Category: Nevin Manimala

Blood. 2022 Jul 15:blood.2022015478. doi: 10.1182/blood.2022015478. Online ahead of print.

ABSTRACT

Here we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy versus standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 (NCT03391466) study of axicabtagene ciloleucel (axi-cel) versus SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for QLQ-C30 Physical Functioning, Global Health Status/QoL, and EQ-5D-5L visual analogue scale (VAS) were tested using mixed-effect models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 Global Health Status/QoL (estimated difference 18.1 [95% CI, 12.3-23.9]), Physical Functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P<.0001 for all). At day 150, scores significantly favored axi-cel versus SOC for Global Health Status/QoL (9.8 [95% CI, 2.6-17.0]; P=.0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P=.0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL.

PMID:35839452 | DOI:10.1182/blood.2022015478

J Clin Oncol. 2022 Jul 15:JCO2102707. doi: 10.1200/JCO.21.02707. Online ahead of print.

ABSTRACT

PURPOSE: Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis.

MATERIALS AND METHODS: We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays.

RESULTS: In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners.

CONCLUSION: We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

PMID:35839444 | DOI:10.1200/JCO.21.02707

JCO Glob Oncol. 2022 Jul;8:e2200131. doi: 10.1200/GO.22.00131.

ABSTRACT

PURPOSE: In describing our ten-year experience with treating chronic myeloid leukemia (CML) as part of the Glivec Patient Assistance Program (GIPAP) in rural Rwanda, we evaluate (1) patient characteristics and treatment outcomes, (2) resource-adapted management strategies, and (3) the impact of diagnostic capacity development.

METHODS: We retrospectively reviewed all patients with BCR-ABL-positive CML enrolled in this GIPAP program between 2009 and 2018. Clinical data were analyzed using descriptive statistics, Kaplan-Meier methods, proportional hazards regression, and the Kruskal-Wallis test.

RESULTS: One hundred twenty-four patients were included. The median age at diagnosis was 34 (range 8-81) years. On imatinib, 91% achieved complete hematologic response (CHR) after a median of 49 days. Seven (6%) and 12 (11%) patients had primary and secondary imatinib resistance, respectively. The 3-year overall survival was 80% (95% CI, 72 to 87) for the cohort, with superior survival in imatinib responders compared with those with primary and secondary resistance. The median time from imatinib initiation to CHR was 59 versus 38 days (P = .040) before and after in-country diagnostic testing, whereas the median time to diagnosis (P = .056) and imatinib initiation (P = .170) was not significantly different.

CONCLUSION: Coupling molecular diagnostics with affordable access to imatinib within a comprehensive cancer care delivery program is a successful long-term strategy to treat CML in resource-constrained settings. Our patients are younger and have higher rates of imatinib resistance compared with historic cohorts in high-income countries. High imatinib resistance rates highlight the need for access to molecular monitoring, resistance testing, and second-generation tyrosine kinase inhibitors, as well as systems to support drug adherence. Hematologic response is an accurate resource-adapted predictor of survival in this setting. Local diagnostic capacity development has allowed for continuous, timely CML care delivery in Rwanda.

PMID:35839427 | DOI:10.1200/GO.22.00131

J Clin Oncol. 2022 Jul 15:JCO2102478. doi: 10.1200/JCO.21.02478. Online ahead of print.

ABSTRACT

PURPOSE: Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children’s Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed.

PATIENTS AND METHODS: Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated.

RESULTS: From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% v 55.4 ± 3.2%, P = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2-containing cycles than granulocyte-macrophage colony-stimulating factor-containing cycles (P < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 (P = .034) and those with a high affinity FCGR3A genotype (P = .0418). Human antichimeric antibody status did not correlate with survival.

CONCLUSION: Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.

PMID:35839426 | DOI:10.1200/JCO.21.02478

J Am Coll Surg. 2022 Aug 1;235(2):278-284. doi: 10.1097/XCS.0000000000000220. Epub 2022 Apr 8.

ABSTRACT

BACKGROUND: Older trauma patients present with poor preinjury functional status and more comorbidities. Advances in care have increased the chance of survival from previously fatal injuries with many left debilitated with chronic critical illness and severe disability. Palliative care (PC) is ideally suited to address the goals of care and symptom management in this critically ill population. A retrospective chart review was done to identify the impact of PC consults on hospital length of stay (LOS), ICU LOS, and surgical decisions.

