tbuckley/cabot-search huggingface dataset:
Phase II study of pembrolizumab or pembrolizumab plus bevacizumab for recurrent glioblastoma (rGBM) patients.
Authors: David A. Reardon, Lakshmi Nayak, Katherine B. Peters, Jennifer Leigh Clarke, Justin T Jordan, John Frederick De Groot, Phioanh Leia Nghiemphu, Thomas Joseph Kaley, Howard Colman, Sarah C. Gaffey, Victoria Caruso, Myriam Bednarek Debruyne, Chinmay Bhavsar, Annette M Molinaro, Timothy Smith, Mariano Severgnini, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2018)

2006 Background: Blockade of programmed-death 1 (PD-1) mediated immunosuppression has achieved meaningful benefit across many cancers. Vascular endothelial growth factor (VEGF), a highly upregulated proangiogenic growth factor in GBM tumors, can contribute to tumor-associated immunosuppression. We evaluated the safety and efficacy of pembrolizumab (P), a fully human IgG4 PD-1 blocking antibody, with and without bevacizumab (Bev) in rGBM patients. Methods: Bev-naïve patients at 1st/2nd recurrence requiring ≤ 4 mg dexamethasone/day were randomized to receive P (200 mg IV Q3W) with (Cohort A; n = 50) or without (Cohort B; n = 30) Bev (10 mg/kg IV Q2W). The primary endpoint, PFS-6 per RANO, was assessed independently per cohort relative to historical benchmarks. Archival tumor PD-L1 expression and inflammatory gene expression signature were explored as potential biomarkers. Results: Grade 2 or 3 treatment related adverse events (TRAEs) occurring in ≥10% patients included: Cohort A- hypertension (50%), fatigue (18%), headache (16%), infection (14%) and proteinuria (14%); Cohort B – headache (30%), and fatigue (17%). There were no grade 4 or 5 TRAEs. With a median follow-up of 25.3 months, PFS-6 was: Cohort A-26.0% (95% CI: 16.3, 41.5); Cohort B-6.7% (95% CI: 1.8, 25.4). Median OS was: Cohort A-8.8 mths (95% CI: 7.7,14.2); Cohort B- 10.3 mths (95% CI: 8.5, 12.5). As of 14Jan18, 10 patients remain alive (cohort A – 7; cohort B – 3) including 2 receiving study therapy (both cohort A). Conclusions: P is well tolerated +/- Bev but has limited monotherapy activity for rGBM. The anti-tumor activity of P+standard-dosed Bev was comparable to historical Bev monotherapy data. Clinical trial information: NCT02337491.
Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238).
Authors: Jeffrey S. Weber, Mario Mandalà, Michele Del Vecchio, Helen Gogas, Ana M. Arance, Charles Lance Cowey, Stéphane Dalle, Michael Schenker, Vanna Chiarion-Sileni, Ivan Marquez Rodas, Jean-Jacques Grob, Marcus Butler, Mark R. Middleton, Michele Maio, Victoria Atkinson, Reinhard Dummer, Veerle de Pril, Anila H. Qureshi, James M. G. Larkin, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2018)

