tbuckley/cabot-search huggingface dataset:
Squamous cell carcinoma of gallbladder: A Surveillance Epidemiology and End Results (SEER) database review of demographics and survival.
Authors: Yi-Tsung Lu, Ankit Mangla, Nikki Agarwal, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2016)

4069 Background: Squamous cell carcinoma of the gallbladder (SCCGB) is a rare subtype of gallbladder cancer (GBC) with its distinct biological behavior, different from gall bladder adenocarcinoma (ACGB). We aimed to study the demographics and survival of patients with SCCGB by reviewing the SEER database. Methods: From 1973-2012, we identified 17328 patients with primary GBC from the SEER data and extracted 384 SCCGB cases to examine patient characteristics and clinical outcomes by histology and stage. Associated factors to SCCGB were estimated with a multivariable logistic regression model. Adjusted hazards ratios (AHR) were calculated using Cox models. Results: 65% of SCCGB patients were women. The ethnic makeup was 55% Caucasian, 25% Hispanic, 12% Afro-American, and 8% other. Compared with ACGB, SCCGB was associated with non-Caucasian ethnicity, less primary tumor resection, more carcinoma in situ, and lower N stage at diagnosis. Survivals varied among different ethnicities in SCCGB patients, and the Hispanic patients had the best outcome (HR 0.83, p = 0.037 vs non-Hispanic Caucasian). Further analysis revealed SCCGB in Hispanic patients was associated with younger age, and when factoring this, Hispanic ethnicity was not an independent predictor of survival. Survival analysis revealed that better outcome was correlated with the performance of primary surgery (AHR 0.33, p = 0.001), lower grade (AHR 0.49, p = 0.03), and lower stage (AHR 0.35, p = 0.003). The year of diagnosis was not correlated with outcome as the survival of SCCGB patients before and after 1998 was not significantly different. Conclusions: SCCGB has its distinct demographics different from ACGB. Primary surgery remained the only curative measure, and patients undergoing surgery had longer survival, regardless of grade or stage. In a disease so heavily associated with cholelithiasis, the younger age of diagnosis in Hispanics may be due to the higher prevalence of cholelithiasis in younger Hispanics. Similar survival across 30 years of SEER registry indicates the need for continued investigation into the treatment strategies in patients with SCCGB.
ECHO-310: A phase 3, randomized trial of epacadostat + nivolumab + chemo vs EXTREME as first-line treatment of recurrent/metastatic SCCHN.
Authors: Ezra E.W. Cohen, Ranee Mehra, Amanda Psyrri, Julie E. Bauman, Richard Schaub, Li Zhou, Li Li, Vijayvel Jayaprakash, Joel Guigay
Journal: Journal of Clinical Oncology (2018)

TPS6092 Background: Novel combination treatments targeting broad immunosuppression in the tumor microenvironment (TME) may improve patient (pt) survival. Nivolumab (N) is a PD-1 inhibitor that was shown to significantly prolong overall survival (OS) in pts with platinum-refractory r/m SCCHN. Epacadostat (E) is a potent, highly selective oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that contributes to immunosuppression in the TME. Preliminary phase 2 findings from the ECHO-204 study suggest encouraging efficacy with E + N in pts with r/m SCCHN. The ECHO-310 study (NCT03342352) compares E + N + chemo vs the EXTREME regimen as first-line treatment for r/m SCCHN. Methods: Eligible pts are ≥18 years old with treatment-naive r/m SCCHN (oral cavity, oropharynx, hypopharynx, and larynx), ECOG PS ≤1, and no prior IDO inhibitors or immune checkpoint therapies. Approximately 550 pts will be randomized (2:2:1) into 3 arms: Arm A receives blinded E 100 mg BID + N 360 mg Q3W + 6 cycles of chemo (cisplatin 100 mg/m2 in Cycle 1, then 75 mg/m2 Q3W in Cycles 2–6 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2 on Days 1–4 of each cycle); Arm B (EXTREME) receives cisplatin 100 mg/m2 Q3W or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2 on Days 1–4 of each cycle + cetuximab 400 mg/m2 on Cycle 1 Day 1, then 250 mg/m2 QW (starting Cycle 1 Day 8); and Arm C receives E-matched placebo BID + N 360 mg Q3W + 6 cycles of chemo (same as Arm A). Randomization will be stratified by PD-L1 status (expressing [≥1%] vs nonexpressing [ < 1%]/nonevaluable), HPV status (oropharyngeal p16 positive vs oropharyngeal p16 negative/nonoropharyngeal SCC), and investigator’s choice of cisplatin vs carboplatin. E and placebo treatment continue for up to 2 years or until permanent discontinuation of N, disease progression, unacceptable adverse event (AE), or consent withdrawal. Primary endpoints: OS and PFS in Arms A and B. Secondary endpoints: ORR and duration of response (DOR) in Arms A and B; ORR, PFS, and DOR in Arm C; and quality of life in Arms A and B. Tumor assessments (RECIST v1.1) are performed Q6W for 48 weeks and Q12W thereafter. AEs, graded per CTCAE v4.0, are evaluated for at least 100 days after end of treatment. Clinical trial information: NCT03342352.
FDA breakthrough therapy designation for oncology products: The CBER experience.
Authors: Harpreet Singh, Richard Pazdur, Lei Xu, Ke Liu
Journal: Journal of Clinical Oncology (2018)

