTT, J. S. P. (eds.). The European higher education area: Between critical reflections and future policies. Dordrecht: Springer, 2015a, p. 67-80.BEELEN, Jos; JONES, Elspeth. Defining ‘internationalization at home’. University World News, Issue 393, 4 dez. 2015b.CRESWELL, John W. Projeto de Pesquisa: Métodos Qualitativo, Quantitativo e Misto; Tradução Magda Lopes. – 3 Ed. – Porto Alegre: Artmed. 2010.DE SAINT-EXUPÉRY, Antoine. O Pequeno Príncipe. São Paulo: Editora Melhoramentos, 2017.DE WIT, Hans. Trends, Issues and Challenges in Internationalisation of Higher Education. Amsterdam. Centre for Applied Research on Economics and Management, Hogeschool van Amsterdam, 2011.DE WIT, Hans. Editorial. Journal of Studies in International Education, v. 17, Issue 5, 2013, p. 511-512. DOI: https://doi.org/10.1177/1028315313508463GOHN, Maria da Glória. Educação não formal e o educador social em projetos sociais. São Paulo: Cortez, 2013.KNIGHT, Jane. Internationalization remodeled: definition, approaches, and rationales. Journal of Studies in International Education. Sage Publications, v. 8, n. 1, spring, 2004. p. 5-31.KNIGHT, Jane; DE WIT, Hans. Quality and internationalisation in higher education. [S. l.]: OECD, 1999. Disponível em: https://www.oecd-ilibrary.org/docserver/9789264173361-en.pdf?expires=1553879992id=idaccname=ocid54025470checksum=39F385EB353EAEC43E278DE262C36C04. Acesso em: 24 fev. 2020. p. 13-18.LEASK, Beth. Internationalizing the curriculum. Internationalization in Higher Education Series. NY: Routledge, 2015. 214 p.MORAES, Roque; GALIAZZI, Maria do Carmo. Análise textual: discursiva. Editora Unijuí, 2007.MOROSINI, Marília Costa; BARANZELI, Caroline. IaH from the perspectives of Brazilian Academic Staff: challenges and possibilities of the IoC. In: ATIAH Conference - Approaches and Tools for IaH. Erasmus Project, 08 September, 2018. Eurac Research Centre, Bolzano, Italy, 2018.MOROSINI, Marília Costa; DALLA CORTE, Marilene Gabriel; GUILHERME, Alexandre Anselmo. Internationalization of Higher Education: A Perspective from the Great South. Creative Education, v. 8, p. 95-113, 2017.NÓVOA, Antônio (coord.). Os professores e sua formação. Lisboa: Dom Quixote, 1997.ROBSON, Sue. Internationalization at home: internationalizing the university experience of staff and students. Educação, Porto Alegre, V. 40, n. 3, p. 368-374, set.-dez. 2017.TEICHLER, Ulrich. The changing debate on internationalization of higher education. Higher Education, Kluwer Academic Publishers, v. 48, 2004. p. 5-26.UNESCO. Educação para a cidadania global: preparando alunos para os desafios do século XXI. Brasília: Unesco, 2015.YIN, Robert K. Estudo de caso: planejamento e métodos. 5. ed. Porto Alegre: Bookman, 2015.ZABALZA, Miguel B. Innovaciones didácticas para la nueva universidad del S. XXI. In: ENGERS, M. E. A.; MOROSINI, M. C.; FELICETTI, V. L. (orgs.). Educação Superior e Aprendizagem. Porto Alegre: EdiPucrs, 2015.
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Imber, Brandon S., Miguel-Angel Perales, Jessica Flynn, Josel D. Ruiz, Sean Devlin, Ana Alarcon Tomas, Carla Hajj et al. "Clinical Impact of Bridging Therapy Prior to Commercial Chimeric Antigen Receptor (CAR) T-Cell Therapies for Relapsed/Refractory Lymphomas". Blood 136, Supplement 1 (5 de novembro de 2020): 1–2. http://dx.doi.org/10.1182/blood-2020-140991.