9502 Background: In the initial report of data from CheckMate 238, at a minimum follow-up of 18 mo, NIVO demonstrated significantly longer recurrence-free survival (RFS) vs IPI in patients (pts) with resected stage III or IV melanoma. Here, we report updated efficacy results from this phase III study with an additional 6 mo of follow-up. Methods: Eligible pts included those ≥15 yrs of age who underwent complete resection of stage IIIB/C or IV melanoma. 906 pts were randomized 1:1 (stratified by disease stage and PD-L1 status at a 5% cutoff) to receive NIVO 3 mg/kg Q2W (N=453) or IPI 10 mg/kg Q3W for 4 doses, then Q12W (from week 24) (N=453) for up to 1 yr, or until disease recurrence or unacceptable toxicity. The primary endpoint was RFS; distant metastasis-free survival (DMFS) in pts with stage III disease was an exploratory endpoint. Results: At a minimum follow-up of 24 mo, RFS continued to be significantly longer for NIVO vs IPI (hazard ratio 0.66, P<0.0001), with 171/453 and 221/453 events, respectively. The 24-mo RFS rates were higher for NIVO vs IPI in subgroups defined by disease stage, PD-L1 expression, and BRAF mutation status (Table). DMFS also continued to be significantly longer for NIVO vs IPI, with 24-mo rates of 70.5% and 63.7%, respectively (hazard ratio 0.76, P=0.034). Subsequent therapies were received by 31.1% of pts in the NIVO group and 41.1% in the IPI group. Per protocol, there was no additional safety assessment for the current analysis given that all pts had been off study treatment >100 days at the time of the previous data cutoff. Conclusions: With extended follow-up, NIVO demonstrated a sustained efficacy benefit vs IPI in pts with resected stage III/IV melanoma at high risk of recurrence, regardless of disease stage, PD-L1 expression, or BRAF mutation status. Clinical trial information: NCT02388906. NIVO IPI RFS, 24-mo rates; % (N) ITT population 62.6% (453) 50.2% (453) Stage IIIB 70.8% (165) 60.7% (148) Stage IIIC 58.0% (203) 45.4% (218) Stage IV 58.0% (82) 44.3% (87) PD-L1 ≥5% 75.5% (152) 58.4% (154) PD-L1 <5% 55.2% (275) 45.5% (286) BRAF mutant 61.9% (187) 51.7% (194) BRAF wild-type 63.5% (197) 46.2% (212)
A phase 1b trial with the combination of trabectedin and olaparib in relapsed patients (pts) with advanced and unresectable bone and soft tissue sarcomas (BSTS): An Italian Sarcoma Group (ISG) study.
Authors: Giovanni Grignani, Lorenzo D'Ambrosio, Ymera Pignochino, Emanuela Palmerini, Massimo Zucchetti, Paola Boccone, Sandra Aliberti, Raimondo Piana, Erica Palesandro, Sara Miano, Silvia Stacchiotti, Angelo Paolo Dei Tos, Emanuela Marchesi, Rossella Bertulli, Maurizio D'Incalci, Piero Picci, Stefano Ferrari, Massimo Aglietta
Journal: Journal of Clinical Oncology (2016)

11018 Background: Given that trabectedin (T) causes single- and double-strand breaks along DNA, we hypothesized to combine trabectedin with the selective PARP1-inhibitor olaparib (O) to induce irreparable DNA damage (Pignochino Y abs 10066 2012 ASCO). We report the results from a trial of T + O combination in advanced BSTS pts (Clinical trial information: NCT02398058). Methods: Pts with radiographic progression after first or further-line therapy received T (24-hour infusion on day 1) and O (tablets BID) in 21-day cycles across 6 dose levels (T: 0.675-1.3 mg/m2; O: 100-300 mg BID), to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and recommended phase 2 dose (RP2D) using a standard 3+3 dosing schema. Other objectives included tumor response assessment (RECIST 1.1 + Choi criteria) every 2 cycles and biomarkers correlation with response. Biomarkers were studied on archival tumor samples; PK and PD were evaluated on peripheral blood at predefined time points. Results: 24 pts, median age 51(19-73), median previous lines 2 (1-8) were enrolled in ISG centers and received a median of 2 cycles (range 1-13) of T + O. In 2/3 patients at dose level 5 (T: 1.3 mg/m2 / O: 200 mg BID), the dose-limiting toxicities were grade 4 neutropenia for ≥ 7 days and thrombocytopenia which precluded further dose escalation. Treatment-related adverse events included anemia, leukopenia, neutropenia, febrile neutropenia (≤3 days), thrombocytopenia, macrocytosis, fatigue, nausea, elevated liver enzymes, mucositis, asymptomatic amylase/lipase increase. No pts interrupted treatment or died for toxicity. PD data demonstrated DNA damage and PARP1 inhibition. In 22 pts evaluable for response we observed 4 (18%) partial responses (synovial sarcoma, LMS) and 5 (23%) stable diseases (LPS, Ewing sarcoma, SFT, MPNST). Data on biomarkers and RP2D will be presented at the meeting. Conclusions: The combination of trabectedin + olaparib was overall well tolerated without marked PK drug-drug interactions. Finally, the preliminary evidences of activity in different histotypes warrant further studies of this combination in BSTS pts. Clinical trial information: NCT02398058.
TCT-141 One-year Readmissions After Transcatheter Aortic Valve Implantation
Authors: Mourad Senussi, John Schindler, Forozan Navid, Ibrahim Sultan, Dustin Kliner, Michael Sharbaugh, Matthew Berezo, Ahmad Masri, Amr Barakat, Andrew Althouse, Joon Lee, Thomas Gleason, Suresh Mulukutla
Journal: Journal of the American College of Cardiology (2018)
Sarcomas in patients over 90: Natural history and treatment—A nationwide study over 6 years.
Authors: Clemence Basse, Antoine Italiano, Nicolas Penel, Olivier Mir, Claire Chemin, Maud Toulmonde, Florence Duffaud, Axel Le Cesne, Christine Chevreau, Carlos Maynou, Philippe Anract, Francois Gouin, Maria Rios, Nelly Firmin, jean Emmanuel Kurtz, Sophie Piperno-Neumann, Francois Bertucci, Isabelle Laure Ray-Coquard, Francoise Ducimetiere, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2018)

