tbuckley/cabot-search huggingface dataset:
Education and Reporting of Diagnostic Errors Among Physicians in Internal Medicine Training Programs
Authors: Thilan P. Wijesekera, Lisa Sanders, Donna M. Windish
Journal: JAMA Internal Medicine (2018)

In September 2015, the National Academy of Medicine released the landmark report "Improving Diagnosis in Health Care," which defined diagnostic error as "the failure to (a) establish an accurate and timely explanation of the patient's health problem(s) or (b) communicate that explanation to the patient." 1 Earlier educational programs that addressed diagnostic error focused on providers' medical knowledge, clinical reasoning, and systems awareness. [1]2][3][4] We evaluated physicians' training for and comfort with communicating diagnostic errors to patients and reporting them to other health care providers.Methods | From June 2, 2016, through March 29, 2017, we surveyed internal medicine resident and attending physicians from 9 residency programs across 2 university-affiliated and 4 community-affiliated hospitals in Connecticut.Participants received electronic surveys via email or paper-based surveys.After providing participants with the National Academy of Medicine definition of diagnostic error, we asked questions about physicians' education and reporting of diagnostic errors, including where the physician was taught to discuss diagnostic errors, whether training programs teach residents how to communicate about diagnostic errors, how institutions typically address diagnostic errors, how trainees are encouraged to report diagnostic errors, how comfortable physicians feel reporting diagnostic errors, and whether the participant agreed with the statement "My current reporting system is helpful in reducing diagnostic errors."We used summary statistics for aggregate responses and Pearson χ 2 test for subgroup analyses.The Figure and theTable give data on responses.
Is lower hip range of motion a risk factor for groin pain in athletes? A systematic review with clinical applications
Authors: Igor Tak, Leonie Engelaar, Vincent Gouttebarge, Maarten Barendrecht, Sylvia Van den Heuvel, Gino Kerkhoffs, Rob Langhout, Janine Stubbe, Adam Weir
Journal: British Journal of Sports Medicine (2017)

Background Whether hip range of motion (ROM) is a risk factor for groin pain in athletes is not known. Objectives To systematically review the relationship between hip ROM and groin pain in athletes in cross-sectional/case–control and prospective studies. Study design Systematic review, prospectively registered (PROSPERO) according to PRISMA guidelines. Methods Pubmed, Embase, CINAHL and SPORTDiscus were systematically searched up to December 2015. Two authors performed study selection, data extraction/analysis, quality assessment (Critical Appraisal Skills Programme) and strength of evidence synthesis. Results We identified seven prospective and four case–control studies. The total quality score ranged from 29% to 92%. Heterogeneity in groin pain classification, injury definitions and physical assessment precluded data pooling. There was strong evidence that total rotation of both hips below 85° measured at the pre-season screening was a risk factor for groin pain development. Strong evidence suggested that internal rotation, abduction and extension were not associated with the risk or presence of groin pain. Conclusion Total hip ROM is the factor most consistently related to groin pain in athletes. Screening for hip ROM is unlikely to correctly identify an athlete at risk of developing groin pain because of the small ROM differences found and poor ROM measurement properties.
Quality of life (QoL) for FDA-approved agents in advanced NSCLC.
Authors: Hamzeh Adel Albaba, Andrea Bezjak, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2016)

e18117 Background: Althoughsymptom control and QoL improvement are among the most important goals of systemic therapy in advanced NSCLC, they are not required for regulatory approval. Approvals appear based on survival benefit, progression-free survival benefit and even response rate. The aim of this analysis is to review published QoL data for FDA approved agents and explore their potential as an important endpoint for nonrandomized targeted therapy trials. Methods: We identified 17 agents approved in the US for various indications in the treatment of advanced NSCLC between 1999 and 2015. Clinical trials associated with regulatory approval of these agents in either the first- or second-line or maintenance setting were identified. QoL results were abstracted from these studies, in addition to trial characteristics (phase, sponsor). Results: 33 trials were identified that were associated with the 17 approved agents. Among these, 26 (79%) were phase 3 randomized trials (including 3 cooperative group studies) and 7 (21%) were phase I/II trials. QoL was reported for 20 trials (61%), including all cooperative group trials. Another 5 (15%) measured QoL but results were not reported. The remaining 8 (24%) trials did not assess QoL. In trials with reported QoL outcomes, better global QoL and cancer-related symptoms were identified in 12/20 (60%) and 13/20 (65%) respectively. Time to symptom deterioration was reported in 13 (65%) studies with all but one showing benefit for the approved agent. The remaining studies reported no significant difference in QoL between study treatment arms. All studies reporting improved QoL parameters also demonstrated improved response rate. In trials showing OS and PFS improvement, 2/7 and 8/12 reported better QoL outcomes respectively. Of 7 early phase trials leading to drug approval of agents with high response rates, 2 reported improved QoL outcomes. Two have not yet reported QoL data and 3 did not measure QoL. Conclusions: QoL remains an important endpoint in advanced NSCLC and is associated with response rate. QoL has the potential to be an important endpoint for drug approval based on early phase trials of highly active agents and should be given further consideration by pharmaceutical sponsors.
ADR-201: A novel cytotoxic drug-conjugate for pancreatic cancer.
Authors: Mark Ricigliano, Brandon Cooper, Andrew Bartlett, Kenneth H. Yu
Journal: Journal of Clinical Oncology (2017)