e18585 Background: Breakthrough therapy (BT) designation is a regulatory program introduced in Section 902 of the Food and Drug Safety and Innovation Act of 2012. Its goal is to expedite the development and review of investigational products intended to treat serious or life-threatening diseases. Designation of a BT requires preliminary clinical evidence indicating that the product may provide substantial improvement over available therapies. FDA’s Center for Biologics Evaluation and Research (CBER) reviews novel cancer therapies such as vaccines, oncolytic viruses, cell therapy and gene therapy. Methods: We reviewed all BT designation (BTD) requests submitted to CBER/Office of Tissues and Advanced Therapies (OTAT) from 2012-2017. The BT designations were based on CBER/OTAT recommendation. Results: CBER has received 46 oncology BTD requests during the period studied: 13 for hematologic malignancies and 33 for solid tumor indications. A total of 16 BTD have been granted. Six requests for solid tumor indications (18%) were granted BTD, with three for high-grade glioma treatment that included oncolytic viruses, tumor vaccines, and gene therapy. Of 13 BTD requests for hematologic malignancies, 10 (77%) were granted BTD, with eight (61%) for chimeric antigen receptor (CAR) T cell therapies for relapsed/refractory hematologic malignancies. BT designation resulted in an expedited review of two CAR-T products which were subsequently approved. The most frequent reasons for denial of BTD were: 1) improvement over available therapy did not appear to be “substantial,” 2) clinical evidence was considered too preliminary to be considered reliable, and 3) proposed product was modified and considered different from the one used to general preliminary clinical evidence Conclusions: Since implementation of the program, FDA/CBER has granted 16 oncology BTDs. Many of these were for emerging new therapies such as CAR-T cells. BTD resulted in an expedited review of two CAR-T cell therapies which have been approved.
Current real-world treatment patterns and outcomes in patients with relapsed/refractory multiple myeloma.
Authors: Jenny Willson, Amanda Bruno, Joanna Opalinska, Jeanenne Joy Nelson, Orsolya Lunacsek, Dana Stafkey-Mailey, Joanne P. Willey
Journal: Journal of Clinical Oncology (2018)

