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Medar, Shivanand S., Sindy Villacres, Shubhi Kaushik, Ruth Eisenberg, and Melvin E. Stone. "Pediatric Acute Respiratory Distress Syndrome (PARDS) in Children With Pulmonary Contusion." Journal of Intensive Care Medicine 36, no. 1 (November 11, 2019): 107–14. http://dx.doi.org/10.1177/0885066619887666.
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Objective: There is paucity of data about prevalence of pediatric acute respiratory distress syndrome (PARDS) in children with pulmonary contusion (PC). We intend to evaluate PC in children with chest trauma and the association between PC and PARDS. Design: Retrospective review of Institutional Trauma Registry for patients with trauma. Setting: Level 1 trauma center. Patients: Age 18 years and younger with a diagnosis of PC. Interventions: None. Measurements and Main Results: Of the 1916 children with trauma, 50 (2.6%) had PC. Patients with PC and PARDS had lower Glasgow Coma Scale (GCS) score (7 [3-15] vs 15 [15-15], P = .0003), higher Injury Severity Scale (ISS) score (29 [22-34] vs 19 [14-22], P = .004), lower oxygen saturations (96 [93-99] days vs 99 [98-100] days, P = .0009), higher FiO2 (1 [1-1] vs 0.21 [0.21-0.40], P < .0001), lower oxygen saturation/FiO2 (S/F) ratios (97 [90-99] vs 457 [280-471], P < .0001), need for invasive mechanical ventilation (IMV; 86% vs 23%, P < .0001), and mortality (28% vs 0%, P = .006) compared to those without PARDS. Forty-two percent (21/50) of patients needed IMV, of these 61% (13/21) had PARDS. Patients who needed IMV had significantly lower GCS score (8 [3-11] vs 15 [15-15], P < .0001), higher ISS score (27 [22-34] vs 18 [14-22], P = .002), longer length of stay (LOS; 7.5 [4-14] days vs 3.3 [2-5] days, P = .003), longer hospital LOS (18 [7.0-25] vs 5 [4-11], P = .008), higher PARDS rate (62% vs 7%, P < .0001), and lower S/F ratios (99 [94-190] vs 461 [353-471], P < .0001) compared to those who did not require IMV. Lower GCS score was independently associated with both PARDS and need for IMV. Conclusions: Pediatric ARDS in children with PC is independently associated with lower GCS score, and its presence significantly increased morbidity and mortality. Further larger studies are needed to explore association of lower GCS and higher injury score in children with PARDS and PC.
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Van Weelderen, Romy E., Kim Klein, Bianca F. Goemans, Christian M. Zwaan, Hester A. De Groot-Kruseman, Jonas Abrahamsson, Nira Arad-Cohen, et al. "Outcome of (Novel) Subgroups in 1257 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia (AML) and the Significance of Minimal Residual Disease (MRD) Status: A Retrospective Study By the I-BFM-SG." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-136064.
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Introduction Outcome of KMT2A-rearranged (KMT2A-r) pediatric AML (pAML) is in general poor with a 5-year probability of event-free survival (5y-pEFS) and overall survival (5y-pOS) of 44% and 56%, respectively (Balgobind et al., 2009). However, over the past decades, the heterogeneity of KMT2A-r pAML has emerged, showing differences in outcome between subgroups based on translocation partners. The predictive value of MRD in KMT2A-r pAML is undefined. This retrospective study aimed to confirm the outcome of pediatric KMT2A subgroups (Balgobind et al., 2009) in a more recent era and to study the significance of MRD status during and after induction. Methods Outcome and MRD data of 1257 KMT2A-rde novo pAML patients from 15 AML groups affiliated with the I-BFM-AML study group, diagnosed between 2005 and 2016 were retrospectively collected. Patients were assigned to KMT2A subgroups, or to the KMT2A-other group in case of unknown translocation partner. Flow cytometry MRD levels <0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier methods were used to estimate probabilities of disease-free survival (pDFS), pEFS and pOS. Cox regression analyses were performed to study the independent impact of KMT2A subgroups and potentially prognostic factors: white blood cell count (WBC), age and MRD status. Results The 1257 patients were assigned to 13 KMT2A subgroups, or the KMT2A-other group. Two novel subgroups were identified: t(X;11)(q24;q23) (n=21, 2%) and t(1;11)(p32;q23) (n=12, 1%). The median age was 2.5 years (range, 0-18.9). The median WBC was 21.4 x 109/L (range, 0.2-727). Overall complete remission rate was 91%. The 5y-pEFS was 46% [SE, 2%] and the 5y-pOS was 62% [SE, 2%]. Differences across subgroups in 5y-pEFS (Figure 1) ranged from 24% [SE, 5%] to 76% [SE, 9%], and in 5y-pOS from 25% [SE, 13%] to 92% [SE, 8%] (both p<0.0001). The median follow-up time of patients at risk was 5 years. The subgroups t(10;11)(p12;q23) (HR 1.7, p<0.0001), t(6;11)(q27;q23) (HR 1.9, p<0.0001), t(4;11)(q21;q23) (HR 2.9, p=.003) and t(10;11)(p11.2;q23) (HR 2.7, p<0.0001), WBC of >100 x 10^9/L (HR 1.3, p=.006), and age >10y (HR 1.3, p=.005) were revealed as independent predictors of poor EFS. These factors also predicted OS. MRD data after induction course one were available for n=635 (MRD-positivity (range, 0.1-94) n=126, 20%) and after course two for n=527 (MRD-positivity (range, 0.1-88) n=51, 10%). In the four KMT2A poor-risk subgroups, MRD-positivity was not significantly more common after induction course one (p=.0232) or two (p=.066), compared with the other subgroups. MRD-positivity was associated with inferior 5y-pDFS after both induction course one (36% [SE, 4%] vs 48% [SE, 2%]; p=.002) and course two (28% [SE, 6%] vs 49% [SE, 2%]; p<0.0001) (Figure 2). Within the t(9;11)(p22;q23) subgroup, MRD-positivity after induction course one, and within the t(10;11)(p12;q23) subgroup after course two, was associated with inferior 5y-pDFS (36% [SE, 8%] vs 56% [SE, 4%]; p=.004, and 0% [SE, 0%] vs 35% [SE, 5%]; p<0.0001, respectively). After induction course one, the subgroups t(10;11)(p12;q23) (HR 1.7, p<0.0001) and t(10;11)(p11.2;q23) (HR 4.0, p<0.0001), and MRD-positivity (HR 1.5, p=.003) were revealed as independent predictors of poor DFS. After induction course two, the subgroups t(10;11)(p12;q23) (HR 1.8, p<0.0001), t(4;11)(q21;q23) (HR 4.9, p=.008) and t(10;11)(p11.2;q23) (HR 3.2, p<0.0001), MRD-positivity (HR 2.0, p<0.0001), and age >10y (HR 1.5, p=.002) were revealed as independent predictors of poor DFS. Within the group of patients with MRD-negativity after induction course two, the subgroups t(10;11)(p12;q23) and t(10;11)(p11.2;q23) were independent predictors of poor EFS (5y-pEFS 35%, HR 1.7, p=.003 and 5y-pEFS 18%, HR 2.7, p=.004, respectively). Conclusion Outcome for KMT2A-r pAML patients has improved slightly, but similar subgroups were identified as poor risk (Balgobind et al., 2009), including t(10;11)(p12;q23), t(10;11)(p11.2;q23) and t(6;11)(q27;q23). In our study, t(4;11)(q21;q23) was poor risk as well. These subgroups should be considered for high-risk pAML therapy protocols. The favorable risk of t(1;11)(q21;q23) could not be confirmed in our cohort. MRD status is highly predictive of outcome within KMT2A subgroups. In MRD-negative patients after induction course two, both t(10;11) KMT2A subgroups were associated with poor outcome. Disclosures Guest: Syndax Pharmaceuticals: Consultancy. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Rubnitz:AbbVie Inc.: Research Funding. Kaspers:Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months; AbbVie: Ended employment in the past 24 months.
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Chang, V. T., D. R. Hoover, J. Cogswell, M. Cholankeril, S. Badin, W. Yang, H. Yan, M. L. Gonzalez, J. Einhorn, and B. S. Kasimis. "Comorbidity and survival in advanced non-small cell lung cancer (NSCLC) veteran patients." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e20675-e20675. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e20675.
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e20675 Background: Prognostic value of comorbidity at diagnosis has received increasing attention. We studied whether the Charlson Comorbidity Index (CMI), Cumulative Illness Rating Scale (CIRS), Kaplan Feinstein Index (KFI), and/or VA Comorbidity Scale (VA) independently predicted survival for NSCLC patients Methods: In an IRB approved protocol, the charts of 101 patients with Stage IIIA, IIIB or IV Non small cell lung cancer seen from 2004 through 2006 at a VA medical center were reviewed of whom 94 have already died. Comorbidity scores ECOG performance status (PS), stage, number of treatments, serum LDH, and albumin levels were obtained or coded from medical records. Survival analyses were performed using proportional hazards models. Results: Median (M) patient age was 69 years (range 51–88), the M ECOG PS was 1 (range 0–4); 13 (13%) had stage IIIA, 27 (26%) IIB and 62 (61%) IV. The M number of treatments was 1 (range 0–6). Histologies were adenocarcinoma in 48 (48%) pts, squamous cell in 37 (37%) pts, and other 17 (15%) pts. The M survival was 207 days (range 4–1785 days). The Median (and ranges) were: 4.2 (1.2–12.8) for CMI, 3 (0–6) for CIRS15, 5(0–11) for CIRS16, 1.8 (0–4) for CIRS17, 0(0–1) for CIRS18, 2 (0–3) for KFI, and 4 (0–8) for VA. The M albumin was 3.7 (range 1.9–5.3) and LDH 201 (range 104–1036). In univariate survival analyses, the stage (p<0.001), ECOG PS (p<0.001), albumin (p<0.003), and the CIRS 17 (p <0.052) were predictive of survival; when, however, bisected by median values, the VA scale (p<0.027), ECOG PS (p<0.052) and albumin (p<.0017) were significantly related to survival but age, LDH, CMI, KFI and subscales of the CIRS (CIRS 16, CIRS 17, CIRS18) were not related to survival. In multivariate proportional hazards analyses that included stage and a comorbidity index, the CIRS16 (p<.032) was an independent predictor of survival; the combinations of stage (p<0.008), ECOG PS (p<.004), stage (p<.006) and albumin (p<.002) were independent predictors of survival. Conclusions: In this small sample, current comorbidity indices did not add to determinations of survival of veterans with advanced NSCLC. Further research is needed in a larger sample. Supported in part by the New Jersey Commission for Cancer Research 09–1133-CCR-EO and VA HSRD IIR 02–103. No significant financial relationships to disclose.
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Atkins, Michael B., John M. Kirkwood, Jedd D. Wolchok, Margaret K. Callahan, Harriet M. Kluger, Michael A. Postow, Neil Howard Segal, et al. "Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9533. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9533.
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9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.
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Thigpen, J. Tate, Mark F. Brady, Howard D. Homesley, John Malfetano, Brent DuBeshter, Robert A. Burger, and Shu Liao. "Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study." Journal of Clinical Oncology 22, no. 19 (October 1, 2004): 3902–8. http://dx.doi.org/10.1200/jco.2004.02.088.
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Purpose Doxorubicin and cisplatin have activity in endometrial carcinoma and at initiation of this study ranked as the most active agents. This trial of stage III, IV, or recurrent disease evaluated whether combining these agents increases response rate (RR) and prolongs progression-free survival (PFS) and overall survival (OS) over doxorubicin alone. Patients and Methods Of 299 patients registered, 281 (94%) were eligible. Regimens were doxorubicin 60 mg/m2 intravenously or doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2 every 3 weeks until disease progression, unacceptable toxicity, or a total of 500 mg/m2 doxorubicin. Results There were 12 (8%) complete (CR) and 26 (17%) partial responses (PR) among 150 patients receiving doxorubicin versus 25 (19%) CRs and 30 (23%) PRs among patients receiving the combination. The overall response rate was higher among patients receiving the combination (42%) compared with patients receiving doxorubicin (25%; P = .004). Median PFS was 5.7 and 3.8 months, respectively, for the combination and single agent. The PFS hazard ratio was 0.736 (95% CI, 0.577 to 0.939; P = .014). Median OS was 9.0 and 9.2 months, respectively, for the combination and single agent. Overall death rates were similar in the two groups (hazard ratio, 0.928; 95% CI, 0.727 to 1.185). Nausea, vomiting, and hematologic toxicities were common. The combination produced more grade 3 to 4 leukopenia (62% v 40%), thrombocytopenia (14% v 2%), anemia (22% v 4%), and nausea/vomiting (13% v 3%). Conclusion Adding cisplatin to doxorubicin in advanced endometrial carcinoma improves RR and PFS with a negligible impact on OS and produces increased toxicity. These results have served as a building block for subsequent phase III trials in patients with disseminated and high-risk limited endometrial carcinoma.
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Sasaki, Koji, Ildefonso Ismael Rodriguez-Rivera, Hagop M. Kantarjian, Susan O'Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Michael J. Burke, Patrick A. Zweidler-McKay, and Jorge E. Cortes. "Correlation of Lymphocyte Count with Treatment Response to Tyrosine Kinase Inhibitors in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase." Blood 124, no. 21 (December 6, 2014): 4538. http://dx.doi.org/10.1182/blood.v124.21.4538.4538.
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Abstract Background: Total lymphocyte count (TLC) has been shown to correlate with outcomes in patients (pts) with acute leukemia. The clinical correlation to TLC in pts with chronic myeloid leukemia in chronic phase (CML-CP) who were treated with a tyrosine-kinase inhibitor (TKI) is unclear. Methods: Lymphocyte data in pts with newly diagnosed CML-CP who were enrolled in consecutive or parallel clinical trials with front-line imatinib (IM), nilotinib (Nilo), or dasatinib (Dasa) were collected at the time of diagnosis, and 3 and 6 months (M) after the start of TKI. Relative lymphocytrosis (RLC) was defined as lymphocyte >150% at 3 or 6M compared with baseline at diagnosis. Absolute lymphocytosis (ALC) was defined as lymphocyte > 4,000 /µL at 3 or 6M after the start of TKI. Pts were assessed for response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) based on ALC and RLC. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test and Cox regression were used for univariate (UVA) and multivariate analysis (MVA), respectively. Results: A total of 483 pts were enrolled in this study: 271 in IM, 105 in Nilo, and 107 in Dasa. Patient characteristics and outcomes are summarized in Table 1. Median age at diagnosis was 48 years, and median follow-up was 85M and ongoing (5-154+). Time from diagnosis to start of TKI, Sokal risk score, and ALC at baseline between groups did not differ clinically. Of 481 pts, 93 (19%) developed RLC at 3 or 6M; IM, 38 (14%); Nilo, 23 (22%); Dasa, 32 (30%) (p= .001). ALC at 3 or 6M was observed in 15 (3%); IM, 3 (1%); Nilo, 1 (1%); Dasa, 11 (10%) (p<.001). Overall, cumulative incidence of complete cytogenetic response (CCyR) at 6M, major molecular response (MMR) at 12M, molecular response with 4.5 log reduction by IS (MR4.5) at 24M did not differ significantly between RLC and non-RLC (3 or 6M), or between ALC and non-ALC (3 or 6M). 5-y TFS, EFS and OS in ALC group were significantly worse than those in non-ALC group (p= .002, p=.016, p=.008, respectively). By UVA and MVA related to OS, age [p <.001; Hazard ratio (HR), 1.062; 95% confidence interval (95%CI), 1.036-1.089], presence of ALC at 3 or 6M [p = .028; HR, 10.948; 95%CI, 1.297-92.415], absence of MMR at 24M [p=.016; HR, 2.263; 95%CI, 1.165-4.393] were identified as adverse prognostic factors for OS. Conclusion: The presence of ALC ≥4,000/µL at 3 or 6M of TKI therapies is rare but is adversely associated with overall survival. Table 1. Patient Characteristics and Outcomes (N=483)a Overall [n= 481] IM [n= 271] Nilo [n= 105] Dasa [n= 107] Age, (year) 48 (15-85) 48 (15-85) 49 (17-82) 48 (16-83) Sokal Risk, No. (%) Low 334 (69) 175 (65) 79 (75) 80 (75) Intermediate 114 (24) 74 (27) 18 (17) 22 (21) High 32 (7) 20 (7) 8 (8) 4 (4) Time from diagnosis to start of TKI, (M) 0.9 (0-12.6) 1.0 (0-12.6) 0.5 (0-5.6) 0.7 (0.1-7.8) ALC at baseline, (/109L) 2.5 (0-86.6) 2.4 (0-16.7) 2.6 (0.4-9.2) 2.7 (0.3-86.6) Incidence of Relative Lymphocytosis, No. (%) At 3M 65 (14) 25 (9) 16 (15) 24 (22) At 6M 76 (16) 32 (12) 20 (19) 24 (22) Overall 93 (19) 38 (14) 23 (22) 32 (30) Incidence of Absolute Lymphocytosis, No. (%) At 3M 8 (2) 1 (0) 0 7 (7) At 6M 11 (2) 3 (1) 1 (1) 7 (7) Overall 15 (3) 3 (1) 1 (1) 11 (10) Outcomes of RLC and ALC at any time in each group, +/- (%/%) (p) <10% BCR-ABL/ABL at 3M RLC 36/40 (.596) 22/44 (.213) 50/37 (.280) 31/38 (.537) ALC 38/39 (.952) 0/42 (.394) 100/39 (.214) 36/35 (.952) Cumulative CCyR at 6M RLC 75/75 (.288) 50/66 (.063) 96/90 (.413) 90/87 (.628) ALC 67/75 (.711) 33/64 (.276) 0/92 (.001) 82/89 (.599) Cumulative MMR at 12M RLC 67/74 (.406) 53/70 (.030) 83/82 (.921) 72/74 (.903) ALC 60/73 (.488) 33/68 (.197) 0/83 (.033) 73/74 (.745) Cumulative MR4.5 at 24M RLC 46/52 (.564) 37/50 (.139) 57/55 (.889) 50/57 (.729) ALC 33/52 (.332) 33/48 (.610) 0/56 (.264) 36/57 (.252) 5-y FFS RLC 61/71 (.133) 56/69 (.167) 62/70 (.710) 61/74 (.285) ALC 50/69 (.076) 0/68 (<.001) 0/70 (<.001) 71/70 (.974) 5-y TFS RLC 90/93 (.369) 88/93 (.597) 91/88 (.115) 91/99 (.213) ALC 72/93 (.002) 67/93 (.014) 0/90 (<.001) 80/97 (.121) 5-y EFS RLC 80/86 (.213) 71/83 (.154) 84/87 (.450) 86/93 (.486) ALC 64/85 (.016) 33/82 (<.001) 0/87 (<.001) 80/92 (.574) 5-y OS RLC 89/93 (.068) 81/94 (.007) 100/84 (.126) 96/99 (.207) ALC 82/93 (.008) 67/93 (.001) 100/88 (.847) 83/99 (.040) a Two in IM and 1 in Dasa were not evaluable due to lack of differential data at 3 and 6M. Figure 1. OS in Pts with ALC Figure 1. OS in Pts with ALC Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.