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Background: CD19-targeted chimeric antigen receptor T-cell therapies (CART) have remarkable overall response rates (ORR) for relapsed/refractory diffuse large B cell lymphoma (DLBCL). Given the time interval between apheresis (Aph) and product delivery, bridging interventions (BI) have been used to provide disease control prior to CART infusion. Real world data suggests about half of patients (pts) require BI such as systemic therapies (ST), radiotherapy (RT) or combined modality therapy (CMT). Early data has associated BI with poorer prognosis however this remains unclear. While no BI strategy has emerged as superior, there is strong rationale to use RT including rapid palliation and cytoreduction with potential immune augmentation. We reviewed BI experience at a comprehensive cancer center. Methods: We analyzed pts who received commercial CART between 2/2018-9/2019. Pts were stratified by BI category including no BI (NBI), ST (any chemoimmunotherapy, targeted agent and/or steroid post Aph), RT (3 months pre-Aph up until CART infusion) or CMT (both ST and RT). Characteristics, toxicities and outcomes were analyzed overall and for 3 subgroups: 1) NBI, 2) ST and 3) RT+CMT. Response assessment was by PET per Lugano Criteria. Progression free survival (PFS) and overall survival (OS) were analyzed from day of CART infusion using Kaplan Meier and univariable proportional hazards. Results: Overall, 69 pts (70% male, median age 64) with 97% DLBCL (41% transformed indolent) received CART. At Aph, 67% were advanced stage and 38% had >1 bulky site (>7.5cm). Pts received axicabtagene ciloleucel (axi-cel, 68%) or tisagenlecleucel (tisa-cel, 32%) following lymphodepletion (LD) with median Aph to infusion time of 35d (range 20-77). Most (77%) received BI, specifically ST (n=35, 51%), RT (n=11, 16%) or CMT (n=7, 10%). Compared to NBI (n=16), +BI pts were less likely to be post autologous transplant (p=0.05), more likely to have osseous disease (p=0.02), and trended to greater median LDH at Aph (NBI: 214 u/L, ST: 301, RT+CMT: 272, p=0.08). Other factors were similar across BI/NBI groups including performance status, cell of origin, share of axi-cel/tisa-cel, pre-CART stage and bulky/extranodal disease. Median hospital stay was 17d and 25% required ICU; both did not vary by BI (p>0.9 and p=0.4, respectively). Rates of cytokine release syndrome (CRS) also did not vary (NBI: 88%, ST: 77%, RT+CMT: 83%, p=0.7). Of 56 total CRS cases, 7 (13%) were grade 3+ and all occurred in +BI pts (ST: n=4/27, 15%; RT+CMT: n=3/15, 20%, p=0.3). Overall rates of immune effector cell-associated neurotoxicity syndrome (ICANS) were 39% and did not differ by BI status (p=0.4). Rates of grade 3+ ICANS were NBI: 1/6 (17%), ST: 9/16 (56%), RT+CMT: 4/5 (80%), p=0.11. Median duration of ICANS was longer for NBI (7.0d) vs. ST (4.5) or RT+CMT (4.0), p=0.04. Tocilizumab and steroid use rates were 45% and 41%, respectively and did not differ by BI (p=0.2, p=0.8). ORR was similar irrespective of BI status (Fig 1A). With median follow-up of 13.5m, there were 30 deaths and median OS was 15.8m. Compared to NBI, +BI did not have significantly worse OS (hazard ratio, HR=1.2, 95%CI: 0.5-3.0, p=0.7, Fig 2A). By BI status, 12m OS is NBI: 66% (95%CI: 45-96%), ST: 62% (48-81%) and RT+CMT: 66% (47-92%) (Fig 2B). Significant predictors of poorer OS are presence of bulk (HR 4.0, p<0.001) and elevated LDH at Aph (HR 2.7, p=0.01). Compared to NBI, +BI pts had nominally, but non-significantly poorer PFS (HR 1.4, 95%CI: 0.7-3.1, p=0.4, Fig 2C). Though limited by sample size, early data suggests ST (6m PFS: 40%, 95%CI: 26-60%) might have inferior PFS to NBI (6m PFS: 56%, 95%CI: 37-87%) or RT+CMT bridging (6m PFS: 56%, 95%CI: 37-84%) (Fig 2D). Presence of >1 bulky site at Aph was also associated with poorer PFS (HR 2.6, p=0.003). Conclusions: Bridging therapies are increasingly used prior to CART infusion and were utilized for >75% of this cohort. This exceeds benchmarks and may reflect a uniquely urgent population or impact of tisa-cel utilization with more baseline bridging at our referral center. Acknowledging the limitation of a small NBI comparator subgroup, we find BI to be safe and not associated with worse toxicity or outcomes. Early data suggest that RT or CMT may be a preferable BI strategy compared to ST though larger cohorts are needed for validation and to clarify the unique impact of RT without ST. More intensive cytoreductive strategies might be beneficial for bulky disease pre-CART. Disclosures Perales: Celgene: Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Research Funding. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Dahi:Kite: Consultancy. Park:Artiva: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Research Funding; Novartis: Consultancy; Fate Therapeutics: Research Funding; Servier: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Intellia: Consultancy; Minverva: Consultancy; AstraZeneca: Consultancy; Allogene: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Scordo:Kite - A Gilead Company: Other: Ad-hoc advisory board; Omeros Corporation: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Giralt:CELGENE: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Sauter:Genmab: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy; Novartis: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Palomba:Genentech: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Pharmacyclics: Honoraria; Merck: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Regeneron: Research Funding.