tbuckley/cabot-search huggingface dataset:
Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial
Authors: A. Kühnl, D. Cunningham, N. Counsell, E.A. Hawkes, W. Qian, P. Smith, N. Chadwick, A. Lawrie, P. Mouncey, A. Jack, C. Pocock, K.M. Ardeshna, J. Radford, A. McMillan, J. Davies, D. Turner, A. Kruger, P.W. Johnson, J. Gambell, A. Rosenwald, G. Ott, H. Horn, M. Ziepert, M. Pfreundschuh, D. Linch
Journal: Annals of Oncology (2017)

BackgroundThere is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19–88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up.Patients and methodsSix hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials.ResultsElderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65–73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22–3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18–4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors.ConclusionsOur data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches.Trial numbersISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).
A randomized phase II study comparing bipolar androgen therapy vs. enzalutamide in asymptomatic men with castration resistant metastatic prostate cancer: The TRANSFORMER trial.
Authors: Benjamin A. Teply, Emmanuel S. Antonarakis, Michael Anthony Carducci, Channing Judith Paller, Hao Wang, Haiyi Cao, Avery N. Spitz, Jun Luo, Mario A. Eisenberger, Samuel R. Denmeade
Journal: Journal of Clinical Oncology (2015)

TPS5079 Background: Prostate cancer can progress despite androgen deprivation therapy through overexpression of the androgen receptor (AR) and expression of AR splice variants. Almost paradoxically, testosterone given to cancer cells in this state can cause growth inhibition. The AR is normally degraded during progression through the cell cycle, but androgen-bound AR is stabilized, thus arresting the cell cycle and inducing DNA strand breaks through interaction with topoisomerase-IIb. Clinically, supraphysiologic testosterone given to men with castration-resistant prostate cancer was found to be safe in a pilot clinical trial, producing responses and re-sensitizing patients to subsequent anti-androgen therapy. In this context, we designed a randomized phase II study comparing bipolar androgen therapy (BAT) to enzalutamide for patients who have experienced progression on abiraterone. Methods: In this multi-center randomized study, funded by a grant from the Department of Defense, eligible patients have asymptomatic metastatic castration-resistant prostate cancer that has radiographically or biochemically progressed after treatment with abiraterone. Patients are enzalutamide-naïve and have not received docetaxel for castration-resistant disease. Patients randomized to BAT will continue on androgen deprivation therapy and receive monthly intramuscular testosterone at the FDA-approved dose of 400mg. This dose produces initial supraphysiologic testosterone levels with return to castrate levels after one month. Patients randomized to enzalutamide will receive 160mg daily. Crossover is encouraged. The primary endpoint is radiographic progression-free survival (rPFS). The trial is powered to detect a 50% improvement in median rPFS in the BAT arm compared to the enzalutamide arm (expected to be ~6 months), with planned accrual of 90 patients in each arm. The arms will be stratified for time to progression on abiraterone. Secondary endpoints include PSA response rates, safety, and quality of life. Correlative studies include the effect of BAT on AR variant expression. Enrollment opened in February 2015. Clinical trial information: NCT02286921.
Evaluation of serum B-cell maturation antigen in multiple myeloma.
Authors: Eric Sanchez, Mingjie Li, Alex Kitto, Jennifer Li, Cathy Wang, Dylan T Kirk, Austin Robinson, Erik Madden, Jean-Phillip Okhovat, Gabriel N. Waterman, Regina A. Swift, Benjamin Bonavida, Haiming Chen, James R. Berenson
Journal: Journal of Clinical Oncology (2012)