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Asnafi, Vahid, Agnes Buzyn, Xavier Thomas, Francoise Huguet, Norbert Vey, Jean-Michel Boiron, Oumedaly Reman, et al. "Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study." Blood 105, no. 8 (April 15, 2005): 3072–78. http://dx.doi.org/10.1182/blood-2004-09-3666.
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AbstractPatients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucémies Aiguës Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)–expressing T-ALL patients (TCRαβ+ or TCRγδ+), pre-αβ T-ALL patients (cTCRβ+, TCR–), and immature (IM) cTCRβ–, TCR– T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-αβ, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.
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de Lima, Marcos, Athanasios Anagnostopoulos, Mark Munsell, Munir Shahjahan, Naoto Ueno, Cindy Ippoliti, Borje S. Andersson, et al. "Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation." Blood 104, no. 3 (August 1, 2004): 865–72. http://dx.doi.org/10.1182/blood-2003-11-3750.
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AbstractIntensity of the preparative regimen is an important component of allogeneic transplantations for myelodysplasia (MDS) or acute myelogenous leukemia (AML). We compared outcomes after a truly nonablative regimen (120 mg/m2 fludarabine, 4 g/m2 cytarabine, and 36 mg/m2 idarubicin [FAI]) and a more myelosuppressive, reduced-intensity regimen (100 to 150 mg/m2 fludarabine and 140 or 180 mg/m2 melphalan [FM]). We performed a retrospective analysis of 94 patients with MDS (n = 26) and AML (n = 68) treated with FM (n = 62) and FAI (n = 32). The FAI group had a higher proportion of patients in complete remission (CR) at transplantation (44% versus 16%, P = .006), patients in first CR (28% versus 3%, P = .008), and HLA-matched sibling donors (81% versus 40%, P = .001). Median follow-up is 40 months. FM was significantly associated with a higher degree of donor cell engraftment, higher cumulative incidence of treatment-related mortality (TRM; P = .036), and lower cumulative incidence of relapse-related mortality (P = .029). Relapse rate after FAI and FM was 61% and 30%, respectively. Actuarial 3-year survival rate was 30% after FAI and 35% following FM. In a multivariate analysis of patient- and treatment-related prognostic factors, progression-free survival was improved after FM, for patients in CR at transplantation, and for those with intermediate-risk cytogenetics. Survival was improved for patients in CR at transplantation. In conclusion, FM provided better disease control though at a cost of increased TRM and morbidity.
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Juul, Filippa, Euridice Martinez-Steele, Niyati Parekh, Carlos A. Monteiro, and Virginia W. Chang. "Ultra-processed food consumption and excess weight among US adults." British Journal of Nutrition 120, no. 1 (May 6, 2018): 90–100. http://dx.doi.org/10.1017/s0007114518001046.
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AbstractUltra-processed foods provide 58 % of energy intake and 89 % of added sugars in the American diet. Nevertheless, the association between ultra-processed foods and excess weight has not been investigated in a US sample. The present investigation therefore aims to examine the association between ultra-processed foods and excess weight in a nationally representative sample of US adults. We performed a cross-sectional analysis of anthropometric and dietary data from 15 977 adults (20–64 years) participating in the National Health and Nutrition Examination Survey 2005–2014. Dietary data were collected by 24-h recall. Height, weight and waist circumference (WC) were measured. Foods were classified as ultra-processed/non-ultra-processed according to the NOVA classification. Multivariable linear and logistic regression was used to evaluate the association between ultra-processed food consumption (% energy) and BMI, WC and odds of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity (men: WC≥102 cm, women: WC≥88 cm). Prevalence of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity was 69·2, 36·1 and 53·0 %, respectively. Consuming ≥74·2 v. ≤36·5 % of total energy from ultra-processed foods was associated with 1·61 units higher BMI (95 % CI 1·11, 2·10), 4·07 cm greater WC (95 % CI 2·94, 5·19) and 48, 53 and 62 % higher odds of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity, respectively (OR 1·48; 95 % CI 1·25, 1·76; OR 1·53; 95 % CI 1·29, 1·81; OR 1·62; 95 % CI 1·39, 1·89, respectively; Pfor trend<0·001 for all). A significant interaction between being female and ultra-processed food consumption was found for BMI (F4,79=4·89, P=0·002), WC (F4,79=3·71, P=0·008) and BMI≥25 kg/m2 (F4,79=5·35, P<0·001). As the first study in a US population, our findings support that higher consumption of ultra-processed food is associated with excess weight, and that the association is more pronounced among women.
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Zang, Rongyu, Tingyan Shi, Rong Jiang, Hong Pu, Huijuan Yang, Dongsheng Tu, Zhiyuan Dai, et al. "Dose-dense early postoperative intraperitoneal chemotherapy in ovarian cancer: Randomized, phase II trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5514. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5514.
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5514 Background: Dose-dense early postoperative intraperitoneal chemo (DD-EPIC) had been carried out in advanced ovarian cancer (OC) pts in China over the past three decades but it was not proved by a prospective study. This trial was designed to confirm the benefit of DD-EPIC in delaying progression and improving survival. Methods: In a multicenter, phase 2 trial, pts with FIGO IIIC-IV OC and optimal debulking surgery (residual disease ≤1cm) were randomly allocated to receive 4 doses of weekly DD-EPIC with cisplatin (50mg/m2) and etoposide (100mg/m2) followed by 6 cycles of intravenous (iv) chemo with carboplatin and taxane every 3 weeks (DD-EPIC group), or standard iv chemo alone (iv group). (ClinicalTrials.gov, NCT01669226). Results: Between 2009 and 2015, 218 pts were randomized, of whom 215 initiated treatment (106 to DD-EPIC and 109 to iv; for efficacy analyses). Totally, 36 pts (16·7%) were received neoadjuvant chemo. With a median of 61·9 mos follow-up, 122 pts died (54 in DD-EPIC and 68 in iv group). Remarkable OS benefit of DD-EPIC was recorded (67·5 mos for DD-EPIC vs. 46·3 mos for iv; HR 0·70, 95% CI 0·49-1·00, P=0·047). Pts in DD-EPIC had a significantly increased median PFS compared with those in iv group (21·7 vs. 16·8 mos; HR 0·64, 95% CI 0·47-0·86, P=0·003). Median TFST was 25·1 vs. 18·0 mos in favor of DD-EPIC (HR 0·62, 95%CI 0·46-0·83, P=0·002). Similar findings were detected in TSST (42·2 vs. 29·3 mos; HR 0·66, 95%CI 0·47-0·94, P=0·019). Grade 3 and 4 Leucopenia (53·8% vs. 35·2%), anemia (23·6% vs. 5·6%) and gastrointestinal events (10·4% vs. 1·9%) were more common in DD-EPIC ( P=0·006, P<0·001 and P=0·010, respectively). Ninety-one pts were detected by gBRCA testing, with 25·3% of cases carrying deleterious BRCAm, but PFS and OS benefit were observed in patients with BRCA-wild type (HR 0·46 and 0·55, 95%CI 0·27-0·81 and 0·27-1·11, respectively). Conclusions: DD-EPIC with a higher completion rate and acceptable treatment burden was associated with longer OS than standard iv alone. Owing to the benefit of relatively long-term OS, DD-EPIC may be considered as a valuable option for OC, particularly in developing countries and BRCA-wild type pts. Clinical trial information: NCT01669226. [Table: see text]
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Siegel, David S., Paul G. Richardson, Meletios A. Dimopoulos, Christine I. Chen, Kevin Song, Ravi Vij, Nizar J. Bahlis, et al. "Efficacy and Safety Of Pomalidomide Plus Low-Dose Dexamethasone In Advanced Multiple Myeloma: Results Of Randomized Phase 2 and 3 Trials (MM-002/MM-003)." Blood 122, no. 21 (November 15, 2013): 3185. http://dx.doi.org/10.1182/blood.v122.21.3185.3185.
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Abstract Introduction Few treatments options are available for patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have previously been treated with lenalidomide (LEN) and bortezomib (BORT), and their prognosis is poor. Pomalidomide (POM) is a distinct IMiD® immunomodulatory agent with a mechanism of action consisting of direct anti-myeloma, stromal-support inhibitory, and immunomodulatory effects. In randomized phase 2 and 3 trials (MM-002 and MM-003), POM plus low-dose dexamethasone (POM+LoDEX) demonstrated marked efficacy in RRMM pts who had received multiple prior therapies, including LEN and BORT. This side-by-side analysis presents the most recent survival and safety data from these trials. Methods The MM-002 and MM-003 trials enrolled pts with ≥ 2 prior therapies, including LEN and BORT. In MM-002, pts received POM (4 mg/day on days 1–21 of each 28-day cycle) alone or in combination with LoDEX (40 mg/week). In MM-003, pts were randomized 2:1 to receive POM+LoDEX or high-dose DEX alone (HiDEX) (40 mg/days 1–4, 9–12, 17–20 in a 28-day cycle); HiDEX was chosen as the comparator to isolate the effects of POM, as at the time of trial design it was the standard salvage therapy for heavily pretreated pts. Thromboprophylaxis was required for all pts treated with POM and pts at high risk of developing venous thromboembolism. Data cutoff was February 1, 2013 for MM-002 and March 1, 2013 for MM-003. The primary endpoint in both trials was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rates, duration of response, and safety. Results In each study, pts had received a median of 5 prior therapies (range 1-17), and all pts had received prior LEN and BORT. In MM-002, 113 pts were treated with POM+LoDEX and 108 were treated with POM alone (60% of POM alone pts subsequently received DEX). A total of 79% of pts were LEN refractory; 62% were refractory to both LEN and BORT; and 35% had received LEN as their last prior therapy. With a median follow-up of 14.2 months (mos), median PFS was 4.2 mos, OS was 16.5 mos, and overall response rate (ORR, defined as at least a partial response) was 33% with POM+LoDEX (Table 1). In MM-003, 302 pts were treated with POM+LoDEX and 153 pts were treated with HiDEX (50% of HiDEX pts subsequently received POM). A total of 94% of pts were LEN refractory; 74% were both LEN and BORT refractory; and 29% had received LEN as their last prior therapy. Survival outcomes were similar in MM-003; with a median follow-up of 10 mos, median PFS was 4.0 mos, OS was 12.7 mos, and ORR was 31% with POM+LoDEX. In both trials, LEN as last prior therapy did not impact response, PFS, or OS vs the overall population. Commonly observed adverse events (AEs) are presented in Table 2 for pts treated with POM+LoDEX. Grade 3 and 4 neutropenia was 28% and 13% in MM-002, and 26% and 22% in MM-003 for the POM+LoDEX arms, respectively. AEs were generally manageable for POM+LoDEX in MM-002 and MM-003 with dose interruptions (67% for both) and reductions (29% and 26%, respectively), and standard supportive care, including growth factor support (46% and 43%), red blood cell transfusions (45% and 49%), platelet transfusions (14% and 20%), and anti-infective agents (89% in both trials). Rates of POM discontinuation due to treatment-related AEs were low (2–4% with POM+LoDEX). In MM-002 and MM-003, 49% and 51% of pts in the POM+LoDEX arms experienced neutropenia of any grade. With appropriate AE management, 9% and 23% had dose interruptions, 4% and 8% had dose reductions, and 1 pt in both MM-002 and MM-003 discontinued due to neutropenia. Febrile neutropenia developed in 3% and 10% of pts; 1% and 4% had dose interruptions, 0% and 2% had dose reductions, and no pts discontinued due to febrile neutropenia in the MM-002 and MM-003 studies, respectively. The majority of infections occurred in the absence of neutropenia of any grade (54% in MM-002 and 66% in MM-003). The rate of POM discontinuation due to infection was low (1% in MM-002 and 2% in MM-003). Conclusion In both the MM-002 and MM-003 trials, POM+LoDEX consistently extended PFS in advanced RRMM pts. PFS, OS, and ORR were not negatively impacted in patients who were refractory to LEN or BORT, even as last prior therapy. Both trials demonstrated that with dose modifications and supportive care POM was well tolerated, leading to few discontinuations. POM+LoDEX should be considered a standard of care for pts with advanced RRMM who have exhausted LEN and BORT. Disclosures: Siegel: Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees. Dimopoulos:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Song:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vij:Onyx: Consultancy, Research Funding; Millenium: Speakers Bureau; Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Bahlis:Celgene Corporation: Consultancy, Honoraria, Research Funding. Baz:Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Celgene Corporation: Research Funding. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Weisel:Celgene Corporation: Consultancy, Honoraria, Research Funding. Jagannath:Millennium: Honoraria; Celgene Corporation: Honoraria. Lonial:Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy; Celgene Corporation: Consultancy. Delforge:Celgene Corporation: Honoraria. Talpaz:Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees; Ariad, Novartis, BMS, Pfizer: Speakers Bureau; Ariad, BMS, Sanofi, INCYTE: Research Funding. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. San Miguel:Jansen, Celgene Corporation, Onyx, Novartis, Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Karlin:Janssen: Honoraria; Celgene Corporation: Consultancy, Expert board committee Other, Honoraria. Goldschmidt:Celgene Corporation, Janssen, Novartis: Consultancy, Honoraria, Research Funding. Oriol:Celgene Corporation: Consultancy. Alegre:Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cavo:Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Martinez-Lopez:Celgene Corporation: Honoraria, Research Funding. Lacy:Celgene Corporation: Research Funding. Chen:Celgene Corporation: Employment, Equity Ownership. Casey:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Anderson:Onyx: Consultancy, Equity Ownership; Gilead: Consultancy, Equity Ownership; sanofi aventis: Consultancy, Equity Ownership; Oncopep: Consultancy, Equity Ownership; Acetylon: Consultancy, Equity Ownership; Celgene Corporation: Consultancy, Equity Ownership.
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O'Doherty, J. V., and T. F. Crosby. "Blood metabolite concentrations in late pregnant ewes as indicators of nutritional status." Animal Science 66, no. 3 (June 1998): 675–83. http://dx.doi.org/10.1017/s1357729800009243.
