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1
Akpek, Görgün, Marianna L. Zahurak, Steven Piantadosi, Jeffrey Margolis, Jon Doherty, Robert Davidson, and Georgia B. Vogelsang. "Development of a prognostic model for grading chronic graft-versus-host disease." Blood 97, no. 5 (March 1, 2001): 1219–26. http://dx.doi.org/10.1182/blood.v97.5.1219.
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The disease-specific survival (DSS) of 151 patients with chronic graft-versus-host disease (cGVHD) was studied in an attempt to stratify patients into risk groups and to form a basis for a new grading of cGVHD. The data included the outcome and 23 variables at the diagnosis of cGVHD and at the primary treatment failure (PTF). Eighty-nine patients (58%) failed primary therapy for cGVHD. Nonrelapse mortality was 44% after a median follow-up of 7.8 years. The probability of DSS at 10 years after diagnosis of cGVHD (DSS1) and after PTF (DSS2) was 51% (95% confidence interval [CI] = 39%, 60%) and 38% (95% CI = 28%, 49%), respectively. According to multivariate analysis, extensive skin involvement (ESI) more than 50% of body surface area; hazard ratio (HR) of 7.0 (95% CI = 3.6-13.4), thrombocytopenia (TP) (< 100 000/μL; HR, 3.6; 95% CI = 1.9-6.8), and progressive-type onset (PTO) (HR, 1.7; 95% CI = 0.9-3.0) significantly influenced DSS1. These 3 factors and Karnofsky Performance Score of less than 50% at PTF were significant predictors for DSS2. The DSS1 at 10 years for patients with prognostic factor score (PFS) at diagnosis of 0 (none), less than 2 (ESI only or TP and/or PTO), 2 to 3.5 (ESI plus either TP or PTO), and more than 3.5 (all 3 factors) was 82%, 68%, 34%, and 3% (P = .05, < .001, < .001), respectively. The DSS2 at 5 years for patients with PFS at PTF of 0, 2 or less, 2 to 3.5, and more than 3.5 were 91%, 71%, 22%, and 4% (P = .2, .005, and < .001), respectively. It was concluded that these prognostic models might be useful in grouping the patients with similar outcome.
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Rugo, Hope, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, et al. "Abstract GS01-05: Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study." Cancer Research 84, no. 9_Supplement (May 2, 2024): GS01–05—GS01–05. http://dx.doi.org/10.1158/1538-7445.sabcs23-gs01-05.
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Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) showed statistically significant improvements in PFS and OS vs placebo + chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10 in the phase 3 KEYNOTE-355 study. Tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. KEYLYNK-009 (NCT04191135) is a randomized open-label phase 2 study to evaluate the efficacy and safety of maintenance pembro + olaparib vs pembro + chemo in pts with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with 1L pembro + platinum-based chemo. Methods: Eligible pts with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembro 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8) every 3 wk (Q3W). Pts with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or pembro + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity; pembro was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Pts were stratified by induction response (CR or PR vs SD, by RECIST v1.1), tumor PD-L1 status (CPS ≥1 vs CPS < 1), and tumor genomic status (tBRCAm vs tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomization in all pts. Secondary endpoints included PFS and OS from randomization in pts with PD-L1 CPS ≥10 tumors and in pts with tBRCAm, and safety. Results: Of the 460 pts who received induction therapy, 271 were randomly assigned to pembro + olaparib (n=135) or pembro + chemo (n=136). At the Dec 15, 2022 data cutoff, median follow-up was 17.2 mo. Maintenance pembro + olaparib did not significantly improve PFS or OS vs pembro + chemo after induction therapy (Table). Median PFS was longer with pembro + olaparib vs pembro + chemo in pts with tBRCAm, but not in pts with PD-L1 CPS ≥10 tumors; a similar trend was observed for OS (Table). In 268 treated pts, treatment-related AEs (TRAEs) occurred in 114 of 135 pts (84.4%) for pembro + olaparib and in 128 of 133 pts (96.2%) for pembro + chemo. Grade ≥3 TRAEs occurred in 44 pts (32.6%) for pembro + olaparib (0 deaths) and in 91 pts (68.4%) for pembro + chemo (2 [1.5%] deaths), with 12 (8.9%) vs 26 (19.5%) discontinuations for TRAEs, respectively. Conclusions: The primary endpoints of PFS and OS were not met in an unselected population of pts with advanced TNBC. However, directionally favorable improvements in PFS and OS were observed in pts with tBRCAm with pembro + olaparib vs pembro + chemo, representing a potential maintenance strategy. Further data are required to confirm this effect. No new safety signals were observed, and there were fewer TRAEs in the pembro + olaparib group vs the pembro + chemo group. PFS and OS were evaluated from the time of randomization. *Based on stratified Cox regression model with Efron’s method of tie-handling with treatment as a covariate. NR = not reached. Citation Format: Hope Rugo, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Nadia Harbeck, Li Fan, Jaime Mejia, Vassiliki Karantza, David Cescon. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-05.
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Soverini, Simona, Sabrina Colarossi, Alessandra Gnani, Gianantonio Rosti, Fausto Castagnetti, Angela Poerio, Ilaria Iacobucci, et al. "Frequency, Distribution and Prognostic Value of ABL Kinase Domain (KD) Mutations in Different Subsets of Philadelphia-Positive (Ph+) Patients (Pts) Resistant to Imatinib (IM) by the Gimema Working Party on CML." Blood 106, no. 11 (November 16, 2005): 435. http://dx.doi.org/10.1182/blood.v106.11.435.435.
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Abstract Using denaturing-high performance liquid chromatography and sequencing, we screened for ABL KD mutations 319 IM-resistant Ph+ pts. Median time between diagnosis and IM start at 400–600 mg/d was 40 (0–160) months. Median duration of IM was 27 (9–62) months. Evaluable pts were 256/319 (80%). At the time of analysis, 178/256 (70%) pts were in chronic phase (CP)(36 previously untreated, 142 post-IFN failure), 16 (6%) pts were in accelerated phase (AP), 26 (10%) pts were in myeloid blast crisis (myBC), 36 (14%) were in lymphoid blast crisis (lyBC) or had Ph+ acute lymphoblastic leukemia (ALL). One hundred and forty-two pts had primary resistance to IM, 114 had acquired resistance. Ninety-eight mutations were found in 91/256 (36%) pts. In 6 pts (2 Ph+ ALL, 2myBC, 1 lyBC, 1 CP post-IFN failure) multiple mutations simultaneously occurred. Mutations mapped to 15 codons, the most frequent ones being E255K/V (15 pts), Y253F/H (12 pts), T315I (10 pts), M351T (10 pts), F359V/I (10 pts), M244V (9 pts), G250E (8 pts). Three novel amino acid substitutions (F311I; E355D; F359I) and a novel mutated codon (P296H) were detected; biochemical/structural characterization will be presented. Mutations were found in 36/178 (26%) CP pts (4/36 (11%) previously untreated, 32/142 (22%) post-IFN failure), 7/16 (44%) AP pts, 19/26 (73%) myBC pts and 29/36 (81%) lyBC/Ph+ ALL pts (CP vs. AP, p=.04; AP vs. BC, p=.01; CP vs. BC, p<.001). Mutations were associated in 41/142 (29%) pts with primary resistance (4/8 hematologic and 37/134 cytogenetic) and in 50/114 (44%) pts with acquired resistance (10/50 pts who lost CCgR, 16/32 pts who lost HR, 24/32 pts who progressed to AP/BC)(primary vs. acquired, p=.009). Thirty-nine out of 49 pts with P-loop or T315I mutations had already progressed to AP/BC at the time of mutation detection; 4 additional pts subsequently progressed. In contrast, only 17 of the 42 remaining pts with mutations had progressed or subsequently progressed (p<.001). In a subset of 93 IM-resistant CP pts who were homogeneously treated in the CML/002/STI571 trial, with a follow-up ranging between 10 and 51 months, presence of a mutation was significantly associated with greater likelihood of progression (Log-Rank p<.001) and shorter survival (Log-Rank p=.005). Pts carrying P-loop or T315I mutations showed a particularly poor outcome both in terms of time to progression (Log-Rank p=.003) and in terms of survival (Log-Rank p=.02). We conclude that: a) there is a significantly higher probability of mutations according to disease phase (Ph+ ALL and BC>AP>CP); b) there is a significantly higher probability of mutations in pts with acquired resistance vs. pts with primary resistance; c) mutations, and in particular those affecting P-loop or codon 315, are associated with a worse outcome. Supported by AIL, AIRC, Fondazione del Monte di Bologna e Ravenna.
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Rogers, Jonathan, Camarie Welgemoed, and Dorothy Gujral. "Does body mass index or subcutaneous adipose tissue thickness affect interfraction prostate motion in patients receiving radical prostate radiotherapy?" Journal of Radiotherapy in Practice 15, no. 4 (September 9, 2016): 334–40. http://dx.doi.org/10.1017/s1460396916000364.
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AbstractAimIt is unclear whether body mass index (BMI) is a useful measurement for examining prostate motion. Patient’s subcutaneous adipose tissue thickness (SAT) and weight has been shown to correlate with prostate shifts in the left/right direction. We sought to analyse the relationship between BMI and interfraction prostate movement in order to determine planning target volume (PTV) margins based on patient BMI.Materials and methodsIn all, 38 prostate cancer patients with three implanted gold fiducial markers in their prostate were recruited. Height, mass and SAT were measured, and the extent of interfraction prostate movement in the left/right, superior/inferior and anterior/posterior directions was recorded during each daily fiducial marker-based image-guided radiotherapy treatment. Mean corrective shift in each direction for each patient, along with BMI values, were calculated.ResultsThe median BMI value was 28·4 kg/m2 (range 21·4–44·7). Pearson’s product-moment correlation analysis showed no significant relationship between BMI, mass or SAT and the extent of prostate movement in any direction. Linear regression analysis also showed no relationship between any of the patient variables and the extent of prostate movement in any direction (BMI: R2=0·006 (ρ=0·65), 0·002 (ρ=0·80) and 0·001 (ρ=0·86); mass: R2=0·001 (ρ=0·87), 0·010 (ρ=0·54) and 0·000 (ρ=0·99); SAT: R2=0·012 (ρ=0·51), 0·013 (ρ=0·50) and 0·047 (ρ=0·19) for shifts in the X, Y and Z axis, respectively). Patients were grouped according to BMI, as BMI<30 (n=25, 65·8%) and BMI≥30 (n=13, 34·2%). A two-tailed t-test showed no significant difference between the mean prostate shifts for the two groups in any direction (ρ=0·320, 0·839 and 0·325 for shifts in the X, Y and Z axis, respectively).FindingsBMI is not a useful parameter for determining individualised PTV margins. Gold fiducial marker insertion should be used as standard to improve treatment accuracy.
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Zucali, Paolo A., Matteo Simonelli, Fabio De Vincenzo, Armando Santoro, Antonio Lambiase, and Claudio Bordignon. "Changes in shedding of soluble tumor necrosis factor receptors (sR1/R2) and in dynamic MRI as early predictors of outcome with NGR-hTNF." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22145-e22145. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22145.
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e22145 Background: Dose-response curve of NGR-hTNF, a selective antivascular agent, is typically biphasic with activity shown either at low dose (LD) or high dose (HD). Receptor shedding may block drug activity. Vascular effects at LD are characterized by early vessel stabilization and late vessel damage, while at HD by rapid vessel disruption. Methods: 60 pts (median age: 61; M/F: 44/16; PS 0/≥1: 25/35; median prior lines: 3) received in 2 ph I trials NGR-hTNF at LD (0.2-1.6 µg/m2; n=14) or HD (60-325 µg/m2; n=46) every 3 weeks. We tested the impact of early changes (post 1st dose) in baseline-normalized plasma receptor levels (n=60) and in DCE-MRI-assessed Ktrans (n=49) on treatment effect, including disease control (DC, rate of pts progression free at 6 weeks by RECIST criteria) and progression free survival (PFS). Results: Baseline receptor levels were not related to outcome. Post-dosing levels of sR1 (median, 4.6 ng/mL; interquartile range, 2.8-5.7) and sR2 (8.6; 4.5-10.7) increased with dose (p<.0001 for both), with median values of sR1 (0.3) and sR2 (0.5) at LD being significantly lower than those of sR1 (4.9) and sR2 (9.6) at HD (p<.0001 for both). Using as cutoff the 1st quartile, low sR1 levels (≤2.8 ng/mL) correlated with improved DC (OR=4.9; p=0.01) and PFS (HR=0.30; p=.003). In low vs high groups, median DC duration was 7.4 vs 2.9 months and 6-month PFS was 29% vs 0%, respectively. By adjusting for baseline covariates (age, sex, PS and prior lines), low sR1 levels remained independently associated with better DC (p=.02) and PFS (p=.008). Similar effects were noted for sR2. Levels of sR1 (r=-0.35; p=.01) and sR2 (r=-0.27; p=.07) inversely correlated with early fractional decreases in Ktrans, which resulted in median values unchanged after LD (4%; p=.73) and reduced after HD (-32%; p=.009). However, Ktrans significantly declined over time after both LD (-24%; p=.04) and HD (-44%; p=.001). Early changes in Ktrans did not relate with DC as defined by RECIST, but smaller decreases in Ktrans were associated with longer PFS (HR=0.56; p=.04). Conclusions: NGR-hTNF at LD is associated with better outcome than at HD likely due to early effects that involve minimal receptor shedding and vessel stabilization. Clinical trial information: NCT00878111-NCT00914628.
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Wang, Jiali, Lijun Zhao, Junlin Zhang, Yiting Wang, Yucheng Wu, Qianqian Han, Tingli Wang, et al. "CLINICOPATHOLOGIC FEATURES AND PROGNOSIS OF TYPE 2 DIABETES MELLITUS AND DIABETIC NEPHROPATHY IN DIFFERENT AGE GROUPS: MORE ATTENTION TO YOUNGER PATIENTS." Endocrine Practice 26, no. 1 (January 2020): 51–57. http://dx.doi.org/10.4158/ep-2019-0238.
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Objective: Our study sought to investigate the clinicopathologic features and renal prognosis of patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in different age groups. Methods: A total of 315 patients with T2DM and biopsy-proven DN were enrolled and divided into three groups by age: the Youth group (≤44 years old), the Middle-aged group (45 to 59 years old), and the Elderly group (≥60 years old). Results: The Youth group, Middle-aged group, and Elderly group accounted for 19.05% (60/315), 59.37% (187/315), and 21.59% (68/315) of the patients in our study, respectively. The patients in the Youth group had a higher estimated glomerular filtration rate (calculated using the Chronic Kidney Disease–Epidemiology collaboration formula) ( P<.001), a higher incidence of diabetic retinopathy ( P = .044), and a higher incidence of being in the lower-risk chronic kidney disease heat map category ( P = .046) but lower duration of diabetes ( P = .016). Histologically, patients in the Youth group had the highest incidence of glomerular classification in class I ( P = .006) and arteriolar hyalinosis score of 0 ( P = .005). The renal survival among the three groups was comparable ( P>.05). Conclusion: This study indicated that there were different clinicopathologic features among Chinese DN patients in different age groups. Although the Youth group had a relatively lower rapid kidney disease progression rate, there were no significant differences in renal survival rate among the three groups, which calls more attention to early supervision and prevention for younger DN patients. Abbreviations: CKD = chronic kidney disease; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; G&Y&O = green and yellow and orange; IFTA = interstitial fibrosis and tubular atrophy; T2DM = type 2 diabetes mellitus
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Paiva, Bruno, Norma C. Gutierrez, Xi Chen, María-Belén Vidriales, María-Angeles Montalbán, Laura Rosiñol, Albert Oriol, et al. "Biological and Clinical Significance of CD81 Expression by Clonal Plasma Cells in High-Risk Smoldering and Symptomatic Multiple Myeloma (MM) Patients,." Blood 118, no. 21 (November 18, 2011): 3936. http://dx.doi.org/10.1182/blood.v118.21.3936.3936.