e18549 Background: B cell maturation antigen (BCMA) is a receptor whose expression increases during B-cell development and is found on malignant cells from multiple myeloma (MM) patients; however, it has not been identified in human serum. Methods: Bone marrow (BM) aspirates and peripheral blood were obtained from patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and healthy control subjects following informed consent (Western IRB BIO 001). Serum was isolated and analyzed with a BCMA enzyme‑linked immunosorbent assay. Values represent the mean of triplicate experiments. BM mononuclear cells (MCs) were isolated using density‑gradient centrifugation and cultured for 72 h in RPMI1640 supplemented with 10% fetal bovine serum. Our human MM xenograft (LAGκ-2)was grown in SCID mice and treated with bortezomib (BORT) with cyclophosphamide (CY); tumor volume and BCMA levels were determined. Statistical significance of differences observed was determined using a Student’s t test and analysis was determined using GraphPad prism software. Results: We showed that the supernatants of cultured BMMCs from MM patients had high concentrations of BCMA (median = 2,250 pg/ml) whereas normal subjects showed minimal amounts (56 ng/ml; P &lt; 0.0001). The serum BCMA levels from newly diagnosed MM patients (n = 51) had much higher levels (13.74 ng/ml) than among controls (n = 40; median 2.58 ng/ml; P &lt; 0.0001) and MGUS subjects (n = 26; median 5.40 ng/ml; P = 0.005). Notably, protein levels were much higher among patients with relapsed or refractory (R/R) disease (n = 79; median 20.02 ng/ml) compared to those with responsive (&gt; partial response) disease (n = 80; median 4.14 ng/ml; P = 0.0038). Following treatment, patients with responsive disease showed decreases in BCMA levels whereas those with R/R disease showed increases. Following treatment with BORT and CY, we also showed a marked decrease in tumor volume and serum human BCMA levels in mice bearing the LAGκ-2 xenograft whereas untreated animals showed marked increases in tumor size and serum BCMA. Conclusions: This is the first report identifying serum BCMA in any human disease and suggests that these levels may be a novel biomarker for monitoring disease status and therapeutic response of MM patients.
Post-antibiotic management of immunocompromised children with febrile neutropenia.
Authors: Carolyn Lucille Russo, Jennifer Morgan
Journal: Journal of Clinical Oncology (2017)

39 Background: Febrile neutropenia in immunocompromised children is a medical emergency and requires prompt administration of antibiotics and supportive care management to prevent death from sepsis. We have previously shown that improvement in time to antibiotic administration from a baseline of 108 minutes was decreased to 64 minutes in 67 children in six St. Jude affiliate clinics. The improvement was achieved by designing a unique order set and process for prompt dispensing of antibiotics at each affiliate site. However, the clinical assessment of patients after antibiotic administration to provide early intervention for treatment of septic shock did not improve. Management of fluid status, oxygen therapy, and blood pressure support are critical for optimal outcome. The time from antibiotic administration to clinical assessment remained above the expected time of 15 minutes at an average of 60 minutes. To improve the post-antibiotic management, additional guidelines were established and monitored for compliance. Methods: Clinical guidelines were written. The guidelines included: patient assessed by nurse and vital signs checked within 15 minutes of arrival, patient assessed by a clinician within 30 minutes of arrival, antibiotic administrated within 60 minutes of arrival, nurse completed post-antibiotic assessment and vital signs rechecked within 15 minutes of administration, and clinician completed post antibiotic assessment within 30 minutes of administration. Results: After establishing guidelines, each site developed a process for implementation using a similar approach of automated order sets, time reminders, and staff education of the initial management of septic shock. Chart reviews were done at one year after implementation and all were in compliance. Conclusions: Clinical guidelines, automated order sets, and continued awareness and education in the management of immunocompromised children with febrile neutropenia improved compliance with this quality project. Continued monitoring is needed to ensure the results are sustained.
Self-Regulation and Psychopathology: Toward an Integrative Translational Research Paradigm
Authors: Timothy J. Strauman
Journal: Annual Review of Clinical Psychology (2017)

This article presents a general framework in which different manifestations of psychopathology can be conceptualized as dysfunctions in one or more mechanisms of self-regulation, defined as the ongoing process of managing personal goal pursuit in the face of internal, interpersonal, and environmental forces that would derail it. The framework is based on the assertion that self-regulation is a critical locus for the proximal influence on motivation, cognition, emotion, and behavior of more distal factors such as genetics, temperament, socialization history, and neurophysiology. Psychological theories of self-regulation are ideal platforms from which to integrate the study of self-regulation both within and across traditional disciplines. This article has two related goals: to elucidate how the construct of self-regulation provides a unique conceptual platform for the study of psychopathology and to illustrate that platform by presenting our research on depression as an example.
Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide
Authors: Laurent L. Reber, Caitlin M. Gillis, Philipp Starkl, Friederike Jönsson, Riccardo Sibilano, Thomas Marichal, Nicolas Gaudenzio, Marion Bérard, Stephan Rogalla, Christopher H. Contag, Pierre Bruhns, Stephen J. Galli
Journal: The Journal of Experimental Medicine (2017)

Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMNDTR mice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPO), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPO contributes importantly to protection from endotoxemia. Our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPO-dependent manner.
Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study.
Authors: Jean-François Flejou, Thierry André, Benoist Chibaudel, Aurelie Scriva, Tamas Hickish, Josep Tabernero, Jean-Luc Van Laethem, Maria Banzi, Eduard Maartense, Adi Shani, Göran Carlsson, Werner Scheithauer, Demetris Papamichael, Markus Moehler, Stefania Landolfi, Pieter Demetter, Alex Duval, Mark Lee, Soudhir Colote, Aimery De Gramont
Journal: Journal of Clinical Oncology (2013)

3524 Background: The MOSAIC study (André T, N Engl J Med, 2004) demonstrated that adding oxaliplatin to adjuvant 5FU and LV improved three-year disease-free survival (DFS) in stage II and III resected CC. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study (Zaanan A, Ann Oncol 2010). Methods: Of the 2,246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1,019 pts were obtained. Thirty-three samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) analysis of the protein products of MLH1, MSH2, PMS2, and MSH6 genes. Results: A total of 986 pts (44%) were evaluable for MMR status and MMR status was not evaluable for 1,260 pts (56%). Relapse-free survival (RFS), DFS and overall survival (OS) were similar in both, MMR and MMR not evaluable population. Ninety (9.1%) and 896 (90.9%) pts had dMMR and proficient MMR (pMMR) CC, respectively. Of the patients with 90 dMMR CC, 45 pts had stage II and 45 stage III. Hazard Ratios (HRs) for stage II and III dMMR are 0.52 (0.21–1.28) for RFS, 0.52 (0.24–1.14) for DFS, and 0.45 (0.19–1.05) for OS, respectively. HR for stage III dMMR are 0.56 (0.19–1.61) for RFS, 0.51 (0.18–1.41) for DFS, and 0.44 (0.15–1.34) for OS, respectively. HR for stage II dMMR are 0.64 (0.11–3.70) for RFS, 0.60 (0.17–2.09) for DFS, and 0.52 (0.13–2.10) for OS, respectively. Conclusions: Analyses ofcolon cancerMMR status in pts included in the MOSAIC study support the use of FOLFOX4 in pts with dMMR stage III cancer. Clinical trial information: NCT00275210. [Table: see text]
Reply:
Authors: Isabelle Durand‐Zaleski, Julie Bulsei, Olivier Seror, Pierre Nahon
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Seror consults for Olympus Celon, Angiodynamics, and Bayer. Dr. Iloabuchi discusses methodological issues in costing the screening interventions for hepatocellular carcinoma. The primary focus of our study was France; costs in the United States were added to the study at the reviewers' request. In France, we had access to the 2013 cost database, while in the United States we used data from different public sources. All costs can be inflated (not discounted) to enter a Markov model; the discounting of both costs and effects occurred as part of the Markov process. In the United States, we used the most recent Medicare/Medicaid data for nonhospital costs: we are aware that Medicare starts only at 65 years but Medicaid does not, and we have no reason to believe that costs to the payer would be different for the same test, e.g., ultrasound between 55 and 65 years of age. For episodes of care such as transplant costs, we used published data and, whenever necessary, adjusted them to the 3‐month time period of our Markov model; thus, when yearly costs were reported, we transformed them into quarterly costs.1 The target population is patients aged 55 and above presenting with cirrhosis. We used data and transition probabilities from two French cohorts; data on US cohorts to recalculate transition probabilities were not available to us. We have no epidemiological or physiopathological evidence, however, that the course of the nodule progression toward cancer would differ between French and US patients. American studies have shown that, although recommended by the American Association for the Study of Liver Diseases,2 underuse of hepatocellular carcinoma surveillance is as detrimental to US patients as it is to French patients because patients monitored regularly in a US cohort were diagnosed 2 years earlier than patients not monitored.3 We agree that guidelines, and more particularly treatment guidelines, may vary according to country. In the case of screening for liver cancer, however, the appropriate screening interval of 6 months, based on randomized trial and exposure‐matched cohort studies suggesting that 12 months is too long and 3 months too short, seems fairly consensual.4 Providing US cost‐effectiveness results as a part of this publication resulted in several assumptions about costs; however, the results of the sensitivity analysis are unambiguous and show that all replications are well into the northeast quadrant of the cost‐effectiveness plane, indicating that there is always a health benefit to patients. It also shows that there are very cost‐effective first‐line curative treatments for de novo tumors, which is another argument in favor of screening.
Outcomes after hospitalization in patients with recurrent glioblastoma.
Authors: Pedro Miguel Coecho Barata, Carlos Kamiya-Matsuoka, Soo Lee-Kim, Monica Elena Loghin, Barbara Jane O'Brien, Ivo Tremont-Lukats
Journal: Journal of Clinical Oncology (2015)