e20038 Background: Limited real-world data exist on treatments for relapsed/refractory multiple myeloma (RRMM) since the recent approval of new agents. This study assessed treatment patterns and outcomes of patients with RRMM in community oncology practices. Methods: A chart review was conducted in patients ≥18 years with MM diagnosed January 1, 2011 – May 31, 2017 from a large electronic medical record database. Results: 233 patients who had received ≥2 prior treatments lines (L) were included (mean age at diagnosis: 69 [±10] years; female: 34.3%; bone involvement at baseline: 66.1%). Common adverse events by line were anemia, bone pain and fatigue. Most common 1L/2L agents were bortezomib (BTZ) and lenalidomide (LEN); use of newly approved drugs like daratumumab increased in ≥3L (Table). Median progression-free (mPFS) and overall survival (mOS) were 11.0 and 44.9 months (mo) for 1L therapy, 6.8 and 21.9, 4.5 and 8.7, 2.8 and 6.9 mo for 2L, 3L and 4L, respectively. Albeit heterogeneous, clinical trial results for newly approved agents in ≥3L showed mPFS ≤4 mo and mOS ≤17.5 mo (Lonial Lancet 2016;387:1551; San Miguel Lancet Oncol 2013;14:1055). Conclusions: While BTZ and LEN were predominant in 1L and 2L, substantial fragmentation was seen in ≥3L. Survival outcomes based on these patterns agreed with trial estimates of early-line standard of care therapies but were lower than those reported for newly approved drugs in later lines. Further work should focus on patient, treatment, and system characteristics associated with improved outcomes. Funding: GSK (HO-17-17767) Clinical trial information: HO-17-17767.N % patients 1L 233 2L 233 3L 91 4L 36 5L 15 BTZ* 33.0 29.6 12.1 13.9 6.7 Carfilzomib* 0 5.6 22.0 19.4 20.0 Ixazomib* 0 0 0 2.8 0 LEN † 17.6 18.5 11.0 8.3 0 Pomalidomide† 0 3.0 15.4 16.7 20.0 Thalidomide† 2.1 0 0 0 6.7 BTZ + LEN§ 43.3 23.2 11.0 2.8 13.3 BTZ + other IMiD§ 1.3 3.9 2.2 0 0 Other PI + LEN§ 0.4 6.4 6.6 2.8 6.7 Other PI + other IMiD§ 0 3.4 2.2 13.9 0 Daratumumab ± other 0 1.3 7.7 8.3 13.3 Elotuzumab ± other 0 1.7 3.3 5.6 0 Panobinostat ± other 0 0 0 2.8 6.7 Other 2.1 3.4 6.6 2.8 6.7 *± non-immunomodulatory drug (IMiD), non-monoamine oxidase inhibitor (MAOI), non-histone deacetylase inhibitor (HDACI)†± non-proteasome inhibitor (PI), non-MAOI, non-HDACI; §± non-MAOI, non-HDACI
TCT-321 Multicenter validation of the Simplified SYNTAX Score: An accurate memorizable tool for rapid objective assessment of anatomical complexity
Authors: Sonya Burgess, Rong Bing, Jun Zhao, Stavroula Papapostolou, William Chan, Craig Juergens, Andrew Ong, Rahul Kurup, Martin Ng, Leonard Kritharides, Sidney Lo, Andy Yong
Journal: Journal of the American College of Cardiology (2018)
Copanlisib treatment in patients with relapsed or refractory indolent B-cell lymphoma: Subgroup analyses of diabetic patients from the phase II CHRONOS-1 study.
Authors: Martin H. Dreyling, Sirpa Leppa, Terrance Comeau, Marina Kosinova, Georg Lenz, Arnon Nagler, Dae Seog Heo, Sung Yong Oh, Liping Huang, Oliver Wirtz, Ashok Miriyala, Jose E. Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2018)

7570 Background: Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity recently approved in the US for treatment of relapsed follicular lymphoma. In the CHRONOS-1 trial, treatment of patients with relapsed or refractory indolent lymphoma resulted in an objective response rate of 59% (JCO 35:2169-2178, 2017). The most prominent adverse event following intravenous administration of copanlisib is transient hyperglycemia, thought to be due to impaired glucose uptake associated with PI3K-α isoform inhibition. We focus here on the diabetic mellitus (DM) patients enrolled in the phase II study. Methods: Indolent B-cell lymphoma patients with well-controlled DM were eligible and required to have fasting glucose < 160 mg/dL prior to each infusion. Patients received copanlisib 60 mg as a 1-hour infusion on days 1, 8, and 15 of a 28-day cycle. On C1D1, glucose was measured at pre-dose, and 3, 5, 6 and 8 hours after infusion. DM patients were instructed to check blood glucose at home 3x per day for 72 hrs after infusion until fasting glucose was < 160 mg/dL or non-fasting glucose was < 200 mg/dL. Results: Twenty patients with DM out of a total of 142 patients were enrolled; 17 patients with a history of DM, 1 with history of impaired glucose tolerance, and 2 diagnosed at screening. Comparing non-DM patients (n = 122) to DM patients, all-grade (G) hyperglycemia was 43% vs 85%, G3 31% vs 40%, and G4 2% vs 35%. In routine laboratory glucose assessments, G3 events were reported in 39% vs 70% and G4 in 2% vs 30%, non-DM vs DM respectively. Objective responses were observed in 9 of 20 patients (45%; 2 non-evaluable), including one complete response and stable disease in 8 patients (40%). Of note, 6 responders were on treatment > 300 days (or > 30 infusions), with 5 of these patients remaining on treatment at data cut-off. Conclusions: These results strongly suggest that the transient hyperglycemia seen with IV administration of copanlisib is also manageable in indolent lymphoma patients with DM as a comorbidity and should thus not preclude treatment of such patients. Clinical trial information: NCT01660451.
G-Protein–Coupled Receptors in Heart Disease
Authors: Jialu Wang, Clarice Gareri, Howard A. Rockman
Journal: Circulation Research (2018)