e14018 Background:Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX or gemcitabine with nab-paclitaxel used in either the front-line or 2 nd line treatment. There is no consensus for 3 rd line treatment. We previously demonstrated that Mitomycin C (M) and Cisplatin (C) as viable 3 rd line treatment options with broad use limited by toxicity. To address the toxicity issues with the prolonged use of M and C, we developed a novel cytotoxic drug conjugate ADR-201 (A), as a treatment option for metastatic PDAC . Methods: (A) is a cytotoxic drug conjugate formed from the APIs of Mitomycin C (M) and Cisplatin (C) conjugated with an amine-to-sulfhydryl crosslinker with a soluble polyethylene glycol (PEG) spacer arm to reduce steric hindrance. In order to conjugate C, the molecule was thiolated prior to crosslinking with a maleimide functional group. In cytotoxic assays, MiaPaca-2 cells were treated with 17uM of A and cell viability was measured at 48hrs, 72hrs and 96hrs. In thin layer chromatography (TLC) A, M and C were spotted at the origin with 0.5uL of 17uM, 10mM and 10mM respectively. Cell cultures comprising circulating tumor and invasive cells (CTICs) obtained from PDAC patients (n = 12) were treated with 17uM of A and cell viability was measured at 72hrs. Results: In TLC, A showed marked solubility in polar neutral solvent EtOAc /hexane (20:80) compared to the polar compounds M and C with Rf values 0.38:1.0:1.0 respectively. In cytotoxic assays with MiaPaca-2 cells, serial dilutions of A at 17uM, 8.5uM and 3.4uM demonstrated a 30%, 11% and 6% reduction in cell viability at 72hrs. In 24 CTIC cultures, A reduced cell viability between treatment v control groups by an average -26%. (range -31% - 0%, paired t-test, p-value = 0.013, ). Conclusions: Improvements in solubility and cytotoxic activity at low dose levels compared to single agents M and C should translate to enhanced permeability and retention (EPR) in tumor tissue with corresponding reduced toxicity.
Heart Failure With Recovered Ejection Fraction
Authors: Jort Merken, Hans-Peter Brunner-La Rocca, Jerremy Weerts, Job Verdonschot, Mark Hazebroek, Georg Schummers, Marcus Schreckenberg, Joost Lumens, Stephane Heymans, Christian Knackstedt
Journal: Journal of the American College of Cardiology (2018)
Interval between last neoadjuvant chemotherapy and surgery and between surgery and first adjuvant chemotherapy in ovarian cancer patients.
Authors: Alexandre Andre B. A. Da Costa, Adriana Regina Goncalves Ribeiro, Henrique Mantoan, Carlos Stecca, Elizabeth Santana dos Santos, Joao Paulo Lima, Audrey Oliveira, Deborah Porto Cotrim, Larissa Von Grapp, Victor Aurelio Ramos Sousa, Joyce Maria L. Maia, Andrea Paiva Guimaraes, Glauco Baiocchi
Journal: Journal of Clinical Oncology (2018)

