bluuebunny/crossref_metadata_2025 huggingface dataset:
Pembrolizumab (MK-3475) for previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: Phase II KEYNOTE-180 study.
Authors: Shah Manish A. , Bennouna Jaafar , Shen Lin , Enzinger Peter C. , Li Qiao , Csiki Ildiko , Koshiji Minori , Doi Toshihiko
Published: February 2017

TPS189

Background: PD-L1 is frequently overexpressed in esophageal cancer. Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor and blocks interaction with PD-L1 and PD-L2. In the multicohort, phase Ib KEYNOTE-028 trial, pembrolizumab showed manageable toxicity, a 30.4% ORR, and median duration of response of 40 wk in 23 patients (pts) with PD-L1+ advanced esophageal cancer. The single-arm, multicenter phase II KEYNOTE-180 trial is designed to further evaluate pembrolizumab as a monotherapy in pts with previously treated advanced/metastatic esophageal cancer. Methods: Key eligibility criteria include age ≥ 18 y, advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction (EGJ), measurable disease, documented progression during or after 2 prior lines of therapy, ECOG PS 0-1, no active autoimmune disease or brain metastases, and provision of a tumor sample for retrospective biomarker analysis. Pts with metastatic Siewert type I EGJ adenocarcinoma must have known HER2 status and, if HER2+, must have documented progression on treatment containing trastuzumab. Eligible pts will receive pembrolizumab 200 mg Q3W for 35 cycles (~2 y) or until progression, unacceptable toxicity, or investigator or pt decision. Response will be assessed every 9 wk per RECIST v1.1 and RECIST adapted for immunotherapy response patterns. Treatment may be discontinued for pts who have a CR, and eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 9 wk. The primary efficacy end point is ORR per RECIST v1.1 by central review. Secondary end points include PFS, OS, and duration of response. Exploratory analyses include evaluation of immune-related gene expression profiles and PD-L1 expression status as predictors of pembrolizumab efficacy. Enrollment in KEYNOTE-180 is expected to begin in October 2015 and will continue until approximately 100 pts are enrolled.
Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors.
Authors: Wainberg Zev A. , Eisenberg Peter D. , Sachdev Jasgit C. , Weise Amy M. , Kaufman David Ross , Hutchinson Marguerite , Tong Sandra , Aromin Ireene , Hu-Lieskovan Siwen , Patnaik Amita
Published: February 2017

TPS465

Background: Tumor-associated macrophages (TAMs) support tumor growth and cause tumor resistance to chemotherapy and radiation therapy; myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity and cause resistance to PD-1 inhibition. TAMs and MDSCs are both regulated by colony stimulating factor 1 (CSF1). Pexidartinib is a small molecule inhibitor of CSF1 receptor, CSF1R. The normal function of PD-1, expressed on the cell surface of activated T-cells, is to suppress excessive immune responses, eg, autoimmune reactions. Tumors utilize PD-1 signaling to downregulate immune-mediated elimination. Pembrolizumab is a potent, highly selective humanized monoclonal antibody that blocks interactions between PD-1 and its ligands, PD-L1 and PD-L2. We present the study design for a Phase 1/2a clinical trial assessing safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of pexidartinib and pembrolizumab in advanced solid tumors (NCT02452424). Methods: In Part 1 of this open-label, uncontrolled trial, patients with advanced solid tumors will receive pembrolizumab (200 mg IV q 3 weeks) and escalating daily oral doses of pexidartinib to establish the safety and tolerability of the combination and a recommended phase 2 dose (RP2D). In Part 2, the combination RP2D will be studied in an expanded panel of solid tumor cohorts in up to 475 patients, to assess safety and preliminary efficacy. The panel will include GI malignancies for which preclinical data support this combination, including gastric and gastro-esophageal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, and GI stromal tumors. Overall response rate (RECISTv1.1) and progression free survival will be evaluated. Exploratory endpoints include novel biomarkers of clinical activity and drug mechanisms of action. A truncated sequential probability ratio test will be employed in each tumor cohort to allow early decision-making for futility or success. The results will support further development of the pexidartinib/pembrolizumab combination in the solid tumors that respond to treatment in this study. Clinical trial information: NCT02452424.
A phase I safety and pharmacokinetic (PK) study of nab-paclitaxel (nab-P) plus gemcitabine (Gem) for patients (pts) with advanced pancreatic cancer (APC) who have cholestatic hyperbilirubinemia (CH) secondary to bile duct obstruction.
Authors: Riess Hanno , Kunzmann Volker , Philip Philip Agop , Seufferlein Thomas , McGovern Desmond Micahel Thomas , Chen Peng , Romano Alfredo , Ramanathan Ramesh K.
Published: February 2017