e13020 Background: We know little about what hospitalization indicates for patients with recurrent glioblastoma (rGB). Our objectives were to determine the reasons for admission; discharge disposition; prior end of life (EoL) discussions in clinic, and survival after discharge. Methods: We reviewed records of patients with glioblastoma admitted to MD Anderson between 01/2010 and 08/2014. We evaluated the effect of selected variables on hospitalization and survival, estimated survival with Kaplan-Meier curves, and compared subgroup survival after admission with log-rank test. Results: Of 143 patients with glioblastoma, 90 (63% men; median age 57 years) 127 (89%) had rGB, with a median hospital stay of 5 days. The most common reason for admission was clinical deterioration (n = 32, 25%). Neuroimaging demonstrated rGB in 49 (39%) patients initially admitted for other causes. Seventy-six (60%) patients were discharged to continue treatment, and forty-five (35%) to hospice (35%); six (5%) died in the hospital. Of patients dispositioned to continue treatment, 19 (25%) never received any further intervention because of continued clinical decline. Median survival for rGB was 9.9 months (95% CI: 8.4-11.4) but only 3.7 months (95% CI: 2.9-4.6) following hospitalization. Only 20 (16%) patients had had EoL discussions and 5 (4%) had documented code status before admission. We found no relation between selected variables and time to admission or survival. A short time from rGB diagnosis to hospitalization ( < 3 months) was associated with poor survival (p < 0.0001). Patients with Karnofsky performance score (KPS) < 70 lived a median of 2.8 months after admission (95% CI: 2.4-3.3) versus 9 months (95% CI: 7.6-10.4) for patients with KPS ≥ 70 (p < 0.0001). Conclusions: In all, two thirds of rGB patients could not continue treatment after discharge. A short time to first admission and KPS < 70 predicted short survival. Very few had documented discussions about prognosis or EoL with their physician before hospitalization. Admission of these patients, especially with clinical decline, could be a sign of terminal illness and should trigger EoL discussions and advance care planning, since further intervention is very unlikely to prolong life or improve its quality.
Establishing best practice recommendations for systemic treatment regimen development and maintenance.
Authors: Andrea Crespo, Erin Redwood, Kathy Vu, Vishal Kukreti
Journal: Journal of Clinical Oncology (2017)

40 Background: A province-wide review of oncology regimens identified discrepancies in a number of regimens in systemic treatment computerized prescriber order entry (ST CPOE) systems. The potential patient harm from such discrepancies includes unnecessary toxicities and reduced treatment efficacy. The regimen review highlighted the need for a high-quality process to improve the safety of systemic treatment prescribing in Ontario. The objective of this work was to develop recommendations on best practices for the development and maintenance of oncology regimens. Methods: An expert multidisciplinary group of oncology clinicians and administrators was formed to review available literature and leverage their expertise to establish oncology-specific recommendations. These were then circulated to broader stakeholder groups for feedback and consensus. Results: Practical, consensus-based best practice recommendations for ST CPOE and pre-printed order regimen development and maintenance were created. Detailed processes for new regimen development are outlined in the table below. Moreover, broad areas of roles and responsibility, frequency of review, and sign-off were highlighted. This was repeated for regimen changes (not shown). Conclusions: There is a lack of guidance in the literature on best practices for oncology regimen development and maintenance. Careful analysis and application of the expertise of oncology professionals resulted in consensus-based best practice recommendations that will enable the advancement of safe, standardized, systemic treatment prescribing.[Table: see text]
Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients
Authors: Kazunari Sugita, Catherine A. Steer, Itziar Martinez-Gonzalez, Can Altunbulakli, Hideaki Morita, Francesc Castro-Giner, Terufumi Kubo, Paulina Wawrzyniak, Beate Rückert, Katsuko Sudo, Susumu Nakae, Kenji Matsumoto, Liam O'Mahony, Mübeccel Akdis, Fumio Takei, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2017)
A multicenter, open-label phase 2a study of ibrutinib with or without cytarabine in patients with acute myeloid leukemia (PCYC-1131).
Authors: Jorge E. Cortes, Elihu Estey, Anthony Selwyn Stein, Thorsten Graef, Nora Cavazos, Taisei Kinoshita, Ying Luan, Ahmed Tawashi
Journal: Journal of Clinical Oncology (2015)

TPS7096 Background: Therapeutic options in patients with acute myeloid leukemia (AML) who are elderly, unfit, or who relapse after induction therapy remain an unmet need. Studies with primary AML s...