11564 Background: Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or very poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc French national database. Methods: Information of soft tissue and visceral sarcoma patients registered from January 1st 2010 to December 31st 2016 in Netsarc were collected, analyzed and compared with younger ( < 90-years old) patient population. Results: Patients with sarcomas aged > 90 have almost exclusively sarcomas with complex genomics (92·0% vs 66·3%), are less frequently metastatic (5·3% vs 14·7%) at diagnosis, have more often superficial tumours (39·8% vs 14·7%), as well as limbs and head and neck sites (75·2% vs 38·7%) (all p < 0·001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (all p < 0·001). However, local relapse free, metastatic relapse free, and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0·001). Patients over 90 who were not operated had a worse overall survival than younger patients (9·9 vs 27·3 months, p < 0·001). Conclusions: Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.
Development of a diagnostic PD-L1 immunohistochemical assay for nivolumab therapy in urothelial carcinoma.
Authors: Rose Ann De Los Santos, Josette William, Debra Ann Hanks, Adam Northrup, Dipeshkumar Jaiswal, Malinka Jansson, Therese Phillips, Rachel Cleveland, Ilana Satnick, Coree Pierce, Bethany Wynne, Hendrick McDonald, Josette Carnahan, Swarnalatha Y. Reddy, Christine Phillips, Dania Brooks, H. David Inzunza, Clive R. Taylor, James Novotny, Emin Oroudjev
Journal: Journal of Clinical Oncology (2017)

e14585 Background: PD-L1 IHC 28-8 pharmDx is a qualitative assay developed by Agilent Technologies for the Autostainer Link 48 platform and is based on EnVision FLEX visualization technology and monoclonal rabbit anti-PD-L1, clone 28-8 antibody. The assay has been co-developed with the immunotherapeutic agent nivolumab; initially as an aid in assessing PD-L1 expression in non-squamous non-small cell lung cancer (NSCLC) and melanoma patients. Here we describe the efforts to validate this assay for urothelial carcinoma (UC). Methods: IHC staining was performed on Autostainer Link 48 platform using an automated staining protocol stated per the assay’s instruction for use (IFU). Specimens were coverslipped and interpreted for % PD-L1 positive tumor cells. The assay was analytically validated on commercially acquired formalin-fixed, paraffin-embedded (FFPE) human UC invasive tumor specimens at ≥1% and ≥5% PD-L1 positive tumor cells expression levels. Results: A wide range of % PD-L1 positive tumor cells at all staining intensity levels have been detected. Assay in-house precision was validated for inter-operator, inter-instrument, inter-day, inter-run and intra-run as well as inter-observer and intra-observer agreement. Robustness studies evaluated the assay under multiple conditions for target retrieval pH, temperature and incubation time, slide type as well as tissue section thickness. Assay reproducibility was evaluated at three external sites by testing samples for intra-site/inter-day and inter-site agreement measures. Specimens were also evaluated by an observer at each site, with three reads for each observer to assess intra-observer and inter-observer agreement. All validation studies demonstrated agreement estimates above 85% with values for lower bound 95% confidence intervals calculated above 84%. Conclusions: Results of all conducted studies show high robustness and reproducibility of the assay on UC.
Multiplex bead-based measurement of humoral immune responses against tumor-associated antigens in stage II melanoma patients: Side study of the EORTC 18961 trial.
Authors: Judith Michels, Natalia Becker, Stefan Suciu, Iris Kaiser, Axel Benner, Sandrine Agoussi, Niels Halama, Michael Pawlita, Tim Waterboer, Stefan Eichmüller, Dirk Jäger, Alexander M. Eggermont, Inka Zoernig
Journal: Journal of Clinical Oncology (2016)