STUDY DESIGN: A Level 1 Trauma Center Registry was used to identify adult patients who were provided PC consultation in a selected 3-year time period. These PC patients were matched with non-PC trauma patients on the basis of age, sex, race, Glasgow Coma Scale, and Injury Severity Score. Chi-square tests and Student’s t-tests were used to analyze categorical and continuous variables, respectively. Any p value >0.05 was considered statistically significant.

RESULTS: PC patients were less likely to receive a percutaneous endoscopic gastric tube or tracheostomy. PC patients spent less time on ventilator support, spent less time in the ICU, and had a shorter hospital stay. PC consultation was requested 16.48 days into the patient’s hospital stay. Approximately 82% of consults were to assist with goals of care.

CONCLUSION: Specialist PC team involvement in the care of the trauma ICU patients may have a beneficial impact on hospital LOS, ICU LOS, and surgical care rendered. Earlier consultation during hospitalization may lead to higher rates of goal-directed care and improved patient satisfaction.

PMID:35839403 | DOI:10.1097/XCS.0000000000000220

J Am Coll Surg. 2022 Aug 1;235(2):227-239. doi: 10.1097/XCS.0000000000000236. Epub 2022 Apr 18.

ABSTRACT

BACKGROUND: Although satisfactory volume reduction in secondary unilateral lower limb lymphedema after lymphaticovenous anastomosis (LVA) in the affected limb has been well reported, alleviation of muscle edema and the impact of LVA on the contralateral limb have not been investigated.

STUDY DESIGN: This retrospective cohort study enrolled patients who underwent supermicrosurgical LVA between November 2015 and January 2017. Pre- and post-LVA muscle edema were assessed using fractional anisotropy (FA) and apparent diffusion coefficient (ADC). The primary endpoint was changes in limb/subfascial volume assessed with magnetic resonance volumetry at least 6 months after LVA.

RESULTS: Twenty-one patients were enrolled in this study. Significant percentage reductions in post-LVA muscle edema were found in the affected thigh (83.6% [interquartile range = range of Q1 to Q3; 29.8-137.1] [FA], 53.3% [27.0-78.4] [ADC]) as well as limb (21.7% [4.4-26.5]) and subfascial (18.7% [10.7-39.1]) volumes. Similar findings were noted in the affected lower leg: 71.8% [44.0-100.1] (FA), 59.1% [45.8-91.2] (ADC), 21.2% [6.8-38.2], and 28.2% [8.5-44.8], respectively (all p < 0.001). Significant alleviation of muscle edema was also evident in the contralateral limbs (thigh: 25.1% [20.4-57.5] [FA]; 10.7% [6.6-17.7] [ADC]; lower leg: 47.1% [35.0-62.8] [FA]; 14.6% [6.5-22.1] [ADC]; both p < 0.001), despite no statistically significant difference in limb and subfascial volumes.

CONCLUSIONS: Our study found significant reductions in muscle edema and limb/subfascial volumes in the affected limb after LVA. Our findings regarding edema in the contralateral limb were consistent with possible lymphedema-associated systemic influence on the unaffected limb, which could be surgically relieved.

PMID:35839398 | DOI:10.1097/XCS.0000000000000236

Scand J Med Sci Sports. 2022 Jul 15. doi: 10.1111/sms.14212. Online ahead of print.

ABSTRACT

The aim of this systematic review and meta-analysis was to identify the genetic variants of (inter)national competing long-distance runners and road cyclists compared to controls. The Medline and Embase databases were searched until 15 November 2021. Eligible articles included genetic epidemiological studies published in English. A homogenous group of endurance athletes competing at (inter)national level and sedentary controls were included. Pooled odds ratios based on genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated using random effects models. Heterogeneity was addressed by Q-statistics and I² . Sources of heterogeneity were examined by meta-regression and risk of bias was assessed with the Clark Baudouin scale. This systematic review comprised of 43 studies including a total of 3938 athletes and 10752 controls in the pooled analysis. Of the 42 identified genetic variants, 13 were investigated in independent studies. Significant associations were found for five polymorphisms. Pooled odds ratio [95%CI] favoring athletes compared to controls was 1.42 [1.12-1.81] for ACE II (I/D), 1.66 [1.26-2.19] for ACTN3 TT (rs1815739), 1.75 [1.34-2.29] for PPARGC1A GG (rs8192678), 2.23 [1.42-3.51] for AMPD1 CC (rs17602729), and 2.85 [1.27-6.39] for HFE GG+CG (rs1799945). Risk of bias was low in 25 (58%) and unclear in 18 (42%) articles. Heterogeneity of the results was low (0-20%) except for HFE (71%), GNB3 (80%), and NOS3 (76%). (Inter)national competing runners and cyclists have a higher probability to carry specific genetic variants compared to controls. This study confirms that (inter)national competing endurance athletes constitute a unique genetic make-up, which likely contributes to their performance level.

