bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Prospective Biomarker Trial of ERCC1 for Comparing Platinum and Nonplatinum Therapy in Advanced Non–Small-Cell Lung Cancer: ERCC1 Trial (ET)
Authors: Lee Siow Ming , Falzon Mary , Blackhall Fiona , Spicer James , Nicolson Marianne , Chaudhuri Abhro , Middleton Gary , Ahmed Samreen , Hicks Jonathan , Crosse Barbara , Napier Mark , Singer Julian M. , Ferry David , Lewanski Conrad , Forster Martin , Rolls Sally-Ann , Capitanio Arrigo , Rudd Robin , Iles Natasha , Ngai Yenting , Gandy Michael , Lillywhite Rachel , Hackshaw Allan 
Published: February 2017

Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non–small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.
High Frequency and Poor Outcome of Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia in Adults
Authors: Roberts Kathryn G. , Gu Zhaohui , Payne-Turner Debbie , McCastlain Kelly , Harvey Richard C. , Chen I-Ming , Pei Deqing , Iacobucci Ilaria , Valentine Marcus , Pounds Stanley B. , Shi Lei , Li Yongjin , Zhang Jinghui , Cheng Cheng , Rambaldi Alessandro , Tosi Manuela , Spinelli Orietta , Radich Jerald P. , Minden Mark D. , Rowe Jacob M. , Luger Selina , Litzow Mark R. , Tallman Martin S. , Wiernik Peter H. , Bhatia Ravi , Aldoss Ibrahim , Kohlschmidt Jessica , Mrózek Krzysztof , Marcucci Guido , Bloomfield Clara D. , Stock Wendy , Kornblau Stephen , Kantarjian Hagop M. , Konopleva Marina , Paietta Elisabeth , Willman Cheryl L. , Mullighan Charles G. 
Published: February 2017

PurposePhiladelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy.Patients and MethodsThe frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non–Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL.ResultsPatients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non–Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes.ConclusionPh-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.
Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial
Authors: Trappe Ralf U. , Dierickx Daan , Zimmermann Heiner , Morschhauser Franck , Mollee Peter , Zaucha Jan M. , Dreyling Martin H. , Dührsen Ulrich , Reinke Petra , Verhoef Gregor , Subklewe Marion , Hüttmann Andreas , Tousseyn Thomas , Salles Gilles , Kliem Volker , Hauser Ingeborg A. , Tarella Corrado , Van Den Neste Eric , Gheysens Olivier , Anagnostopoulos Ioannis , Leblond Veronique , Riess Hanno , Choquet Sylvain 
Published: February 2017

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective.
Antineoplastic Treatment of Advanced-Stage Non–Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011)
Authors: Bradley Cathy J. , Yabroff K. Robin , Mariotto Angela B. , Zeruto Christopher , Tran Quyen , Warren Joan L. 
Published: February 2017

Purpose Multiple agents for advanced non–small-cell lung cancer (NSCLC) have been approved in the past decade, but little is known about their use and associated spending and survival. Methods We used SEER-Medicare data for elderly patients with a new diagnosis of advanced-stage NSCLC and were treated with antineoplastic agents between 2000 and 2011 (N = 22,163). We estimated the adjusted percentage of patients who received each agent, days while on treatment, survival, and spending in the 12 months after diagnosis. Results During the 12-year study period, a marked shift in treatment occurred along with a rapid adoption of pemetrexed (39.2%), erlotinib (20.3%), and bevacizumab (18.9%) and a decline in paclitaxel (38.7%), gemcitabine (17.0%), and vinorelbine (5.7%; all P < .05). The average total days on therapy increased by 5 days (from 103 to 108 days). Patients who received bevacizumab, erlotinib, or pemetrexed had the longest treatment durations on average (approximately 146 days v 75 days for those who did not receive these agents). Approximately 44% of patients received antineoplastic agents in the last 30 days of life throughout the study period. Acute inpatient spending declined (from $29,376 to $23,731), whereas outpatient spending increased 23% (from $37,931 to $46,642). Median survival gains of 1.5 months were observed. Conclusion Considerable shifts in the treatment of advanced-stage NSCLC occurred along with modest gains in survival and total Medicare spending. More precise outcome information is needed to inform value-based treatment decisions for advanced-stage NSCLC.
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology
Authors: Bartley Angela N. , Washington Mary Kay , Colasacco Carol , Ventura Christina B. , Ismaila Nofisat , Benson Al B. , Carrato Alfredo , Gulley Margaret L. , Jain Dhanpat , Kakar Sanjay , Mackay Helen J. , Streutker Catherine , Tang Laura , Troxell Megan , Ajani Jaffer A. 
Published: February 2017

Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials
Authors: Shi Qian , Flowers Christopher R. , Hiddemann Wolfgang , Marcus Robert , Herold Michael , Hagenbeek Anton , Kimby Eva , Hochster Howard , Vitolo Umberto , Peterson Bruce A. , Gyan Emmanuel , Ghielmini Michele , Nielsen Tina , De Bedout Sabine , Fu Tommy , Valente Nancy , Fowler Nathan H. , Hoster Eva , Ladetto Marco , Morschhauser Franck , Zucca Emanuele , Salles Gilles , Sargent Daniel J. 
Published: February 2017

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.
Development of a Patient Registry to Evaluate Hospital Admissions Related to Chemotherapy Toxicity in a Community Cancer Center
Authors: Krzyzanowska Monika K. , Treacy Jean , Maloney Betty , Lavino Antoinette , Jacobson Joseph O. 
Published: February 2017

Purpose Most chemotherapy (CT) administration occurs in routine care settings, yet little is known about treatment-related toxicity outside of clinical trials. To examine trends in toxicity, modify practice, and establish benchmarks for severe toxicity in a community cancer center we created a prospective registry of all treatment-related hospitalizations at the North Shore Medical Center Cancer Center, a community-based cancer facility in Peabody, MA. Methods Eligible population consisted of all adult cancer patients admitted to the hospital within 30 days of their last CT administration. Each admission was reviewed by a panel of hospital staff to determine whether admission was treatment-related. Information on admission was collected using a standard form. Results Between October 2001 and December 2003, there were 365 hospitalizations among patients receiving CT, 117 (32%) of which were deemed treatment-related. The median age of the cohort with treatment-related toxicity was 67 years, and 41% were male. Most frequent diagnoses were non-Hodgkin's lymphoma (23%) and colorectal cancer (21%), with 49% of the patients receiving treatment with palliative intent. The most common reasons for admission were gastrointestinal toxicity or infection. The mean length of stay was 7.1 days. Seven patients (6%) died during hospitalization. When the registry was reviewed to identify areas where care may be improved, several admissions for decadron-related hyperglycemia in nondiabetic patients with myeloma were noted. This led to introduction of glucose monitoring guidelines with no subsequent admissions for this toxicity since then. Conclusions About one third of hospital admissions in patients receiving CT are treatment-related and most occur in patients with advanced disease. Collection of data on toxicity in the routine care setting is feasible and may facilitate quality improvement.
Cancer Patient Survival Improvement Is Correlated With the Opening of a Community Cancer Center: Comparisons With Intramural and Extramural Benchmarks
Authors: Dillman Robert O. , Chico Sherri D. 
Published: February 2017