GPCRs (G-protein [guanine nucleotide-binding protein]-coupled receptors) play a central physiological role in the regulation of cardiac function in both health and disease and thus represent one of the largest class of surface receptors targeted by drugs. Several antagonists of GPCRs, such as βARs (β-adrenergic receptors) and Ang II (angiotensin II) receptors, are now considered standard of therapy for a wide range of cardiovascular disease, such as hypertension, coronary artery disease, and heart failure. Although the mechanism of action for GPCRs was thought to be largely worked out in the 80s and 90s, recent discoveries have brought to the fore new and previously unappreciated mechanisms for GPCR activation and subsequent downstream signaling. In this review, we focus on GPCRs most relevant to the cardiovascular system and discuss traditional components of GPCR signaling and highlight evolving concepts in the field, such as ligand bias, β-arrestin-mediated signaling, and conformational heterogeneity.
Real world eligibility of treatment-refractory stage IV colorectal cancer patients for palliative intent regorafenib monotherapy.
Authors: Arkhjamil Angeles, Wayne Hung, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

e15007 Background: The CORRECT trial demonstrated overall survival benefits of regorafenib monotherapy in patients with metastatic colorectal cancer (CRC) who were refractory to prior chemotherapy and biological therapy. However, stringent criteria used to determine treatment eligibility in the trial setting may limit its external validity in the real world. We aimed to examine treatment attrition rates and eligibility of regorafenib in routine clinical practice. Methods: All patients diagnosed with metastatic CRC between 2009 and 2014 who received 2 or more lines of systemic therapy at the British Columbia Cancer Agency were identified. During the study timeframe, cetuximab (cmab) and panitumumab (pmab) were only used in the chemo-refractory setting. Data on clinical factors, pathological variables and outcomes were ascertained and analyzed. Eligibility was defined based on criteria outlined in the CORRECT trial. Results: A total of 391 patients were included among whom only 39% were considered eligible for regorafenib. Median age was 61 (range 22-84) years. 247 (63%) were men, 305 (78%) were Caucasian, and 237 (60%) had a colonic primary. The disease burden at diagnosis was high: 267 (81%) had lymph node involvement, and 225 (59%) had distant metastases. In patients previously treated with cmab, main reasons for regorafenib ineligiblity were Eastern Cooperative Oncology Group performance status (ECOG PS) &gt; 1 (26.9%), aspartate aminotransferase (AST) &gt; 2 x upper limit of normal (ULN) (6.5%), and arterio-venous thrombotic or embolic events in the preceding 6 months (6.5%). In the group treated with pmab previously, main reasons for ineligibility were ECOG PS &gt; 1 (46.6%), total bilirubin &gt; 1.5 x ULN (14.1%), and thrombotic or embolic events in the past 6 months (5.7%). Additional analyses showed that regorafenib-eligible patients had increased median overall survival compared to ineligible patients (44.0 vs 37.1 months, P= 0.028). Conclusions: The strict trial eligibility criteria disqualified the majority of real world patients with metastatic CRC for regorfenib. As ineligibility predicts poorer outcomes, trials aimed at serving protocol-ineligible patients are warranted.
TCT-451 Incidence, Correlates and impact of left ventricular ejection fraction improvement on short- and long-term clinical outcome of patients undergoing high-risk percutaneous coronary intervention. A single center experience
Authors: Serdar Farhan, Birgit Vogel, Usman Baber, Madhav Sharma, Sabato Sorrentino, Gennaro Giustino, Alston Gremillion, Samuel Zucker, Nitin Barman, Jeffrey Bander, Asaad Khan, Roxana Mehran, George Dangas, Annapoorna Kini, Samin Sharma
Journal: Journal of the American College of Cardiology (2018)
Do accountable care organizations impact prevalence of mammography and colonoscopies among Medicare beneficiaries?
Authors: Maxine Sun, Alexander P Cole, Anna Krasnova, Sebastian Berg, Marieke Krimphove, Ashwin Ramaswamy, Sean A. Fletcher, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2018)