e17558 Background: Neoadjuvant chemotherapy (NCT) is an option to treat ovarian cancer patients with bulky peritoneal disease who are not good candidates to complete primary debulking surgery. The best timing of NCT pause before surgery and restart after surgery is not clearly established. A recent paper suggested a longer interval between last NCT and first adjuvant chemotherapy (ACT) could have a negative prognostic impact. In this paper we evaluated the optimal timing between last NCT and surgery and between surgery and first ACT. Methods: We retrospectively evaluated ovarian cancer patients treated with NCT and debulking surgery at A.C.Camargo Cancer Center – Brazil from 2007 to 2017. At our institution, primary debulking surgery is the standard care, and patients are treated with NCT if there is a high risk for incomplete debulking in primary surgery or the patient have a poor performance status. Interval between last NCT and surgery and between surgery and first ACT were calculated and other clinical characteristics and outcomes collected. We used a cut-off finder method that optimizes the cut-off according to the statistical significance of the hazard ratio for overall survival (OS). Results: There were 122 patients treated with NCT and with available clinical data. Median age was 62.2 years old, 87.7% of patients had high grade serous carcinoma, 6.6% had ECOG performance status of 2 or worse, 78.8% had FIGO stage IIIC disease and 19.7% had FIGO stage IV disease. Interval debulking surgery with residual disease smaller than 1cm was achieved in 73.0%. Median interval between last NCT and surgery was 55.0 days and between surgery and first ACT was 49 days. With a median follow-up of 46.6 months median OS was 48.3 months. Interval between last NCT and surgery longer than 55 to 60 days had a negative impact on survival, and interval between surgery and first ACT between 50 and 60 day had a negative impact on survival. Other cut-off values for this interval resulted in no significant impact on OS. Number of NCT cycles had no impact on OS. Conclusions: Interval between NCT and surgery and between surgery and ACT should be no longer than 60 days.
Potential role of circulating tumor DNA (ctDNA) in the early diagnosis and post-operative management of localised pancreatic cancer.
Authors: Belinda Lee, Joshua Cohen, Lara Rachel Lipton, Jeanne Tie, Ammar Asrar Javed, Lu Li, David Goldstein, Prasad Cooray, Adnan Nagrial, Matthew E. Burge, Niall C. Tebbutt, Mehrdad Nikfarjam, Marion Harris, Anne Marie O'Broin-Lennon, Christopher Lee Wolfgang, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2017)

4101 Background: Pancreatic cancer remains a devastating disease, with the diagnosis typically being made late. ctDNA has shown promise as a screening test for various tumor types. The detection of ctDNA post curative intent surgery has been associated with a high risk of recurrence in multiple solid tumors. We explored the potential of ctDNA to improve pancreatic cancer outcomes. Methods: Data from separate US and Australian series were combined. Plasma samples were collected prior to surgery in both studies and post-operative samples were collected in Australia from cases undergoing curative intent surgery. Clinicians were blinded to ctDNA results and adjuvant therapy was at clinician discretion. Tissue samples from both series were analyzed at Johns Hopkins University. Next generation sequencing was used to search for somatic KRAS mutations in the primary tumors and in cell-free DNA in the plasma. Clinico-pathologic, treatment and outcome data were collected. Results: 119 pts had a ctDNA sample at diagnosis (median age 67 years, 56.3% male). Sixty six pts (55.5 %) had detectable ctDNA, including 3/7 (42.9%) with stage I disease, 54/99 (54.5%) with stage II disease, 4/8 (50%) with stage III disease and 5/5 (100%) with metastases. Specific codon 12 KRAS (G12D, G12V or G12R) mutations were identified in the tumor tissue of 12/16 (75%) patients who had a ctDNA sample collected post-surgery. At a median follow-up of 15.2 months, 7/12 (58.3%) pts had recurred, including 3/8 (37.5%) with no detectable ctDNA and 4/4 (100%) with detectable ctDNA post-surgery (HR 4.9, p = 0.04). Detectable ctDNA post-surgery was significantly associated with poor overall survival (HR 6.93, p = 0.006), with a median of 8 months for pts with detectable ctDNA. Conclusions: ctDNA shows promise as a pancreatic cancer screening test, being detectable in a high proportion of pts with early stage disease. The detection of ctDNA post operatively predicts a very high risk of recurrence. The clinical utility of ctDNA to guide adjuvant therapy decision making, and its potential as a real-time marker of treatment effect, are being explored in further studies. Clinical trial information: ACTRN12612000763842.
Race, Ancestry, and Medical Research
Authors: Phil B. Fontanarosa, Howard Bauchner
Journal: JAMA (2018)

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Phase III (IKEMA) study design: Isatuximab plus carfilzomib and dexamethasone (Kd) vs Kd in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Thomas G. Martin, Meletios A. Dimopoulos, Kwee Yong, Joseph Mikhael, Marie-Laure Risse, Gaëlle Asset, Philippe Moreau
Journal: Journal of Clinical Oncology (2018)

