tbuckley/cabot-search huggingface dataset:
Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC).
Authors: Richard S. Finn, Baek-Yeol Ryoo, Philippe Merle, Masatoshi Kudo, Mohamed Bouattour, Ho-Yeong Lim, Valeriy Vladimirovich Breder, Julien Edeline, Yee Chao, Sadahisa Ogasawara, Thomas Yau, Marcelo Garrido, Stephen Lam Chan, Jennifer J. Knox, Bruno Daniele, Scot Ebbinghaus, Erluo Chen, Abby B. Siegel, Andrew X. Zhu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2019)

4004 Background: Pembro received accelerated approval based on results of KEYNOTE-224, a phase 2 trial in pts with advanced HCC in the second line setting. KEYNOTE-240 (NCT02702401) was a randomized, placebo (Pbo) controlled, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Methods: Eligible pts had a radiographic or pathologic diagnosis of HCC, radiographic progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to receive Pembro 200 mg + BSC or Pbo + BSC IV every 3 wk, stratified by geographic region, macrovascular invasion and ɑ-fetoprotein levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk per RECIST v1.1 by central imaging review. Co-primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR and safety. Data cutoff was Jan 2 2019 for OS; Mar 26 2018 for PFS and ORR. Results: 413 patients were randomized; 278 to Pembro and 135 to Pbo. After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro and 3.0% on Pbo. Pembro improved OS (HR: 0.78; one sided p = 0.0238) and PFS (HR: 0.78; one sided p = 0.0209) vs Pbo; these differences did not meet significance per the prespecified statistical plan. ORR was 16.9% (95% CI 12.7-21.8%) for Pembro vs 2.2% (95% CI 0.5-6.4%) for Pbo (nominal one sided p = 0.00001); responses on Pembro were durable (median DOR: 13.8 mo [1.5-23.6+]). Off study, new therapy use was 42% for Pembro and 47% for Pbo. The safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported in Pembro studies; no cases of HBV/HCV flare were identified. Conclusions: Pembro reduced the risk of death by 22% and improved PFS over Pbo in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. ORR in the Pembro arm was consistent with that of KEYNOTE-224. Subsequent anticancer therapy in the Pbo arm likely impacted the OS results. The safety profile was comparable to that established for Pembro monotherapy. These results are overall consistent with those of KEYNOTE-224 further supporting second line therapy with Pembro in HCC pts. Clinical trial information: NCT02702401.
Epidemiology, national trends and clinical associations of pancreatic adenocarcinoma in chronic pancreatitis patients: A nationwide inpatient sample (NIS) study.
Authors: Ahmed Elkafrawy, Samia Asif, Hasan F. Othman, Anuj Shrestha
Journal: Journal of Clinical Oncology (2019)