e18516 Background: Accountable care organizations (ACO) are an alternative payment model designed to financially incentivize efficient, coordinated care. Rather than paying individual providers, ACOs are reimbursed at the level of the institution, with incentives for high value care. The effect of ACOs on cancer screening is unknown. We analyzed trends in utilization of mammography and colonoscopy in US adults seen by ACO-affiliated providers. Methods: We relied on Medicare claims data to identify hospitals and providers who joined ACOs between 2010 and 2014. We examined whether trends in mammography and colonoscopy usage from 2010 to 2104 were different in men and women with ACO-affiliated and non-ACO affiliated primary care providers. Inverse-probability weighting and difference-in-differences analyses were used to compare trends in both screening groups. In mammography women were stratified by age: 1) 66-69 and 2) ≥70. Results: For providers who joined ACOs between 2010 and 2014, the prevalence of colonoscopy rose from 11.6% to 12.7%. Among those seen by non-ACO providers the prevalence changed from 11.4% to 11.6%. The trend was significantly different at ACOs and non-ACOs (p < 0.001, difference in difference). Among women aged 66-69, the prevalence of mammography rose in both ACO and non-ACO's (54.4% to 55.7% and 52.9% to 55.7%, respectively). Women 70 and above saw small declines in use of mammography in both ACO and non-ACOs (39.7% to 39.0% and 38.3% to 37.4%, respectively). The difference in trends between ACOs and non-ACOs was not significant (p = 0.14 and 0.24, respective). (Table 1). Conclusions: While patients seen by ACO providers had a significantly greater increase in colonoscopy compared to patients seen by non-ACO affiliated providers, a similar trend was not seen in mammography. The impact of ACOs on cancer screening may vary between cancers. Table 1:. Prevalence of Colonoscopy and Mammography in 2010 and 2014 Among Individuals Seen by ACOs and Non-ACO Providers ACO Cohort Non-ACO Cohort Difference in Difference 2010 2014 2010 2014 P value Colonoscopy 11.6 12.7 11.4 11.6 < 0.0001 Mammography 66-69 54.4 55.7 52.9 55.7 0.14 Mammography 70+ 39.7 39.0 38.3 37.4 0.24
Safety and antitumor activity of durvalumab monotherapy in patients with pretreated extensive disease small-cell lung cancer (ED-SCLC).
Authors: Jonathan Wade Goldman, Afshin Dowlati, Scott Joseph Antonia, John J. Nemunaitis, Marcus O. Butler, Neil Howard Segal, Pamela Ann Smith, Jared Weiss, Dan Paul Zandberg, Feng Xiao, Natasha Angra, Shaad Essa Abdullah, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2018)

8518 Background: SCLC is an aggressive lung cancer with high rate of relapse following initial treatment; immunotherapy holds potential as a novel treatment option for this disease. The anti-PD-L1 antibody durvalumab has demonstrated clinical activity with manageable toxicity in several tumor types, including NSCLC. Here we report on the SCLC expansion cohort of a phase 1/2 study of durvalumab monotherapy. Methods: Patients with pretreated ED-SCLC, ECOG PS 0-1, regardless of PD-L1 expression, received durvalumab 10 mg/kg every 2 weeks for up to 12 months. The primary objective was to determine the safety profile; antitumor activity was evaluated using investigator-assessed RECIST v1.1. Results: As of 16 October 2017, 21 patients with ED-SCLC (median age 65.0 y, 62% male, 91% ECOG PS 1, 90% current/former smokers) were treated with durvalumab, median 3 cycles, median duration of follow-up 36.4 months (range 1.4–37.9). 20 patients (95.2%) received prior anti-cancer therapy (median, 2 lines). 7 patients (33.3%) had treatment-related AEs, all were grade 1 or 2; the most common were nausea, fatigue, and rash maculo-papular (each 9.5%). There were no treatment-related AEs leading to discontinuation and no treatment-related deaths. Confirmed ORR was 9.5% (2 PR; 95% CI 1.2–30.4) and DCR24 was 14.3% (95% CI 3.0–36.3). Duration of response was 14.6 months for one patient (treatment-naïve), and 29.5+ months for the other patient (platinum refractory with 3 prior lines of therapy), who continued to maintain response 25.5 months after completing protocol-defined initial treatment with durvalumab. Median PFS was 1.5 months (95% CI 0.9–1.8), median OS was 4.8 months (95% CI 1.3–10.4), and 12-month OS rate was 27.6% (95% CI 10.2–48.4). Conclusions: Consistent with studies in other tumor types and with other anti-PD-1/PD-L1 therapies, durvalumab monotherapy demonstrates durable clinical activity in certain patients with pretreated ED-SCLC with no new safety signals. Clinical trial information: NCT01693562.