TPS474

Background: In pts with APC, the distal common bile duct is frequently obstructed, which can lead to elevated bilirubin levels. Normalization of bilirubin by stenting can take weeks, so treatment options that could be initiated in pts with elevated bilirubin are desirable. In a phase III trial of pts with metastatic PC, nab-P + Gem demonstrated superior efficacy vs Gem alone for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio, 0.72; P < 0.001). This study will be the first to analyze safety and PK profiles of nab-P + Gem in pts with APC and CH secondary to bile duct obstruction. Methods: Treatment-naive pts (≈ 12 to 40) with APC, Karnofsky performance status ≥ 70, and CH due to bile duct obstruction are eligible. Pts with a biliary stent must have 2 stable (within 20% of each other) bilirubin readings within 48 to 72 hours of each other taken between 5 and 21 days after stenting. Exclusion criteria consist of brain metastases, any other active malignancy, infection requiring systemic therapy, a history of myocardial infarction, or current use of medications known to be strong inducers of CYP3A4 and CYP2C8. Pts will enter 1 of 2 cohorts based on bilirubin level: cohort 1, > 1.5 to 3 × upper limit of normal (ULN), or cohort 2, > 3 to 5 × ULN. Cohort 2 will proceed only after review of safety and PK data from cohort 1 by a safety monitoring committee (SMC) and a decision has been made to proceed. The starting doses are nab-P 100 mg/m2 and Gem 800 mg/m2 for cohort 1 and nab-P 75 mg/m2 and Gem 600 mg/m2 for cohort 2. Treatment will be administered on days 1, 8, and 15 of each 28-day cycle. Doses in each cohort will be modified according to tolerability as determined by the SMC. The primary endpoints are determination of maximum tolerated dose for each cohort and PK profile. Secondary endpoints include investigator-assessed objective response rate, progression-free survival, OS, PK profile of Gem, and safety. The exploratory endpoint is change in serum CA19-9 level from baseline. Enrollment is ongoing. ClinicalTrials.gov: NCT02267707. Clinical trial information: NCT02267707.
nab-paclitaxel (nab-P) + nivolumab (Nivo) ± gemcitabine (Gem) in patients (pts) with advanced pancreatic cancer (PC).
Authors: Firdaus Irfan , Waterhouse David Michael , Gutierrez Martin , Wainberg Zev A. , George Ben , Kelly Karen , Bekaii-Saab Tanios S. , Carrizosa Daniel R. , Soliman Hatem Hussein , Fraser Cindy Duval , Ko Amy , Pierce Daniel W , Manax Victoria G. , Stergiopoulos Sotirios G. , Hochster Howard S.
Published: February 2017

TPS475

Background: Nivo, an antibody against PD-1, is approved for unresectable or metastatic melanoma and metastatic squamous non-small cell lung cancer (NSCLC) after initial standard therapies. nab-P does not require immunosuppressive steroid premedication and is approved for treatment of metastatic breast cancer (MBC) after initial chemotherapy (CT) including an anthracycline, and for advanced NSCLC (+ carboplatin), and metastatic PC (+ Gem). This 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P— based therapy in MBC, advanced NSCLC, and advanced PC. The study design for the pancreatic portion (arm A: nab-P + Nivo; arm B: nab-P + Gem + Nivo) is described below. Methods: This 2-part study will identify dose-limiting toxicities (DLTs) in Part 1 and assess safety and explore antitumor activity in Parts 1 and 2 (Table). If Arm A, Part 1, is deemed safe (≤ 1 DLT in up to 6 pts), then Arm B, Part 1, will initiate enrollment. Regimens in Part 1 may be expanded in Part 2. Enrollment in Arm A, Part 1, is ongoing. ClinicalTrials.gov: NCT02309177. Clinical trial information: NCT02309177. [Table: see text]
Using technology to improve quality metric adherence.
Authors: Jacobsen Paul B. , Gaguski Michele , Thomas Kathryn A , Hathaway Amanda , Halilova Karina I. , Stricker Carrie Tompkins , Hammelef Karen , Panzer SarahLena , Blayney Douglas W. , Rocque Gabrielle Betty
Published: February 2017