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AbstractIn a feeding experiment β-hydroxybutyrate (BHB), glucose, albumin, total protein, globulin and urea concentrations in the plasma of twin-bearing ewes were analysed. Mature Suffolk cross ewes were given either formic acid (FA)-treated grass silage or grasslmolassed sugar-beet pulp (MSBP) silage in late pregnancy. The experiment commenced on day 91 of pregnancy and the dietary treatments were FA-treated silage (Tl), FA-treated silage + soya-bean meal (SBM) (T2), MSBP silage (T3), MSBP silage + SBM (T4), FA-treated silage + MSBP (T5), FA-treated silage + MSBP + SBM (T6) or FA-treated silage + 150 g crude protein (CP) per kg concentrate (T7). SBM was given only in the last 22 days of pregnancy aiming for a total CP intake of 220 g per ewe per day. Blood samples were collected by jugular venipuncture from each ewe 3 h following consumption of the morning dietary allowance on days 121, 128, 135 and 142 of pregnancy. Daily metabolizable energy (ME) intakes of 6·8, 11·4, 9·6, 12·8, 10·5, 13·7 and 14·7 (s.e. 0·58) MJ per ewe were recorded for Tl to T7 respectively over the last 3 weeks of pregnancy. Respective CP intakes of 72, 213, 110, 225, 109, 215 and 175 (s.e. 5·64) g per ewe were recorded for Tl to T7 respectively over the last 3 weeks of pregnancy. BHB concentrations (mmol/l) on day 121 of pregnancy of 1·18, 1·25, 0·52, 0·52, 0·56, 0·39 and 0·45 (s.e. 0·17), on day 128 of pregnancy of 1·17, 0·94, 0·52, 0·51, 0·72, 0·62 and 0·39 (s.e. 0·20), on day 135 of pregnancy of 1·53, 0·68, 0·68, 0·66, 0·71, 0·62 and 0·46 (s.e. 0·20) and on day 142 of pregnancy of 1·43, 0·60, 0·62, 0·56, 0·62, 0·56 and 0·63 (s.e. 0·20) were recorded for Tl to T7 respectively. There was a quadratic relationship between plasma BHB concentration and ME intake on days 121 (R2 = 0·538, P < 0·001), 128 (R2 = 0·324, P < 0·001), 135 (R2 = 0·429, P < 0·001)) and 142 (R2 = 0·344, P < 0·002) of pregnancy. There was a positive relationship between plasma glucose concentration and ME intake on day 222 (R2 = 0·208, P < 0·002), 228 (R2 = 0·203, P < 0·05), and 135 (R2 = 0·160, P < 0·02) of pregnancy. Albumin concentrations (gll) on day 128 of pregnancy of 21·8, 21·7, 23·6, 22·9, 22·5, 22·9 and 24·3 (s.e. 0-75), on day 135 of 20·9, 23·6, 24·2, 24·1, 22·4, 24·1 and 23·8 (s.e. 0·75), and on day 142 of 16·9, 22·6, 20·7, 22·2, 20·4, 22·7 and 21·1 (s.e. 1·05) were recorded for Tl to T7 respectively. Plasma albumin concentrations were significantly affected by SBM supplementation (P < 0·05). Despite the lower than generally recommended energy concentrations in T2 to T7, the concentrations of plasma BHB were within the normal range for healthy sheep.
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Iland, Harry J., Marnie Collins, Mark S. Hertzberg, Michael Seldon, Andrew P. Grigg, Frank Firkin, Shane G. Supple, Lynda J. Campbell, Kenneth F. Bradstock, and John F. Seymour. "Final Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 Trial: All-Trans Retinoic Acid (ATRA), Intravenous Arsenic Trioxide (ATO) and Idarubicin (IDA) As Initial Therapy for Acute Promyelocytic Leukemia (APL)." Blood 124, no. 21 (December 6, 2014): 375. http://dx.doi.org/10.1182/blood.v124.21.375.375.
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Abstract BACKGROUND The combination of ATRA and anthracycline-based chemotherapy has traditionally been regarded as the gold standard for induction and consolidation in previously untreated APL patients (pts), with ATO usually reserved for relapse. Recent data in Sanz low-risk (LR) and intermediate-risk (IR) APL indicate ATRA + ATO is superior to ATRA + chemotherapy (N Engl J Med 2013), but the optimal therapy for high-risk (HiR) pts remains unclear. In an attempt to improve anti-leukemic efficacy whilst limiting reliance on anthracyclines for all risk categories of APL, the ALLG incorporated ATO into an ATRA + reduced chemotherapy backbone, and the results of an interim analysis with a median follow-up of 2 years (yr) have been published (Blood 120:1570, 2012). Herein, we report results of the protocol-specified final analysis, conducted when all surviving pts had been followed for at least 2 yr after completion of consolidation. METHODS As published, APML4 protocol treatment comprised: (i) induction with ATRA (45 mg/m2 d1-36), IDA (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9-36), prophylactic prednisone (1 mg/kg d1-10) and aggressive hemostatic support; (ii) consolidation with ATRA and ATO (continuous in cycle 1, intermittent in cycle 2); (iii) 2 yr oral maintenance with ATRA, 6-mercaptopurine and methotrexate. Between 2004-2009, 124 evaluable pts were accrued, and median follow-up by the censor-reversing Kaplan-Meier method in this final analysis is 4.2 yr. RESULTS Median age was 44 (3-78) yr, median white cell count was 2.4 x 109/L (0.1-85.8), and median platelet count 22 x 109/L (2-173). Risk groups were 33 LR, 67 IR, 23 HiR, 1 unknown. FLT3 mutations were present in 44%, and 11% had ≥ 2 additional cytogenetic abnormalities (2+ACA). There were 4 (3.2%) deaths during induction (myocardial infarction d1, cerebral hemorrhage d3 and d7, cerebral edema and seizures d30). Grade 3-4 non-hematological adverse events included differentiation syndrome in 14%, and frequent but reversible biochemical hepatic and gastrointestinal toxicity. Q-Tc prolongation > 500 msec occurred in 14%, but there were no cases of ventricular arrhythmias or torsades de pointe. Significant neurological and cutaneous toxicity were infrequent. After induction, 118 pts (95%) achieved hematological complete remission; 112 commenced consolidation, and all were in molecular remission after cycle 2. A total of 5 relapses and 3 deaths have occurred post-induction, but none of the deaths were attributable to protocol therapy. Severe adverse events were less common during the chemotherapy-free consolidation cycles, especially cycle 2. The frequency of grade 3-4 neutropenia was 62% in cycle 1 and 27% in cycle 2, but there was no grade 3-4 thrombocytopenia. The following table lists event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and cumulative incidence of relapse (CIR): Table All pts LR IR HiR 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr EFS 92% 90% 97% 97% 93% 89% 83% 83% DFS 97% 95% 100% 100% 97% 93% 95% 95% OS 94% 94% 97% 97% 96% 96% 87% 87% CIR 3% 5% 0% 0% 3% 7% 5% 5% In univariate analysis, 2+ACA predicted for inferior DFS (P = .04), whereas age > 70 was associated with increased risk of early death (ED, P = .02), inferior EFS (P = .0002), and inferior OS (P = .001). Neither Sanz risk category nor FLT3 mutation status was significantly correlated with these outcome endpoints (all P > .05). In multivariate analysis, the significant associations of 2+ACA (P = .04 for DFS) and age > 70 (P = .0002 for EFS, P = .005 for OS) were retained. In addition, Sanz risk category was correlated with EFS (P[trend] = .003) and OS (P[trend] = .02). When compared with our previous ALLG APML3 trial (ATRA + IDA for induction and consolidation without ATO; Haematologica 2012), treatment with APML4 was associated with substantial and statistically significant improvements (see Figure) in EFS (P = .002), DFS (P = .001) and OS (P = .02). The significance of trial assignment was retained in multivariate analysis when APML3 and APML4 data were combined. CONCLUSIONS APML4 is a potent anti-leukemic regimen with manageable toxicity and a low ED rate. EFS and OS remain impressive with mature follow-up, and were influenced primarily by advanced age and Sanz risk category. The CIR was 5%, and was only associated with 2+ACA. Our results support the inclusion of ATO in induction and consolidation as front-line therapy for APL whilst simultaneously limiting cumulative anthracycline exposure. Figure 1 Figure 1. Disclosures Off Label Use: Arsenic trioxide is currently only registered in the US, Europe and Australia for the treatment of relapsed APL. This report includes its use in the initial treatment of APL.
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Tsimberidou, Apostolia-Maria, Elihu Estey, Maher Albitar, Sijin Wen, Mark Brandt, Sherry Pierce, Hagop Kantarjian, and Razelle Kurzrock. "Prognostic Significance of Tissue Necrosis Factor-Alpha in Newly Diagnosed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndromes." Blood 110, no. 11 (November 16, 2007): 4263. http://dx.doi.org/10.1182/blood.v110.11.4263.4263.
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Abstract Background: Tissue necrosis factor (TNF)-α is a naturally occurring cytokine involved in the pathogenesis of several hematologic malignancies, but an independent prognostic role for TNF-α in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) has not been established. The purpose of this study was to determine the association between TNF-α levels and pretreatment characteristics and clinical outcomes in these diseases. Methods: From 9/94 through 1/01, serum levels of TNF-α were prospectively measured in 198 patients with AML or high-risk MDS. Serum TNF-α was quantified using commercially available ELISA kits (R&D Systems, Minneapolis, MN) (lower limits of sensitivity were 4.4 pg/mL). The appropriate recombinant cytokine was used to create a standard curve for each cytokine, and serum level was ascertained using the appropriate standard curve. All values represent the means of 3 sets of duplicate experiments. Results: The median patient age of the 198 patients with serum TNF-α measurements was 65 years (range, 21–84 years); 62% were ≥ 60 years. Cytogenetics were favorable in 6% of patients, intermediate in 53%, poor-risk in 38%, and 3% of patients had insufficient metaphases or unknown cytogenetics. Zubrod performance status (PS) was 0–1 in 66% of patients, 2 in 25%, and 3–4 in 9%. Forty-nine percent had a history of an antecedent hematologic disorder (AHD), and 93% received ara-C-based therapy. High TNF-α levels were associated with poor Zubrod PS (cor= .28); high levels of β2 microglobulin (cor=.50), creatinine (cor=.35), uric acid (p=.35), or LDH (p=.32); low albumin levels (cor=−.22); and longer duration of AHD (cor=.74) (p<.0001 for all variables). High TNF-α levels were more common in patients with AML (vs. MDS, p=.026) and M4-M5 subtypes according to the French-American-British classification (p=.02). The median follow-up of surviving patients was 5.6 years. Clinical outcomes by TNF-α are shown in the Table: TNF-α (pg/mL_ TNF-α <10pg/mL TNF-α ≥10 pg/mL p-value No. pts 98 100 CR (%) 72 (73) 52 (52) .0018 Median EFS, months 9.3 2.5 .0009 Median survival, months 1.2 0.6 .0003 In multivariate analysis, independent factors predicting response to therapy were younger age (p=.03), shorter duration of AHD (p=.007), higher hemoglobin levels (p=.04), lower TNF-α levels (p=.038), and better PS (p=.02). Factors independently prognostic of longer survival were younger age (p=.0008), better-risk cytogenetics (p=.049), lower TNF-α levels (p=.049), lower leukocyte counts (p=.003), higher hemoglobin levels (p=.03), lower β2-microglobulin levels (p=.03), female gender (p=.02), no history of chemotherapy or radiotherapy (p=.02), and race other than African American (p=.02). Factors independently prognostic of longer event-free survival (EFS) were better-risk cytogenetics (p=.002), lower β2-microglobulin levels (p=.008), lower leukocyte counts (p=.03), and younger age (p=.04). Conclusions: These data indicate that an elevated serum TNF-α level is associated among others with poorer Zubrod PS and higher levels of β2 microglobulin and it is an independent adverse prognostic factor for response and survival in the context of established prognostic factors for AML.
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Petrella, Robert J., Donald A. Cunningham, and David H. Paterson. "Effects of 5-Day Exercise Training in Elderly Subjects on Resting Left Ventricular Diastolic Function and VO2max." Canadian Journal of Applied Physiology 22, no. 1 (February 1, 1997): 37–47. http://dx.doi.org/10.1139/h97-004.
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We evaluated the effects of short-term, high-intensity exercise training and detraining on resting left ventricular diastolic function (LVDF) and maximal aerobic power (VO2max) in 7 sedentary older (age = 68 ± 4 years) men (n = 5) and women (n = 2). Training consisted of cycling for 60 min with power output set at 70% (Day 1), 80% (Day 2), and 90% (Days 3-5) of the pretraining peak work rate. Detraining consisted of a return to regular exercise habits. LVDF increased 10% in the early (E) flow velocity, decreased 18% in the late (A) flow velocity wave, and decreased 31% in the isovolumic relaxation time. VO2max was increased 12% while plasma volume (PV) increased 10% following, training and returned to baseline after detraining. The exercise-induced change in VO2max was directly related to the change in E/A (r =.52) and indirectly related to the change in IVRT (r = −.62). It was concluded that short-term, high-intensity exercise training improves LVDF and is tolerated well in older subjects, and that the calculated changes in PV and aerobic power are similar to those observed previously in a younger population. Key words: aging, training, cardiac filling
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Zada, Gabriel, Paul G. Pagnini, Cheng Yu, Kelly T. Erickson, Jonah Hirschbein, Vladimir Zelman, and Michael L. J. Apuzzo. "Long-term Outcomes and Patterns of Tumor Progression After Gamma Knife Radiosurgery for Benign Meningiomas." Neurosurgery 67, no. 2 (August 1, 2010): 322–29. http://dx.doi.org/10.1227/01.neu.0000371974.88873.15.
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Abstract OBJECT To characterize the timing and patterns of long-term treatment failure after Gamma Knife radiosurgery (GKRS) for benign meningiomas. METHODS Data were retrospectively reviewed in 116 patients who underwent 136 GKRS treatments for benign intracranial meningiomas from 1996 to 2004. Patients with atypical or malignant meningiomas were excluded. Surgical resection preceded GKRS in 72 patients (62%). The median tumor volume was 3.4 cm3, and the median prescription dose to the 50% isodose line was 16 Gy. RESULTS The median follow-up time was 75 months (range, 4–146 months). Overall tumor control was achieved in 128 of 136 lesions (94%), of which tumor size was stable in 68% and decreased in 26%. Seven patients experienced disease progression in 8 tumors, occurring at a mean time of 90 months. The overall 5-year and 10-year actuarial tumor control rate was 98.9% and 84%, respectively. Characteristics corresponding to tumor progression included insufficient tumor coverage (98% vs 93%, P = .007), cavernous sinus lesions, and meningiomatosis. Complications after GKRS developed in 8% of patients, in whom the mean tumor volume was nearly double that in patients with no adverse effects (11 vs 5.7 cm3, P = .003). CONCLUSIONS GKRS demonstrates excellent long-term tumor control in the management of benign meningiomas. Tumor progression occurred at a mean time of 7.5 years after GKRS, reinforcing the need for long-term surveillance despite initial tumor control. Treatment failure was related to undercoverage of lesions in the majority of cases, with the remainder demonstrating evidence of abnormal tumor biology.
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Peng, Zhen-Wei, Yao-Jun Zhang, Min-Shan Chen, Li Xu, Hui-Hong Liang, Xiao-Jun Lin, Rong-Ping Guo, Ya-Qi Zhang, and Wan Yee Lau. "Radiofrequency Ablation With or Without Transcatheter Arterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Prospective Randomized Trial." Journal of Clinical Oncology 31, no. 4 (February 1, 2013): 426–32. http://dx.doi.org/10.1200/jco.2012.42.9936.
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Purpose To compare radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). Patients and Methods A randomized controlled trial was conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009. Patients were randomly asssigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95). The primary end point was overall survival. The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects. Results At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died. Thirty-three patients and 52 patients had developed recurrence in the TACE-RFA group and RFA group, respectively. The 1-, 3-, and 4-year overall survivals for the TACE-RFA group and the RFA group were 92.6%, 66.6%, and 61.8% and 85.3%, 59%, and 45.0%, respectively. The corresponding recurrence-free survivals were 79.4%, 60.6%, and 54.8% and 66.7%, 44.2%, and 38.9%, respectively. Patients in the TACE-RFA group had better overall survival and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95% CI, 0.335 to 0.822; P = .002; hazard ratio, 0.575; 95% CI, 0.374 to 0.897; P = .009, respectively). There were no treatment-related deaths. On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for overall survival, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival. Conclusion TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.
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Borwick, S. C., S. M. Rhind, S. R. McMillen, and P. A. Racey. "Effect of undernutrition of ewes from the time of mating on fetal ovarian development in mid gestation." Reproduction, Fertility and Development 9, no. 7 (1997): 711. http://dx.doi.org/10.1071/r97011.
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Ewes were fed either 150% (High, H) or 50% (Low, L) of their energy requirements for maintenance of liveweight during early gestation. Effects of maternal nutrition on fetal ovarian size, histological structure and steroidogenic capacity were studied at Day 47 and on ovarian size and structure at Day 62 of gestation. At Day 47 of gestation, there were significantly higher concentrations of oogonia in the ovaries of L fetuses than H fetuses (105·9 v. 76·9 germ cells mm-2; s.e. 4·94; P < 0·001). The capacity of the ovaries to secrete oestradiol (pg/ovary/24 h) at Day 47 was not affected by treatment when they were incubated either with (H, 773; L, 740; s.e. 179; not signicant, n.s.) or without (H, 260; L, 290; s.e. 92·7; n.s.) ovine luteinizing hormone (oLH). At Day 62 of gestation, the process of germ cell degeneration was less advanced in L than H fetal ovaries, as indicated by higher oocyte concentrations in the former (68·4 v. 48·6 germ cells mm-2; s.e. 3·85; P < 0·01). There was a greater percentage of meiotic cells in L ovaries (76·5 v. 18·6; s.e. 5·82; P < 0·001). It is concluded that undernutrition of the ewe from the time of mating signicantly retards ovarian development in fetal ovaries
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Zuurbier, Charlotte CM, Eva Stokhuijzen, Cor van den Bos, Antoinette YN Schouten-van Meeteren, and C. Heleen Van Ommen. "The Effect of Fresh Frozen Plasma On the Incidence of Venous Thromboembolism and Haemorrhages in Children with Acute Lymphoblastic Leukaemia." Blood 120, no. 21 (November 16, 2012): 1471. http://dx.doi.org/10.1182/blood.v120.21.1471.1471.