3032 Background: Tumor associated antigen (TAA)-specific humoral immune responses have been previously shown to correlate with dismal prognosis in early stage melanoma patients. GM2 vaccination does not improve outcome for patients with stage II melanoma. Methods: The serum IgG antibody responses were assessed at baseline against a panel of 44 antigens by a bead-based multiplex assay in 970 stage II melanoma patients of the randomized EORTC 18961 trial, in which an adjuvant ganglioside GM2-KLH/QS-21 vaccination (vacc) versus observation (obs) was compared. Cox multivariate models were used to assess the prognostic/predictive importance of antibody responses adjusted for gender, Breslow thickness (Breslow), ulceration status, confirmation of lymph node-negative involvement by sentinel or elective node dissection (LN-negative) and treatment arm. Results: Significant prognostic clinical variables for relapse free survival (RFS) and overall survival (OS) were ulceration status, Breslow, LN-negative and gender. We found spontaneous antibody responses with a significant dismal or good prognostic impact on RFS and OS (table). Moreover predictive spontaneous antibody responses were depicted based on significant interaction with treatment for RFS (RhodN p=0.03; Rab38 p=0.04; RhodE2 p=0.08) and OS (RhodE2 p=0.004; Recoverin p=0.04; NA17.A p=0.05) respectively. Subgroups for RFS RhodN negative (n=849) HR(vacc vs. obs) 1.07, p=0.62; RhodN positive (n=121) HR(vacc vs. obs) 0.42, p=0.01; Rab38 negative (n=682) HR(vacc vs obs) 1.12, p=0.42; Rab38 positive (n=288) HR(vacc vs obs) 0.65, p=0.04 and OS RhodE2 negative (n=633) HR(vacc vs obs) 0.72, p=0.13; RhodE2 positive (n=337) HR(vacc vs obs) 1.85, p=0.01 were determined. Conclusions: This panel of TAA antibody responses defined a prognostic signature for patients with stage II melanoma. A set of antibody responses correlated with a beneficial or detrimental outcome for GM2 vaccination. Multivariate cox regression for prognostic antibody responses. RFS OS HR p HR p GM2 1.40 0.04 1.21 0.40 Rhod_E2 1.26 0.06 1.43 0.02 SSX2 1.42 0.01 1.13 0.50 CyclinB1 0.83 0.17 0.67 0.03 SCYE1v1 0.87 0.30 0.63 0.02
Hidden Curricula, Ethics, and Professionalism
Authors: Lisa Soleymani Lehmann, Lois Snyder Sulmasy, Sanjay Desai
Journal: Annals of Internal Medicine (2018)

Letters18 September 2018Hidden Curricula, Ethics, and ProfessionalismLisa Soleymani Lehmann, MD, PhD, Lois Snyder Sulmasy, JD, and Sanjay Desai, MDLisa Soleymani Lehmann, MD, PhDVeterans Health Administration, Washington, DC (L.S.L.)Search for more papers by this author, Lois Snyder Sulmasy, JDAmerican College of Physicians, Philadelphia, Pennsylvania (L.S.S.)Search for more papers by this author, and Sanjay Desai, MDJohns Hopkins University, Baltimore, Maryland (S.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0351 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We agree with Drs. John and George that near-miss reporting is buried deep in our clinical culture. Attending physicians should seize the opportunity to create a culture of speaking up by encouraging discussion of potentially harmful errors that serendipitously did not cause patient harm. Reporting these close calls and taking the time to reflect on why the near miss took place, what harm was averted, and how we can develop systems to prevent the error are essential to create a culture of improvement in which patient safety is paramount. The ability to infuse ethics and professionalism into our ... Author, Article, and Disclosure InformationAffiliations: Veterans Health Administration, Washington, DC (L.S.L.)American College of Physicians, Philadelphia, Pennsylvania (L.S.S.)Johns Hopkins University, Baltimore, Maryland (S.D.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2058. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHidden Curricula, Ethics, and Professionalism: Optimizing Clinical Learning Environments in Becoming and Being a Physician: A Position Paper of the American College of Physicians Lisa Soleymani Lehmann , Lois Snyder Sulmasy , Sanjay Desai , and Hidden Curricula, Ethics, and Professionalism Dinesh John and Tanya George Hidden Curricula, Ethics, and Professionalism Mano Soshi and Yasuharu Tokuda Metrics 18 September 2018Volume 169, Issue 6Page: 425-426KeywordsBehaviorComplex systemsDisclosureFearPatientsSafety ePublished: 18 September 2018 Issue Published: 18 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Is cancer history associated with asset ownership, debt, and net worth in the United States?
Authors: Maryam Doroudi, Diarmuid Coughlan, Matthew P. Banegas, K Robin Yabroff
Journal: Journal of Clinical Oncology (2017)