257

Background: Many barriers to adherence to quality standards exist, including patient, provider, and system barriers to delivery and documentation of timely, evidence-based care. Gaps in clinician knowledge about care standards likely contribute to non-adherence. Methods: Prior to an intervention study, providers completed a questionnaire assessing their knowledge of and ability to influence institutional attainment of specific QOPI metrics. Providers’ ability to influence meeting each of 9 QOPI metrics was measured on a 1-4 scale from “not at all” to “significantly” able to influence. Providers also identified barriers to meeting each metric. Results: 28 providers completed surveys; 43% from a university based cancer center and 57% from a community based cancer center. Respondents include oncology MDs (43%), NPs (7%) and RNs (46%). Perceived ability to influence 9 quality metrics are detailed in the Table below. Providers felt the least able to influence metrics related to fertility preservation with 32% reporting no influence. 21% credited ‘lack of visibility into current data’ to be a main barrier. Providers reported limited ability to address emotional well-being with 36% reporting a ‘lack time to assess/manage’. Providers felt most able to influence physical symptoms such as pain. Conclusions: The most frequently cited barriers to meeting study-specific quality metrics included lack of a) current knowledge/latest evidence and, b) time to assess/manage. Employing methods to address these barriers may improve quality care. In part 2 of this study providers engage with the Carevive Care Planning System, designed to address these barriers by assessing patient needs at the point of care and providing evidence-based recommendations for treatment. [Table: see text]
The influence of treatment facility volume on the mortality of multiple myeloma patients.
Authors: Go Ronald S. , Bartley Adam C , Crowson Cynthia S , Shah Nilay D. , Habermann Elizabeth B. , Holton Sara , Holmes David R
Published: February 2017

284

Background: MM is an uncommon cancer with annual incidence of only 27,000 cases in the US. Our study determined the extent to which the number of MM patients treated annually in a treatment facility affected all-cause mortality. Methods: We used the National Cancer Data Base (NCDB) to identify adult patients with MM diagnosed from 2003-2011. NCDB is sourced from over 1,500 Commission on Cancer-accredited cancer registries representing 70% of cancer cases in the US. We classified treatment facilities by quartiles based on facility volume (mean patients/year): Quartile 1 (Q1: < 3.6), Quartile 2 (Q2: 3.6-6.1), Quartile 3 (Q3: 6.1-10.3) and Quartile 4 (Q4: > 10.3). We used hot deck imputation to account for missing data, Cox regression to analyze the association between facility volume and time-to-death, and random intercepts to adjust for multiple patients per facility. Results: There were 94,722 MM patients cared for at 1,333 facilities. Most patients (73.5%) were diagnosed and treated in the same facility. The median age at diagnosis was 67 years and 54.7% were males. The median annual facility volume was 6.1 patients/year (IQR: 3.6-10.3; range: 0.2-109.9). The distribution of patients according to facility volume was Q1 (5.2%), Q2 (12.6%), Q3 (21.9%) and Q4 (60.3%). The unadjusted median overall survival by facility volume was: Q1: 26.9 months, Q2: 29.1 months, Q3: 31.9 months and Q4: 49.1 months. After multivariable analysis adjusting for demographic (sex, age, race, ethnicity), socioeconomic (income, education, insurance type), geographic (area of residence, treatment facility location), co-morbidity (Charlson-Deyo score), and disease-specific (year of diagnosis) factors, we show that facility volume remains an independent predictor of all-cause mortality. Compared to patients treated at Q4 facilities, patients treated at lower quartile facilities had a higher risk of death (Q3 HR: 1.16 [95% CI, 1.12-1.20]; Q2: 1.21 [1.17-1.26]; Q1: 1.27 [1.22-1.34]). We observed an inverse volume-outcome relationship up to an annual facility volume of approximately 60 patients. Conclusions: MM patients treated at higher volume facilities had lower risk of mortality compared to those treated at lower volume facilities.
RO-ILS: Radiation Oncology Incident Learning System data trends 2014-2015.
Authors: Hoopes David J. , Ford Eric C. , Eads Nadine L. , Kapetanovic Ksenija , Tomlinson Cindy
Published: February 2017