TPS8060 Background: Multiple myeloma (MM) remains an incurable disease requiring multiple lines of therapy, in which carfilzomib-based treatments are a standard of care. Isatuximab (ISA), an anti-CD38-targeted monoclonal antibody with antitumor and immunomodulatory activities in preclinical models of MM, has shown clinical activity as monotherapy and in combination with current standard of care in patients (pts) with RRMM. Methods: This Phase III, prospective, randomized, open-label study (NCT03275285; IKEMA) will evaluate the clinical benefit of ISA in combination with Kd versus Kd alone in pts with RRMM, who have received 1–3 prior lines of therapy. Pts who have received prior carfilzomib therapy, have primary refractory disease, or have free light chain measurable disease only will be excluded. Approximately 300 pts will be randomized according to 2 stratification factors (prior lines of therapy: 1 vs > 1; revised international staging system at baseline: I or II vs III vs unknown) in a 3:2 ratio to receive either ISA (10 mg/kg weekly in Cycle 1 then once every 2 weeks thereafter) in combination with carfilzomib (56 mg/m2 on Days [d] 1, 2, 8, 9, 15, and 16, 20 mg/m2 on d 1 and 2 of Cycle 1) and dexamethasone (20 mg on d 1, 2, 8, 9, 15, 16, 22, and 23) or Kd in 28-d cycles until disease progression, pt choice, or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) according to International Myeloma Working Group Criteria. Key secondary endpoints include overall response rate, rate of very good partial response or greater, minimal residual disease negativity rate, complete response rate, and overall survival. Other secondary endpoints include safety, duration of response, time to progression, PFS2, pharmacokinetics, and quality of life. Safety evaluations will include adverse events and laboratory parameters, vital signs, and physical examination. The IKEMA study is currently enrolling pts; recruitment is planned in 16 countries worldwide. Study funding: Sanofi. Clinical trial information: NCT03275285.
A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).
Authors: Ignacio Matos Garcia, Enrique Grande, Rocio Garcia-Carbonero, Carlos Lopez, Alexandre Teule, Jaume Capdevila
Journal: Journal of Clinical Oncology (2017)

TPS4146 Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. Clinical trial information: 2016-002858-20.
The safety and early efficacy of high-dose ipilimumab (IPI) and the combination nivolumab plus ipilimumab (NIVO + IPI) in patients (pts) with uveal melanoma (UM).
Authors: Sapna Pradyuman Patel, Isabella Claudia Glitza, Adi Diab, Rodabe Navroze Amaria, Michael A. Davies, Patrick Hwu, Hussein Abdul-Hassan Tawbi, Wen-Jen Hwu
Journal: Journal of Clinical Oncology (2017)

9554 Background: UM metastases occur in 50% of cases and high-risk pts are identified by a gene expression profile. High-dose IPI is approved for adjuvant (adj) treatment (tx) of cutaneous melanoma and NIVO + IPI for metastatic (met) melanoma, yet the safety and efficacy of high-dose IPI or NIVO + IPI has not been established in UM in the adj or met settings. Methods: We performed a phase I/II trial of IPI for the tx of high-risk &amp; met UM (CA184-187). The study consisted of two arms: an adj arm (AA) &amp; met arm (MA) with two dose levels, 3 mg/kg &amp; 10 mg/kg. Dose-finding proceeded on each arm in a 3 + 3 fashion. Pts received IPI once every 3 weeks for four doses followed by maintenance IPI every 12 weeks (for up to one year in AA). The AA treated pts with a Class 2 gene expression profile. This score imparts a 3-year distant metastasis-free survival (DMFS) of 50%. The primary endpoint for the AA was maximum tolerated dose (MTD) and improvement in 3-year DMFS to 70%. The primary endpoint for the MA was MTD &amp; overall survival. The study was later amended to include a cohort of UM pts treated with combination NIVO + IPI in the standard FDA approved schedule. Results: Ten pts were enrolled on AA, 18 on MA, and 20 on NIVO + IPI. Adverse events (AEs) of any Grade (Gr) related to tx occurred in 80% of pts on AA. Gr 3/4 related toxicities observed in more than one pt were: transaminitis (30%) &amp; pruritus (20%). Of these, 10% of the elevated AST and ALT and 10% of the pruritus occurred during the dose-finding portion of the trial at 3 mg/kg. One pt developed biopsy-proven colitis, and one developed diarrhea. Both were treated with high-dose steroids. One pt developed vasculitis manifesting as temporal arteritis with resultant blindness. AEs of any Gr occurred in 44% of pts on MA. Gr 3/4 toxicities observed in more than one pt were: Fatigue (11%) and Hyperbilirubinemia (11%). Only 1 pt (5.6%) developed Gr 3/4 diarrhea, and this was at the 3 mg/kg dose. In the NIVO + IPI cohort, Gr 3 transaminitis &amp; elevated TSH occurred in 10%. Conclusions: High-dose IPI in UM did not demonstrate new or unexpected toxicities. Similarly, the combination of NIVO + IPI was well-tolerated with no new toxicities. Efficacy data will be presented at the meeting. Clinical trial information: NCT01585194.