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Abstract Abstract 3936 The presence of CD19 in myelomatous plasma cells (MM-PC) correlates with adverse prognosis in MM. Although CD19 expression is up-regulated by CD81, this marker has been poorly investigated and its prognostic value in myeloma remains unknown. Herein, we assessed the frequency and the prognostic value of the immunophenotypic detection of CD81 surface expression in MM-PC of high-risk smoldering (SMM) and symptomatic MM patients at diagnosis and its role as a potential therapeutic target. The study included 230 elderly MM patients treated according to the Spanish GEM05>65y trial, and a validation set based on 325 transplant candidates MM patients enrolled in the GEM05<65y trial was used. In addition we analyzed a total of 56 high-risk SMM patients. The median follow-up was 32 and 22 months for the MM and SMM, respectively. Expression of CD81 on MM-PC was assessed by multiparameter flow cytometry (MFC). FISH was performed at baseline in immunomagnetic-enriched PCs from 211 of the 230 elderly MM patients, and in a subset of these patients (N=23) mRNA gene expression profiling (GEP) was also performed. MFC immunophenotyping showed the presence of CD81+ MM-PC in 20 of 56 (36%) SMM, and 90 of 230 (39%) MM patients. CD81+ SMM cases had a shorter TTP to symptomatic disease than CD81− patients (NR vs 37 months, P =.02). Similarly, CD81+symptomatic MM patients showed shorter PFS (3y: 29% vs 48%, P <.001) and OS (3y: 64% vs 76%, P =.008) rates compared to CD81− cases. Multivariate analysis including other baseline variables showed that the best combination of independent predictive parameters for PFS were: CD81+ expression on MM-PC (HR=1.8; P =.004), high-risk cytogenetics (HR=1.8; P =.02) and percentage of MM-PC in S-phase (>2%; HR=1.7; P =.02); in turn for OS, CD81+ expression (HR=2.2; P =.005), high-risk cytogenetics (HR=2.2; P =.006) and age (≥75 years; HR=1.8; P =.03) were selected. To validate the adverse impact of CD81+ expression, we explored whether this new marker would retain its prognostic value in a series of 325 transplant candidates, symptomatic MM patients. CD81+ cases (138 out of 325, 42%) showed shorter PFS (3y: 44% vs 62%, P <.001) and OS (3y: 74% vs 89%, P =.004) rates as compared to CD81− cases. The prognostic influence of CD81 expression prompted us to investigate its potential role as a therapeutic target in MM cell lines. 5 out of the 13 cell lines analyzed were homogeneously positive for CD81 (RPMI-8226, RPMI-LR5, NCI-H929, OPM-2, JJN3) while the others exhibited no expression; these results were further validated by western blotting. We then tested the effect of two different anti-CD81 antibodies on cell proliferation on 2 CD81+ cell lines (RPMI-8226 and JJN3) as well as in 1 CD81− (MM1S) MM cell line. Interestingly, the two antibodies tested decreased cell proliferation (around 30%, P ≤.005) in the two CD81+ cell lines, whereas no differences were found for the CD81− MM1S cell line. To assess whether anti-CD81 antibodies facilitate immune effector cell function, we performed in vitro ADCC. However, no effect was noted in the CD81+ RPMI-8226 cell line, using either PBMCs or the macrophage cell line RAW264.7, and at different cell ratios. Similar results were also found upon using CDC assay in CD81+ RPMI-8226 and JJN3 cell lines. Finally, we explored in a subgroup of MM patients (n=23) in which information was available, the relationship between positivity for CD81 by MFC and its genomic expression. The expression level of CD81 mRNA was significantly decreased in CD81− MM cases (P <.001) vs. both healthy adults and CD81+ patients (P <.001), with no significant differences between these two latter subgroups. Moreover, we found a highly significant correlation between the expression of CD81 mRNA by GEP and the percentage of CD81+ MM-PC by MFC (r=.812; P <.001). We further investigated by GEP, differences in other genes involved in the CD81 signaling pathway, and CD81+MM patients showed significantly higher levels of CD79A (P =.03) and SYK (P =.02) mRNA than CD81−cases. In summary, our findings show the existence of a phenotypic-genomic correlation of CD81 expression in patients with myeloma. Expression of CD81 in MM-PC is an independent prognostic factor for patients with symptomatic MM and a marker for risk of progression in SMM. Blockage of CD81 with anti-CD81 antibodies does not show significant anti-myeloma activity; therefore, the precise mechanism of CD81 activation of MM-PC deserves further investigations. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.
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Awada, Hassan, Cassandra M. Kerr, Vera Adema, Carmelo Gurnari, Simona Pagliuca, Heesun J. Rogers, Hetty E. Carraway, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, and Valeria Visconte. "The Clonal Trajectories of SF3B1 Mutations in Myeloid Neoplasia." Blood 136, Supplement 1 (November 5, 2020): 8. http://dx.doi.org/10.1182/blood-2020-139528.
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Molecular lesions have diagnostic and prognostic impacts in myeloid neoplasia (MN). The beau idéal is the presence of SF3B1MT in MDS with ringed sideroblasts. Although most of these patients have a classic phenotype, little is known about the factors diverting it during the clonal evolution. Clinical trajectories of patients with SF3B1MT might depend on clonal hierarchy, dynamics and subclonal diversity in relation to other lesions. Herein, we studied the molecular architecture of patients with SF3B1MT to determine whether clonality and rank might infer distinct MDS features. We collected molecular and clinical information of 3561 patients with MN from Cleveland Clinic and publicly shared data. Results of targeted deep sequencing of 176 MDS/ AML genes were included. We applied an in-house variant allele frequency (VAF) based bioanalytic method to resolve clonal hierarchy. VAF (adjusted for copy number and zygosity) was used to classify the mutations into dominant (if a cutoff of at least 5% difference between VAFs existed), secondary (any subsequent subclonal hit) and codominant hits (<5% difference of VAFs between 2 hits). SF3B1 MT were detected in 9% of patients (n=335): 140 were SF3B1DOM (42%), 121 were SF3B1SEC (36%) and 74 were codominant (SF3B1COD, 22%). Comparison of SF3B1MT VAFs among the 3 groups showed no significant difference (40 vs 39 vs 44%, P= .6). Due to lack of distinct partition, we delved into the implications of SF3B1COD on mutational stability, disease phenotypes, molecular associations and overall survival (OS) as compared to the other 2 configurations. Serially-collected samples (n=21) showed clear scenarios of dominant clones remaining stable or switching to secondary due to impending acquisition of other hits or secondary clones remaining as such but denoted an ambivalent framework of codominant clones with "sweeping" features. Cases with SF3B1COD had a trend of OS similar to that of SF3B1SEC (median OS: 18 vs 15.9 mo.) and as such a poorer outcome compared to that of SF3B1DOM (39.8 mo.; P= .02). Moreover, the mutational profile of SF3B1CODvsSF3B1DOM was partially similar to that of SF3B1SECvs.SF3B1DOM with significantly higher odd ratios for DNMT3A (P< .0001), ASXL1, FLT3, RUNX1, TET2 (P≤ .05 for each). No variant morphologic features were observed when comparing SF3B1COD to the other 2 groups. By virtue, we strictly compared only cases with SF3B1DOM and SF3B1SEC, further supported by our single cell analysis(n=5), to showan unambiguous distinction between these two statii. Mutational burden analysis revealed that SF3B1DOM patients had a fewer number of mutations than those with SF3B1SEC (median 1.0 vs 2.6). SF3B1DOM was mostly detected in patients with a normocellular bone marrow as compared to SF3B1SEC (46 vs 29%, P= .02) and had a lower proportion of multidysplastic myeloid cells (29 vs 53%, P= .01). On the other side, SF3B1SEC were often present in the context of bilineage dysplasia (47vs. 26%, P= .02). Focused morphologic analysis revealed that SF3B1DOM cases were significantly associated with a higher RS% (median 37 vs 3%, P= .002; frequency of RS ≥15%: 77 vs 44%, P= .003) with higher VAF% significantly correlating with higher RS%. Patients with SF3B1SEC had shorter OS than those with SF3B1DOM (15.9 vs 39.7 mo., P< .0001). Even by dichotomizing according to VAF, the median OS of cases with VAF>40% was significantly shorter than those with VAF<20% (14.4 vs 33.9 mo.; P= .001) and between 20% and 40% (39.3 mo.). When the VAF of SF3B1SEC was >40%, the OS was shortened compared to SF3B1DOM (31 vs 11.6 mo., P= .001) and similarly when it laid between 20% and 40% (49.7 vs 25.6 mo., P= .01) suggesting a strong impact of associated hits. In SF3B1SEC, univariate analyses showed significantly higher odds of hits in RUNX1 (43 vs 19%, P< .0001), TET2 (29 vs 11%, P= .0005), FLT3 (22 vs 11%, P= .02), DNMT3A (20 vs 7%, P= .004), ASXL1 (16 vs 5%, P= .06), BCOR/L1 (17 vs 5%, P= .005), IDH1/2 (11 vs 2%, P= .008), CBL (8 vs 1%, P= .009) and CEBPA (7 vs 2%, P= .04) compared to SF3B1DOM. Interestingly, cases with co-existing TET2 mutations had a marked decrease in OS in SF3B1SECvsSF3B1DOM(10.1 vs 96.1 mo., P= .02) suggesting that the mutational ranking in a disease triggered by SF3B1MT can be skewed by stronger hits. In sum, our study suggests that molecular ranking in the context of SF3B1 clonal configuration is a key factor diverting the clinical and phenotypic trajectories of patients with MN and SF3B1MT. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.
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Heikura, Ida A., Louise M. Burke, Dan Bergland, Arja L. T. Uusitalo, Antti A. Mero, and Trent Stellingwerff. "Impact of Energy Availability, Health, and Sex on Hemoglobin-Mass Responses Following Live-High–Train-High Altitude Training in Elite Female and Male Distance Athletes." International Journal of Sports Physiology and Performance 13, no. 8 (September 1, 2018): 1090–96. http://dx.doi.org/10.1123/ijspp.2017-0547.
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Purpose: The authors investigated the effects of sex, energy availability (EA), and health status on the change in hemoglobin mass (ΔHbmass) in elite endurance athletes over ∼3–4 wk of live-high–train-high altitude training in Flagstaff, AZ (2135 m; n = 27 women; n = 21 men; 27% 2016 Olympians). Methods: Precamp and postcamp Hbmass (optimized carbon monoxide rebreathing method) and iron status were measured, EA was estimated via food and training logs, and a Low Energy Availability in Females Questionnaire (LEAFQ) and a general injury/illness questionnaire were completed. Hypoxic exposure (h) was calculated with low (<500 h), moderate (500–600 h), and high (>600 h) groupings. Results: Absolute and relative percentage ΔHbmass was significantly greater in women (6.2% [4.0%], P < .001) than men (3.2% [3.3%], P = .008). %ΔHbmass showed a dose–response with hypoxic exposure (3.1% [3.8%] vs 4.9% [3.8%] vs 6.8% [3.7%], P = .013). Hbmasspre was significantly higher in eumenorrheic vs amenorrheic women (12.2 [1.0] vs 11.3 [0.5] g/kg, P = .004). Although statistically underpowered, %ΔHbmass was significantly less in sick (n = 4, −0.5% [0.4%]) vs healthy (n = 44, 5.4% [3.8%], P < .001) athletes. There were no significant correlations between self-reported iron intake, sex hormones, or EA on Hbmass outcomes. However, there was a trend for a negative correlation between LEAFQ score and %ΔHbmass (r = −.353, P = .07). Conclusions: The findings confirm the importance of baseline Hbmass and exposure to hypoxia on increases in Hbmass during altitude training, while emphasizing the importance of athlete health and indices of EA on an optimal baseline Hbmass and hematological response to hypoxia.
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Fonseca, Rafael, Emily Blood, Montserrat Rue, David Harrington, Martin M. Oken, Robert A. Kyle, Gordon W. Dewald, et al. "Clinical and biologic implications of recurrent genomic aberrations in myeloma." Blood 101, no. 11 (June 1, 2003): 4569–75. http://dx.doi.org/10.1182/blood-2002-10-3017.
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Abstract Nonrandom recurrent chromosomal abnormalities are ubiquitous in multiple myeloma (MM) and include, among others, translocations of the immunoglobulin heavy chain locus (IgH). IgH translocations in MM result in the up-regulation of oncogenes, and include more commonly t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23). Based on the recurrent nature of these translocations and their finding since the early stages of the plasma cell (PC) disorders, we hypothesized that they would confer biologic and clinical variability. In addition, deletions of 13q14 and 17p13 have also been associated with a shortened survival. We used cytoplasmic Ig—enhanced interphase fluorescent in situ hybridization to detect deletions (13q14 and 17p13.1), and translocations involving IgH in 351 patients treated with conventional chemotherapy entered into the Eastern Cooperative Oncology Group clinical trial E9486/9487. Translocations were frequently unbalanced with loss of one of the derivative chromosomes. The presence of t(4; 14)(p16;q32) (n = 42; 26 vs 45 months, P < .001), t(14;16)(q32;q23) (n = 15; 16 vs 41 months, P = .003), – 17p13 (n = 37; 23 vs 44 months, P = .005), and – 13q14 (n = 176; 35 vs 51 months, P = .028) were associated with shorter survival. A stratification of patients into 3 distinct categories allowed for prognostication: poor prognosis group (t(4;14)(p16;q32), t(14; 16)(q32;q23), and – 17p13), intermediate prognosis (– 13q14), and good prognosis group (all others), with median survivals of 24.7, 42.3, and 50.5 months, respectively (P < .001). This molecular cytogenetic classification identifies patients into poor, intermediate, and good risk categories. More importantly it provides further compelling evidence that MM is composed of subgroups of patients categorized according to their underlying genomic aberrations.
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Mora, O., J. L. Romano, E. González, F. J. Ruiz, R. Gómez, and A. Shimada. "Presence of fed β-carotene in digesta, excreta, blood, and hepatic and adipose tissues of Holstein steers." Canadian Journal of Animal Science 81, no. 1 (March 1, 2001): 133–39. http://dx.doi.org/10.4141/a00-004.
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Eight animals were fed a diet without added β-carotene for 49 d and then supplemented with four levels of β-carotene (0, 5.5, 44 or 352 mg kg–1dry matter) for 30 d; the two-phase procedure was then repeated. Steers were killed at the end of the second period. Concentrations of β-carotene were: 0, 0, 227.2 and 2011 mg dL–1 (P < 0.05) in ruminal fluid; 0, 0, 533.7 and 4418 mg dL–1 (P < 0.05) in duodenal fluid; 0, 4.03, 14.91 and 90.64 mg g–1 (P < 0.05) in dry faeces; 0.8, 1.2, 4.7 and 8.1 mg g–1 (P < 0.05) in liver; 0.07, 0.15, 0.5 and 3.7 mg g–1 (P < 0.05) in subcutaneous fat; 0, 0, 0.09 and 0.23 mg g–1 (P < 0.05) in kidney fat for dietary treatments with 0, 5.5, 44 and 352 mg β-carotene kg–1 DM, respectively. The dose of β-carotene was reflected in retinol concentrations in liver: 101.1, 113.6, 161.7 and 199.6 mg g–1 (P < 0.05), but not in subcutaneous or kidney fat (P > 0.1). The estimated β-carotene digestibilities were 66.25, 84.39 and 88.14% for treatments with 5.5, 44 and 352 mg β-carotene kg–1 DM, respectively (P < 0.01). The results suggest a high capacity of bovine tissues to store β-carotene and probably a limited capability to convert β-carotene into vitamin A. Key words: β-carotene digestion, blood concentration, deposition, steers
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Farquhar, Douglas R., Maheer M. Masood, Andrew K. Pappa, Samip N. Patel, and and Trevor G. Hackman. "Predictors of Adverse Outcomes in Free Flap Reconstruction: A Single-Institution Experience." Otolaryngology–Head and Neck Surgery 159, no. 6 (July 17, 2018): 973–80. http://dx.doi.org/10.1177/0194599818787801.