59

Background: Incident learning is one of the most effective ways to improve quality care. To facilitate patient safety improvement at a national level, American Society for Radiation Oncology (ASTRO) and American Association of Physicists in Medicine (AAPM) launched RO-ILS: Radiation Oncology Incident Learning System in June 2014. RO-ILS mission is to facilitate safer and higher quality care through a shared learning environment that is secure and non-punitive. Methods: To ensure the security and protection of data, ASTRO contracted with Clarity PSO, a federally-certified patient safety organization that operates under the auspices of the Patient Safety and Quality Improvement Act of 2005. Radiation oncology practices sign a no-fee contract with Clarity PSO to participate in RO-ILS and then enter safety data into a customized web-based portal. Submitted data are analyzed and interpreted by the Radiation Oncology Healthcare Advisory Council (RO-HAC), a multi-professional team. Practices receive aggregate quarterly reports and institutional reports when substantial data are submitted. Results: During the first year, 61 US practices (123) facilities signed contracts. 42 practices entered 1259 events and 619 of these events (49%) were submitted to the national database. Types of events included: 242 (39%) incidents that reached the patient with or without harm; 206 (33%) near-misses; and 171 (28%) unsafe conditions. RO-HAC identified risk-prone processes including ineffective communication, compressed timelines to start treatment, changes to treatment during the course of therapy and junior practitioners’ errors not remedied by experienced staff. Conclusions: Data suggests that quality assurance processes were effective in catching errors; however, continued work needs to address the origin of these errors and suggest robust solutions. To facilitate improved communication, effective protocols and software enhancements are recommended to alert staff to changes in patients’ management. Policies and procedures on patient hand-offs, emergency cases and oversight of junior staff will help error mitigation. While in its infancy, RO-ILS provides useful data and will serve to improve the quality and safety of radiotherapy.
Understanding the patient experience with soft tissue sarcoma: A systematic review of the literature.
Authors: Hess Lisa M. , Winnette Randall , Nicol Steven , Tai Datchen Fritz , Copley-Merriman Kati
Published: February 2017

61

Background: Soft tissue sarcomas (STS) are a heterogenous group of rare tumors that involve the connective tissue in the body. As with many rare tumors, little is known about the impact of STS on patient well-being. The objective of this review was to understand patient experience and quality of life (QOL) following diagnosis of STS. Methods: This was a systematic review of English language articles published between 2005-2015 in PubMed/Medline, Embase, PsychINFO, and Evidence-Based Medicine. The review included recent conference proceedings and resources from advocacy websites. Articles were considered relevant if they included adult STS patient reported outcomes (PROs) or details on patient experience. Results: Of the 3,430 articles identified, 20 were eligible for inclusion. Of these, 14 were clinical studies that included PRO measures, 1 summarized PRO measures used in STS studies, and 5 described the STS patient experience. Patients with STS report a variety of concerns including emotional well-being (e.g. anxiety, depression), body image, functional deficit following surgery, and practical considerations such as obtaining child care and ability to work. Reports of patient experience vary widely given the heterogeneity of STS and individualized treatment. In clinical studies that used PROs, the European Organization for Research and Treatment of Cancer QOL Questionnaire Core 30 (EORTC QLQ-C30) was the most commonly used cancer-specific measure (N = 5) followed by the Functional Assessment of Cancer Therapy–General (N = 2). The generic EQ-5D was used in 5 publications but was limited to the visual analog scale portion of the measure in two of these studies. Similar to other cancers, STS patients report lower QOL when compared to the general population. Conclusions: Few studies have published either qualitative or quantitative data on the patient experience with STS. While STS has a measurable impact on QOL, there is a lack of detailed information in the published literature. Although PROs are often used in clinical studies of STS, they are not STS-specific tools and may not capture the unique needs of this population. There is a need for qualitative research to better understand the patient perspective of STS.
What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis
Authors: Ribassin-Majed Laureen , Marguet Sophie , Lee Anne W.M. , Ng Wai Tong , Ma Jun , Chan Anthony T.C. , Huang Pei-Yu , Zhu Guopei , Chua Daniel T.T. , Chen Yong , Mai Hai-Qiang , Kwong Dora L.W. , Cheah Shie-Lee , Moon James , Tung Yuk , Chi Kwan-Hwa , Fountzilas George , Bourhis Jean , Pignon Jean Pierre , Blanchard Pierre ,   on behalf of the Meta-Analysis of Chemotherapy in Nasopharyngeal Collaborative Group
Published: February 2017