e18085 Background: Financial hardships experienced by cancer survivors in the United States have become significant social and public health issues. Few studies have assessed the underlying financial holdings, including ownership and values of assets and debts, of individuals following a cancer diagnosis. This study assessed the association between a cancer history and asset ownership, debt, and net worth. Methods: We identified 1,603 cancer survivors and 34,915 individuals without a history of cancer aged 18-64 from the nationally representative Medical Expenditure Panel Survey (MEPS) Household Component and Asset sections (years 2008-2011). Descriptive statistics were used to assess demographic characteristics, cancer history, asset ownership, debt, and net worth by cancer history. Regression analysis was conducted to assess the association between cancer history and net worth, stratified by age group (18-34, 35-44, 45-54, and 55-64 years) to reflect stages of the life-course. Results: Asset ownership was least common for cancer survivors and individuals without a cancer history in the 18-34 age group and most common in the 55-64 age group. Cancers survivors aged 45-54 had a lower proportion of home ownership than individuals without a cancer history (59% vs 67%; p = 0.001). Nearly 20% of all respondents reported at least some debt. The proportion of cancer survivors with debt was higher than individuals without a history of cancer, especially in the 18-34 age group (41% vs 27%; p &lt; 0.001), although it did not vary by age group. When asset and debt values were combined to assess net worth, cancer survivors aged 45-54 were significantly more likely to have a negative net worth and significantly less likely to have a positive net worth than those individuals without a history of cancer in fully adjusted models. Findings on net worth were similar in the 18-34 age group, although only statistically significant in unadjusted and partially adjusted models. Conclusions: We found that cancer history is associated with asset ownership, debt, and net worth, especially in those aged 45-54 years. Longitudinal studies to assess patterns of financial holdings throughout the cancer experience are warranted.
Molecular underpinnings of clinical disparity patterns in African American (AA) versus Caucasian American (CA) multiple myeloma (MM) patients.
Authors: Elizabeth M. Hill, Mary Kwok, Venkata Yellapantula, Malin Hultcrantz, Neha Korde, Sham Mailankody, Elli Papaemmanuil, Irina Maric, Dickran Garo Kazandjian, Ola Landgren
Journal: Journal of Clinical Oncology (2018)

8036 Background: Due to unclear reasons, the AA population, compared to the CA population, has a 2-fold increased incidence of MM, has an earlier average age of diagnosis by 10 years, and has gained less benefit from novel treatments. To better understand underlying biological mechanisms of these disparities, we characterized genetic alterations using a first-in-kind targeted next generation sequencing (NGS) assay called myTYPE, allowing capture of both somatic mutations as well as gene translocations and gains/losses.Methods: Bone marrow clot sections were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort. A total of 91 samples underwent DNA extraction, 81 met minimal quality control (QC) criteria and underwent NGS library preparation. Of these, 74 (51CA, 23 AA) passed all QC and sequenced using the Illumina platform with 100 bp paired end reads and a coverage of 600x. An additional 16 unmatched normal controls were sequenced for somatic analysis. Mutations were manually curated to select somatic based on COMSIC, MMRF, Bolli or truncating databases. myTYPE captures 120 genes including driver mutations, signaling pathways, therapeutic targets, IGH translocations, and copy number variations.Results: Of the 74 samples sequenced, 27 patients (37%) had at least one mutation. 12 genes with somatic mutations were identified. KRAS was most common, identified in 16% of patients (14% CA, 22% AA), followed by NRAS (4% CA, 9% AA) and BRAF (2% of CA, 13% AA). Mutations were also observed in FAM46C, DIS3, FGFR3, TP53, RASA2, KLHL6, KDM6A and SP140. Well-defined poor prognosis TP53 somatic mutations were more common in CA (6%) than AA (4%). Conversely, we found higher frequency of poor prognosis chromosomal alterations (1p deletions and 1q gains) in AA (23%) than in CA (13%) patients.Conclusions: This proof-of-principle analysis confirms the presence of varying underlying tumor biology between racial groups which likely contributes to the variance in CA and AA clinical outcomes. Our results support the need of future prospective interventional trials designed to capture these molecular characteristics in relation to specific therapies.