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Objective Understanding the independent predictors of poor outcomes in free flap surgery is essential for patient selection. We aim to determine the independent predictors of major complications, flap survival, and extended hospital stays. Study Design Retrospective cohort study. Setting Tertiary medical center. Subjects and Methods We reviewed medical records from all vascularized tissue transfers in the head and neck between 2007 and 2014 at our institution. We recorded demographics, medical comorbidities, disease characteristics, flap characteristics, and intraoperative events. We defined outcomes as major complications in the 30-day postoperative period, flap death or partial flap survival, and a length of stay ≥14 days. We used bivariate and multivariate methods to test for associations. Results Of 170 free flap operations, 44% had major complications; 11% fully or partially failed; and 27% required an extended hospital stay. Independent predictors of major complications were age ≥60 years (odds ratio [OR], 3.7; P = .001), revision surgery (OR, 3.5; P = .004), and a prior neck dissection (OR, 3.5; P = .004). Independent predictors of flap failure were revision surgery (OR, 4.1, P = .01) and the use of a plate (OR, 3.7; P = .03). Revision surgery was independently associated with a longer stay (OR, 3.0; P = .01), and the use of a radial forearm flap was associated with a shorter stay (OR, 0.3, P = .047). Conclusion These results underscore that caution is warranted in revision flap surgery, patients with prior neck operations, and patients aged ≥60 years.
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Katsanis, E., PM Anderson, AH Filipovich, DE Hasz, ML Rich, CM Loeffler, AC Ochoa, and DJ Weisdorf. "Proliferation and cytolytic function of anti-CD3 + interleukin-2 stimulated peripheral blood mononuclear cells following bone marrow transplantation." Blood 78, no. 5 (September 1, 1991): 1286–91. http://dx.doi.org/10.1182/blood.v78.5.1286.1286.
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Abstract We evaluated the proliferation, cytolytic function, and phenotypic characteristics of anti-CD3 plus interleukin-2 (IL-2) stimulated peripheral blood mononuclear cells (PBMCs) from 44 patients with leukemia or non-Hodgkin's lymphoma (NHL) treated with multiagent chemotherapy or following bone marrow transplantation (BMT). BMT patients had decreased cell growth with only a 1.35 +/- 0.25 (autologous BMT for acute lymphoblastic leukemia [ALL]), 1.24 +/- 0.25 (autologous BMT for NHL), and 0.8 +/- 0.1 (allogeneic BMT for leukemia) mean fold increase by day 5 of culture compared with controls (4.0 +/- 0.4), P less than .001. Anti-CD3 + IL-2 activated cells from patients with ALL and NHL who had received autologous BMT and cells from patients with leukemia who underwent allogeneic BMT were more effective in lysing the natural killer (NK) sensitive target, K562, and the NK- resistant target, Daudi, compared with controls. In contrast, cytolysis of K562 and Daudi by cultured PBMCs from patients with ALL and NHL receiving multi-agent chemotherapy was similar to that of controls. Cultures from BMT recipients had a significant increase in CD16+ (autologous ALL 5.7 +/- 1.5%, P less than .01; autologous NHL 12.4 +/- 3.5%, P less than .001; allogeneic 14.3 +/- 2.9%, P less than .001) and CD56+ cells (autologous ALL 27.6 +/- 12.0%, P less than .01; autologous NHL 39.3 +/- 9.5%, P less than .001; allogeneic 42.7 +/- 7.4%, P less than .001) compared with controls (CD16+ 2.5 +/- 0.4%; CD56+ 6.9 +/- 0.9%). Stimulation of PBMCs with anti-CD3 + IL-2 is effective in generating cells with high cytolytic function post-BMT.
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Katsanis, E., PM Anderson, AH Filipovich, DE Hasz, ML Rich, CM Loeffler, AC Ochoa, and DJ Weisdorf. "Proliferation and cytolytic function of anti-CD3 + interleukin-2 stimulated peripheral blood mononuclear cells following bone marrow transplantation." Blood 78, no. 5 (September 1, 1991): 1286–91. http://dx.doi.org/10.1182/blood.v78.5.1286.bloodjournal7851286.
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We evaluated the proliferation, cytolytic function, and phenotypic characteristics of anti-CD3 plus interleukin-2 (IL-2) stimulated peripheral blood mononuclear cells (PBMCs) from 44 patients with leukemia or non-Hodgkin's lymphoma (NHL) treated with multiagent chemotherapy or following bone marrow transplantation (BMT). BMT patients had decreased cell growth with only a 1.35 +/- 0.25 (autologous BMT for acute lymphoblastic leukemia [ALL]), 1.24 +/- 0.25 (autologous BMT for NHL), and 0.8 +/- 0.1 (allogeneic BMT for leukemia) mean fold increase by day 5 of culture compared with controls (4.0 +/- 0.4), P less than .001. Anti-CD3 + IL-2 activated cells from patients with ALL and NHL who had received autologous BMT and cells from patients with leukemia who underwent allogeneic BMT were more effective in lysing the natural killer (NK) sensitive target, K562, and the NK- resistant target, Daudi, compared with controls. In contrast, cytolysis of K562 and Daudi by cultured PBMCs from patients with ALL and NHL receiving multi-agent chemotherapy was similar to that of controls. Cultures from BMT recipients had a significant increase in CD16+ (autologous ALL 5.7 +/- 1.5%, P less than .01; autologous NHL 12.4 +/- 3.5%, P less than .001; allogeneic 14.3 +/- 2.9%, P less than .001) and CD56+ cells (autologous ALL 27.6 +/- 12.0%, P less than .01; autologous NHL 39.3 +/- 9.5%, P less than .001; allogeneic 42.7 +/- 7.4%, P less than .001) compared with controls (CD16+ 2.5 +/- 0.4%; CD56+ 6.9 +/- 0.9%). Stimulation of PBMCs with anti-CD3 + IL-2 is effective in generating cells with high cytolytic function post-BMT.
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Zhan, Fenghuang, Bart Barlogie, Varant Arzoumanian, Yongsheng Huang, Klaus Hollmig, Mauricio Pineda-Roman, Guido Tricot, et al. "A Gene Expression Signature of Benign Monoclonal Gammopathy Evident in Multiple Myeloma Is Linked to Good Prognosis." Blood 108, no. 11 (November 16, 2006): 3393. http://dx.doi.org/10.1182/blood.v108.11.3393.3393.
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Abstract Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM), often through a phase of smoldering MM (SMM). We hypothesized that a molecular signature of MGUS may be detectable in a subset of patients with MM. Applying Significance Analysis of Microarrays, 52 genes, involved in important pathways related to cancer, were found to be differentially expressed between plasma cells from 22 healthy subjects, 24 strictly defined MGUS/SMM and 351 symptomatic MM (P < .001). Unsupervised hierarchical clustering of 351 MM and 44 cases of MGUS and 16 cases of MM with a MGUS history, created two major cluster branches, one containing 82% of the MGUS cases and 28% of the MM, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 213 MM revealed 27% were MGUS-L. The MGUS-L MM signature was associated with a higher prevalence of low-risk clinical and molecular features and superior survival (P < .01), despite a lower incidence of complete remission (P = .006). The MGUS-L signature was also seen in 15 of 20 patients surviving more than 10 years after autotransplant. These data reveal molecular switches associated with the development and progression of plasma cell dyscrasias.
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Virappane, Priya, Rosemary Gale, Robert Hills, Ioannis Kakkas, Karin Summers, Jane Stevens, Christopher Allen, et al. "Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party." Journal of Clinical Oncology 26, no. 33 (November 20, 2008): 5429–35. http://dx.doi.org/10.1200/jco.2008.16.0333.
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Purpose To determine the clinical relevance of Wilms’ tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK). Patients and Methods Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis. Results Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor. Conclusion WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.
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Reis, A. M., M. Jankowski, S. Mukaddam-Daher, J. Tremblay, T.-V. Dam, and J. Gutkowska. "Regulation of the natriuretic peptide system in rat uterus during the estrous cycle." Journal of Endocrinology 153, no. 3 (June 1997): 345–55. http://dx.doi.org/10.1677/joe.0.1530345.
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Abstract Uterine natriuretic peptides may be involved in the alterations that occur in the uterus during the estrous cycle through its role in hydromineral balance. The following studies were performed to determine whether uterine natriuretic peptides and receptors follow a cyclic pattern during the estrous cycle. The results obtained show that atrial natriuretic peptide (ANP) content in rat uterine tissue was low in proestrus (8·5 ± 2·6 pg/g) and significantly increased (P<0·001) in estrus (71·5 ± 16·6 pg/g), metestrus (82·6 ± 19·7 pg/g) and diestrus (91·0 ± 19·4 pg/g), whereas plasma ANP was not altered during the cycle. Similarly, measurement of uterine ANP mRNA by reverse transcribed polymerase chain reaction (RT-PCR) indicated lowest levels of ANP mRNA at proestrus. Measurement of C-type natriuretic peptide (CNP) by a specific and sensitive radioimmunoassay revealed that uterine CNP also varies with the estrous cycle. Uterine CNP was low in diestrus (143·2 ± 22·4 pg/mg protein) as compared with proestrus, estrus and metestrus (305·3 ± 51·5, 267·5 ± 44·9, 291 ± 41·2 pg/mg protein respectively, P<0·05). Autoradiography performed on uterine tissue slices localized natriuretic peptide receptors to myometrial smooth muscle layers and to endometrial uterine glands. High binding of 125I-ANP was observed in proestrus and estrus with 60–75% decreases during metestrus and diestrus. Binding of 125I-tyr0CNP to uterine slices was also high during proestrus, but declined by 35% at estrus, metestrus and diestrus. The alterations in the receptors were also observed at the level of synthesis. RT-PCR detection of guanylyl cyclase A (GC-A) receptor mRNA and guanylyl cyclase B (GC-B) mRNA showed high signals at proestrus but 4- and 2-fold reductions respectively at metestrus and diestrus. In conclusion, variations in uterine ANP and CNP and their receptors during the rat estrous cycle imply the involvement of the natriuretic peptides in uterine hydromineral balance and myometrial motor activity. Journal of Endocrinology (1997) 153, 345–355
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Yalniz, Fevzi F., Rima M. Saliba, Orhan K. Yucel, Guillermo Garcia-Manero, Jeremy Ramdial, Uday Popat, Stefan O. Ciurea, et al. "Somatic Mutations Improve Risk Classification By Cytogenetic Abnormalities in Patients with Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 512. http://dx.doi.org/10.1182/blood-2019-125937.
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Background: Hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for patients with myelodysplastic syndrome (MDS) but disease progression after HSCT remains a major reason for failure after transplant. Identification of risk factors for progression of MDS after HSCT would allow to identify target population for early initiation of preventive treatments to improve outcomes. Methods: Patients with a diagnosis of MDS who received first HSCT between 2013 and 2018 with available pre-transplant genetic profile obtained from next generation sequencing of genes were included for the retrospective analysis. Cytogenetic findings were categorized by the revised International Prognostic Scoring System (R-IPSS). Primary outcome of interest was risk of disease progression. Classification and regression tree (CART) analysis was performed to evaluate independent predictors on multivariate analysis using standard methods. Results: Of 378 MDS patients transplanted within the study period, 225 were eligible to be included in this analyses. As shown in the table 1, the study cohort was high risk; cytogenetic risk groups were very-poor and poor in 50 (23%) and 32 (15%) patients, respectively. At least one pathogenic mutation was identified in 215 (91%) of patients prior to transplant. Most frequently mutated genes included, TP53 (24%, 54/225), RAS pathway genes (NRAS, KRAS, FLT3, PTPN11 and KIT) (20%, 44/225), TET2 (16%, 37/172), ASXL1 (12%, 27/172) and DNMT3A (11%, 25/200). In our cohort, patients with very-poor cytogenetics had a high frequency of TP53 mutations (73%), and TP53 mutations occurred almost exclusively in patients with very-poor cytogenetics (76% v 7%; P < .001). That makes those two groups almost inseparable from each other. The median follow-up in 121 (54%) survivors was 24 months (range, 1.8 to 74 months). Of the 225 patients, 65 (29%) had disease progression after HSCT, with a median of 154 days to progression (range, 28 to 1196). By univariate analyses, presence of TP53 (HR, 3.2; CI, 1.9-5.4; P<.001), DNMT3A (HR, 2.6; CI, 1.5-4.7; P=.001), RAS pathway mutations (HR, 2.01; CI, 1.2-3.4; P=.01), therapy related MDS (HR, 2.05; CI, 1.2-3.5; P=.008), very poor risk cytogenetics (HR, 3.4; CI, 1.9-6.3; P<.002), and use of post-transplant cyclophosphamide (PTCy) (HR, 0.5; CI, 0.3-0.96; P=.003) were significant predictors of progression rate. As previously mentioned, we used CART analysis to evaluate independent predictors of progression. The results demonstrated that given the significant overlap with TP53 and very poor cytogenetics, when both variables were forced into the model, only very poor cytogenetics remained significant for progression. Based on CART analysis, 4 mutually exclusive risk groups for progression were identified (Figure 1): high risk (very poor risk cytogenetics or DNMT3Amut), intermediate risk (good, intermediate or poor risk cytogenetics/RAS-pathmut/DNMT3Awt), low risk (poor risk cytogenetics/RAS-pathwt /DNMT3Awt) and a very low risk group (very good, good or intermediate risk cytogenetics/RAS-pathwt /DNMT3Awt). The correlation between R-IPSS based cytogenetic risk and our identified risk groups is shown in table 2. This illustrates how the addition of molecular data upstaged 25% of the patients to a higher risk category as well as downstaged 23% of the patients to a lower risk category for disease progression when compared to the original R-IPSS classification. The cumulative incidence of disease progression at 2 years was 6% (reference), 26% (P=.005), 42% (P<.001) and 56% (P<.001) in very-low, low, intermediate and high risk groups, respectively (Figure 2). Within the risk groups identified, progression incidence was comparable by conditioning intensity and the use of PTCy. The actuarial 2-year progression-free survival for the defined 4 risk groups was, 69% (reference), 48% (HR, 2; P=.04), 38% (HR, 2.2; P=.009), 22% (HR, 3.2; P<.001) and 14% (HR, 4.8; P<.001), in very-low, low, intermediate and high-risk groups, respectively. Non-relapse mortality was similar across the identified risk groups. Conclusion: The proposed model, by incorporating DNMT3A and RAS pathway molecular mutation status to cytogenetic risk per R-IPSS, improves upon the classification of risk groups and enables the physician to better risk stratify and predict likelihood of progression after transplantation. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Amgen: Research Funding. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding.
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Krishnaswami, Sumi, Anant K. Agarwal, Jim Richmond, Craig Capell, Sei Hyung Ryu, John W. Palmour, Bruce Geil, Dimos Katsis, and Charles Scozzie. "High Temperature Characterization of 4H-SiC Bipolar Junction Transistors." Materials Science Forum 527-529 (October 2006): 1437–40. http://dx.doi.org/10.4028/www.scientific.net/msf.527-529.1437.