Purpose

The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments.

Methods

All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied.

Results

The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity.

Conclusion

The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.
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

Purpose

Philadelphia 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 Methods

The 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.

Results

Patients 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.

Conclusion

Ph-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.
Hematology in the United Kingdom
Authors: Prentice Archie
Published: February 2017

This article is the first in a series of features comparing and contrasting aspects of oncology care delivery in non-US settings. The Journal of Oncology Practice will occasionally publish similar pieces in anticipation of discovering best practices from international health care systems. Dr Prentice's contribution is based on his presentation to the Committee on Practice of the American Society of Hematology at their December 2005 meeting.
FGF signaling enforces cardiac chamber identity in the developing ventricle
Authors: Pradhan Arjana , Zeng Xin-Xin I. , Sidhwani Pragya , Marques Sara R. , George Vanessa , Targoff Kimara L. , Chi Neil C. , Yelon Deborah
Published: February 2017

Atrial and ventricular cardiac chambers behave as distinct subunits with unique morphological, electrophysiological and contractile properties. Despite the importance of chamber-specific features, chamber fate assignments remain relatively plastic, even after differentiation is underway. In zebrafish, Nkx transcription factors are essential for the maintenance of ventricular characteristics, but the signaling pathways that operate upstream of Nkx factors in this context are not well understood. Here, we show that FGF signaling plays an essential part in enforcing ventricular identity. Loss of FGF signaling results in a gradual accumulation of atrial cells, a corresponding loss of ventricular cells, and the appearance of ectopic atrial gene expression within the ventricle. These phenotypes reflect important roles for FGF signaling in promoting ventricular traits, both in early-differentiating cells that form the initial ventricle and in late-differentiating cells that append to its arterial pole. Moreover, we find that FGF signaling functions upstream of Nkx genes to inhibit ectopic atrial gene expression. Together, our data suggest a model in which sustained FGF signaling acts to suppress cardiomyocyte plasticity and to preserve the integrity of the ventricular chamber.
Severe preeclampsia is associated with alterations in cytotrophoblasts of the smooth chorion
Authors: Garrido-Gomez T. , Ona K. , Kapidzic M. , Gormley M. , Simón C. , Genbacev O. , Fisher S. J.
Published: February 2017

Preeclampsia (PE), which affects ∼8% of first pregnancies, is associated with faulty placentation. Extravillous cytotrophoblasts (CTBs) fail to differentiate properly, contributing to shallow uterine invasion and deficient spiral artery remodeling. We studied the effects of severe PE (sPE) on the smooth chorion portion of the fetal membranes. The results showed a significant expansion of the CTB layer. The cells displayed enhanced expression of stage-specific antigens that extravillous CTBs normally up regulate as they exit the placenta. Transcriptomics revealed the dysregulated expression of many genes (e.g., placental proteins, markers of oxidative stress). We confirmed a sPE-related increase in production of PAPPA1, which releases IGF-1 from its binding protein. IGF1 enhanced proliferation of smooth chorion CTBs, a possible explanation for expansion of this layer, which may partially compensate for the placental deficits.
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

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.