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Abstract Abstract 1471 Background: Venous thromboembolism (VTE) and haemorrhages frequently occur during asparaginase (ASP) treatment in paediatric patients treated for acute lymphoblastic leukaemia (ALL). These complications cause significant morbidity and mortality. The effect of fresh frozen plasma (FFP) to prevent these complications in ALL patients is not entirely clear. The aims of this study were to assess the effect of FFP on the incidence of VTE and haemorrhages and the plasma levels of antithrombin (AT) and fibrinogen (FG) during the induction phase in paediatric ALL patients treated according to the Dutch Childhood Oncology Group ALL IX or ALL X protocol. In addition, we compared the incidences of VTE and haemorrhages and the plasma levels of AT and FG between both ALL protocols. Methods: A retrospective observational cohort study was performed among paediatric patients, aging from 0 to 18 years, with newly diagnosed ALL receiving induction therapy according to the ALL IX or ALL X protocol between February 1997 and January 2012. Treatment during the induction phase of the ALL IX protocol, day 0–49, included dexamethasone and 4 doses of 6 000 IU/m2 ASP intravenously over a period of 2 weeks (day 29–40). FFP supplementation was recommended if FG levels were < 1.0 g/L. Treatment during the induction phase of the ALL X protocol, day 0–64, included prednisone and 8 doses of 5 000 IU/m2ASP intravenously over a period of 3 weeks (day 12–33). In the ALL X protocol, FFP supplementation was recommended if FG levels were < 0.6 g/L. Medical records were reviewed and all VTE and haemorrhages during induction treatment were recorded. Plasma levels of AT (normal value: 80–140%) and FG (normal value: 0.7–4 g/L) and the frequency of FFP supplementation during the induction phase were also recorded. Results: In this study, 199 patients were included. During the induction phase, VTE and haemorrhages occurred in 7 (3.5%; 95% CI: 1.0–6.2%) and 2 (1%; 95% CI: 0.4–2.4%) of the 199 paediatric ALL patients treated according to both ALL protocols, respectively. Four VTE occurred in the central nervous system (57%) and 3 VTE were central venous line (CVL) related (43%) and occurred in the subclavian vein. Both haemorrhages were intracranial. 42% of all paediatric ALL patients received FFP supplementation. No statistical significant effect of FFP supplementation was seen on the incidence of VTE and haemorrhages. The mean AT and FG levels significantly decreased after ASP administration from 130% to a minimum of 78% and from 1.6 g/l to a minimum of 0.9 g/l, respectively. In general, the AT and FG levels did not increase by FFP supplementation. The paediatric patients treated according to the ALL IX protocol (n=94) consisted of significantly less male, younger patients, and less T-ALL patients than patients of the ALL X protocol (n=105). The incidence of VTE during the induction phase was significantly lower in children treated according to the ALL IX protocol (n=1), including dexamethasone and 24 000 IU/m2 ASP than in those included in the ALL X protocol (n=6) treated with prednisone and 40 000 IU/m2ASP (p=0.038). 25% of the ALL IX patients and 62% of the ALL X patients received FFP. After the third and fourth administration of ASP, the FG plasma levels were significant higher in the ALL IX protocol than in the ALL X protocol (p= 0.034 and 0.01, respectively). Conclusion: FFP has no significant effect on the incidence of VTE and haemorrhages and the plasma level of AT and FG during the induction phase in paediatric ALL patients treated according to the Dutch Childhood Oncology Group ALL IX or ALL X protocol. VTE occurred significantly less often in ALL IX patients treated with dexamethasone and 24 000 IU/m2 ASP than in ALL X patients treated with prednisone and 40 000 IU/m2 ASP. Disclosures: No relevant conflicts of interest to declare.
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Ball, Jennette J., Kristina L. Petrocco-Napuli, and Michael P. Zumpano. "An International Survey of Gross Anatomy Courses in Chiropractic Colleges." Journal of Chiropractic Education 26, no. 2 (October 1, 2012): 175–83. http://dx.doi.org/10.7899/jce-12-004.
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Purpose: The purpose of this study is to provide the first comprehensive description of gross anatomy course design in chiropractic colleges internationally and to provide baseline data for future investigation, future comparison with other health care professions, and identification of trends. Methods: A 72-question cross-sectional electronic survey was sent to the anatomy department chair at 36 chiropractic colleges internationally using Zoomerang, a web-based survey instrument. To augment the survey response data, public sources of data also were collected. Results: Forty-four percent of the electronic surveys were returned and information was gathered for 31 institutions from public sources. These results indicate (1) the most common degrees held by anatomy faculty were MS and PhD in anatomy, and DC degrees; (2) 75% of institutions utilized human cadavers and 75% presented laboratory anatomical demonstrations; (3) 62% used PowerPoint and 100% provided students with copies of lecture presentations; (4) 88% required attendance in laboratory and 50% in lecture; (5) 69% issued one grade for lecture and laboratory; (6) 100% of laboratory examinations were anatomical identification; and (7) 80% of written examinations were multiple-choice format. Conclusions: While individual variations existed, chiropractic institutions internationally have similar gross anatomy faculty, course design, delivery methods, and assessment methods.
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Ezzat, Abdelrahman E. M., Mohammed A. Salem, Colin O’Rourke, and John E. Fenton. "Our Experience in Pulsatile Tinnitus and a Normal Tympanic Membrane in 66 Patients." Annals of Otology and Neurotology 2, no. 02 (September 2019): 56–58. http://dx.doi.org/10.1055/s-0040-1703971.
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Abstract Introduction Pulsatile tinnitus (PT) can harbor potentially life-threatening conditions (LTCs), whereby a delay in diagnosis could be disastrous. Objective The purpose of this study was to ascertain whether associated signs and symptoms at presentation could help identify a subgroup of high-risk patients. Materials and Methods A total of 66 patients with PT were retrospectively assessed. The diagnoses were classified as group I with an LTC or not in group II. Results There were 4 patients (6%) with a final diagnosis of LTC (group I) and 62 patients (94%) without a final diagnosis of LTC or no diagnosis (group II). The results were not quite statistically significant regarding the trauma and were strongly statistically significant regarding headache and the cranial nerve paralysis. Conclusion The combination of PT with any of the three features of occipital headache, cranial nerve palsy, and recent trauma should alert the clinician to potentially serious causes.
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Yaseen, Amna, Umema Tariq, Neha Mohammad Ismail, and Ayesha Sheikh. "A SURVEY OF OCCUPATIONAL STRESS REACTIONS AMONG HEALTHCARE WORKERS." Pakistan Journal of Rehabilitation 11, no. 1 (January 3, 2022): 11–16. http://dx.doi.org/10.36283/pjr.zu.11.1/004.
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ABSTRACT BACKGROUND AND AIM The objective of the present study was to identify occupational stress and its reaction to psychological and physical health among different healthcare professionals in Karachi. METHODOLOGY An observational cross-sectional study was performed on 257 healthcare workers, including the physiotherapists, general physicians, nurses age between 25-55 years and working for 8 or more hours. A Convenient non- probability purposive sampling technique was used to collect the data. Data was collected from hospitals in 4 districts of Karachi, through the Brief Job Stress Questionnaire (BJSQ) and Job Stress Questionnaire. SPSS (Statistical Package for Social Sciences) Version 16.0 was used. ANOVA & Post HOC analysis was used to compare the effects of variables. (P-value <0.05 considered significant). RESULTS Out of 257 participants n= 94 were males and n=163 were females. Among the total sample n=102 were General Physicians, n= 79 were Physiotherapists and n=76 were nurses. Insignificance was found when the occupation was compared with both occupational stressors (p=0.093) and with stress reactions (p=0.456). CONCLUSION Overall general physicians experience more occupational stressors than nurses and physiotherapists. Moreover, the study found that female health-care workers are more affected by occupational stress than men. KEY WORDS Mental health, anxiety, health personnel, physical health, stress reaction, occupational stress.
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FAHMY, MOHAMED H., and JACQUES J. DUFOUR. "THE ACCUMULATIVE EFFECT OF FINNSHEEP BREEDING IN CROSSBREEDING SCHEMES: REPRODUCTIVE PERFORMANCE." Canadian Journal of Animal Science 68, no. 1 (March 1, 1988): 69–81. http://dx.doi.org/10.4141/cjas88-007.
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Reproductive performance and body weight were studied on 361 ewes, representing Finnsheep (F), DLS (a population of 1/2 Dorset, 1/4 Leicester, 1/4 Suffolk) and seven combinations ranging from 1/8 to 7/8 Finnsheep breeding. Conception rate in yearlings was 61.5% for DLS compared to 89.0% for F with the crosses being intermediate. Conception rate in older ewes was similar in the different genetic groups (avg. 94%). Ovulation rate and litter size at birth of DLS ewes were 1.72 and 1.44 lambs, which was less than half those of F ewes (3.51 and 2.86 lambs, respectively). Both traits increased progressively with an increase in F breeding in crosses and with advances in age. DLS ewes weaned 1.22 lambs compared to 2.03 lambs for F ewes and 1.84 lambs for 4/8 F ewes. The heaviest litters at weaning (31.7 kg) were raised by 4/8 F ewes, followed by 7/8 F (30.8 kg) while those raised by DLS ewes weighed 23.0 kg and F ewes 29.1 kg. Percentage of ova lost per ewe mated averaged 24% and ranged between 18% (DLS and 1/8 F) and 29% (6/8 F). About 3.6% of lambs were born dead and a further 13.8% died before weaning. Preweaning mortality rate was highest in F (22.9%) and lowest in 3/8 F (9.4%). Average kilograms of lambs weaned per ewe exposed was highest in 4/8 F (27.6 kg) followed by F (26.0 kg), whereas that of DLS was the lowest at 18.1 kg. The 4/8 F cross showed 25% heterosis in kg of lambs weaned per ewe exposed and 52.5% increase over DLS. Significant positive linear regressions were calculated for ovulation rate, litter size and preweaning mortality rate on proportion of Finnsheep breeding in crosses. The relation was quadratic for percent ova lost and lamb mortality at weaning. Yearling DLS females weighted 36 kg compared to 44 kg for F yearlings. However, at 5 yr of age DLS ewes weighed 62 kg, 5 kg heavier than F ewes. The heaviest ewes at all ages were the 4/8 F (45 kg at 1 yr, 65 kg at 5 yr). Key words: Reproduction, DLS sheep, Finnsheep, crossbreeding, heterosis, repeatabilities
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Stannard, James P., and James L. Cook. "Prospective Assessment of Outcomes After Primary Unipolar, Multisurface, and Bipolar Osteochondral Allograft Transplantations in the Knee: A Comparison of 2 Preservation Methods." American Journal of Sports Medicine 48, no. 6 (March 5, 2020): 1356–64. http://dx.doi.org/10.1177/0363546520907101.
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Background: Articular cartilage lesions in the knee remain a challenging clinical problem. Hypothesis: A novel graft preservation method combined with surgical technique and patient management improvements would lead to consistently successful outcomes after osteochondral allograft (OCA) transplantation. Study Design: Cohort study; Level of evidence, 3. Methods: With institutional review board approval and informed consent, patients were prospectively enrolled into a registry to follow outcomes after OCA transplantation. Patients were included when ≥1-year follow-up data were available, including complications and reoperations, patient-reported outcome measures (PROMs), compliance with rehabilitation, revisions, and failures. Results: For patients meeting inclusion criteria (N = 194), mean ± SD age was 37.9 ± 12.2 years and mean BMI was 28.9 ± 5; 38% received unipolar transplants (44% multisurface) and 62% received bipolar transplants. OCAs were preserved by standard tissue bank methods (standard preservation [SP]; 29%) or the novel method (Missouri Osteochondral Preservation System [MOPS]; 71%). Initial success rates were 79% for all cases combined, 60% for SP, and 84% for MOPS. MOPS cases were significantly ( P = .028) more likely to be associated with successful outcomes when compared with SP cases. PROMs improved significantly ( P < .05) for all cohorts through 3 to 4 years of follow-up. Revisions were performed in 19 cases (10%). MOPS grafts were associated with a significantly ( P = .0014) lower revision rate (5%) than SP grafts (21%). Failures occurred in 26 patients (13%), with all undergoing total knee arthroplasty. Bipolar cases were significantly ( P = .008) more likely to be associated with failure. MOPS grafts were associated with a significantly ( P = .048) lower failure rate (11%) than were SP grafts (19%). Noncompliance with the prescribed rehabilitation protocol was significantly ( P = .00008) more likely to be associated with failure. Conclusion: Prospective data for 194 cases revealed that OCA transplantation for unipolar, multisurface, and bipolar cartilage restoration can be associated with consistently successful outcomes. The 5% revision rate, 11% failure rate, 82%-94% survival probability estimates, and continually improving PROMs through postoperative 3 to 4 years underscore major advances in outcomes as compared with previous reports. These encouraging results were realized with the use of a novel graft preservation method; autogenous bone marrow concentrate pretreatment of donor bone; advancements in graft cutting, implantation, and stabilization techniques; and procedure-specific rehabilitation protocols.
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Fenaux, Pierre, Agnes Guerci-Bresler, Petra Muus, Mikkael A. Sekeres, Aristoteles Giagounidis, H. Joachim Deeg, Peter Greenberg, Barry Skikne, Xujie Yu, and Alan F. List. "Efficacy and tolerability of lenalidomide (LEN) in patients (pts) 75 and older versus those younger than 75 with RBC transfusion-dependent low/int-1-risk MDS and del 5q." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 6522. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6522.
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6522 Background: LEN is the approved treatment for pts with RBC transfusion-dependent Low/Int-1-risk MDS and del 5q. In 2 multicenter trials (MDS-003/-004) LEN lead to RBC transfusion independence (TI) for ≥ 26 wks in 35–58% of pts and cytogenetic response (CyR) in 25–73%. Most common grade (G) 3–4 adverse events (AE) were neutropenia and thrombocytopenia, a safety concern in elderly pts. We evaluated efficacy and tolerability of LEN in pts ≥ 75 y vs < 75 y in MDS-003/-004 trials. Methods: Pts received LEN 5 mg × 28 d, 10 mg × 21 d, or 10 mg × 28 d (all 28 d cycles). Dose reductions were required for G4 neutropenia (both trials) and platelet counts < 30 x 109/L (MDS-003) or < 25 x 109/L (MDS-004). Results: 32% of the 286 pts were ≥ 75 y. Baseline (BL) characteristics, LEN treatment, and optional G-CSF use are shown in Table. In pts ≥ 75 y vs < 75 y: RBC-TI ≥ 26 wks was 39 vs 47% (P = NS); CyR was 64 vs 54% (P = NS); 2-y AML progression rates were 10 vs 19% (P = NS); 2-y overall survival rates were 62 vs 73% (P = .001); G3–4 AE: neutropenia (63 vs 76%; P = .024), thrombocytopenia (56 vs 49%; P = NS), infection (36 vs 20%; P = .003); median time to recovery to ANC > 1 x 109/L was 0.7 vs 0.7 mo (P = NS) and to platelet counts > 100 x 109/L was 3.3 vs 1.7 mo (P = NS). 59% pts ≥ 75 y and 49% pts < 75 y discontinued LEN due to AE (33 vs 26%; P = NS), lack of effect (32 vs 49%; P = NS), or death (15 vs 6%; P = NS). Dose reduction and discontinuation rates are shown in Table. Conclusions: Pts ≥ 75 y and < 75 y had comparable response and AML progression rates. In pts ≥ 75 y, LEN appears to be well tolerated but the higher infection rate justifies close follow-up. [Table: see text]
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Gruson, Berengere, Sarah Ivanoff, Céline Berthon, Veronique Harrivel, Olivier Nibourel, Cécile Frimat, Claude Preudhomme, and Jean-Pierre Marolleau. "Rural but Not Urban AML Exhibit Cytogenetic and Molecular Characteristics of Therapy-Related AML." Blood 124, no. 21 (December 6, 2014): 2353. http://dx.doi.org/10.1182/blood.v124.21.2353.2353.