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This paper summarizes the recent demonstration of 3200 V, 10 A BJT devices with a high common emitter current gain of 44 in the linear region, and a specific on-resistance of 8.1 mΩ- cm2 (10 A at 0.90 V with a base current of 350 mA and an active area of 0.09 cm2). The onresistance increases to 40 mΩ-cm2 at 350°C, while the DC current gain decreases to 30. A sharp avalanche behavior was observed with a leakage current of 10 μA at a collector voltage of 3.2 kV.
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Atabani, G. S., B. O. Saeed, E. M.-A. El Mahdi, M. E. Adam, and D. A. Hassan. "Glycated Haemoglobin and other Biochemical Parameters in Sudanese Diabetics." Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 26, no. 4 (July 1989): 332–34. http://dx.doi.org/10.1177/000456328902600406.
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Fasting levels of glycated haemoglobin, cholesterol and triglycerides were studied in 44 patients with non-insulin-dependent diabetes mellitus (NIDDM), 31 patients with insulin-dependent diabetes mellitus (IDDM) and 28 healthy Sudanese individuals. Results confirmed previous observations showing correlation of glycated haemoglobin with fasting blood glucose in NIDDM ( r=0·634; P < 0·001), and with cholesterol in IDDM ( r=0·355; P < 0·05). No correlation of glycated haemoglobin with triglycerides was observed in either group of diabetics. A negative correlation was demonstrated between glycated haemoglobin and the duration of diabetes ( r= −0·552; P < 0·01) in IDDM. It seemed that control improved in these patients as their diabetes progressed, probably through self-education.
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Summers, MPH, April D., Elizabeth C. Ailes, PhD, Michele K. Bohm, MPH, Emmy L. Tran, PharmD, MPH, Cheryl S. Broussard, PhD, Meghan T. Frey, MPH, Suzanne M. Gilboa, PhD, Jean Y. Ko, PhD, Jennifer N. Lind, PharmD, MPH, and Margaret A. Honein, PhD. "Opioid prescription claims among women aged 15-44 years—United States, 2013-2017." Journal of Opioid Management 17, no. 2 (March 1, 2021): 125–33. http://dx.doi.org/10.5055/jom.2021.0623.
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Objective: To estimate the annual percentage of women of reproductive age with private insurance or Medicaid who had opioid prescription claims during 2013-2017 and describe trends over time.Design: A secondary analysis of insurance claims data from IBM MarketScan® Commercial and Multi-State Medicaid Databases to assess outpatient pharmacy claims for prescription opioids among women aged 15-44 years during 2013-2017.Participants: Annual cohorts of 3.5-3.8 million women aged 15-44 years with private insurance and 0.9-2.1 million women enrolled in Medicaid.Main Outcome Measure: The percentage of women aged 15-44 years with outpatient pharmacy claims for opioid prescriptions.Results: During 2013-2017, the proportion of women aged 15-44 years with private insurance who had claims for opioid prescriptions decreased by 22.1 percent, and among women enrolled in Medicaid, the proportion decreased by 31.5 percent.Conclusions: Opioid prescription claims decreased from 2013 to 2017 among insured women of reproductive age. However, opioid prescription claims remained common and were more common among women enrolled in Medicaid than those with private insurance; additional strategies to improve awareness of the risks associated with opioid prescribing may be needed.
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Osofsky, Robin, Ross Clark, Jaideep Das Gupta, Nathan Boyd, Garth Olson, LeAnn Chavez, Sundeep Guliani, Mark Langsfeld, John Marek, and Muhammad Ali Rana. "The effect of preoperative embolization on surgical outcomes for carotid body tumor resection." SAGE Open Medicine 9 (January 2021): 205031212110052. http://dx.doi.org/10.1177/20503121211005229.
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Objective: Compare the effects of preoperative embolization for carotid body tumor resection on surgical outcomes to carotid body tumor resections without preoperative embolization. Methods: Single-center retrospective review of all consecutive patients who underwent carotid body tumor resection from 2001 to 2019. Surgical outcomes with emphasis on operative time (estimated blood loss and cranial nerve injury) of patients undergoing carotid body tumor resection following preoperative embolization were compared to those undergoing resection alone using unpaired Student’s t-test and Fisher’s exact test. Results: Forty-six patients (15% male, mean age 50 ± 15 years) underwent resection of 49 carotid body tumors. Patients undergoing preoperative embolization ( n = 20 (40%)) had larger mean tumor size (4.0 ± 0.7 vs 3.2 ± 1 cm, p = 0.006), increased Shamblin II/III tumor classification (18 (90%) vs 22 (76%), p < 0.001), operative time (337 ± 195 vs 199 ± 100 min, p = 0.004), and cranial nerve injuries overall (8 (40%) vs 2 (10%), p = 0.01) compared to patients undergoing resection without preoperative embolization ( n = 29 (60%)). In subgroup analysis of Shamblin II/III classification tumors ( n = 40), preoperative embolization ( n = 18) was associated with increased tumor size (4.1 ± 0.6 vs 3.5 ± 0.9 cm, p = 0.01), operative time (351 ± 191 vs 244 ± 105 min, p = 0.02), and cranial nerve injury overall (8 (44%) vs 2 (9%), p = 0.03) compared to resections alone ( n = 19). In further subgroup analysis of large (⩾ 3 cm) tumors ( n = 37), preoperative embolization ( n = 18) was associated with increased operative time (350 ± 191 vs 198 ± 99 min, p = 0.006) and cranial nerve injury overall (8 (44%) vs 2 (11%), p = 0.03) compared to resections alone ( n = 19). There were no significant differences in estimated blood loss, transfusion requirement, or hematoma formation between any of the embolization and non-embolization subgroups. Conclusion: After controlling for tumor Shamblin classification and size, carotid body tumor resections following preoperative embolization were associated with increased operative time and inferior surgical outcomes compared to those tumors undergoing resection alone. Nonetheless, such results remain susceptible to the confounding effects of individual tumor characteristics often used in the decision to perform preoperative embolization, underscoring the need for prospective studies evaluating the utility of preoperative embolization for carotid body tumors.
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Zhan, Fenghuang, Bart Barlogie, Varant Arzoumanian, Yongsheng Huang, David R. Williams, Klaus Hollmig, Mauricio Pineda-Roman, et al. "Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis." Blood 109, no. 4 (October 5, 2006): 1692–700. http://dx.doi.org/10.1182/blood-2006-07-037077.
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Abstract Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n = 22) and patients with stringently defined MGUS/smoldering MM (n = 24) and symptomatic MM (n = 351) (P < .001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24 + 20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P = .006), was associated with low-risk clinical and molecular features and superior survival (P < .01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias.
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Haddad, Firas, and Joanna S. Saade. "Performance of ChatGPT on Ophthalmology-Related Questions Across Various Examination Levels: Observational Study." JMIR Medical Education 10 (January 18, 2024): e50842. http://dx.doi.org/10.2196/50842.
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Background ChatGPT and language learning models have gained attention recently for their ability to answer questions on various examinations across various disciplines. The question of whether ChatGPT could be used to aid in medical education is yet to be answered, particularly in the field of ophthalmology. Objective The aim of this study is to assess the ability of ChatGPT-3.5 (GPT-3.5) and ChatGPT-4.0 (GPT-4.0) to answer ophthalmology-related questions across different levels of ophthalmology training. Methods Questions from the United States Medical Licensing Examination (USMLE) steps 1 (n=44), 2 (n=60), and 3 (n=28) were extracted from AMBOSS, and 248 questions (64 easy, 122 medium, and 62 difficult questions) were extracted from the book, Ophthalmology Board Review Q&A, for the Ophthalmic Knowledge Assessment Program and the Board of Ophthalmology (OB) Written Qualifying Examination (WQE). Questions were prompted identically and inputted to GPT-3.5 and GPT-4.0. Results GPT-3.5 achieved a total of 55% (n=210) of correct answers, while GPT-4.0 achieved a total of 70% (n=270) of correct answers. GPT-3.5 answered 75% (n=33) of questions correctly in USMLE step 1, 73.33% (n=44) in USMLE step 2, 60.71% (n=17) in USMLE step 3, and 46.77% (n=116) in the OB-WQE. GPT-4.0 answered 70.45% (n=31) of questions correctly in USMLE step 1, 90.32% (n=56) in USMLE step 2, 96.43% (n=27) in USMLE step 3, and 62.90% (n=156) in the OB-WQE. GPT-3.5 performed poorer as examination levels advanced (P<.001), while GPT-4.0 performed better on USMLE steps 2 and 3 and worse on USMLE step 1 and the OB-WQE (P<.001). The coefficient of correlation (r) between ChatGPT answering correctly and human users answering correctly was 0.21 (P=.01) for GPT-3.5 as compared to –0.31 (P<.001) for GPT-4.0. GPT-3.5 performed similarly across difficulty levels, while GPT-4.0 performed more poorly with an increase in the difficulty level. Both GPT models performed significantly better on certain topics than on others. Conclusions ChatGPT is far from being considered a part of mainstream medical education. Future models with higher accuracy are needed for the platform to be effective in medical education.
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Hehlmann, Rüdiger, Michael Lauseker, Susanne Jung-Munkwitz, Armin Leitner, Martin C. Müller, Nadine Pletsch, Ulrike Proetel, et al. "Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia." Journal of Clinical Oncology 29, no. 12 (April 20, 2011): 1634–42. http://dx.doi.org/10.1200/jco.2010.32.0598.
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Purpose Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted. Patients and Methods In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months. Results A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission. Conclusion Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
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Demetriou, Eleni, and Roee Holtzer. "Mild Cognitive Impairments Moderate the Effect of Time on Verbal Fluency Performance." Journal of the International Neuropsychological Society 23, no. 1 (October 17, 2016): 44–55. http://dx.doi.org/10.1017/s1355617716000825.
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AbstractObjectives: Mild cognitive impairments (MCI) is a transitional state in aging associated with increased risk of incident dementia. The current study investigated whether MCI status moderated the effect of time on word generation during verbal fluency tasks. Specifically, the objective was to determine whether MCI status had differential effects on initial automatic or latter more effortful retrieval processes of fluency tasks. Methods: Participants were community residing older adults enrolled in a longitudinal cohort study. Of the 408 participants, 353 were normal (age=76.06±6.61; %female=57.8) and 55 were diagnosed with MCI (age=78.62±7.00; %female=52.7). Phonemic and category fluency were each administered for 60 s, but performance was recorded at three consecutive 20-s intervals (0–20 s [T1], 21–40 s [T2], 41–60 s [T3]. Separate linear mixed effects models for each fluency task were used to determine the effects of group, time, and their interaction on word generation. Results: In both fluency tasks, word generation declined as a function of time. Individuals with MCI generated fewer words compared to controls during the first 20 s of phonemic (beta=−1.56; p<.001; d=0.28) and category fluency (beta=−1.85; p<.001; d=0.37). Group by time interactions revealed that individuals with MCI demonstrated attenuated declines in word generation from the first to the second and third time intervals of both phonemic ([T1 vs. T2] beta=2.17, p=.001; d=0.41; [T1 vs. T3]beta=2.28, p=.001; d=0.45) and category ([T1 vs. T2] beta= 2.22, p=.002; d=0.50; [T1 vs. T3]beta=3.16, p<.001; d=0.71) fluency. Conclusions: Early automatic retrieval processes in verbal fluency tasks are compromised in MCI. (JINS, 2017, 23, 44–55)
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Scully, Mary-Frances, David MacGregor, Meghan Walsh, Brendan Barrett, Marc Kawaja, and Charlotte Sheppard. "The Clinical Impact of Mild Hemophilia A, Report of a Cohort Study." Blood 106, no. 11 (November 16, 2005): 3210. http://dx.doi.org/10.1182/blood.v106.11.3210.3210.
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Abstract Due to a founder affect certain regions of the Canadian province of Newfoundland and Labrador have a very high prevalence of mild Hemophilia A. To accurately plan for future health related needs of these patients, a base-line cross-sectional study of a large cohort segregating a known founder mutation (Val2016Ala) was undertaken. Characteristics of Study Participants Characteristic Affected Males Control Males P-Values (Affected vs Control) Carrier Females Control Females P-Value (Carrier vs Control) Values are expressed as number, mean*, median(interquartile range)†, or percentage Overall N 61(5–76yrs) 44(4–81yrs) 0.883 88(8–88yrs) 65(16–78yrs) 0.935 Factor VIII* 0.15(0.05) 1.29(0.37) <0.001 0.78(0.31) 1.34(0.41) <0.001 Hepatitis Bc Antibodies 15.8%(9/57) 0%(0/28) 0.012 0%(0/75) 0%(0/58) - Hepatitis C Positive 19.7%(12/61) 0%(0/33) 0.001 0%(0/88) 0%(0/65) - HIV Positive 1.6%(1/61) 0%(0/33) 0.420 0%(0/88) 0%(0/65) - Diabetes 24.4%(11/45) 6.1%(2/33) 0.031 - - - BMI†(Adults Only) 30.0(27.0–33.0) 27.0(26.0–30.0) 0.028 29.0(20–57) 28.0(19–46) .446 Statistically Significant Difference SF-36 & Colorado PE-05 Mean Scores for Affected and Unaffected Males Affected Males Affected Males Affected Males Unaffected Siblings Unaffected Siblings Unaffected Siblings t-test Difference vs References Dimension n Mean SD n Mean SD P-Value P<0.05)* Affected Males(age 23–76 years) Unaffected Siblings(age 20–81 years) SF-36 Scores General Health Scale 44 58.1 28.7 32 71.4 21.4 0.024* Role Emotional 44 89.2 19.9 33 98.0 5.5 0.007* Colorado PE-05 Musculoskeletal Scores Axial Deformity 47 0.9 1.4 33 0.2 0.8 0.008* Range of Motion 47 4.2 2.0 33 2.9 1.8 0.005* Gait 47 2.4 3.5 33 0.4 1.4 0.002* Left Ankle 47 3.3 5.0 33 1.0 2.9 0.015* Right Ankle 47 3.2 4.6 33 0.7 1.3 0.002* There was a positive association between the SF-36 General Health Scale scores and the following values of the Colorado PE-05 Scores. Gait (R -.45, p<.001), Range of Motion (R-.08, P=.508), Axial Deformity (R -.35, P<.001), Right Ankle (R -.42, p<.001), and Left Ankle (R-.49, p<.001). The association between the SF-36 Role Emotional Scales for affected males and the values of the Colorado PE-05 was also positive. Gait (R -.52, P<.001), Range of Motion (R - .30, P = .01), Axial Deformity (R -.54, P<.001), Right Ankle (R -.06, P<.001) and Left Ankle (R-.52, p<.001). No patients studied have acquired an inhibitor to Factor VIII. Obese males (BMI >30) had significantly greater impairment in their Range of Motion than non-obese males (4.59 vs (3.34), p<0.05) independent of whether or not they had hemophilia. These results are consistent with our clinical experience that mild Hemophilia A causes episodic bleeding, lack of recognition and delayed treatment leads to significant morbidity. The association with diabetes was unexpected. Future interventions will now focus on prevention and early treatment of ankle bleeds and will include strategies to reduce the risk of obesity.
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Saju, Leya, Debra Rosenbaum, Deanne Wilson-Costello, Katherine Slain, Anne Stormorken, and Steven L. Shein. "Acute Neuro-Functional Morbidity Upon Discharge From the Pediatric Intensive Care Unit After Critical Bronchiolitis." Hospital Pediatrics 12, no. 4 (March 22, 2022): 353–58. http://dx.doi.org/10.1542/hpeds.2021-006166.