PMID:35839336 | DOI:10.1111/sms.14212

J Addict Med. 2022 Jul 16. doi: 10.1097/ADM.0000000000001034. Online ahead of print.

ABSTRACT

BACKGROUND: Los Angeles County Department of Health Services provides medical care to a diverse group of patients residing in underresourced communities. To improve patients’ access to addiction medications during the COVID-19 pandemic, Los Angeles County Department of Health Services established a low-barrier telephone service for DHS providers in March 2020, staffed by DATA-2000-waivered providers experienced with prescribing addiction medications. This study describes the patient population and medications prescribed through this service during its initial 12 months.

METHODS: We performed a retrospective evaluation of a provider-entered call registry for the telephone consult line. Information was collected between March 31, 2020, and March 30, 2021. The registry includes information related to patient demographics, the reason for visit, and which addiction medications were prescribed. We conducted descriptive statistics in each of these domains.

RESULTS: During the study period, 11 providers on the MAT telephone service logged 713 calls. These calls represented a total of 557 unique patients (mean age of 40 years, 75% male, 41% Latino, 49% experiencing homelessness). Most patients either had Medicaid insurance (77%) or were uninsured (20%). The most prescribed addiction medication was buprenorphine-naloxone (90%), followed by nicotine replacement therapy (5.3%), naltrexone (4.2%), and buprenorphine monotherapy (1.8%).

CONCLUSION: A telephone addiction medication service is feasible to deliver low-barrier medications to treat addiction in underresourced communities, especially to individuals experiencing homelessness. This can mitigate but does not eliminate disparities in access to addiction medications for communities of color.

PMID:35839323 | DOI:10.1097/ADM.0000000000001034

Colorectal Dis. 2022 Jul 15. doi: 10.1111/codi.16266. Online ahead of print.

ABSTRACT

BACKGROUND: Learning curve of total mesorectal excision (TME) by minimally invasive surgery (MIS) beyond the competency phase has not been adequately reported with large numbers or using a statistical control limit. We aimed to study the learning curves of MIS TME in the proficiency phase.

METHODS: Risk-adjusted (RA) cumulative sum (CUSUM) and RA Bernoulli CUSUM charts were plotted for sequential MIS TME performed by a surgical team over 1000 cases. Surgical failure, a composite endpoint of conversions, ≥ grade IIIA complications, R1 resections and inadequate nodal yield was used to monitor the performance.

RESULTS: The risk-adjusted CUSUM detected an inflection point around the 600^th operation. Two peaks were identified that could be traced back to probable causes for surgical failures. Similar inflection points were detected at 450^th case for laparoscopic TME and 367^th case for sphincter preservation. No single definite threshold point was noticed for robotic or abdominoperineal operations. At no point did the curves cross the safety threshold. Surgical failure probability reduced with increasing experience in the multivariate regression (OR – 0.899; p – 0.000). This association persisted irrespective of the surgical approach (laparoscopic vs robotic) or the type of operation (sphincter preservation vs abdominoperineal resection).

CONCLUSIONS: The learning curves for MIS TME did not cross the safety threshold beyond the competency phase. However, a 10% relative risk reduction in surgical failures was observed for every 100 cases operated.

PMID:35839321 | DOI:10.1111/codi.16266

Bipolar Disord. 2022 Jul 15. doi: 10.1111/bdi.13243. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established.

OBJECTIVES: To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators.

METHODS: We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges’ g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668).

RESULTS: The literature search identified 6,034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators.

CONCLUSION: We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

PMID:35839276 | DOI:10.1111/bdi.13243