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Abstract Background:There are few established risk factors for AML. Benzene, radiation, prior chemotherapy treatments for cancer, and cigarette smoking have been causally linked with AML. Few studies have shown that incidence rates are highest in the agricultural region and it has been hypothesized that farming and its related exposures (e.g., pesticides) may account for this increased risk. Nonetheless, there are no do data regarding clinical, cytogenetic and molecular differences between rural and urban area. The primary objective of this study is to look for cytogenetic features of rural patients. Secondary objectives are to search for clinical and molecular characteristics. Patients and methods: We conducted a retrospective analysis of 521 AML patients treated in 2 french institutions (Amiens University Hospital and Lille University Hospital) between 2008 and 2013. Patients with therapy related AML have been excluded. Patient demographics as well as clinical, hematological, cytogenetics and molecular data were collected from the Nord-pas de Calais and Picardie observatory. European Leukemia Net (ELN) classification was used for cytogenetics prognosis. We geocoded addresses using the geographic information system of the french National institute of statistics and economics (INSEE, http://www.insee.fr). According to the INSEE criteria, a location of residence was defined as rural for a city of population under 2,000 inhabitants without a contiguous built area of more than 200 m. Moreover, the population was divided into quartiles according to the percentage of farm in local companies. Results: In our population 120/521 patients (23%) lived in a rural area and 401/521 (77%) in an urban area. Sex ratio (1.6 vs 1.2, p=0.2) and median age at diagnosis (64 vs 61 years, p=0.05) were similar. There was no difference in complete blood count (hemoglobin, platelets, leukocytes and circulating blasts levels) as well as bone marrow blasts percentage, type of AML (de novo vs post MDS or MPN) and WHO classification at diagnosis between the two groups. Concerning cytogenetic anomalies, proportion of favorable and intermediate AML were similar between the two groups. However, there are more patients with unfavorable cytogenetics in rural area (41% vs 28%, p=0.04). Moreover, we observed more 11q23 anomalies in the rural patients group (22% vs 9%, p=0.04). Concerning molecular anomalies, rural patients seem to have less FLT3-ITD positivity (11% vs 19%, p=0.2), and CEBPAmutation (2% vs 7% p= 0.07) without significance. Overall survival was similar between the two groups. Same results have been obtained when we compared patients depending on the proportion of farm in their area (table 1.) with more MLL anomalies (p=0.03) and unfavorable cytogenetics (p=0.005). Conclusions:Our results showed that rural AML might present specific features. These AML would present more like therapy-related AML with more 11q23 anomalies and more unfavorable cytogenetics feature. Abstract 2353. Table 1. Characteristics of AML according to the proportion of farm in the area Proportion of farm p %≤ 0.8 n= 144 0.8<% ≤ 3.9 n=122 3.9<% ≤ 11.3 n=128 %> 11.3 n=130 Age, median (range) 63 (61-65) 62 (60-66) 61 (56-64) 63 (61-66) 0.34 Sex ratio (M/F) 1.25 1.28 1.32 1.43 0.9 Type of AML, secondary (%) 28/136 (20) 18/109 (17) 15/116 (13) 24/124 (19) 0.4 White blood cells, 109/L 6.8 (4.5-10.8) 7.8 (4.6-14.2) 7.9 (5.6-14.4) 4.5 (3.4-7) 0.08 Bone marrow blasts, % 53 (49-60) 59 (46-66) 54 (43-62) 47 (38-56) 0.2 WHO classification, (%) AML with reccurent genetic abnomalities 32/122 (30) 26/103 (25) 26/104 (27) 21/107 (20) 0.7 AML with myelodysplasia related changes 49/122 (40) 33/103 (32) 33/104 (33) 46/107 (43) 0.8 AML NOS 42/122 (34) 43/103 (42) 39/104 (37) 39/107 (36) 0.6 Cytogenetics, (%) Favorable 35/100 (35) 27/93 (29) 29/95 (31) 22/92 (24) 0.4 Intermediate 40/100 (40) 44/92 (48) 32/95 (34) 33/92 (36) 0.2 Unfavorable 25/100 (25) 21/92 (23) 33/94 (35) 37/92 (40) 0.03 MLL rearrangement, (%) 3/78 (4) 3/63 (5) 14/79 (18) 14/82 (17) 0.005 Molecular biology, (%) FLT3 ITD 18/105 (17) 18/92 (19) 21/93 (22) 7/77 (9) 0.22 NPM mutation 31/93 (33) 22/89 (25) 24/89 (27) 13/75 (17) 0.3 CEBPA mutation 7/94 (7) 3/86 (3) 5/83 (6) 4/73 (5) 0.6 Disclosures No relevant conflicts of interest to declare.
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GEBREMEDHIN, E. Z., G. TESFAMARYAM, H. A. YUNUS, R. DUGUMA, G. TILAHUN, V. DI MARCO, and M. VITALE. "Seroepidemiology ofToxoplasma gondiiinfection in free-range chickens (Gallus domesticus) of Central Ethiopia." Epidemiology and Infection 143, no. 3 (April 24, 2014): 608–17. http://dx.doi.org/10.1017/s0950268814000971.
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SUMMARYWe performed a seroepidemiological study ofToxoplasma gondiiinfection in free-range chickens from October 2012 to May 2013. We used cross-sectional two-stage cluster sampling to collect blood samples from wing veins of 601 chickens from central Ethiopia.T. gondii-specific antibodies were assayed by modified agglutination test (MAT). We collected information about risk factors by questionnaire and used univariable and multivariable logistic regression to assess risk factors. An overall seroprevalence of 30·5% [95% confidence interval (CI) 26·27–34·14] and 54·2% (95% CI 47·06–61·36) was found at animal- and flock-level, respectively. The MAT end titre of seropositive chickens (n = 183) were 1 : 60 in 46, 1 : 180 in 28, 1 : 540 in 29, ⩾1 : 1620 in 48, 1 : 6000 in 22, 1 : 18 000 in five, 1 : 54 000 in one, and ⩾1 : 162 000 in four. Animal-level risk factors identified using multivariable logistic regression model were: midland altitude [odds ratio (OR) 2·53, 95% CI 1·12–5·72], cross and exotic breeds (OR 3·17, 95% CI 1·39–7·23), increased age of chickens (OR 2·32, 95% CI 1·19–4·49), extensive management (OR 6·92, 95% CI 1·34–35·86) and the presence of cats (OR 2·08, 95% CI 1·20–3·61). Similarly, flock-level risk factors were midland altitude (OR 3·62, 95% CI 1·31–9·99) and the presence of cats (OR 1·19–4·94). The knowledge of the local people about the health risk of cats to humans and animals is poor. Housing and management of cats and chickens are also poor. The widespread presence ofT. gondiiinfection in free-range chickens of Central Ethiopia provides suggestive evidence for the high level of contamination of the living environment of people withT. gondiioocysts. Meat from free-range chickens might be an important source of infection for humans. Altitude, breed, age, management and presence of cats are independent predictors of seropositivity. Education of farmers about toxoplasmosis and further studies to elucidate the burden of toxoplasmosis in animals and humans warrants consideration.
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Gökbuget, Nicola, Joachim Beck, Kalina Brandt, Monika Brüggemann, Thomas Burmeister, Helmut Diedrich, Christoph Faul, et al. "Significant Improvement Of Outcome In Adolescents and Young adults (AYAs) Aged 15-35 Years With Acute Lymphoblastic Leukemia (ALL) With a Pediatric Derived Adult ALL Protocol; Results Of 1529 AYAs In 2 Consecutive Trials Of The German Multicenter Study Group For Adult ALL (GMALL)." Blood 122, no. 21 (November 15, 2013): 839. http://dx.doi.org/10.1182/blood.v122.21.839.839.
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Abstract Several groups have reported results from smaller series of AYAs with ALL. Outcomes with so-called protocols for adults were generally inferior compared to so-called pediatric protocols. The GMALL protocols were originally based on pediatric BFM protocols and have been consecutively optimized for adults since 1981. We report the results of two recent protocols 05/93 (Goekbuget et al, Blood 98(11):802a, 2001) and 07/03 (Goekbuget et al, Blood 110(11):12a, 2007). In study 07 high risk (HR) pts were identified by one of the factors: B-lin with WBC>30.000, late CR (>3 wks), pro-B, early T, mature T, MLL1/AF4/t(4;11). Pts without risk factors were standard risk (SR) and those with BCR-ABL/t(9;22) very high risk (VHR). HR/VHR pts were candidates for SCT in CR1. The major innovations in study 07 were: intensified, shortened induction with dexamethasone instead of prednisone, PEG-asparaginase (ASP) instead of native ASP, intensified first consolidation, 6x HDMTX/ASP during consolidation, matched unrelated SCT for HR/VHR pts without sibling donor and SCT indication in pts with persistent MRD. After amendments in trial 07 pts partly also received intensified PEG-ASP, rituximab in CD20+ ALL and imatinib in Ph+ ALL. Overall, 1529 of 3060 (50%) pts recruited into both trials were aged between 15-35 yrs. 642 pts from 94 centres were recruited to study 05 and 887 pts from 130 centres to study 07. Patient characteristics were similar for both trials. 70% had B-Lin and 30% T-ALL (61% c/preB, 9% proB, 7% early T, 6% mature T, 17% thy T) with no significant differences across age subgroups (15-17,18-25 and 26-35 yrs). Allocation to SR, HR and VHR was 51%, 35% and 14%. VHR incidence increased from 3%, 11% to 19% in age groups (p<.0001). The CR rate increased in studies 05 to 07 from 88% to 91% (p=.001), most prominently within the age range of 26-35 yrs (86% to 90%;p=.001) (table). The OS increased from 46% to 65% (p<.0001) (significant in all age groups). Remission duration (RD) at 5 yrs increased from 49% to 61% (p=.0001), most prominently within the age range of 26-35 yrs (46% vs 59%; p=.005). OS improved from study 05 to study 07 in B-Lin (45% vs 66%; p<.0001) and T-ALL (47% vs 63%; p=.0007) overall and in subgroups as c/pre B (50% vs 68%;p<.0001), pro B (45% vs 67%;p=.05), mature T (19% vs 61%; p=.005) and thymic T (59% vs 70%;p=.09) but to a lesser extent in early T (35% vs 48%;p>.05). OS increased in SR (58% to 74%; p<.0001), HR (24% to 58%; p<.0001) and VHR (36% vs 55%;p=.0003).Table 1Results of Induction and Overall Outcome in GMALL-Studies 05/93 and 07/0305/9307/03Total15-1718-2526-35Total15-1718-2526-35Evaluable64210625238488753458376CR88%91%88%86%91%94%91%90%ED3%1%3%3%4%0%3%6%Failure9%8%8%11%5%6%5%4%RD at 5y49%52%50%46%61%60%62%59%OS at 5y46%57%45%42%65%73%69%60% 15% vs 43% of all CR pts underwent SCT in CR1 in studies 05 and 07. The proportion of SCT increased from 22% to 68% (p<.0001) in HR and from 62% to 73% (p<.0001) in VHR in studies 05 vs 07. The OS after SCT improved from 36% to 68% (p<.0001), mainly due to a decrease of TRM from 34% to 12% (p<.0001). In trial 07 MRD in week 16 (after consolidation I) was tested in 353 pts. The proportion of molecular failure (MRD>0.01%) was 26% with no differences across age groups. OS was 90% in pts with mol. CR vs 53% in mol. failure (p<.0001). Amendments in study 07 led to further improvement with an OS of 71% in 274 pts aged between 15-35 yrs treated according to the final protocol version. We present here results of the so far largest cohort of AYA ALL pts treated according to pediatric-derived adult ALL protocols. Outcomes have significantly improved and reached a 73% OS in pts aged 15-17 yrs. Intensified treatment with ASP, MTX and targeted therapies as rituximab and imatinib and MRD based stratification have contributed to the improvement in study 07. SCT led to improved OS in HR and VHR ALL. Obviously, there is no indication for SCT in CR1 in young SR pts with an OS of 74%. Future GMALL studies will attempt to optimize further the combination of pediatric approaches and targeted therapies in adults. Supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971. Disclosures: Off Label Use: RItuximab in ALL.
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Kourelis, Taxiarchis, Surendra Dasari, Paul J. Kurtin, Marina Ramirez-Alvarado, Steven R. Zeldenrust, Jason D. Theis, Morie A. Gertz, Ahmet Dogan, and Angela Dispenzieri. "Immunoglobulin Variable Region Family Usage and Outcomes of Patients with Systemic Light Chain Amyloidosis." Blood 124, no. 21 (December 6, 2014): 3402. http://dx.doi.org/10.1182/blood.v124.21.3402.3402.
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Abstract Introduction: AL amyloidosis is a very heterogeneous disease. Prognosis is a function of organ tropism, extent of organ damage, and ability of tissues to heal, the last of which relates both to hematologic response and intrinsic toxicity of the light chain. Using mass spectroscopy (MS) technology, we are able to distinguish immunoglobulin light chain variable gene family (IGVL) usage on clinical samples. The goal of this study was to evaluate if IGVL usage impacts patient outcomes in patients with light chain amyloidosis (AL). Methods: IGVL usage was determined by mass spectroscopy (MS) of amyloid in clinical tissue specimens of Mayo Clinic patients. Specimens were from fat pad (n=257), bone marrow (n=172), myocardium (n=113), gastrointestinal (n=58), kidney (n=20), lung (n=15), and nerve (n=5). For those cases for which the IGVL could not be identified--not otherwise specified (NOS)—but constant region could be identified as lambda or kappa, we assume that the amyloid consisted primarily of immunoglobulin light chain gene constant regions or variable genes with somatic mutations making them uninterpretable to our matching algorithms. The medical records from these 700 patients were abstracted for relevant clinical and laboratory data. Results: The baseline characteristics of patients are shown in table 1. Three hundred and thirty-two patients have died with a median follow-up of surviving patients of 38 months. The estimated median survival for the entire population is 59 months. Out of 700 patients, 214 (31%) achieved a CR or a VGPR, 432 (62%) were not evaluable (NE) for hematologic or organ response, and 54 (8%) achieved a PR or did not respond (NR). The distribution of IGVL cases is shown in table 2. Overall survival (OS) for the whole group was not different across different IGVLs on univariate analysis, but when corrected for hematologic response, outcomes differed significantly based on IGVL. Patients could be further assembled into two groups, based on risk for death on univariate analyses: an IGVL high risk, which included KV1, LV1, LV2, LV3, and LV6; and low risk, which included all other cases (Figure). In a multivariate model that included level of hematologic response (CR/VGPR versus PR/NR/NE) and IGVL, IGVL family was independently associated with overall survival (RR=1.5 (95% CI 1.2-1.9, p=0.008). The risk ratio for CR/VGPR was 0.28 (95% CI 0.20-0.38, p<0.0001). This effect persisted when either the Mayo 2006 or the 2012 staging system was included in the multivariate. Conclusion: IGVL usage appears to have prognostic significance in patients who have not achieved VGPR or better to initial chemotherapy. Table 1. Baseline characteristics of patients N= 700 Age 63 (32-94) Male, (%) 447 (64%) Biopsy site Solid organ/Soft tissue 271 (39%) Fat pad 257 (37%) Bone Marrow 172 (25%) Organ involvement Cardiac 432 (62%) Renal 346 (49%) Gastrointestinal 168 (24%) Liver 56 (8%) Nerve 107 (15%) Lung 42 (6%) Soft Tissue 92 (13%) Organs involved 1 321 (46%) 2 228 (33%) ≥3 151 (22%) Laboratory characteristics NTBNP, pg/ml 2547 (11.3-70000) Troponin, ng/ml 0.03 (0.001-0.84) dFLC, mg/dl 26 (0.04-2330) Cardiac Stage 1 59 (18%) 2 125 (38%) 3 144 (44%) Table 2. Variable region family distribution. Light Chain N=700 N (%) KV1 107 (15%) KV2 3 (0.4%) KV3 17 (2%) KV4 25 (4%) KV6 1 (0.1%) LV1 85 (12%) LV2 64 (9%) LV3 118 (17%) LV4 3 (0.4%) LV6 97 (14%) LV8 1 (0.1%) LV9 1 (0.1%) Kappa NOS1 34 (4%) Lambda NOS1 140 (19%) Heavy chain amyloidosis 4 (0.6%) 1 No IGVL family could be identified Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Borquist-Conlon, Debra S., Brandy R. Maynard, Kristen Esposito Brendel, and Anne S. J. Farina. "Mindfulness-Based Interventions for Youth With Anxiety: A Systematic Review and Meta-Analysis." Research on Social Work Practice 29, no. 2 (January 6, 2017): 195–205. http://dx.doi.org/10.1177/1049731516684961.
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Purpose: To examine the effects on anxiety of mindfulness-based interventions (MBIs) among youth with anxiety disorders. Method: Systematic review and meta-analytic procedures were employed to synthesize experimental and quasi-experimental studies authored between 1980 and 2015. Results: The search yielded five studies from five countries reporting results for a total of 188 youth between the ages of 5 and 18 (mean age 13.26) who met criteria for an anxiety disorder. Risk of bias varied across studies. Meta-analytic results suggest a moderate and significant effect ( g = .62; 95% confidence interval = [0.20, 1.04], p = .004). Heterogeneity was moderate ( I2 = 47.22) and not statistically significant ( Q = 7.58, df = 4, p = .11), thus moderator analyses were not warranted. Discussion: The findings of this review suggest that MBIs for the treatment of anxiety in youth with anxiety disorders are effective.
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B. Jagan Mohan Reddy and S.P. Girish. "Assessment of Usefulness of CRP, PMN Elastase, PCT and Il- 6 as Prognostic Factors in Patients with Acute Pancreatitis." Academia Journal of Surgery 3, no. 2 (December 27, 2020): 1–4. http://dx.doi.org/10.47008/ajs/2020.3.2.1.
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Background: Acute pancreatitis is an inflammatory disease of the exocrine pancreas with rapid onset. The present study was conducted to assess the usefulness of CRP, PMN elastase, PCT and IL- 6 as prognostic factors in patients with acute pancreatitis. Subjects and Methods: The present study comprised 53 patients who presented with a diagnosis of Acute Pancreatitis. CRP was estimated by turbidimetric immunoassay using CRP/U2A-000 kit. PMN-Elastase was estimated by solid-phase enzyme immunoassay. Procalcitonin was estimated by the immuno- chromatographic test. IL-6 was estimated by Immuno-enzymatic assay. Results: There were 47 males and 6 females in the present study. The mean SD CRP in patients with mild pancreatitis was 44.35 53.04 and in severe pancreatitis was 174.80 14.55, PCT was seen in 4 in mild pancreatitis patients and 12 in severe pancreatitis patients, PMN- elastase level was 3.89 1087 in mild pancreatitis and 3.99 2.75 inn severe pancreatitis patients, IL-6 level was 129.63 319.08 in mild pancreatitis and 1166.76 818.06 in severe pancreatitis patients. The difference was significant (P< 0.05). CRP had higher (100) specificity as compared to PCT (81), PMN- E (10) and IL- 6 (90), Specificity found to be 88, 81, 97 and 94 respectively, PPV was 84, 74, 67 and 90 respectively, NPV was 100, 87, 62 and 94 respectively, accuracy was 92, 81, 62 and 92 respectively, AUC was 0.97, 0.81, 0.43 and 0.95 respectively. Conclusion: Authors found that CRP is the single best predictor of the severity of acute pancreatitis. IL-6 and PCT also are reliable predictors. PMN-Elastase needs to be assessed in patients with acute pancreatitis presenting early in the course of the illness.