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BACKGROUND AND OBJECTIVE Improved survival has shifted research focus toward understanding alternate PICU outcomes, including neurocognitive and functional changes. Bronchiolitis is a common PICU diagnosis, but its neuro-functional outcomes have not been adequately described in contemporary literature. The objective of the study is to describe the epidemiology and associated clinical characteristics of acute neuro-functional morbidity (ANFM) in critical bronchiolitis. METHODS Patients <2 years old admitted with bronchiolitis between 2014 and 2016 were identified. Demographics, medical history, length of stay (LOS), and need for intubation were collected. Children with a history of neurologic illness or illness associated with neurologic sequelae were termed “high risk”; others were termed “low risk.” ANFM was defined both at PICU and hospital discharge as the presence of swallowing difficulty, nasogastric tube feeds, hypotonia, or lethargy. Variables were compared by using χ2 and Wilcoxon rank tests. RESULTS Among 417 children, 16.7% had ANFM, predominantly swallow difficulties (95.7%). Children with ANFM had lower weight (5.9 [4.4–8.2] vs 7.7 [5.5–9.7] kg, P = .001), longer LOS (6.6 [2.5–13.3] vs 1.9 [0.9–3.5] days, P < .001), intubation (51.4% vs 6.1%, P < .001) and high-risk status (37.1% vs 8.4%, P < .001). Among 362 low risk subjects, ANFM was identified in 44 (12%). In a multivariate logistic regression model, high-risk status, intubation, and ICU LOS were associated with ANFM. ANFM persisted to hospital discharge in 46% of cases. CONCLUSIONS One out of 6 patients with critical bronchiolitis had documentation consistent with ANFM at PICU discharge. Risk factors included previous neurologic conditions, longer LOS, and intubation. Many were low-risk and/or did not require intubation, indicating a risk for neuro-functional morbidities despite moderate acuity.
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Kumanthem, P., L. Kumar, D. Janga, R. Hariprasad, R. Patnaik, A. Gupta, S. Kumar, and R. Singh. "Recurrent epithelial ovarian cancer (EOC): What determines the outcome?" Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 15003. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.15003.
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15003 Background: Recurrent EOC is a common clinical problem and treatment is not curative. We retrospectively analyzed the data on 354 patients with recurrent EOC to determine the impact of various prognostic factors on outcome. Methods: Between August, 1989 and June, 2005, 354 patients (median age 49 years, range, 28 to 80 years) were diagnosed as recurrent EOC. 259 patients received chemotherapy alone, 44 were treated with combination of secondary debulking surgery and chemotherapy or radiotherapy. Remaining 51 (14.4%) patients had no treatment. Main types of salvage chemotherapy included- cisplatin + cyclophosphamide (CP, n = 53), CP + adriamycin (CAP, n = 68), paclitaxel + carboplatin/cisplatin (TP, n = 78). 10 factors were analyzed for survival. Results: 56.5% of patients responded to chemotherapy; complete (CR)-34.2% and partial response (PR) in 22.3% of patients. 124 (35%) patients had no response or progressive disease. 10 (2.8%) died of chemo-toxicity and in remaining 20 status was not known. Median overall survival for patients who received treatment is 19 months vs 3 months for 51 patients who did not receive treatment, p < .001. Predictors of survival were - response to salvage chemotherapy (20 vs 8 months, p < .001), treatment-free interval (>6 months vs ≤ 6 months, 23 vs 9 months p < .001), site of relapse (single vs multiple, 22 vs 16 months, p < .001), Chemotherapy regimen (CP vs CAP vs Paclitaxel + carboplatin) p < .003 on univariate analysis. Age (≤50 years vs >50 years, p = 0.02), initial stage (I vs II vs III vs IV, p = 0.079), histology (serous vs others, p = 0.849), site of relapse (vault vs others, p = 0.156) were not significant predictors. On multivariate logistic regression analysis- response to salvage chemotherapy (HR 0.21, 95% CI 0.15–0.30), treatment-free interval (HR 0.36, 95% CI, 0.20–0.64), and site of relapse (vault vs others, HR 1.22, 95% CI 0.78–1.94) attained significance among 10 factors analyzed. Conclusions: Present study confirms that all patients with recurrent EOC should receive treatment. Response to salvage chemotherapy, a longer treatment-free interval (>6 months) and single site of metastasis are predictors of significantly superior outcome. No significant financial relationships to disclose.
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Chouhab, Y., T. Lefebvre, C. Forestier, P. Parsis, and M. Martinez. "Analyse des courriers de plainte adressés au service d’urgence d’un centre hospitalier général." Annales françaises de médecine d’urgence 9, no. 6 (June 17, 2019): 362–68. http://dx.doi.org/10.3166/afmu-2019-0176.
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Objectif : L’objectif principal de notre travail était d’analyser les courriers de plainte (CP) adressés à un service d’urgence (SU). L’objectif secondaire était de déterminer s’il existait une corrélation entre CP et temporalité de passage au SU. Matériel et méthodes : Étude rétrospective monocentrique sur six ans portant sur les CP concernant les prises en charge en SU. Résultats : Quatre-vingt-un CP ont été analysés, la moyenne annuelle et l’incidence étaient de 13,5 CP/an et de 5,5 CP/ 10 000 passages. L’incidence était de 3,5 CP/10 000 passages pour les enfants vs 6,1 CP/10 000 passages pour les adultes (p = 0,11). Le plaignant était la famille dans 44 CP (55 %) et le patient dans 34 CP (42 %). Il n’y avait pas de différence significative entre le jour et la nuit (5,7 CP/10 000 vs 4,8 CP/ 10 000 passages ; p = 0,57) ni entre horaires de garde et horaires hors garde (5,6 CP/10 000 vs 5,2 CP/10 000 passages ; p = 0,78). Nous avons dénombré 133 doléances, avec une cause médicale dans 64 CP (48 %), une cause organisationnelle dans 44 CP (33 %), une cause relationnelle dans 25 CP (19 %). Une indemnisation financière a été demandée dans 13 CP (16 %) et a été accordée pour deux dossiers (2 %). Aucun CP n’a entraîné de poursuite en justice. Conclusion : L’incidence des CP de notre SU reste dans la moyenne basse des données retrouvées au niveau national et sans relation avec la temporalité du passage. L’analyse des CP permet d’améliorer la qualité de la prise en charge et de proposer des mesures correctives en relation avec la commission des usagers.
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Mohan, Sanjay R., Paul Elson, Ramon V. Tiu, Anjali Advani, Yogen Saunthararajah, Ronald Sobecks, Matt Kalaycio, Edward Copelan, Jaroslaw P. Maciejewski, and Mikkael A. Sekeres. "Duration of Antecedent Complete Blood Cell Count (CBC) Abnormalities Predicts Response and Survival Rates In De Novo and Secondary AML." Blood 116, no. 21 (November 19, 2010): 1040. http://dx.doi.org/10.1182/blood.v116.21.1040.1040.
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Abstract Abstract 1040 Introduction: Secondary acute myeloid leukemia (sAML) is a heterogeneous disease classification comprising patients (pts) with a history of myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) and pts with prior exposure to chemotherapy or radiation. Though sAML pts typically have lower complete remission (CR) and worse overall survival (OS) rates with induction chemotherapy, it is unknown whether pts with antecedent CBC abnormalities but without formal hematologic diagnoses prior to AML display similar poor outcomes. Methods: We retrospectively evaluated all pts with newly diagnosed, pathologically-confirmed AML treated with cytarabine-based induction chemotherapy at a single institution between 1997 and 2008 to identify both those with known antecedent hematologic disorders and those with antecedent CBC abnormalities irrespective of preceding myeloid diagnosis. sAML was classified as AML from MDS, AML from MPN, and therapy-related AML (t-AML); these groups were compared to pts classified as de novo AML with antecedent CBC abnormalities using univariate and multivariate regression analyses and recursive partitioning to determine cut-points. A CBC abnormality was defined as persistent white blood cell count (WBC) <3.5 or >12 k/uL, hemoglobin <10 or >16 g/dL, or platelet count <100 or >500 k/uL. Results: Of 413 AML pts who received induction chemotherapy, 140 were identified with sAML or antecedent CBC abnormalities; 46 (33%) had t-AML, 41 (29%) had AML from MDS, 23 (16%) had AML from MPN, and 30 (21%) had de novo AML with an antecedent CBC abnormality. The median age at AML diagnosis was 62 years (range 24–77) and differed among groups (MDS 67 years, MPN 61, t-AML 80, and de novo 62, p=.003); 49% were male. Overall, the median time from identification of a CBC abnormality to AML diagnosis was 5 months (range 2–83). The time from preceding event to sAML differed among groups (MDS 7 months, MPN 50, t-AML 53, p<.001). Unfavorable risk cytogenetics were more frequent in MDS (44%) and MPN (42%) than in t-AML (26%) or de novo (27%, p=.008). Median presenting WBC differed among groups (MDS 4.0 k/uL, MPN 9.9, t-AML 6.9, de novo with antecedent CNC abnormalities 2.7, p=.02). Among pts with de novo AML with antecedent CBC abnormalities, 18 (60%) had abnormal WBCs, 13 (43%) had anemia, and 8 (27%) had thrombocytopenia; 7 (23%) had multilineage cytopenias. Univariable analysis of CR rates among sAML pts without an antecedent CBC abnormality identified age <60 (71% vs 50% in age ≥ 60, p=.02), unfavorable cytogenetics (28% vs 75% in intermediate or favorable, p<.0001), and AML precursor (34% in MDS, 61% in MPS, and 65% in t-AML, p=.002) as significant factors. t-AML also exhibited better OS compared to prior MDS (hazard ratio [HR] 2.40, 95% confidence interval [CI] 1.38–4.19, p=.002) or MPN (HR 1.84, 95% CI 0.95–3.56, p=.07). In multivariable analysis, unfavorable cytogenetics (p=.0001) and prior MDS or MPN (vs t-AML) (HR 1.83, 95% CI 1.04–4.05), p=.04) were prognostic for worse OS. However, when an antecedent CBC abnormality was identified (n=55), t-AML exhibited poorer OS compared to prior MDS (p=.04) and de novo AML with a CBC abnormality (HR 4.79, 95% CI 1.95–11.77, p=.001). Pts whose CBC abnormality was present for ≥10 months prior to AML diagnosis had poorer OS than those for whom it was present <10 months (HR 2.06, 95% CI 1.08–3.93, p=.03), controlling for factors such as age and cytogenetics. By recursive partition analysis, pts with prior MDS, prior MPN, or de novo AML with CBC abnormality of fewer than 10 months had significantly longer median OS (20.8 months) than those with a CBC abnormality of greater than 10 months or with t-AML regardless of duration of CBC abnormality (5.9 months, HR 3.27, 95% CI 1.73–6.20, p=.0003) (Figure 1), and also exhibited higher CR rate to induction chemotherapy (78% vs 39%, p=.005). Conclusions: The presence of an antecedent CBC abnormality of greater than 10 months in both de novo and sAML patients negatively impacts CR and OS following induction chemotherapy. These pts should be considered for alternative therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.
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Holm, Jan, Steen Ingemann Hansen, and Mimi Høier-Madsen. "A high-affinity folate binding protein in human amniotic fluid. Radioligand binding characteristics, immunological properties and molecular size." Bioscience Reports 10, no. 1 (February 1, 1990): 79–85. http://dx.doi.org/10.1007/bf01116855.
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The presence of a folate binding protein of high-affinity type (affinity constant 5 · 109M−1, maximum folate binding 3 nM) in human amniotic fluid was demonstrated in equilibrium dialysis experiments (37°C, pH 7.4) with the radioligand3H-folate. Dissociation of3H-folate from the binding protein was slow at pH 7.4 but rapid at pH 3.5. By use of rabbit antibodies against low molecular weight folate binding protein from human milk we determined the concentration of folate binding protein in 5 amniotic fluids (range 1.5–2.3 nM) in an Enzyme-Linked Immunosorbent Assay (ELISA). ultrogel AcA 44 chromatography of amniotic fluid showed that immunoreactive and radioligand bound folate binding protein coeluted in two peaks: a major one (Mr~25 000) and a minor one (Mr~100 000).
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Wattel, E., A. Guerci, B. Hecquet, T. Economopoulos, A. Copplestone, B. Mahe, ME Couteaux, et al. "A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group." Blood 88, no. 7 (October 1, 1996): 2480–87. http://dx.doi.org/10.1182/blood.v88.7.2480.bloodjournal8872480.
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We performed a randomized study of hydroxyurea (HY) versus VP16 in advanced chronic myelomonocytic leukemia (CMML) patients with CMML (according to French-American-British group criteria) and either documented visceral involvement (excluding liver and spleen infiltration) or at least 2 of the following: (1) neutrophils > 16 x 10(9)/I (2) Hemoglobin < 10 g/dL (3) platelets < 100 x 10(9)/L (4) marrow blasts > 5% (5) spleen > 5 cm below costal margin were eligible for this trial. Initial dosage was 1 g/d for HY and 150 mg/week for VP16, orally (doubled in case of visceral involvement). Doses were scheduled to be escalated up to HY 4 g/d and VP16 600 mg/week in the absence of response, and finally adjusted to maintain white blood cells (WBCs) between 5 and 10 x 10(9)/L. Crossing over was scheduled only in case of life threatening visceral involvement or major progression. The major endpoint of the study was survival. The study was closed on first interim analysis that showed a superiority of HY over VP16, after inclusion of 105 pts (HY arm: 53, VP16 arm: 52). Results of the second interim analysis, performed 7 months later, are presented here. Median age was 71 (range 38 to 91), median WBC count 20.10(9)/L (range 10 to 187). Thirteen pts had visceral involvement (3 serous effusions, 8 cutaneous infiltrations, 1 kidney, 1 bone infiltrations). Initial characteristics were similar in the HY and VP16 groups. Median follow up was 11 months in both groups (range 1 to 43+). Response to treatment was seen in 60% of the pts in the HY group, versus 36%, respectively, in the VP16 group (P = .02). Time to response was significantly shorter in the HY group (2.1 v 3.5 months, in the VP16 group, P = .003) and response duration was significantly longer in the HY group (median 24 v 9 months, in the VP16 group, P = .0004). The response rate of patients with visceral involvement was 3 out of 7 in the VP16 arm versus 5 out of 6 in the HY group. Three of the 10 pts crossed over from HY to VP16 responded as compared to 6 pts of the 11 pts crossed over from VP16 to HY. HY yielded better response on leukocytosis (P = .002). The effect on splenomegaly platelets, on hemoglobin level and transfusion requirement was similar in the 2 treatment groups. A significantly higher incidence of alopecia was noted in the VP16 arm (20% v 3%, P = .03). Fourteen (27%) and 20 (38%) patients in the HY and the VP16 group respectively, progressed to acute myeloid leukemia (difference NS). Twenty five (53%) and 44 (83%) patients in the HY and the VP16 group, respectively, had died (P = .002). Median actuarial survival was 20 months in the HY arm, versus 9 months in the VP16 arm (P < 10(-4)). Main factors associated with poor survival were allocation to the VP16 arm, “unfavorable” karyotype (ie, monosomy 7 or complex abnormalities) and anemia. In the HY group, unfavorable karyotype (P = .006), and low hemoglobin level (P = .004) were significantly associated with low response rates. Prognostic factors for poor survival in the HY group were also unfavorable karyotype (P = .001), and low hemoglobin level (P < 10(-4). In conclusion, we found that HY gave higher response rates and better survival than VP16 in advanced CMML. However, even with HY responses were only partial and survival was generally poor. This stresses the need for new agents in the treatment of CMML, that will have to be compared with HY in future randomized studies.
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Porro, A., T. Luster, C. Gao, C. George, M. Parizi-Robinson, D. Quigley, P. Zinke, and M. K. Scullin. "0197 Chronotype is Influenced by Behavioral Choices and Can Fluctuate Across the Semester in STEM Students." Sleep 43, Supplement_1 (April 2020): A77—A78. http://dx.doi.org/10.1093/sleep/zsaa056.195.