Purpose We sought to determine whether survival of patients managed at a large community hospital improved after an affiliated facility opened and its associated programs were initiated. Methods Survival data for patients with invasive cancer was obtained from the Hoag Hospital tumor registry for the successive periods 1986-1991 and for 1992-1999 for historical intramural comparisons; national Surveillance, Epidemiology, and End Results (SEER) program data for the same periods were used for contemporary and historical extramural comparisons. Results We observed survival improved significantly during 1992-1999 compared with 1986-1991 for all patients with invasive cancers (P < .0001), and specifically for cancers of the breast (P = .026), lung (P = .012), prostate (P < .0001), stomach (P = .006), pancreas (P = .0001), and oral cavity (P = .024), with strong trends for improved survival for leukemia (P = .051) and rectal cancer (P = .063). Relative 5-year survival rates increased from 63% during 1986-1991 to 71% during 1992-1999, and were higher for 22 of 24 tumor types during the more recent period (P < .0001). Compared with SEER data, Hoag relative survival for all patients with invasive cancer was 63% versus 58% during 1986-1991, and 71% versus 64% during 1992-1999. Survival for Hoag patients was better than SEER rates for only 50% of malignancies (12 of 24) during 1986-1991 compared with 87% (21 of 24) during 1992-1999 (P = .013). In the most common tumor types, there were substantial improvements in survival for patients with regional disease at diagnosis. Improved survival was associated with earlier diagnosis and increased use of systemic treatment and combined modality therapy. Conclusion Patients with invasive cancer who were treated at an integrated community cancer center had better survival compared with historical survival and patients from the SEER registry. The findings are consistent with the hypothesis that the accelerated dissemination of new information resulted in earlier adoption of improved screening, diagnostic, and multidisciplinary treatment approaches, leading to higher survival rates.
Prevalence of Burnout in the U.S. Oncology Community: Results of a 2003 Survey
Authors: Allegra Carmen J. , Hall Ray , Yothers Greg 
Published: February 2017

Purpose To investigate the level of burnout in the oncology community in the United States. Patients and Methods Seven thousand seven hundred fifteen oncology physicians were queried by e-mail or during attendance at oncologic meetings and asked to complete a 22-question survey concerning their feelings of personal burnout and their perceptions of physician burnout in the oncology community. The data were analyzed using standard statistical methods including a multivariate analyses using logistic regression with stepwise selection. Results One thousand seven hundred forty oncologists (22.6%) completed and returned the survey, with 92.6 % representing medical oncologists or hematologist-oncologists. Two thirds of the respondents were from community practice and one third from academia. Overall, 61.7% of the respondents reported feelings of burnout, with the top three signs being frustration (78%), emotional exhaustion (69%), and lack of satisfaction with their work (50%). The highest-ranked causes for their feelings of burnout included overwork, lack of time away from the office, and reimbursement concerns. The top remedies for burnout were felt to be fewer patients, more time away from the office, and increased attendance at medical meetings. The multivariate analyses demonstrated highly significant associations between burnout and hours spent on patient care, personal time off, and number of educational meetings attended. Conclusion The rate of burnout in the oncology community of the United States exceeds 60%. This report suggests causes and potential solutions for the high rate of burnout. Such information may lead to an improved understanding of the needed steps to improve the quality of life for the oncology community with the ultimate goal of further improving patient care. Patients deserve optimal medical and emotional support that is best provided by caring and well-informed practitioners.
Lineage-specific proteins essential for endocytosis in trypanosomes
Authors: Manna Paul T. , Obado Samson O. , Boehm Cordula , Gadelha Catarina , Sali Andrej , Chait Brian T. , Rout Michael P. , Field Mark C. 
Published: February 2017

ABSTRACT
Clathrin-mediated endocytosis (CME) is the most evolutionarily ancient endocytic mechanism known, and in many lineages the sole mechanism for internalisation. Significantly, in mammalian cells CME is responsible for the vast bulk of endocytic flux and has likely undergone multiple adaptations to accommodate specific requirements by individual species. In African trypanosomes, we previously demonstrated that CME is independent of the AP-2 adaptor protein complex, that orthologues to many of the animal and fungal CME protein cohort are absent, and that a novel, trypanosome-restricted protein cohort interacts with clathrin and drives CME. Here, we used a novel cryomilling affinity isolation strategy to preserve transient low-affinity interactions, giving the most comprehensive trypanosome clathrin interactome to date. We identified the trypanosome AP-1 complex, Trypanosoma brucei (Tb)EpsinR, several endosomal SNAREs plus orthologues of SMAP and the AP-2 associated kinase AAK1 as interacting with clathrin. Novel lineage-specific proteins were identified, which we designate TbCAP80 and TbCAP141. Their depletion produced extensive defects in endocytosis and endomembrane system organisation, revealing a novel molecular pathway subtending an early-branching and highly divergent form of CME, which is conserved and likely functionally important across the kinetoplastid parasites.