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Roux, Clémence, Karim Tifratene, Nicole Raus, Gerard Socie, Claire Galambrun, Yves Bertrand, Fanny Rialland, et al. "Outcome after Relapse or Progression Following First Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia. a Retrospective Analysis from the French Society of Bone Marrow Transplantation and Cell Therapies." Blood 124, no. 21 (December 6, 2014): 2510. http://dx.doi.org/10.1182/blood.v124.21.2510.2510.
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Abstract Background Hematopoietic stem cell transplantation (HSCT) has contributed to improve outcome for pediatric patients with acute leukemia (AL). However, post-transplantation relapse is still associated with a dismal prognosis and its optimal treatment remains unclear. Therapeutic strategies may vary according to the relapse delay, as well as centers and child's specific requirements. Aim We aimed to compare patients' related factors and treatment strategy, in case of relapse or progression post-allogeneic HSCT in children with acute leukemia in a recent ten-year period. Methods We analysed all consecutive 334 children (<18 years, 134 Females) who received a first allogeneic HSCT for ALL or AML from January 2000 to December 2009 and experienced a relapse or progression thereafter. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by the 33 centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) who participated to this study. The primary endpoint was overall survival (OS) after diagnosis of relapse or progression post first HSCT whatever the treatment post relapse was. Secondary endpoints included OS after a) second HSCT, b) chemotherapy alone, c) donor lymphocytes infusion (DLI) d) chemotherapy followed by DLI or e) supportive and palliative care. We also assessed prognostic risk factors for survival after failure post-HSCT. Results 279 patients (110 females and 169 males) with a median age of 8.8 years at transplantation (range: 0.52-17.99) were included. Diseases were 149 ALL (B-cell phenotype, n=120; T-cell phenotype, n=29), 122 AML and 8 biphenotypic AL. At transplantation, 233 patients were in complete remission (CR) (CR1 n=121, CR2 n=94, CR3 n=18) while 46 had a cytologically detectable disease. Donors were matched related siblings (36%), mismatched related (4%), matched unrelated (18%), mismatched unrelated (24%), unrelated without precision (16%) or syngenic (2%). Stem cell source was bone marrow, peripheral stem cells, umbilical cord blood in 65%, 12%, 23% of cases, respectively. Median time from diagnosis to first HSCT was 263 days. 91% (n=254) children received myeloablative conditioning and 9% (n=25) received reduced intensity conditioning regimens. Total body irradiation (TBI) was performed in 153 children. Acute GVHD after first HSCT occurred in 157 patients (grade I n= 62 grade II to IV n= 94). The median delay from first HSCT to relapse/progression was 182 days. The treatments for relapse after first HSCT consisted in chemotherapy alone (n=103), chemotherapy followed by second HSCT (n=70), supportive and palliative care (n=66), combination of chemotherapy and DLI (n=27), or isolated reinfusion of donor lymphocytes (DLI) (n=13). At the time of analysis 40 patients (12%) were alive with a median follow up of 1315 days (range 58;4182). The median OS duration after relapse was 149 days among the 334 patients. The median survival duration in days according to therapy was as follows [confidence interval]: DLI after chemotherapy = 407 [156;658], Second allograft: 391 [264;518], chemotherapy: 180 [121;239], DLI alone: 140 [10;270], Palliative care: 43 [33;53] (see Figure 1). A Cox model analysis on 260 patients with complete files showed the impact of the following factors on survival, when comparing to the best line of treatment, ie chemotherapy+DLI; treatment by chemotherapy alone (HR 2.05, p=.008), palliative care (HR=5,7, p<.001), first transplant performed in complete remission (HR= 1.57, p=.031). The time interval from transplantation to relapse was also associated with prognosis: when comparing to relapses occuring within the first 90 days, day 90-179, day 180-269, and >270 days yielded hazard ratios of respectively .549, .479 and .293 (p <.003). There was no impact on outcome from the following variables: gender, age at transplant, leukemia subtype, type of conditioning, conditioning with TBI , GVHD occurrence after the first transplant, stem cell source. Conclusion Despite evident limitations due to the retrospective setting of our analysis, best treatment consisted in second transplantation or the combination of chemotherapy plus DLI, both yielded similar long-term results. Those results favor the use of immune based strategies when possible in this particular situation of relapse post-HSCT, which should be evaluated in prospective trials. Figure 1 Figure 1. Disclosures Mohty: Gentium S.p.A./Jazz Pharmaceuticals Inc.: Honoraria, Research Funding.
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Miller, Thomas P., Joseph M. Unger, Catherine Spier, Baldassarre Stea, Emilia Cantu, Michael LeBlanc, and Richard I. Fisher. "Effect of Adding Rituximab to Three Cycles of CHOP Plus Invoved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma (SWOG-0014)." Blood 104, no. 11 (November 16, 2004): 158. http://dx.doi.org/10.1182/blood.v104.11.158.158.
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Abstract The 5-year survival rate of patients with limited disease (LD) and aggressive histologies of non-Hodgkin lymphoma (NHL) who have at least one adverse risk factor is about 70% after treatment with three cycles of CHOP followed by involved-field radiotherapy (CHOP(3) plus RT). We tested the effect of adding four infusions of rituximab to CHOP(3) plus RT in 62 evaluable patients. Patients had an aggressive histology of diffuse B-cell NHL (diffuse large cell or Burkitt’s-like) and had LD. LD is defined as stage I with at least one adverse risk factor (age > 60 years, elevated serum LDH, or a performance status of 2) OR non-bulky stage II disease. Adverse risk factors are defined using a stage-modified IPI system and include: non-bulky stage II, age >60 years, elevated serum LDH and a performance status of 2. Patients with bulky stage II disease were excluded as their prognosis is similar to advanced disease, and patients with stage I disease and no risk factors were excluded as their prognosis exceeds 90% survival at 10 years with CHOP(3) plus RT. Rituximab was infused at 375 mg/m2 on days −7, 1, 22, and 43, and CHOP was given at standard doses on days 3, 24, and 45 (CHOP(3) plus R plus RT). Involved-field RT was given as previously described (N Engl J Med1998;339:21–26). With a median follow-up of 2.4 years, the progression-free survival (PFS) and overall survival (OS) measured at 2 years was 94% and 95%, respectively. In order to estimate whether the addition of rituximab adds benefit to CHOP(3) plus RT, and therefore, would be worth testing in a comparative trial, we identified 68 patients from SWOG study 8736 treated with CHOP(3) plus RT using the same criteria to include LD and aggressive diffuse B-cell histologies. These previously reported patients treated with CHOP(3) plus RT (ref above) have a median follow-up of 12.0 years. The PFS and OS for this group measured at 2 years was 85% and 93%, respectively. Four patients have relapsed in the rituximab-treated group and 10 patients had relapsed in the CHOP(3) plus RT alone treated group within the first 2 years. Three patients have died in the rituximab- treated group and five patients had died on the CHOP(3) plus RT alone treated group within the first 2 years (see Table). Short-term toxicity appeared similar. We conclude that the addition of rituximab to standard treatment with CHOP(3) plus RT results in outcome which compares favorably to our historical experience and merits further study. Effect of Rituximab in Treating Limited Disease MEASUREMENT CHOP(3) + R + RT (0014) CHOP(3) + RT (8736) Results of SWOG study 0014 compared to SWOG study 8736 No. patients 62 68 2-year PFS 94% 85% 2-year OS 95% 93% No. relapses 2 yrs 4 10 No. deaths 2 yrs 3 5
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Xicoy, Blanca, Ulrich Germing, Maria-Jose Jimenez, Regina García, Olga Garcia, Carme Pedro, Jennifer Schemenau, et al. "Aplicability Of The Predictive Model Of Response To Erythropoetic Stimulating Agents (ESA) From Myelodysplastic Syndromes (MDS) and Analysis Of Response and Overall Survival (OS) In a Series Of 99 Patients (Pts) With Chronic Myelomonocytic Leukemia (CMML) From The Spanish Registry Of MDS and The Düsseldorf-MDS Registry, Germany." Blood 122, no. 21 (November 15, 2013): 2813. http://dx.doi.org/10.1182/blood.v122.21.2813.2813.
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Abstract Background There is scarce information about the efficacy of ESA in CMML although their use is common in clinical practice. The objective of this study was to analyze the response and OS in a series of 99 pts with CMML treated with ESA and to evaluate the feasibility of the predictive model of response to ESA used in MDS (Hellström-Lindberg, et al. Br J Haematol. 1997; 99: 344-51). Method Between January 1997 and March 2013 99 pts with CMML from the Spanish Registry of MDS and the Düsseldorf-MDS registry were studied. Clinical characteristics, response and OS were analyzed. Predictive model of response to ESA (0 good, 1 intermediate, and 2 poor) based on erythropoetin (EPO) level (< or ≥ 500 U/L) and red blood cell (RBC) transfusion need (< 2 or ≥ 2 RBC/month) was applied. Results 66 (67%) pts were males. Median age (range) was 75 (52-93) years. CMML subtype: myelodysplastic 58 (59%), myeloproliferative 41 (41%), CMML-I 84/98 (86%), CMML-II 14/98 (14%). CPSS score: Low/Int-1 65/90 (72%), Int-2/High 25/90 (28%). Transfusion dependence on initiation of ESA 24/86 (28%). Score based on predicted model of response to ESA: 0 43/62 (69%), 1 15/62 (24%), 2 4/62 (7%). ESA type: EPO alfa 22/94 (24%), EPO beta 16/94 (17%), EPO theta 3/94 (3%) darbepoetin 53/94 (56%). Concomitant medication: hydroxyurea 19 (39%), iron 18 (37%), steroids 4 (8%), azacitidine 3 (6%), etoposide 2 (4%), G-CSF 1 (2%), romiplostim 1 (2%) and oral chelation 1 (2%). Four pts were excluded for response analysis because they received azacitidine (3) and oral chelation (1). Response: Erythroid response (ER) 55/86 (64%), transfusion independence 5/22 (23%). ER according to CPSS (Low/Int-1 vs. Int-2/High): 71% vs. 43%, p=0,032. Median (min,max) time of ER was 4 months (0,88). Pts with 0 score according to predictive model of response to ESA presented significantly higher ER than pts with 1-2 score (77% vs. 24%, p<0.001) (Table 1). Median (range) follow-up was 2.1 years (0.1-10.5) years and median OS was 3.3 years (95%CI 2.7-4). OS of pts of Low/Int-1 risk group with ER (n= 40) was significantly higher than that of non-responding pts (n=16) (median in years (4.4, 95%CI (0.4-8.3) vs. 2.3, 95%CI (1.5-3), p<0.001). Conclusions A high frequency of ER was observed in this series of pts with CMML, the majority belonging to Low-risk CPSS. Predictive model of response to ESA from MDS was feasible, with a similar ER than that of MDS pts. Pts with low-risk CPSS with ER to ESA had a better OS than non-ER patients Supported by RD12/0036/0029 from RTICC-Instituto Carlos III, Spain Disclosures: Germing: Celgene: Honoraria, Research Funding; Jansen-Cilag: Honoraria; Novartis: Research Funding; GSK: Research Funding; Amgen: Research Funding.
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Liu, M. H., M. J. Li, H. H. Qi, R. Guo, X. M. Liu, Q. Wang, and Y. Q. Cheng. "Occurrence of Grapevine Leafroll-Associated Viruses in China." Plant Disease 97, no. 10 (October 2013): 1339–45. http://dx.doi.org/10.1094/pdis-01-13-0048-re.
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To characterize the prevalence of viruses associated with grapevine leafroll disease in China, 249 grapevine (Vitis spp.) samples (86 popular cultivars and a rootstock) from 19 provinces and regions were collected and tested for Grapevine leafroll-associated virus 1 (GLRaV-1), GLRaV-2, GLRaV-3, GLRaV-4, and GLRaV-4 strain 5 by SYBR Green real-time reverse-transcription polymerase chain reaction (RT-PCR), and RT-PCR and sequencing. GLRaV-3 was found in 100% of the samples while GLRaV-1, GLRaV-2, and GLRaV-4 were detected in 24.9% (62/249), 15.3% (38/249), and 0.80% (2/249) of the samples, respectively. Single infections with GLRaV-3 were found in 66.3% (165/249) of the samples, and the remaining samples were mixed infections of GLRaV-3 with one or two other GLRaVs, those with GLRaV-1 being the most common (18.5%, 46/249). The genetic variability of Chinese GLRaV-3 isolates was characterized based on the coat protein (CP) gene. In total, 153 full-length CP gene sequences (94 sequences newly generated) of Chinese GLRaV-3 isolates from different grapevine-growing regions showed 89.3 to 100.0% and 92.7 to 100.0% identity at the nucleotide and amino acid levels, respectively. The average nucleotide diversity for the population of Chinese GLRaV-3 isolates was estimated at 0.037 (standard error = 0.0032). GLRaV-3 isolates from China segregated into five distinct phylogenetic groups and two novel recombination events were found in the viral population. This is the first and most extensive report of the prevalent species of GLRaV in China, which also provides an assessment of genetic variability of GLRaV-3 Chinese isolates.
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Byrd, John C., Jennifer Ann Woyach, Richard R. Furman, Peter Martin, Susan Mary O'Brien, Jennifer R. Brown, Deborah Marie Stephens, et al. "Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: Mature results from phase II study demonstrating durable remissions and long-term tolerability." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 8024. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8024.
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8024 Background: The next-generation Bruton tyrosine kinase inhibitor acalabrutinib was approved in patients (pts) with treatment-naïve (TN) and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on two complementary phase 3 studies, ELEVATE-TN and ASCEND. This report of ACE-CL-001 (NCT02029443), the first phase 2 study of acalabrutinib, provides the longest safety and efficacy follow-up to date in symptomatic TN CLL pts. Methods: Adults with TN CLL/SLL were eligible if they met iwCLL 2008 criteria for treatment, were inappropriate for/declined standard chemotherapy and had ECOG performance status 0–2. Pts received acalabrutinib 100 mg BID or 200 mg QD, later switching to 100 mg BID, until progressive disease (PD) or unacceptable toxicity. Primary endpoint was safety. Events of clinical interest (ECI) were based on combined AE terms for infections, bleeding events, hypertension, and second primary malignancies (SPM) excluding non-melanoma skin, and on a single AE term for atrial fibrillation. Additional endpoints included investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), and event-free survival (EFS). Results: Ninety-nine pts (n = 62 100 mg BID; n = 37 200 mg QD), were treated [median age: 64 years, 47% Rai stage 3–4 disease, 10% del(17p), 62% unmutated IGHV]. At median follow-up of 53 months (range, 1–59), 85 (86%) pts remain on treatment; most discontinuations were due to AEs (n = 6) or PD (n = 3 [n = 1 Richter transformation]). Most common AEs (any grade) were diarrhea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). All-grade and grade ≥3 ECIs included infection (84%, 15%), bleeding events (66%, 3%), and hypertension (22%, 11%). Atrial fibrillation (all grades) occurred in 5% of pts (incidence: 1% in years 1, 2, 4; 3% in year 3). SPMs excluding non-melanoma skin (all grades) occurred in 11%. Serious AEs were reported in 38% of pts; those in > 2 pts were pneumonia (n = 4) and sepsis (n = 3). ORR was 97% (7% complete response; 90% partial response). Median TTR was 3.7 months (range, 2–22). Response rates were similar across high-risk groups. Median DOR and median EFS were not reached; 48-month DOR rate was 97% (95% CI, 90%–99%), and 48-month EFS rate was 90% (95% CI, 82%–94%). Conclusions: Long-term data from ACE-CL-001 further support the favorable results with acalabrutinib in phase 3 studies and demonstrate durable responses with no new long-term safety issues. Clinical trial information: NCT02029443 .
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Evans, M. R., J. P. Tromans, E. L. S. Dexter, C. D. Ribeiro, and D. Gardner. "Consecutive salmonella outbreaks traced to the same bakery." Epidemiology and Infection 116, no. 2 (April 1996): 161–67. http://dx.doi.org/10.1017/s0950268800052390.
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SUMMARYTwo consecutive community outbreaks of Salmonella enteritidis phage type 4 (PT4) traced to the same bakery occurred in Cardiff, Wales during August–September 1992. In the first outbreak, illness was associated with eating custard slices (odds ratio 23·8, 95% confidence interval 6·5–94·4, P < 0·0001), and in the second, with eating fresh cream cakes (odds ratio 15·8, 95% confidence interval 1·6–374, P = 0·004). Environmental investigations implicated cross-contamination during preparation of the cold-custard mix as the cause of the first outbreak, and inadequate cleaning and disinfection of nozzles used for piping cream in the second outbreak. S. enteritidis PT4 was isolated from fresh cream sponge cake retained by a case and from two fresh cream cakes and four environmental swabs obtained at the bakery. This incident illustrates the hazard of widespread environmental contamination with salmonella and the need for thorough environmental cleansing of any premises implicated in an outbreak of food poisoning.