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Abstract Introduction A delay in endogenous biological rhythms is assumed to cause undergraduate students to be “night owls,” but neurodevelopmental effects may only partially explain chronotype (circadian preference). Instead, perceived chronotype in students may result from poor sleep hygiene practices including bedtime social media use, afternoon caffeine consumption, and daytime napping. If so, then chronotype should be malleable in students to the extent that behavioral choices change. Methods We surveyed 1,120 undergraduate students who were enrolled in STEM courses across up to 3 time points during the semester. The survey assessed perceived chronotype (morning/evening type), global sleep quality, and daily habits that impact alertness and sleep hygiene (e.g., social media usage and timing, caffeine consumption and timing, and napping behavior). Results Relative to Morning Types, students who perceived themselves as being Evening Types showed 23.1% greater bedtime social media usage (t=3.14, p=.002), 35.1% greater daytime napping duration (t=4.44, p<.001), and a 44 minute later average time of caffeine consumption (even though total caffeine consumption was reduced; t=2.30, p=.022). Evening Types also reported lower subjective health (t=3.55, p<.001), with 14.2% of the association between chronotype and subjective health being mediated by bedtime social media use (direct effect: b=0.050, p=.002; indirect effect: b=0.009, p<.05). Ninety-one students reported switching from being Evening Types at baseline to Morning Types at a later survey; those who switched to Morning Types used less social media and consumed less caffeine after 5pm and they showed significant improvements across the semester in sleep duration, sleep quality, and exam scores (ps<.05). Conclusion Perceived chronotype is related to social media and caffeine consumption behaviors and is modifiable. Students who perceive themselves as night owls may find better health and academic success if they behave like morning larks. Support National Science Foundation (DRL 1920730)
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Bardet, Stéphane, Renaud Ciappuccini, Elske Quak, Jean-Pierre Rame, David Blanchard, Dominique de Raucourt, Emmanuel Babin, Jean-Jacques Michels, Dominique Vaur, and Natacha Heutte. "Prognostic Value of Microscopic Lymph Node Involvement in Patients With Papillary Thyroid Cancer." Journal of Clinical Endocrinology & Metabolism 100, no. 1 (January 1, 2015): 132–40. http://dx.doi.org/10.1210/jc.2014-1199.
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Abstract Context: The impact of microscopic nodal involvement on the risk of persistent/recurrent disease (PRD) remains controversial in patients with papillary thyroid carcinoma (PTC). Objective: The goal of the study was to assess the risk of PRD and the 4-year outcome in PTC patients according to their initial nodal status [pNx, pN0, pN1 microscopic (cN0/pN1) or pN1 macroscopic (cN1/pN1)]. Design: We conducted a retrospective cohort study. Patients: The study included 305 consecutive PTC patients referred for radioiodine ablation from 2006 to 2011. Main Outcome Measure: We evaluated the risk of structural PRD and the disease status at the last follow-up. At ablation, persistent disease was consistently assessed by using post-radioiodine ablation scintigraphy combining total body scan and neck and thorax single-photon computed tomography-computed tomography (SPECT-CT) acquisition. Results: Of 305 patients, 128 (42%) were pNx, 84 (28%) pN0, 44 (14%) pN1 microscopic, and 49 (16%) pN1 macroscopic. The 4-year cumulative risk of PRD was higher in pN1 macroscopic than in pN1 microscopic patients (49% vs 24%, P = .03), and higher in pN1 microscopic than in pN0 (12%, P = .01) or pNx patients (6%, P < .001). On multivariate analysis, tumor size of 20 mm or greater [relative risk (RR) 3.4; P = .0001], extrathyroid extension (RR 2.6; P < .003), pN1 macroscopic (RR 4.5; P < .0001), and pN1 microscopic (RR 2.5; P < .02) were independent risk factors for PRD. At the last visit, the proportion of patients with no evidence of disease decreased from pNx (98%), pN0 (93%), and pN1 microscopic (89%) to pN1 macroscopic patients (70%) (P < .0001, Cochran-Armitage trend test). Extrathyroid extension (odds ratio 9.7; P < .0001) and N1 macroscopic (OR 4.9; P < .001) independently predicted persistent disease at the last visit, but N1 microscopic did not. Conclusions: Patients with microscopic lymph node involvement present an intermediate outcome between that observed in pN0-pNx patients and pN1 macroscopic patients. These data may justify modifications to the risk recurrence staging systems.
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Belli, Carolina, Ronald Feitosa Pinheiro, Maria Gabriela Flores, Silvia M. M. Magalhaes, Laura Kornblihtt, Alicia Enrico, Juliana Cordeiro, et al. "Clinical Characteristics and Prognosis in South-American Patients with Myelodysplastic Syndrome: A Multicenter Study." Blood 124, no. 21 (December 6, 2014): 4651. http://dx.doi.org/10.1182/blood.v124.21.4651.4651.
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Abstract There are previous reported data describing differences between European and Asian patients with Myelodysplastic Syndromes (MDS), and little is known about South-American (SA) patients. Our aim was to describe clinical characteristic of SA MDS population, to compare our series with diverse ethnicity, to evaluate scoring systems and prognostic factors. We retrospectively analysed a series of 1080 patients with de novo MDS (1981-2014) from Argentine (Ar-635), Brazil (Br-345), and Chile (Ch-100). Patients were classified following FAB and WHO criteria, excluding patients with bone marrow (BM) blasts >30% and CMML with white blood cells count >12x109/L. Patients undergoing hematopoietic stem cell transplantation (5%) or hypomethylating therapy (12%) were censored at treatment initiation. Chilean patients were younger (mean age: 59 vs 66-Ar, p<.001 and vs 65 years old-Br, p=.003), with a female preponderance (ratio M/F: 0.8-Ch, 1.3-Ar, 1.3-Br, p=.061). Since Ch did not include patients with CMML, distributions among FAB and WHO categories were different (p<.001). Br series showed a higher predominance of RARS (17% vs 9%-Ar vs 1%-Ch), and a lower percentage of RCMD (38% vs 43%-Ar vs 49%-Ch), while the frequency of the other subtypes were comparable. BM blast categories according to IPSS and IPSS-R were similar (p=.626 and =.508). Hemoglobin (Hb) level was significantly higher in Ar series (9.6g/dL vs 8.6g/dL-Ch, p<.001, and vs 8.7g/dL-Br, p=.002), with no differences in ANC and platelets (p=.842 and .763). There were no differences in the distribution of cytogenetic groups of risk (CGR) according to IPSS (p=.157). With respect to IPSS-R CGR distribution, Ar series showed a higher frequency of Very Good and Intermediate findings (4% and 19%, vs 2% and 15%–Br, 0% and 9%-Ch, respectively, p=.037). The distribution among IPSS categories was similar with a higher predominance of the high risk group in Ch (17%, 9%-Ar, 9%-Br, p=.056). IPSS-R distribution confirmed a higher frequency of very high risk in Ch series (20%, 13%-Br, 10%-Ar) and a lower predominance of very low risk (5%, 15%-Br and 22%-Ar) (p<.001). We also evaluated different prognostic factors in each MDS population and in the whole population (table). Overall survival (OS) was lower in Ch patients, consistent with the higher prevalence of higher risk group categories (36 months vs 56m-Ar; 63m-Br, p=.026). Hb, BM blast, CGR, IPSS and IPSS-R were useful to predict survival in the three series and in the overall SA MDS population. Age was not useful for Br patients and showed a borderline influence for the whole SA series. The ANC was neither a predictive variable for Br nor for Ch patients, and platelets count was not useful in Ch series. Epidemiological and clinical characteristics, distribution among prognostic subgroups and OS were similar for Ar and Br compared to Ch MDS series. This will need further analysis in a larger group of patients. Nevertheless, the IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole SA population. Abstract 4651. Table 1 Argentine Brazil ChileWhole SASurvival (50%, m)pSurvivalpSurvivalpSurvivalpAll patients56633655.026Gender M/F42/66<.00140/87=.00117/49ns41/70<.001Age ≤/>60 years77/50=.01944/68ns74/31=.00264/49=.052Hb ≥10/8-<10/<8g/dL98/50/31<.001135/44/36<.001NR/15/13=.002121/43/30<.001ANC ≥/<800/µL58/37=.03668/36=.06535/NRns57/37=.046Platelets ≥100/50-<100/<50 x103/µL71/44/40<.00170/47/40=.02941/36/17ns63/44/29<.001BM Blast ≤2/>2-<5/5-10/>10%80/63/21/17<.00175/70/36/11<.00148/36/15/7<.00177/60/25/13<.001CGR VG-G/I/P/VP66/35/20/12<.00170/20/9/16<.00174/13/4/7<.00168/32/16/12<.001IPSS121/44/19/14<.001116/55/13/9<.00150/49/6/7<.001116/49/18/10<.001IPSS-R136/64/34/18/14<.001135/70/32/17/11<.001NR/50/NR/13/6<.001135/70/41/18/11<.001 Disclosures No relevant conflicts of interest to declare.
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Virappane, Priya, Rosemary E. Gale, Robert Hills, Ioannis Kakkas, Karin Summers, Jane Stevens, Claire Green, et al. "Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated with Chemoresistance in Normal Karyotype Acute Myeloid Leukemia." Blood 110, no. 11 (November 16, 2007): 361. http://dx.doi.org/10.1182/blood.v110.11.361.361.
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Abstract The Wilms’ tumour 1 (WT1) gene is highly expressed in various types of leukemia, suggesting a role both as a target for immunotherapy and a means for monitoring minimal residual disease. More recently WT1 has been recognised as an important mutational target in normal karyotype (NK) acute myeloid leukemia (AML), with clustering of mutations to exons 7 and 9. In this study, we set out to determine the clinical relevance of these mutations. Diagnostic DNA samples were obtained from peripheral blood or bone marrow of 470 young adult AML patients entered into the UK Medical Research Council AML 10 and 12 trials. Mutation analysis was performed using standard PCR-based direct sequencing and/or high-resolution capillary electrophoresis of exons 7 and 9. Overall, 51 mutations were observed in 47 cases (10%). Of these, 42 cases had 46 frameshift mutations arising from insertions (n=41) or deletions (n=5) of between 1 and 28 bps that would result in disruption of the C-terminal DNA binding domain of the protein. Median mutant level was 45% (range 8–86%). The remaining 5 cases were non-synonymous amino acid substitutions in exon 9, D396N (n=3) which is implicated in Denys-Drash syndrome, and 1 each of H397Y and H397Q that are of unknown functional significance. There was a borderline inverse relationship between the presence of WT1 mutations and NPM1 exon 12 mutations (p=.05), and an increased proportion of FLT3-ITDs in WT1 mutant cases (p=.08). In order to determine the clinical relevance of WT1 mutations we compared patient characteristics between WT1 mutated and WT1 wild-type cases. There was no difference between the 2 groups in age, gender, presenting WBC, or type of AML (de novo/secondary). Patients with WT1 mutations had an inferior response to therapy compared to WT1 wild-type cases (complete remission [CR] 79% Vs 90% respectively, odds ratio [OR] 3.02, 95% confidence intervals [CI] 1.17–7.82, p=.02) which was due to a higher rate of resistant disease (RD) (15% Vs 4%, OR 9.33, CI 2.38–36.6, p=.001). In univariate analysis mutated cases also had a significantly reduced disease free survival (DFS), 22% Vs 44% at 5 years (OR 2.16, CI 1.32–3.55, p=.005) and overall survival (OS), 26% Vs 47%, OR 1.91, CI 1.23–2.95, p=.007). In multivariate analysis considering age, gender, type of leukemia, WBC, FLT3-ITD and NPM1 mutant status, a WT1 mutation remained an independent adverse prognostic factor for both response to therapy (CR: OR 3.19, CI 1.25–8.13, p=.01; RD: OR 4.93, CI 1.58–15.37, p=.006) and survival (DFS: OR 1.60, CI 1.07–2.38, p=.02; OS: OR 1.52, CI 1.05–2.18, p=.03). These results indicate that WT1 mutations are an additional prognostic marker in NK AML and may be suitable for targeted therapy.
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Marquez, Carina, Andrew D. Kerkhoff, John Schrom, Susana Rojas, Douglas Black, Anthea Mitchell, Chung-Yu Wang, et al. "COVID-19 Symptoms and Duration of Rapid Antigen Test Positivity at a Community Testing and Surveillance Site During Pre-Delta, Delta, and Omicron BA.1 Periods." JAMA Network Open 5, no. 10 (October 10, 2022): e2235844. http://dx.doi.org/10.1001/jamanetworkopen.2022.35844.
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ImportanceCharacterizing the clinical symptoms and evolution of community-based SARS-CoV-2 infections may inform health practitioners and public health officials in a rapidly changing landscape of population immunity and viral variants.ObjectivesTo compare COVID-19 symptoms among people testing positive with a rapid antigen test (RAT) during the Omicron BA.1 variant period (December 1, 2021, to January 30, 2022) with the pre-Delta (January 10 to May 31, 2021) and Delta (June 1 to November 30, 2021) variant periods and to assess the duration of RAT positivity during the Omicron BA.1 surge.Design, Setting, and ParticipantsThis cross-sectional study was conducted from January 10, 2021, to January 31, 2022, at a walk-up community COVID-19 testing site in San Francisco, California. Participants included children and adults seeking COVID-19 testing with an RAT, regardless of age, vaccine status, or symptoms.Main Outcomes and MeasuresFisher exact tests or χ2 tests were used to compare COVID-19 symptoms during the Omicron BA.1 period with the pre-Delta and Delta periods for vaccination status and age group. Among people returning for repeated testing during the Omicron period, the proportion with a positive RAT between 4 and 14 days from symptom onset or since first positive test if asymptomatic was estimated.ResultsAmong 63 277 persons tested (median [IQR] age, 32 [21-44] years, with 12.0% younger than 12 years; 52.0% women; and 68.5% Latinx), a total of 18 301 people (28.9%) reported symptoms, of whom 4565 (24.9%) tested positive for COVID-19. During the Omicron BA.1 period, 3032 of 7283 symptomatic participants (41.6%) tested positive, and the numbers of these reporting cough and sore throat were higher than during pre-Delta and Delta periods (cough: 2044 [67.4%] vs 546 [51.3%] of 1065 participants, P &lt; .001 for pre-Delta, and 281 [60.0%] of 468 participants, P = .002, for Delta; sore throat: 1316 [43.4%] vs 315 [29.6%] of 1065 participants, P &lt; .001 for pre-Delta, and 136 [29.1%] of 468 participants, P &lt; .001, for Delta). Compared with the 1065 patients with positive test results in the pre-Delta period, congestion among the 3032 with positive results during the Omicron BA.1 period was more common (1177 [38.8%] vs 294 [27.6%] participants, P &lt; .001), and loss of taste or smell (160 [5.3%] vs 183 [17.2%] participants, P &lt; .001) and fever (921 [30.4%] vs 369 [34.7%] participants, P = .01) were less common. In addition, during the Omicron BA.1 period, fever was less common among the people with positive test results who had received a vaccine booster compared with those with positive test results who were unvaccinated (97 [22.5%] of 432 vs 42 [36.2%] of 116 participants, P = .003), and fever and myalgia were less common among participants who had received a booster compared with those with positive results who had received only a primary series (fever: 97 [22.5%] of 432 vs 559 [32.8%] of 1705 participants, P &lt; .001; myalgia: 115 [26.6%] of 432 vs 580 [34.0%] of 1705 participants, P = .003). During the Omicron BA.1 period, 5 days after symptom onset, 507 of 1613 people (31.1%) with COVID-19 stated that their symptoms were similar, and 95 people (5.9%) reported worsening symptoms. Among people testing positive, 80.2% of participants who were symptomatic and retested remained positive 5 days after symptom onset.Conclusions and RelevanceIn this cross-sectional study, COVID-19 upper respiratory tract symptoms were more commonly reported during the Omicron BA.1 period than during the pre-Delta and Delta periods, with differences by vaccination status. Rapid antigen test positivity remained high 5 days after symptom onset, supporting guidelines requiring a negative test to inform the length of the isolation period.