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Nazarchuk, Evgeny V., Oleg I. Siidra, Atali A. Agakhanov, Evgeniya A. Lukina, Evgeniya Y. Avdontseva, and Gennady A. Karpov. "Itelmenite, Na2CuMg2(SO4)4, a new anhydrous sulfate mineral from the Tolbachik volcano." Mineralogical Magazine 82, no. 6 (May 15, 2018): 1233–41. http://dx.doi.org/10.1180/minmag.2017.081.089.
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ABSTRACTItelmenite, ideally Na2CuMg2(SO4)4, was found in a fumarole of the Naboko scoria cone of the Tolbachik volcano Fissure Eruption (2012–2013), Kamchatka Peninsula, Russia. Itelmenite occurs as irregularly shaped grains as well as microcrystalline masses associated with anhydrite, saranchinaite, hermannjahnite, euchlorine, thénardite, aphthitalite and hematite. Itelmenite is orthorhombic, Pbca, a = 9.568(2) Å, b = 8.790(2) Å, c = 28.715(8) Å, V = 2415.0(11) Å3 and Z = 4 (from single-crystal diffraction data). The nine strongest lines of the powder X-ray diffraction pattern are [d(I)(hkl)]: 7.9614(41)(102), 7.1803(32)(004), 5.9122(64)(112), 3.8455(87)(122), 3.6292(52)(214), 3.3931(62)(215), 3.0003(44)(027), 2.9388(100)(312) and 2.4975(56)(230). The chemical composition determined by the electron-microprobe analysis is (wt.%): Na2O 10.77, K2O 0.20, MgO 11.10, CuO 15.38, ZnO 5.61, SO3 56.42, total 99.48. The empirical formula based on O = 32 apfu is (Na3.93K0.05)Σ3.98Mg3.12(Cu2.19Zn0.78)Σ2.97S7.97O32. The simplified formula is Na2CuMg2(SO4)4 taking into account structural data. The crystal structure was solved by direct methods and refined to an agreement index R1 = 0.034 on the basis of 1855 independent observed reflections. The structure of itelmenite is based on a unique type of [A2+3(SO4)4]2– (A = Mg, Cu and Zn) heteropolyhedral framework with voids filled by Na+ cations.
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Gandemer, Virginie, Marie-Françoise Auclerc, Arnaud Petit, Benoît Brethon, Paola Ballerini, Gerard Michel, Yves Perel, et al. "Excellent Prognosis of Children with ETV6-RUNX1 Positive (+) Acute Lymphoblastic Leukemia (ALL) in the FRALLE 2000 Protocol." Blood 114, no. 22 (November 20, 2009): 1628. http://dx.doi.org/10.1182/blood.v114.22.1628.1628.
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Abstract Abstract 1628 Poster Board I-654 Since the cloning of the t(12 ;21) in 1995 the prognosis of children with ETV6-RUNX1(+)ALL seems to further increase in the current era. From december 2000 to july 2008, 1461 children and adolescents aged from 1 to 20 years with B cell lineage ALL have been treated according the FRALLE protocols: one for standard-risk (SR) ALL (age 1-9 y, WBC < 50 G/L, no extra medullary involvement) F2000-A; the other one FRALLE 2000-B for high and very high risk ALL (HR) (all other pts). The two protocols mainly differ by a larger use of dexamethasone and a reduced use of anthracyclins in F2000A and the use of HDMTX and a double delayed intensification in FRALLE 2000B. ETV6-RUNX1 presence has been assessed by RT-PCR in 1392 pts (i.e. 96%) and found positive in 321 pts, i.e. 23%. Initial features include a median age of 4.2 y (1.2-15.6), a sex ratio (M/F) of 1.2, a median WBC of 10 G/L(1-293). Both peripheral blood D8 response to prednisone (PRED) and D21 marrow response to chemotherapy were evaluable in 316 pts: 94% of the pts have a rapid early response at D8 and D21. Only 3% of the pts were qualified as D8 poor PRED responders and 3% slow marrow responders at D21. The D35-42 CR rate is 100%. End of induction (EOI) minimal residual disease (MRD) using Ig-TCR methods is known in 259 out of 321 pts (81%) pts. Only 4 pts (2%) had a very high (≥10-2) EOI-MRD. Five year EFS, DFS and OS are 95±2%, 95±2%, 98±1%, respectively. The 5y EFS is 96±2% for the 252 SR pts and 90±7% for the 69 HR pts, p=0.30. The 5y EFS is significantly better for children with ETV6-RUNX1(+)ALL compared to those with ETV6-RUNX1(-) B-lineage ALL: 95±2% vs 84±2%, respectively (p=.001). Nine relapses have been reported in the bone marrow (4) the testis (4), the CNS (1) after a median time of 44 m (25-68), i.e. significantly longer than in the ETV6-RUNX1(-) cases (28m (1-92), p=.01). More testis relapses are observed in boys with ETV6-RUNX1(+)ALL (4 out 7 relapses vs 2 out of 62 in boys with ETV6-RUNX1(-) ALL). These results represent a significant progress compared to the previous protocol F 93 (191 children) both in terms of EFS and overall survival (5y EFS: 95±2% vs 78±3%, p=.001; 5 y OS: 98±1% vs 92±2%, p=.001). Conclusion an excellent prognosis of children with t(12;21)/ETV6-RUNX1 positive acute lymphoblastic leukemia is now observed in the FRALLE 2000 protocol. The question of a cautious de-escalation in this subgroup will be envisaged in the next protocol. Disclosures No relevant conflicts of interest to declare.
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Livezey, Sabrina, Nisha B. Shah, Robert McCormick, Josh DeClercq, Leena Choi, and Autumn D. Zuckerman. "Specialty pharmacist integration into an outpatient neurology clinic improves pimavanserin access." Mental Health Clinician 11, no. 3 (May 1, 2021): 187–93. http://dx.doi.org/10.9740/mhc.2021.05.187.
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Abstract Introduction Access to pimavanserin, the only Parkinson disease–related psychosis treatment approved by the FDA, is restricted by insurance requirements, a limited distribution network, and high costs. Following initiation, patients require monitoring for safety and effectiveness. The primary objective of this study was to evaluate impact of specialty pharmacist (SP) integration on time to insurance approval. Additionally, we describe a pharmacist-led monitoring program. Methods This was a single-center, retrospective study of adults prescribed pimavanserin by the neurology clinic from June 2016 to June 2018. Patients receiving pimavanserin externally or through clinical trials were excluded. Pre- (June 2016 to December 2016) and post-SP integration (January 2017 to June 2018) periods were assessed. Proportional odds logistic regression was performed to test association of approval time with patient characteristics (age, gender, insurance type) postintegration. Interventions were categorized as clinical care, care coordination, management of adverse event, or adherence. Results We included 94 patients (32 preintegration, 62 postintegration), 80% male (n = 75) and 96% white (n = 90) with a mean age of 73 years. Median time to approval was 22 days preintegration and 3 days postintegration. Higher rates of approval (81% vs 95%) and initiation (78% vs 94%) were observed postintegration. Proportional odds logistic regression suggested patients with commercial insurance were likely to have longer time to approval compared with patients with Medicare/Medicaid (odds ratio 7.1; 95% confidence interval: 1.9, 26.7; P = .004). Most interventions were clinical (51%, n = 47) or care coordination (42%, n = 39). Conclusion Median time to approval decreased postintegration. The SP performed valuable monitoring and interventions.
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Steuber, C. P., C. Civin, J. Krischer, S. Culbert, A. Ragab, F. B. Ruymann, Y. Ravindranath, B. Leventhal, R. Wilkinson, and T. J. Vietti. "A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study." Journal of Clinical Oncology 9, no. 2 (February 1991): 247–58. http://dx.doi.org/10.1200/jco.1991.9.2.247.
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Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).
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Jimenez, Rafael E., Hugues Sicotte, Poulami Barman, Jason P. Sinnwell, Patrick W. Eiken, Thomas D. Atwell, Brendan P. McMenomy, et al. "Feasibility analysis of pathology and genetic yield from a prospective trial of tissue biopsies in metastatic castrate-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 249. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.249.
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249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.
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Scordo, Michael, Valkal Bhatt, Meier Hsu, Antonio M. Omuro, Matthew J. Matasar, Lisa DeAngelis, Parastoo B. Dahi, Craig H. Moskowitz, Sergio A. Giralt, and Craig S. Sauter. "A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning." Blood 126, no. 23 (December 3, 2015): 4354. http://dx.doi.org/10.1182/blood.v126.23.4354.4354.
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Abstract Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables. Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction. Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity. Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 <60 23 (68%) 15 (71%) 8 (62%) ≥60 11 (32%) 6 (29%) 5 (38%) Gender 0.72 Female 13 (38%) 9 (43%) 4 (31%) Male 21 (62%) 12 (57%) 9 (69%) Disease 0.30 PCNSL 19 (56%) 10 (48%) 9 (69%) SCNSL 15 (44%) 11 (52%) 4 (31%) KPS 0.99 ≥80 32 (94%) 20 (95%) 12 (92%) <80 2 (6%) 1 (5%) 1 (8%) BMT HCT CI 0.99 ≤2 17 (50%) 11 (52%) 6 (46%) >2 17 (50%) 10 (48%) 7 (54%) Number of Prior Regimens 0.04 ≤2 21 (62%) 16 (76%) 5 (38%) >2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%) Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.
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Palmer, Ty B., and Ryan M. Thiele. "Passive Stiffness and Maximal and Explosive Strength Responses After an Acute Bout of Constant-Tension Stretching." Journal of Athletic Training 54, no. 5 (May 1, 2019): 519–26. http://dx.doi.org/10.4085/1062-6050-62-18.
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Context Constant-tension (CT) stretching has been used to reduce hamstrings passive stiffness; however, the time course of hamstrings stiffness responses during a short bout of this type of stretching and the effects on maximal and explosive strength remain unclear. Objective To examine the time course of hamstrings passive-stiffness responses during a short, practical bout of manual straight-legged–raise (SLR) CT passive stretches and their effects on maximal and explosive strength in healthy young women. Design Descriptive laboratory study. Setting Research laboratory. Patients or Other Participants Eleven healthy women (age = 24 ± 4 years, height = 167 ± 4 cm, mass = 65 ± 8 kg) participated. Intervention(s) Participants underwent four 15-second SLR CT passive stretches of the hamstrings. Main Outcome Measurement(s) Hamstrings passive stiffness was calculated from the slopes of the initial (phase 1) and final (phase 2) portions of the angle-torque curves generated before and after the stretching intervention and at the beginning of each 15-second stretch. Hamstrings peak torque and rate of torque development were derived from maximal voluntary isometric contractions performed before and after the stretching intervention. Results The slope coefficients (collapsed across phase) for the third and fourth stretches and the poststretching assessment were lower than the prestretching assessment (P range = .004–.04), but they were not different from each other (P > .99). In addition, no differences in peak torque (t10 = −0.375, P = .72) or rate of torque development (t10 = −0.423, P = .68) were observed between prestretching and poststretching. Conclusions A short bout of SLR CT passive stretching may effectively reduce hamstrings stiffness without negatively influencing maximal and explosive strength.
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Santini, Valeria, Pierre Fenaux, Ghulam J. Mufti, Eva Hellström-Lindberg, Lewis B. Silverman, Alan List, Steven D. Gore, et al. "Management and Supportive Care Measures of Adverse Events (AEs) in Higher-Risk MDS Patients (Pts) Treated with Azacitidine (AZA)." Blood 112, no. 11 (November 16, 2008): 1653. http://dx.doi.org/10.1182/blood.v112.11.1653.1653.
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Abstract Background: The phase III AZA-001 trial showed AZA is the first treatment to significantly extend OS in higher-risk MDS pts, who received a median of 9 treatment cycles (range 1 to 39) (Fenaux, Blood2007;110:817). Management of AEs is important to prevent early discontinuation of AZA, before therapeutic benefit may be achieved. This analysis evaluated the frequency of the most commonly reported (≥20% of pts) AEs with AZA by cycle, and the supportive care measures used to ameliorate AEs. Methods: Pts with higher-risk MDS (FAB-defined RAEB, RAEB-T, or CMML and IPSS Int-2 or High) were enrolled in the AZA-001 study. Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28 days or to a conventional care regimen. AZA dosing cycles could be delayed based on hematologic recovery and AEs. Prophylactic G-CSF and erythropoietin were not allowed. Results: Of 179 pts randomized to AZA, 175 received the drug and were evaluable for safety. Most patients (86%) remained on the initial dose of 75mg/m2 and did not require dose adjustments for AEs. Of the patients requiring dose reduction, 71% were managed with a single dose reduction primarily for neutropenia or thrombocytopenia. Median cycle length was 34 days (range: 15 – 92); 50% of AZA cycles were administered with no delays (at 28 days), 27% at 35 days, and 23% at >35 days. The majority of the most common AEs (≥20%), which included non-hematologic administration-related (injection site reactions, gastrointestinal) and hematologic events, were transient (median duration 13 days), nonserious, and resolved during the study. Less than 1% of AEs resulted in discontinuation of AZA and instead were commonly managed with delays in the next AZA cycle, concomitant medications, transfusions, and other measures. The median duration of injection site reactions was 12 days; none resulted in adjustment in AZA and <15% required treatment with concomitant medications (typically corticosteroids and/or antihistamines). The majority (95%) of gastrointestinal events were transient with a median duration of 1–4 days (diarrhea, nausea, vomiting) or approximately 1 week (constipation). No gastrointestinal events resulted in discontinuation of AZA and were more commonly managed (72%) with concomitant medications (eg, anti-emetics, laxatives). Most hematologic AEs were transient (>86%), occurred during the first 1–2 cycles and were mainly grade 3 or 4; however, £10% of pts experienced neutropenia, anemia, or thrombocytopenia that required hospitalization. For patients remaining on therapy, hematologic AEs decreased with subsequent cycles, paralleling response. The majority of hematologic events were managed with delays in the next AZA cycle (99%) or transfusions for anemia (87%) or thrombocytopenia (29%); <5% of pts discontinued due to a hematologic event. The median duration of fatigue and pyrexia was approximately 1 week; none of the events resulted in discontinuation or dose decrease of AZA and instead were managed by delay in the next AZA cycle in approximately 5% of patients. There were no cumulative or delayed toxicities. Conclusions: The majority of the most common AEs (≥20%) in the AZA-001 study were transient (median duration 13 days), nonserious, and were managed by either dose delays for hematological events or supportive care measures. Clinicians should be alert to the onset, duration, and management of these events to allow patients to achieve maximum therapeutic benefit. Table. Most Frequent (≥20% of Patients) Treatment-Emergent Adverse Events With Azacitidine in AZA-001 Study Percent of Patients Per Cycle System Organ Class Preferred Term * Cycles 1–2 (N=175) Cycles 3–4 (N=147) Cycles 5–6 (N=130) Cycles 7–8 (N=107) Cycles 9–10 (N=89) *Multiple reports of the same preferred term for a patient are counted only once. Patients with at least 1 individual AE occurring in ≥20% of patients in the AZA group (%) 94 79 65 65 65 Blood and lymphatic system disorders (%) 75 54 42 36 36 Anemia 33 18 14 11 14 Neutropenia 50 31 28 19 20 Thrombocytopenia 54 30 25 20 21 Gastrointestinal disorders (%) 62 42 25 27 30 Constipation 35 20 13 9 17 Diarrhea 12 8 4 5 5 Nausea 36 19 12 14 11 Vomiting 18 11 5 8 6 General disorders & administration site conditions (%) 62 44 32 32 28 Fatigue 13 10 3 6 3 Injection site erythema 35 21 18 16 11 Injection site reaction 21 13 9 9 9 Pyrexia 16 6 4 6 7
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Abeysekara, Saman, Philip D. Chilibeck, Hassanali Vatanparast, and Gordon A. Zello. "A pulse-based diet is effective for reducing total and LDL-cholesterol in older adults." British Journal of Nutrition 108, S1 (August 23, 2012): S103—S110. http://dx.doi.org/10.1017/s0007114512000748.
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Our purpose was to determine the effects of a pulse-based diet in individuals 50 years or older for reducing CVD risk factors. A total of 108 participants were randomised to receive pulse-based foods (two servings daily of beans, chickpeas, peas or lentils; about 150 g/d dry weight) or their regular diet for 2 months, followed by a washout of 1 month and a cross-over to the other diet for 2 months. Anthropometric measures, body composition and biochemical markers (i.e. serum LDL-cholesterol (LDL-C), as the primary outcome, and other lipids, glucose, insulin and C-reactive protein) were assessed before and after each diet phase. A total of eighty-seven participants (thirty males and fifty-seven females; 59·7 (sd 6·3) years, body mass 76 (sd 16) kg) completed the study. Compared with the regular diet, the pulse-based diet decreased total cholesterol by 8·3 % (pulse, 4·57 (sd 0·93) to 4·11 (sd 0·91) mmol/l; regular, 4·47 (sd 0·94) to 4·39 (sd 0·97) mmol/l; P < 0·001) and LDL-C by 7·9 % (pulse, 2·93 (sd 0·84) to 2·55 (sd 0·75) mmol/l; regular, 2·96 (sd 0·86) to 2·81 (sd 0·83) mmol/l; P = 0·01). In a sub-analysis of individuals with high lipid levels at baseline (twenty individuals with high cholesterol), the pulse-based diet reduced cholesterol by 6 % compared with the regular diet (pulse, 5·62 (sd 0·78) to 5·26 (sd 0·68) mmol/l; regular, 5·60 (sd 0·91) to 5·57 (sd 0·85) mmol/l; P = 0·05). A pulse-based diet is effective for reducing total cholesterol and LDL-C in older adults and therefore reduces the risk of CVD.