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Ellis, Matthew J., Yu Tao, Oliver Young, Sharon White, Alan D. Proia, Julliette Murray, Lorna Renshaw, et al. "Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole." Journal of Clinical Oncology 24, no. 19 (July 1, 2006): 3019–25. http://dx.doi.org/10.1200/jco.2005.04.3034.
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Purpose To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) –positive (ER ≥ 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials. Patients and Methods FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67. Results HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors. Conclusion Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.
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Abrisqueta, Pau, Graham W. Slack, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Laurie H. Sehn, Kerry J. Savage, and Diego Villa. "Outcome of Observation As Initial Strategy in Patients with Mantle Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 2699. http://dx.doi.org/10.1182/blood.v126.23.2699.2699.
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Abstract Background Patients with mantle cell lymphoma (MCL) follow a heterogeneous clinical course ranging from very indolent to very aggressive. While patients with MCL generally require treatment initiation shortly after diagnosis, it is unclear whether deferring treatment in patients with "indolent" MCL affects their overall outcome. Because it is difficult to identify such patients at the time of diagnosis, their course can only be retrospectively described as indolent after a prolonged period of observation. The aim of this study was to describe the subgroup of patients with MCL who underwent observation as their initial management, including their clinical and biological characteristics and outcomes. Methods Patients diagnosed with MCL from 1998-2015 who were initially observed for ≥3 months from the date of definitive diagnosis were identified in the BCCA Lymphoid Cancer and Pharmacy Databases. Pathology was centrally reviewed at the time of diagnosis, and only cases positive for CCND1 by immunohistochemistry and/or t(11;14) by FISH were included. During the study period, there were no predefined criteria guiding observation or active treatment. Eventual treatment indications included high tumor burden, disease associated symptoms or peripheral blood cytopenias. Clinical-biological features at diagnosis, treatment and outcomes, were analyzed. Results A total of 725 patients with MCL were initially identified, but 286 were excluded: missing data (n=179), treatment refusal (n=7), no treatment due to frailty (n=16), or absence of CCDN1 or t(11;14) confirmation (n=84). 365 (83%) patients received early treatment (ET) and 74 (17%) were observed >3 months (OBS), as shown in Table 1. In the OBS group, 52 (71%) patients had measurable lymph nodes at presentation, 16 (22%) a non-nodal presentation (defined as peripheral blood, bone marrow, and/or spleen only), and 5 (7%) only had gastro-intestinal involvement. Patients in the OBS group were older, with favorable presenting features including good performance status, less frequent B symptoms or increased LDH, and lower Ki67 (<30% vs ≥ 30%) than the ET group. However, MIPI scores were similar between both groups. The majority of patients received rituximab-containing chemotherapy (most commonly R-CHOP or R-bendamustine) at the time of initial treatment in both the ET group (70%) and the OBS group (72%). In the OBS cohort, with a median follow-up of 47 months (range 3.4 - 158 months) in living patients, the median time to treatment (TtT) was 35.5 months (range 5 - 79 months). 10 patients (14%) were observed for > 5 years without requiring treatment. Factors associated with longer TtT included clinical presentation (non-nodal vs nodal, median not reached vs 29 months; P=.005) and Ki-67 (<30% vs ≥ 30%, median 59 vs 20 months, P=.033). Median OS was significantly longer in the OBS group than in the ET group (66 vs 50 months, respectively, P=.024) reflecting the more favorable disease characteristics of the OBS group. Clinical presentation (ie, non-nodal vs nodal) was the only factor associated with OS (median 123 vs 47 months, P=.003) in the OBS group. Finally, the median OS from date of treatment initiation for patients eventually requiring therapy in the OBS group was 34.4 months. With a median age at treatment initiation of 71 yrs (range 40 - 91 yrs) in the OBS group, OS was not significantly different in comparison with the ET group when the analysis was adjusted by age at treatment. Conclusions A subgroup of patients with MCL may be safely observed at diagnosis of the disease without negatively impacting their outcomes, including not only those patients with non-nodal presentation but also asymptomatic patients with low burden nodal presentation, particularly those with a low proliferative rate. Table 1. Patients characteristics by treatment group Observation (n=74) Early treatment (N=365) p-value Median age, years (range) 68 (39 - 90) 66 (22 - 94) 0.05 Male sex 47/74 (64%) 262/365 (72%) 0.16 Performance status >1 7/71 (10%) 97/337 (29%) <.001 B symptoms 1/73 (1%) 116/353 (33%) <.001 Elevated LDH 5/66 (8%) 110/310 (36%) <.001 Ann Arbor Stage I/II 7/73 (10%) 40/357 (11%) 0.80 Ki-67 ≥30% 6/24 (25%) 89/151 (59%) 0.002 Blastoid morphology 0/74 (0) 44/365 (12%) <.001 Nodular pattern 30/58 (52%) 139/304 (46%) 0.40 MIPI 0.73 - Low risk 20/64 (31%) 83/288 (29%) - Intermediate risk 19/64 (30%) 77/288 (27%) - High risk 25/64 (39%) 128/288 (44%) Disclosures Scott: Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Villa:Roche: Research Funding.
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Ohnuma, Hiroyuki, Yasushi Sato, Ginji Omori, Naoki Onoyama, Saki Ameda, Ryo Ito, Kota Hamaguchi, et al. "Survival benefit of conversion therapy after intensive chemotherapy for unresectable metastatic gastric cancer: A propensity score-matched analysis." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 354. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.354.
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354 Background: The significance of conversion therapy (CT), whereby patients (pts) with unresectable disease respond to chemotherapy and subsequently receive surgery with curative intent (adjuvant surgery: AS), has been specifically established for metastatic colorectal cancer. However, such a strategy for advanced or recurrent gastric cancer (AGC) remains controversial. This study aims to clarify the clinical significance of CT for AGC. Methods: In this retrospective multi-institution observational study, we analyzed 168 AGC pts who received chemotherapy consisting of docetaxel, cisplatin or oxaliplatin, and S-1 ± trastuzumab between 2003 and 2019. We divided pts into two groups: those who underwent CT (group CT) or chemotherapy only (group C). Propensity score analysis with 1:1 matching minimized confounding bias when comparing efficacy and safety between groups. Results: A tumor response to chemotherapy was observed in 82.4% of all cases, while 34.5% (58/168) underwent AS. Fifty-one of the 58 pts underwent an R0 resection, and 79.3% were deemed histological responders. After matching, 44 pairs of C and CT pts were selected; significant differences in baseline characteristics were not observed. Incidences of adverse events during chemotherapy were similar between groups, with neutropenia and febrile neutropenia as common grade 3–4 events. Compared with group C, group CT had a significantly better median overall survival (OS) (15.5 vs. 46.0 months; hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.18–0.58; p < .001), and a prolonged progression-free survival (6.5 vs.22.6 months; HR 0.33; 95% CI 0.19–0.56; p < .001). Subgroup analysis of OS showed a favorable trend for CT for almost all parameters. In a multivariate analysis, ECOG performance status (HR 0.10; 95% CI 0.03–0.31) and AS (HR 0.20; 95% CI 0.10–0.40) correlated with favorable OS. In the CT group, pathological response was an independent prognostic factor (HR 0.16; 95% CI 0.06–0.39). Conclusions: CT was associated with better outcomes in AGC pts, even after baseline adjustment. Our data warrants further large-scale studies to establish a conversion therapeutic strategy.
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Balcells, J., M. Fondevila, J. A. Guada, C. Castrillo, and J. C. E. Surra. "Urinary excretions of purine derivatives and nitrogen in sheep given straw supplemented with different sources of carbohydrates." Animal Science 57, no. 2 (October 1993): 287–92. http://dx.doi.org/10.1017/s0003356100006905.
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AbstractEstimations of purine derivatives excretion and urinary-nitrogen loss were used to test the response of rumen fermentation to supplementation of straw with different sources of carbohydrate. Two groups of Rasa Aragonesa ewes (44 (s.e. 0·75) kg live weight were given ad libitum basal diets of either ammonia-treated (ATS) or urea-supplemented (USS) barley straw, with 12 animals per basal diet group. Three supplements, barley grain, sugar-beet pulp or grass hay, respectively, were given to each basal diet group, giving a total of six dietary treatments with four animals per treatment group. Four levels of supplementation were studied (150, 300, 450 and 600 g air dry matter per day), one in each of four experimental periods. Each 45-day experimental period comprised 38 days of adjustment followed by a 7-day measurement period. Digestible organic matter (DOM) intake was higher in animals receiving ATS than in animals receiving USS (504 v. 474 (s.e. 21·1) g/day, P < 0·005) and higher in animals receiving barley grain and sugar-beet pulp than in those receiving grass hay (512 and 496 v. 370 (s.e. 25·9) g/day, P < 0·005). DOM intake also increased with the level of supplementation and this increase was greater with barley grain (504 to 634 and 314 to 554 g/day for ATS and USS) and sugar-beet pulp (440 to 582 and 315 to 522 g/day) than with grass hay (430 to 407 and 267 to 370 for ATS and USS). Urinary excretions of hypoxanthine, xanthine and uric acid were not affected by the experimental treatment whereas allantoin excretion (y, mmol) increased in response to DOM intake (x, kg) (y = 13·72 × − 0·26; r = 0·79; P < 0·001; no. = 96). The response in allantoin excretion was mainly explained by the increase in DOM intake. However when data were expressed per unit of DOM intake significant differences were still evident. Allantoin/DOM intake (mmol·kg) ratio and calculated microbial nitrogen (g·kg DOM intake) supply were lower with USS diets and sugar-beet pulp supplemented diets (P< 0·05) and increased significantly with level of supplementation (P < 0·001).
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Frendak, Lynn S., Scott M. Wright, and David Shih Wu. "The Effect of a Standardized Triage Process on Efficiency and Productivity of an Inpatient Palliative Care Team." American Journal of Hospice and Palliative Medicine® 37, no. 6 (September 18, 2019): 413–17. http://dx.doi.org/10.1177/1049909119876928.
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Context: Studies have shown that palliative care involvement delivers a multitude of benefits to patients and caregivers. The existing palliative care workforce is inadequate to meet growing demand. Innovative strategies to triage inpatient consults are necessary. Objectives: To describe the implementation of a new palliative care triage process and to demonstrate its impact on efficiency, teamwork, and patient care. Methods: A quasi-experimental study design, comparing clinical consult data from a 6-month period before and a 6-month period after implementation of the novel consult triage model. Results: Across the 2 study periods, consult demand increased by 44% while the physician staffing (full time equivalent [FTE]) decreased by 38%. Penetration rate per clinical FTE increased (from 1.9%-2.4%; P = .004). Monthly physician work relative value units (RVUs) per FTE increased from 909 to 1678. Physician encounters with hospitalized patients increased from 284 to 353, and total team visits increased from 596 to 891 ( P < .001). Average time to consult decreased by 2.4 hours ( P = .54). Conclusion: An efficient and streamlined consult triage process had a positive impact on our palliative care team’s ability to reach patients. We were able to generate more physician visits and RVUs despite a decrease in physician clinical time, and our penetration rate per physician clinical FTE improved. Our findings highlight the importance of thoughtful and appropriate triage, not to mention teamwork, in helping to augment patient access to palliative care.
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Borthakur, Gautam, Nitin Jain, Hagop Kantarjian, E. Lin, Farhad Ravandi, Sherry Pierce, and Elihu Estey. "Survival Is Poorer in Patients with Secondary Core Binding Factor Acute Myelogenous Leukemia Compared with De Novo Core Binding Factor Leukemia." Blood 110, no. 11 (November 16, 2007): 2856. http://dx.doi.org/10.1182/blood.v110.11.2856.2856.
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Abstract Translocation (8;21)(q22;q22) and inversion of chromosome 16 [inv(16) (p13q22)] are considered good-risk cytogenetic abnormalities in acute myeloid leukemia (AML) accounting for 15% of primary AML cases (Blood. 2002 Dec 15;100(13):4325–36) and are characterized at the molecular level by disruption of genes encoding subunits of core binding factor (CBF). Increasing age, increasing peripheral blast percentage and complex cytogenetics are associated with poor overall survival in these patients (Br J Haematol. 2006 Oct;135(2):165–73). Here we assess differences in patient characteristics and outcomes between the primary and secondary core binding factor AML. One hundred eighty nine CBF AML patients treated at our institution were studied; 18 (9.5%) had secondary AML. Patients with secondary CBF AML were older (p= 0.02, median ages 57 vs. 44 years) and had lower WBC counts (p=0.03) (Table1). Overall survival (OS) was worse in the secondary AML patients (94 weeks versus 621 weeks, p=0.0016) (Figure 1). Age, hemoglobin, platelet count, and bilirubin were significantly associated with OS in the univariate analysis. In the multivariate analysis, after adjusting for age, hemoglobin, WBC, and bilirubin, secondary CBF AML was marginally significantly associated with worse OS (hazard ratio 1.884, CI95% 0.979–3.625, p=0.058) but not worse PFS (p= 0.15) (Table 2). These data suggest that the secondary CBF AML has much poorer prognosis than the primary CBF AML, further indicating that “CBF AML” is not a homogeneous entity with a uniformly good prognosis. Table 1: Summary statistics of patients’ continuous characteristics by abnormality status Patient characteristics Total patients Primary AML (n=171, male=96) Secondary AML (n=18, male=8) p-value (primary vs secondary AML) Median (range) Median (range) Median (range) Age (years) 44 (16–88) 44 (16–88) 57 (31–75) 0.02 WBC (103/mm3) 14.7 (0.6–387) 16.4 (0.6–387) 6.6 (0.8–103.8) 0.03 Hemoglobin (g/dl) 8.1 (2.5–14.3) 8.2 (2.5–14.3) 7.8 (4.8–10.8) 0.33 Platelet count (103/mm3) 38 (5–350) 38 (5–350) 39 (9–139) 0.88 Bilirubin (mg/dl) 0.6 (0.0–15.3) 0.6 (0.0–5.0) 0.6 (0.1–15.3) 0.94 Creatinine (mg/dl) 0.9 (0.5–2.9) 0.9 (0.5–2.9) 0.9 (0.5–1.8) 0.66 Table 2: Multivariate Cox proportional hazards model in estimating the association between covariates and patients’ survival Variable Hazard ratio (95% CI) p-value Abnormality (secondary vs primary) 1.884 (0.979–3.625) 0.058 Age (1 year increase) 1.028 (1.012–1.044) 0.0004 Hemoglobin (1gm/dl increase) 0.864 (0.769–0.970) 0.014 WBC (103/mm3 increase) 1.003 (1.000–1.007) 0.061 Bilirubin (1 mg/dl increase) 1.179 (1.044–1.332) 0.008 Figure Figure
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Darwash, A. O., G. E. Lamming, and M. D. Royal. "A protocol for initiating oestrus and ovulation earlypost partumin dairy cows." Animal Science 72, no. 3 (June 2001): 539–46. http://dx.doi.org/10.1017/s1357729800052073.
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AbstractThe objective of the present study was to evaluate the efficacy of a prostaglandin F2α(PGF2α) and progesterone (P4) treatment in initiating oestrus and ovulation post partum (PP) in Holstein-Friesian cows. Using four herds, the treatment protocol consisted of a single intra-muscular injection of PGF2α(Estrumate) between days 12 to 14 PP followed 48 h later by progesterone treatment via intra-vaginal CIDR insertion for a period of 7 days. Milk samples for progesterone determination were collected three times weekly from 7 to 65 days PP. The ovarian activity and reproductive performance of treated (T, no. = 153) animals and untreated control cows (C, no. = 315) were compared. Treatment was effective (P< 0·001) in reducing the mean interval to PP commencement of luteal activity from 29·62 (s.e. 0·82) days to 22·09 (s.e. 0·70) days. The mean interval to first PP oestrus in the T animals was significantly reduced (P< 0·001) from 55·62 (s.e. 1·58) days to 44·91 (s.e. 1·44) days and the incidence of silent ovulation in cycles between days 21 to 65 PP was reduced (P< 0·001) from 56·28% to 42·27%. In two herds under one management regime and with a similar block-calving pattern (no. = 280 animals), the treatment protocol was beneficial to the overall reproductive performance as there was a significant shortening in the mean interval to first PP service (75·82 (s.e. 1·93) v. 80·86 (s.e. 1·32) days) and in the interval to PP conception (83·07 (s.e. 2·49) v. 88·90 (s.e. 1·95) days), bothP< 0·05.
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Sasaki, Koji, Nina Shah, Qaiser Bashir, Chitra M. Hosing, Uday R. Popat, Yago Nieto, Simrit Parmar, et al. "Outcome of Patients with Light Chain Multiple Myeloma Compared to IgG/IgA Myeloma after Autologous Stem Cell Transplant." Blood 126, no. 23 (December 3, 2015): 3194. http://dx.doi.org/10.1182/blood.v126.23.3194.3194.
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Abstract Introduction: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT) is the standard of care for younger patients with newly diagnosed multiple myeloma (MM). In approximately 15% of MM patients the monoclonal (M) spike consists of k or l light chains only as opposed to heavy + light chains. It remains unclear whether light chain (LC) MM has a different prognosis compared to other monoclonal protein subtypes after an auto-HCT. Methods: We retrospectively analyzed 1067 patients with MM who underwent auto-HCT between January 1, 2004 and January 1, 2011 at our institution. We evaluated the outcome of newly diagnosed patients with LCMM and compared it to patients with IgG or IgA MM, who underwent an auto-HCT after induction therapy. Primary endpoints were complete remission (CR), progression-free survival (PFS) and overall survival (OS) from the date of auto-HCT. Kaplan-Meier analysis with the log-rank test was performed for univariate comparison of survival. Cox proportional hazards regression method was used for univariate and multivariate analyses. Results: Of 1067 patients who underwent auto-SCT during the period, 223 underwent auto-SCT after relapse, and were excluded. From the remaining 844 who underwent auto-SCT in first remission, we excluded 102 patients (AL amyloidosis 60, POEMS and other plasma cell disorders 10, non-secretory MM 15, IgD 10, IgM 6 and IgE 1) from the analysis. The remaining 742 patients were divided as follows: IgA, 162 patients (22%); IgG, 444 (60%) and LC, 136 (18%). Baseline patient characteristics are described in Table 1. Patients with LCMM were younger and had a higher CR rate to induction. Median follow-up for the entire cohort after auto-HCT was 38 months (range, 0.2-87.0). Post auto-HCT, 28% with IgG/IgA MM and 38% with LCMM achieved a CR (p=0.015). Median PFS was 26.0 months and 27.7 months in IgG/IgA MM and LCMM groups, respectively (p= 0.742). Median OS was not reached and 71.1 months in IgG/IgA MM and LCMM groups, respectively (p= 0.18, Figure 1). Multivariate Cox regression analysis for PFS identified <PR after auto-SCT, non-diploid karyotype, and induction chemotherapy without thalidomide or bortezomib as adverse prognostic factors. Multivariate Cox regression analysis for OS identified presence of hypodiploidy or monosomy 13/del13, higher lactate dehydrogenase pre-transplant, lower hemoglobin pre-transplant, and <PR after auto-HCT as adverse prognostic factors. M protein subtype did not affect PFS (hazard ratio [HR], 1.040; 95% confidence interval [CI], 0.825-1.311; p=0.742) or OS (HR, 1.313; 95% CI, 0.874-1.971; p=0.190). Conclusions: Patients with LCMM have a higher CR rate after auto-HCT, but their PFS and OS were similar to patients with IgG/IgA MM. Table 1. Patient Characteristics Variables, No. (%)/median (range) IgG/IgA myelomaN= 606 Light chain myelomaN= 136 P Median age at transplant, (y) 59 (31-80) 56 (32-78) .004 Age >65 years 138 (23) 23 (17) .134 Male 357 (59) 74 (54) .337 Ethnicity .731 Caucasian 399 (66) 94 (69) African American 99 (16) 22 (16) Mixed 87 (14) 18 (13) Asian 16 (3) 2 (2) Cytogenetic abnormalities at diagnosis by conventional cytogenetics Diploid 180 (30) 36 (27) .159 Hyperdiploid 93 (15) 9 (7) .008 Hypodiploid 27 (5) 11 (8) .082 t(11;14) 4 (1) 3 (2) .092 Monosomy 13 / del 13 44 (7) 9 (7) .789 Other high-risk abnormalities 2 (0) 1 (1) .456 Induction chemotherapy Bortezomib or IMiD-based 507 (84) 123 (90) .046 Pre-transplant evaluation Bone marrow plasma cell, (%) 2 (0-71) 2 (0-50) .136 Bone marrow plasma cell >10% 90 (15) 18 (13) .735 Hemoglobin, (g/dL) 11.3 (4.4-16.0) 10.8 (6.8-15.3) .025 Lactate dehydrogenase, (IL/L) 526 (221-5062) 526 (239-2748) .522 Calcium, (mg/dL) 9.0 (7.6-10.4) 9.0 (7.5-11.0) .055 Creatinine, (mg/dL) 0.9 (0.4-12.5) 0.9 (0.5-9.8) .017 Beta-2 microglobulin (mg/dL) 2.4 (1.1-40.0) 2.8 (1.2-33.8) .001 Time from diagnosis to auto-HCT (month) 8.0 (1.9-174.4) 6.8 (2.4-44.6) .001 Pre-transplant disease status .004 ≥ CR 24 (4) 15 (11) VGPR/PR 545 (90) 109 (80) SD/PD 37 (6) 12 (9) Conditioning regimen .008 Melphalan alone 508 (84) 126 (93) Melphalan-based regimen 98 (16) 10 (7) Final response after transplant .080 ≥ CR 168 (28) 52 (38) VGPR/PR 353 (58) 70 (52) SD/PD 81 (13) 14 (10) Figure 1. a) Progression-free survival, b) Overall survival in patients with light chain myeloma compared to those with IgG/IgA myeloma Figure 1. a) Progression-free survival, b) Overall survival in patients with light chain myeloma compared to those with IgG/IgA myeloma Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding.
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Oflazoglu, Kamilcan, Suzanne C. Wilkens, Hinne Rakhorst, Kyle R. Eberlin, David Ring, and Neal C. Chen. "Postoperative Dorsal Proximal Interphalangeal Joint Subluxation in Volar Base Middle Phalanx Fractures." Journal of Hand and Microsurgery 12, no. 01 (November 2, 2019): 32–36. http://dx.doi.org/10.1055/s-0039-1697063.
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Abstract Introduction This study was designed to assess factors associated with postoperative dorsal proximal interphalangeal (PIP) joint subluxation after operative treatment of volar base middle phalanx fractures. Our second purpose was to study the association between postoperative dorsal subluxation with postoperative arthritis. Materials and Methods We identified 44 surgically treated volar base PIP joint fractures with available pre- and postoperative radiographs between 2002 and 2015 at two academic medical systems with a median follow-up of 3.5 months. Demographic, injury, radiographic, and treatment data that might be associated with postoperative dorsal subluxation were collected. Three hand surgeons independently assessed subluxation and arthritis on radiographs. Bivariate analysis was performed to analyze our two study purposes. Results Six of 44 (14%) had postoperative dorsal subluxation after initial surgery. Bivariate analysis showed no factors with statistically significant association with postoperative subluxation, assessed independently by three hand surgeons on radiographs. Fifty per cent of the joints with postoperative arthritis had postoperative subluxation compared with 21% of joints without postoperative subluxation. No significant association was found between postoperative dorsal subluxation with postoperative arthritis. Conclusion The association of persistent subluxation and early arthrosis in dorsal PIP joint fracture dislocations needs further study. At this time, it is unclear in what ways persistent subluxation or arthrosis affects the rate of reoperation. Level of Evidence This is a therapeutic level IV study.
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Dugas, Clermont. "Étude des facteurs de modification de la répartition du peuplement dans l’Est du Québec (1966-1971)." Cahiers de géographie du Québec 19, no. 46 (April 12, 2005): 167–88. http://dx.doi.org/10.7202/021252ar.
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La région de l'Est du Québec, située au sud du fleuve Saint-Laurent et s'étendant du comté de Kamouraska à l'ouest à celui des Îles-de-la-Madeleine à l'est, couvre une superficie de l'ordre de 44 000 kilomètres carrés dont au moins 85% est occupée par la forêt. Ce vaste territoire renfermait, en 1971, une population de 325 000 personnes réparties en 214 localités. Le peuplement, qui s'étire le long de 9 000 kilomètres de routes, demeure très dispersé et mal hiérarchisé. Depuis 1961, une véritable désorganisation de l'espace s'est amorcée. Seulement 49 localités ont pu bénéficier d'une stabilité ou de légers gains démographiques. Compte tenu du caractère rural de la région, il est logique de se demander si l'abandon des terres et de l'agriculture est responsable du fort courant migratoire vers l'extérieur et, par conséquent, de la décroissance démographique de la plupart des localités. D'autre part, on peut aussi rechercher à quels facteurs on peut attribuer la croissance démographique de certaines localités. Par l'utilisation de méthodes statistiques telles que l'analyse factorielle et la régression multiple, on arrive à cerner un peu mieux le rôle joué par l'agriculture, la mauvaise structuration de l'espace, la production industrielle et les équipements commerciaux sur les modifications de la structure du peuplement.
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Wendt, T. G., G. G. Grabenbauer, C. M. Rödel, H. J. Thiel, H. Aydin, R. Rohloff, T. P. Wustrow, H. Iro, C. Popella, and A. Schalhorn. "Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study." Journal of Clinical Oncology 16, no. 4 (April 1998): 1318–24. http://dx.doi.org/10.1200/jco.1998.16.4.1318.
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PURPOSE A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.
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Shimony, Shai, Jan Philipp Bewersdorf, Rory M. Shallis, Yiwen Liu, Eva Johanna Schaefer, Amer M. Zeidan, Aaron D. Goldberg, et al. "What Is the Optimal Treatment Modality in Molecularly Defined Secondary AML? a Multicenter Cohort Study." Blood 142, Supplement 1 (November 28, 2023): 1478. http://dx.doi.org/10.1182/blood-2023-172763.
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Introduction Secondary ontogeny acute myeloid leukemia (AML), defined by the presence of mutations in ASXL1, BCOR, EZH2, SF2B1, SRSF2, STAG2, U2AF1 or ZRSR2 was recently integrated into both the ICC and WHO diagnostic criteria, as well as into the ELN 2022 risk classification as adverse risk. However, it is unknown whether cytarabine + anthracycline (7+3), liposomal cytarabine and daunorubicin (CPX-351) or hypomethylating agent + venetoclax (HMA+VEN) is the optimal frontline treatment for these patients (pts). We performed the largest multicenter retrospective cohort study to date, dedicated to pts with molecular-defined secondary ontogeny AML, comparing treatment modalities and assessing the impact of clinical and molecular characteristics on response and survival. Methods We included pts with newly diagnosed (ND) AML who were treated at 4 large academical centers with 7+3, CPX-351 or HMA+VEN. Secondary ontogeny was defined as absence of TP53 mutation and presence of at least one of the aforementioned mutations. Composite complete response (cCR) was defined as complete response (CR) + CR with incomplete count recovery (CRi). Logistic regression was fitted to evaluate odds ratio (OR) for cCR. Overall survival (OS) was compared between groups by log-rank test. COX regression for OS were fitted to evaluate effect of secondary/co-mutations within each treatment group, as well as the effect of treatment and allogeneic stem cell transplantation (SCT) as a time-varying covariate. Results Out of 1132 ND AML pts in the entire cohort, 401 (35%) were molecularly defined as secondary ontogeny and included in the final analysis. Initial treatment was 7+3 in 173 (43%), HMA+VEN in 162 (40%) and CPX-351 in 66 pts (17%). Pts in the HMA+VEN group were older (median age 74 years[yrs]; CPX351 66 yrs; 7+3 63 yrs, p<0.001), while pts in the CPX351 group were more likely to have prior myeloid neoplasm (n=52 [79%]; HMA+VEN n=72 [44%]; 7+3 n=48 [28%], p<0.001) and prior HMA exposure (n=27 [41%]; HMA+VEN n=23 [14%]; 7+3 n=28 [16%], p<0.001). The cCR rates were 56% (97/173), 56% (90/162) and 44% (29/66) in 7+3, HMA+VEN and CPX-351, respectively (p=0.21). In the 7+3 group, the presence of RUNX1 co-mutation was associated with lower cCR rate (OR 0.8, 95% confidence interval [CI] 0.7-0.95, p=0.01), while PTPN11 was associated with higher cCR rate (OR 1.4, 95% CI 1.1-1.8, p=0.011). In the HMA+VEN group, monosomal karyotype (OR 0.7, 95% CI 0.5-0.9, p=0.002), NRAS co-mutation (OR 0.6, 95% CI 0.5-0.8, p<.001) and SF3B1 mutation (OR 0.76, 95% CI 0.6-0.9, p=0.008) were associated with lower cCR rate and FLT3-TKD with higher cCR rate (OR 1.5, 95% CI 1.1-2.1, p=0.01). In the CPX-351 group, NRAS co-mutation was associated with lower cCR rate (OR 0.65, 95% CI 0.5-0.9, p=0.005). As most younger pts (aged ≤ 60 yrs, n=85) were treated with 7+3 (n=64) or CPX-351 (n=13) and almost exclusively older pts (age >75, n=78) were treated with HMA+VEN (n=74), we performed age-group based analyses. In pts aged > 60 yrs (n=318), the median OS (mOS) was comparable between groups (7+3: 16 months [mo], 95% CI 13-27; HMA+VEN 15 mo, 95% CI 13-19; CPX-351 11 mo, 95% CI 9-28 p=0.57). Similar results were seen in pts 60-75 yrs (n=238): 7+3 mOS 16 mo, 95% CI 13-27; HMA+VEN mOS 16 mo, 95% CI 13-26; CPX-351 mOS 10 mo, 95% CI 8-28, p=0.74. The effect of secondary/co-mutations on survival differ between groups: For 7+3 splicing mutations were associated with worse OS, whereas IDH1/2 were associated with improved OS ( Figure). Conversely, in HMA+VEN and CPX351 groups K/NRAS co-mutations were associated with worse survival. NPM1 co-mutation did not affect survival in any treatment group. In multivariable analysis, age, prior myeloid disease, K/NRAS co-mutations and monosomal karyotype were associated with worse OS ( Table). Conversely, BCOR mutation, IDH1/2 co-mutation and SCT were associated with improved OS. Treatment with HMA+VEN or CPX351 were not statistically different vs 7+3, although there was a trend for better OS with HMA+VEN vs 7+3 (HR 0.68, 95% CI 0.44-1.03, p=0.069). Conclusion In pts with ND secondary ontogeny AML the OS with HMA+VEN was at least comparable to 7+3 or CPX351 when adjusted for multiple covariates. The effect of co-mutations on response and OS differed between treatment modalities and may aid in optimal treatment selection in this population. Prospective trials should evaluate the potential superiority of HMA+VEN and effect of co-mutations in secondary ontogeny AML.