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Garcia-Gutierrez, J. Valentin, Pilar Herrera, Lorena L. Abalo, Maria Dolores Rey, Maria Calbacho, Lourdes Ramos, Paloma Ramos, Carlos Montalban, and Javier Lopez-Jimenez. "Impact of Second-Generation Tyrosine Kinase Inhibitors As Second Line Treatment for Patients with Chronic Myeloid Leukemia,." Blood 118, no. 21 (November 18, 2011): 3780. http://dx.doi.org/10.1182/blood.v118.21.3780.3780.
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Abstract Abstract 3780 Background: Imatinib has shown an outstanding improvement in the prognosis of chronic myeloid leukemia (CML) patients. Nevertheless, some of them have proven to be resistant or intolerant to imatinib. For these patients, second-generation tyrosine kinase inhibitors (TKIs) are available. These drugs may be indicated in different circumstances as primary or second resistance, suboptimal responses or intolerance.The real benefits of second-generation TKIs as salvage treatment are surely in dependence with the indication in each case and are, therefore, difficult to evaluate. Second-generation TKIs are being evaluated as first line treatment compared to imatinib with quite favourable outcomes so long, but have not yet been compared with a strategy combining imatinib followed by second-generation TKIs for patients with previous unfavourable responses. Aims: Evaluate the real benefit of second-generation TKIs in second line treatment for CML patients regardless of the indication for its use. Study groups and methods: We have studied 98 patients treated with imatinib as first tyrosin kinase inhibitor (TKI) in our centre. These patients have been classified according whether second-generation TKIs were available or not. Group 1 includes 60 patients treated since 2001 to 2005, when the only salvage treatment was an increased imatinib dose, chemotherapy or allogenic stem cell transplantation. Group 2 includes 38 patients treated since 2005 until today. In the second group second-generation TKIs (dasatinib or nilotinib) were used according to the indications mentioned above. Follow up period was 39 months and 32 months for group 1 and 2 respectively. Sokal risk index was high in 14% and 16%; intermediate 42 % and 40%; and low in 44% and 44 % for group 1 and 2 respectively. Results: The use of second-generation TKIs as second line resulted in significant benefit to patients in terms of responses. Complete cytogenetic responses (CCR) at any time were achieved in 73% and 86% for patients in group 1 and 2 (p=.09). Probability of the achievement of mayor molecular responses (MMR) was 42% vs 71% for group 1 and 2 respectively [p=.009; ratio=0.3 (0.1–0.7)]. Response rates at the last follow up for group 1 and 2 were: MMR: 33% vs 62%; CCR: 68% vs 94% and failure 32% vs 6% (p=.008). Progression free survival (including all the patients who started treatment) was 88% vs 94% for group 1 and 2 respectively. We found no correlation among responses and some prognostic factors (Sokal index, mutations at the TK domain or imatinib plasma levels). Imatinib doses were increased in 21 patients (35%) in group 1 (reasons for increasing doses were failure in 14 patients and suboptimal responses in 7 patients). 10 patients (26%) in group 2 received second-line TKIs as second line treatment (4 because imatinib failure, 3 by suboptimal responses and 3 due to intolerance). Conclussions: The use of second-generation TKIs as salvage has improved the responses of CML patients treated with TKIs. Once the second-generation TKIs has shown benefit compared to imatinib in first line treatment, this therapeutic strategy should be compared vs the use of imatinib followed of second-line TKIs for patients without optimal responses to imatinib. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.
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Brierley, Charlotte K., Francesca M. Jones, Katherine Hanlon, Andrew Peniket, Patrick Medd, Andrew Clark, Anne Parker, et al. "Outcomes and Impact of Donor Lymphocyte Infusion after Reduced Intensity Conditioned-Alemtuzumab Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Mature Lymphoid Malignancies." Blood 128, no. 22 (December 2, 2016): 3500. http://dx.doi.org/10.1182/blood.v128.22.3500.3500.
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Abstract Allogeneic hematopoetic stem cell transplantation (allo-HSCT) offers long-term remission for patients with lymphoid malignancies. In particular, reduced intensity conditioned (RIC) protocols with Alemtuzumab T-cell depletion lead to durable engraftment and reduced graft versus host disease (GvHD). However, such regimens may be associated with reduced graft-versus-lymphoma (GvL) effect and higher incidence of disease progression, leading to increased use of donor lymphocyte infusion (DLI). This study examined transplant outcomes and use of DLI in a large UK RIC-Alemtuzumab conditioned HSCT cohort. 288 consecutive adult patients from three UK transplant centres (Birmingham, Glasgow, Oxford) undergoing first Alemtuzumab-based RIC HSCT for Hodgkin's lymphoma (57%), Non-Hodgkin's lymphoma (24%) and chronic lymphocytic leukemia (19%) between 2000 and 2012 were included. Overall survival (OS), current progression-free survival (CPFS), relapse incidence (RI), transplant-related mortality (TRM), incidence of GvHD and effects of DLI were analyzed. Median age was 49y (range 17-68) and 60% were male. Patients were heavily pre-treated with 58% having received ≥3 prior lines of treatment and 49% having failed a previous autograft. 55% received stem cells from an HLA-matched unrelated donor and 94% received a peripheral blood stem cell harvest. The most frequent conditioning regimen was Fludarabine, Melphalan and Alemtuzumab (FMC) (70%) and the median total Alemtuzumab dose was 50mg (range 30-100). Median duration of follow-up for survivors was 64 months. 3y OS and CPFS were 53% and 50%, respectively. Factors negatively associated with OS in univariate (UV) analysis were previous autograft (p=0.01), no requirement for DLI (p=0.05), disease status not CR (p=0.05), previous treatment number ≥3 (p=0.007) and failure to engraft plts (p=0.001). On multivariate (MV) analysis, only previous autograft (HR 1.58 p=0.01) and failure to engraft plts (HR 2.3 p=0.0001) retained significance. Factors negatively associated with CPFS on UV analysis were no requirement for DLI (p=0.006), failure to engraft plts (p=0.0003) and previous treatment lines ≥3 (p=0.04). On MV analysis, no DLI remained a significant predictor of adverse CPFS (HR 1.8 p=0.01), as did failure to engraft plts (HR 1.77 p=0.005) and ≥3 treatment lines (HR 1.46 p=0.04). At 3y, the cumulative incidence of relapse and TRM was both 27%. The incidence of grade 2-4 acute GvHD (aGvHD) and extensive chronic GvHD (cGvHD) was 22% and 18%, respectively. UV predictors of RI were unrelated donor (p=0.0009), HLA mismatch (p=0.04), age > median (p=0.04) and lack of aGvHD (p=0.04). The presence of cGvHD may have been protective against relapse (p=0.08). No variables retained significance on MV modelling. UV predictors of TRM were failure to engraft plts (p=0.001), HLA mismatch (p=0.005), age > median (p=0.004), previous autograft (p=0.02), FMC conditioning (p=0.03), ≥3 previous lines of treatment (p=0.001) and development of aGvHD (p=0.04). On MV modelling, failure to engraft plt (p=0.001), HLA mismatch (p=0.03), age > median (p=0.003) and treatment number ≥3 (p=0.04) retained significance. 62/288 patients received DLI; 37 receiving prophylactic DLI (pDLI) for mixed chimerism and 25 receiving therapeutic DLI (tDLI) for disease relapse. The median dose of DLI was 1x 10^6 CD3+ cells/kg (range 0.1 - 10 x 10^6). Median time from HSCT to first DLI was 10.5 months (range 3-30), to 2nd DLI 15 months (6-51) and to 3rd DLI 19 months (9-30). At 3y, OS after pDLI was 75% and after tDLI was 29%. 29/37 (78%) of pDLI and 14/25 (56%) of tDLI recipients achieved full or stable mixed chimerism. 3y RI after pDLI was 29% and after tDLI was 59% (p=0.02). Overall, the incidence of GvHD post-DLI was 32% (48% tDLI, 22% pDLI, p=ns). Median time to GvHD after last DLI was 46 days (range 17-249). There was no significant impact of post-DLI GvHD on RI (RI at 1y post DLI 18% in GvHD cohort vs 21% with no GvHD, p=ns), but GvHD increased TRM at 1y post DLI (17% in the GvHD cohort vs 3% with no GvHD, p=0.05). This is the largest series to date with long-term follow-up examining outcomes after Alemtuzumab-based RIC HSCT for mature lymphoid malignancy. Our data indicate that allo-HSCT is effective and is associated with good long term outcomes. Use of pDLI for was associated with excellent outcomes and supports use of DLI in patients developing mixed chimerism following allo-HSCT for lymphoid malignancies. Disclosures No relevant conflicts of interest to declare.
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Abdelali, Raouf Ben, Agnes Buzyn, Vahid Asnafi, Sandrine Le Noir, Norbert Ifrah, Herve Dombret, and Elizabeth Macintyre. "NOTCH1/FBXW7 Mutations, but Not Low ERG/BAALC Expression, Identify a Major Subgroup of Adult T-ALL with a Favorable Outcome: a GRAALL Study." Blood 114, no. 22 (November 20, 2009): 1568. http://dx.doi.org/10.1182/blood.v114.22.1568.1568.
Full textAbstract:
Abstract Abstract 1568 Poster Board I-592 Several somatic genetic abnormalities have been identified in T-ALL but therapeutic stratification still relies on clinical markers. NOTCH1 and/or FBXW7 (N/F) mutations both lead to activation of the NOTCH1 pathway and are amongst the most frequent mutations in T-ALL. We identified N/F mutations as a good prognostic marker, found in 70% of patients within the French LALA-94 and GRAALL-2003 prospective adult T-ALL trials, whereas the German GMALL group reported that low ERG and BAALC (E/B) transcript expression also predicts a highly favorable outcome in 41% of adult T-ALL (Baldus et al. J Clin Oncol. 2007 25(24):3739-45). In order to compare the predictive prognosis value of N/F mutations versus low E/B expression, we analyzed 189 adult T-ALL for both, including 107 previously reported cases and 82 unreported cases included within the ongoing GRAALL-2005 trial up to the first planned interim analysis. E/B were quantified by real time RT-PCR and the comparative cycle threshold (Ct) method was used to determine the relative expression levels for ERG and BAALC to ABL. T-ALL patients were classified as low E/B expressers (E/Blow) or high E/B expressers (E/Bhigh) as previously reported by Baldus et al. Despite the use of ABL rather than GPI as internal control, we observed the same incidence of E/Blow. 41% (n=77) of T-ALLs were classified as E/Blowand 59% (n=112) as E/Bhigh. 68% (n=128) of cases were mutated for NOTCH1 and/or FBXW7 (N/Fmut) and 32% (n=61) were germline for both (N/FGL). As expected E/Bhigh correlated with an immature phenotype (p<0.0001). There was no association between E/B expression level and F/Nmut (p=0.5) and no significant correlation for either N/F or E/B status with age and leucocytosis at diagnosis. There was no difference in overall survival (OS) and event free survival (EFS) between E/Bhigh and E/Blow (4-years OS: 57% v 55 %; 4-years EFS: 46% v 47%). In contrast, N/Fmut compared with N/FGL had a better OS (67% v 36%; P= .002) and EFS (56% v 32%; P=.008). When the LALA and GRAALL protocols were analyzed separately, N/Fmut retained their significant favorable outcome, including in the GRAALL-2003 and GRAALL-2005 trials, which give overall good results for T-ALL. E/B expression did not impact on prognosis in either the GRAALL trials (E/Bhigh OS =68% EFS= 64% v E/Blow OS= 62% EFS=50%) or the LALA trials (E/Bhigh OS =46% EFS= 30% v E/Blow OS= 39% EFS=29%) individually. Taken overall, our data demonstrate that N/Fmut, but not low E/B expression, identify a major subgroup (68%) of adult T-ALL with a highly favorable outcome that could justify individual therapeutic stratification for T-ALL. N/F mutation status is also better suited to individual patient stratification than the continuous spectrum of ERG and BAALC transcript expression. Disclosures No relevant conflicts of interest to declare.
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Yerushalmi, Ronit, Noga Shem-Tov, Yulia Volchek, Ivetta Danylesko, Abraham Avigdor, Arnon Nagler, and Avichai Shimoni. "Favorable Outcome For Patients With Lymphoid Malignancies Following Allogeneic Stem Cell Transplantation Using Fludarabine Treosulfan, Compared With Other Reduced Intensity Conditioning Regimen." Blood 122, no. 21 (November 15, 2013): 3380. http://dx.doi.org/10.1182/blood.v122.21.3380.3380.
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Abstract Allogeneic stem cell transplantation (SCT) is potentially a curative therapy for patients (pts) with lymphoid malignancies. A myeloablative preparative regimen is often not feasible in these pts due to advanced age, medical condition or extensive prior therapy leading to high non-relapse mortality (NRM) rates. Reduced intensity condition (RIC) allows SCT by reducing NRM but may be associated with increased relapse rate, especially in pts with advanced malignancy. Novel regimens with intensive anti malignancy activity but limited toxicity will be of benefit. The combination of fludarabine and treosulfan (FT) is a dose intense reduced toxicity regimen. It has been predominantly explored in myeloid malignancies but there is only limited data on the relative outcomes of this regimen in pts with lymphoid malignancies in comparison to more commonly used RIC regimens. We evaluated the outcome of 144 pts with lymphoid malignancies given allogeneic SCT with FT (30-36 gr/m2, n=50), fludarabine and intravenous busulfan (6.4 mg/m2, FB2, n=38) or fludarabine melphalan (100-140 mg/m2, FM, n=56). 115 (80%) had non Hodgkin lymphoma of various histologies and 29 (20%) pts had Hodgkin lymphoma. Pts with CLL, Burkitt and lymphoblastic lymphoma were excluded. The median age was 52 (16-69) years, 90 male and 54 female. 26 pts (18%) had more than 3 lines of prior chemotherapy and 87 (60%) had a prior autologous SCT. 13 pts (9%) had a comorbidity index (HCT-CI) ≥3. 69 pts (48%) had chemo-sensitive disease at SCT and 75 (52%) had chemo refractory disease. The donor was an HLA-matched sibling (n= 83, 58%) or matched unrelated donor (n=61, 42%). The FT and FB2 groups included more pts with a prior autologous SCT than the FM group, 76%, 79% and 34%, respectively (p=0.001). There were no other differences between the 3 treatment groups in pt's characteristics. With a median follow up of 39 months (4-149), 58 pts are alive and 86 died, 52 of NRM and 34 of relapse. The 3 year overall survival (OS) rate for the whole group was 42% (32-49%). Disease status at SCT was the most significant predictor of OS. Pts with chemo sensitive disease had OS of 62% (50-75%) whereas pts with chemo refractory disease had OS of 20% (10-30%, p<0.001). The 3 year OS was 54% (36-72), 43% (27-59) and 29% (17-40) after FT, FB2 and FM, respectively (p=0.02). Multivariate analysis (MVA) identified age>50 (HR=2.0, 1.1-3.8, p=0.03), HCT-CI≥3 (HR=6.0, 2.8-12.6, p<0.001), FM (HR=3.1, 1.3-7.6, p=0.01) and chemo refractory disease (HR=3.5, 2.0-6.2, p<0.001) to be associated with shortened OS. The correlation between OS and conditioning regimen was dependant on disease status at SCT. There was no significant difference among the regimens in pts with chemo sensitive disease, 3-year OS of 67% (45-87), 74% (54-94) and 48% (26-69) after FT, FB2 and FM, respectively (p=0.28). However, among pts with chemo refractory disease there was an advantage for FT. OS was 34% (3-65), 11% (0-25) and 17% (2-25), respectively (p=0.03 for FT vs others). MVA limited to pts with chemo refractory disease showed HCT-CI≥3 (HR=5.0, 1.6-16.1, p=0.007) and treatment with FT (HR-0.4, 0.12-1.1, p=0.07) to be significant factors in this subgroup. The 3 year cumulative incidence of NRM was 24% (14-41%), 22% (12-40%) and 54% (42-68%) after FT, FB2 and FM, respectively (p=0.004). MVA for NRM identified age>50 (HR=2.1, 0.9-4.4, p=0.07), HCT-CI≥3 (HR=6.3, 2.6-15.7, p=0.001), FM (HR=5.1, 1.6-16.3, p=0.007) and chemo refractory disease (HR=2.0, 1-4.0, p=0.04) as independent adverse factors. A sibling donor had a protective effect (HR=0.5, 0.2-0.9, p=0.03). Relapse mortality was 22% (11-44), 35% (23-55) and 18% (11-31), respectively (p=0.4). MVA identified HCT-CI≥3 (HR=4.2, 1.1-16.7, p=0.04) chemo refractory disease (HR=13.9, 4.7-41.9, p<0.001) and prior autologus transplant (HR=5.1, 1.1-23.5, p=0.03) as adverse factors. In conclusion, FT is a promising preparative regimen for allogeneic SCT in pts with lymphoid malignancies. Dose intensity is important in lymphoid malignancies. FT and FM are both dose intensive cyto-reductive regimens as reflected by lower relapse rates than FB2. FT is associated with lower NRM than FM, in similarity to the known favorable profile of FB2. These effects result in a more favorable OS with FT, in particular in advanced disease. A subset of pts with chemo refractory disease could also be salvaged. This regimen merits further study in larger comparative studies. Disclosures: No relevant conflicts of interest to declare.