e15737 Background: Chronic pancreatitis (CP) is a known risk factor for pancreatic adenocarcinoma (PA). The aim of this study was to evaluate epidemiology, national trends and clinical associations of PA in hospitalized US patients with CP using the NIS database. Methods: ICD-9 CM codes were used to identify patients with CP and PA between 2002-2014. Age, gender, race, mortality, length of stay (LOS) and commonly associated comorbidities were correlated. Statistical analysis was done using SPSS 25. Results: We identified 1,677,517 patients with CP between 2002-2014. Patients with concurrent PA comprised 1.3 % (21,832) of total patients with CP. During the study period, the prevalence of PA in CP patients remained nearly steady (1.2% in 2002 and 1.3% in 2014). Median LOS was 8 days and decreased from 10 days in 2002 to 6 days in 2014. Overall mortality was 3.5% during hospitalization with the trend of mortality not showing a significant change in the study period (4.2% in 2002 and 4.1% in 2014). Median cost of total hospitalization for CP with PA was 52,116 USD, almost three-folds higher than for CP alone (18,797 USD) and increased from 42,241 USD in 2002 to 55,525 USD in 2014. For patients with CP and PA, 87.5% were above 50-years-old; 55.6% were males; Caucasians and African-Americans represented 72.2% and 12.6% of patients respectively. Interestingly, factors less associated with PA in CP included alcohol (OR 0.27, 95% CI 0.26-0.29, P &lt; .0001), Diabetes Mellitus (DM) (OR 0.78, 95% CI 0.74-0.82, P &lt; 0.0001), Chronic hepatitis C (OR 0.56, 95%CI 0.48-0.66, P &lt; 0.0001) and pancreatic cysts and pseudocyst (OR 0.76, 95%, CI 0.69-0.83, P &lt; 0.0001). Tobacco use, metabolic syndrome, Chronic hepatitis B and H. Pylori infection were not statistically associated with PA. Conclusions: In hospitalized patients with CP, 1.3% had PA. During the study duration, trends of prevalence and mortality did not show significant change, median LOS decreased and hospitalization cost of charge increased. Risk factors for PA like alcohol, DM, chronic hepatitis C, and pancreatic cysts were less associated with PA in patients with CP. Future studies are needed for early detection of PA in patients with CP.
ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early-stage triple-negative breast cancer.
Authors: Heather L. McArthur, Michail Ignatiadis, Sebastian Guillaume, Andrew Bailey, Jorge Luis Martinez, Mariana Brandao, Otto Metzger, Catherine Lai, Debora Fumagalli, Fergus Daly, Aicha Bouhlel, Valeria Karusinova, Christie Freeman, Giuseppe Viale, Vanessa Honvault, Carter Dufrane, Anh Nguyen Duc, Martine J. Piccart, Eric S. Winer, Richard D. Gelber
Journal: Journal of Clinical Oncology (2019)

TPS598 Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with the anti–PD-L1 antibody, atezolizumab, in Phase 1/1b metastatic TNBC trials. Furthermore, the randomized phase 3 IMpassion130 study demonstrated enhanced anti-tumor activity when atezolizumab was co-administered with chemotherapy in the first line metastatic setting, with benefit mainly observed in PD-L1+ cohort. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard anthracycline/taxane adjuvant chemotherapy in early TNBC patients. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients with operable stage II or III TNBC, confirmed by central pathology review, will be randomized. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant treatment will consist of weekly paclitaxel 80 mg/m 2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m 2 or doxorubicin 60 mg/m 2 ) and cyclophosphamide 600 mg/m 2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on August 2nd 2018, and approximately 430 sites are expected to be opened globally in 30 countries. Clinical trial information: NCT03498716.
Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors
Authors: Sonia Domingos-Pereira, Gabriele Galliverti, Douglas Hanahan, Denise Nardelli-Haefliger
Journal: Journal for ImmunoTherapy of Cancer (2019)

High-risk human papillomavirus (HPV) are responsible for genital and oral cancers associated with the expression of the E6/E7 HPV oncogenes.Therapeutic vaccines targeting those oncogenes can only partially control tumor progression, highlighting the necessity to investigate different treatment strategies.Using the genital orthotopic HPV16 TC-1 model, herein we sequentially investigated in progressively more stringent settings the effects of systemic administration of carboplatin/paclitaxel (C + P) chemotherapy combined with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation with the synthetic toll-like-receptor-9 agonist CpG.Our data show that systemic delivery of C + P prior to E7LP vaccination significantly increased mice survival.This survival benefit was associated with both reduced genital tumor growth at the time of vaccination, and a decreased infiltration of Ly6G myeloid cells and tumor-associated macrophages.Adding intravaginal CpG, which results in increased E7-specific CD8 T cells locally, to E7LP vaccination and the chemotherapy formed a tri-therapy, which significantly increased mice survival as compared to any of the dual treatments.When the tri-therapy was further refined by using a recently optimized nanoparticle-conjugated E7LP vaccine, even larger end-stage genital-TC-1 tumors responded, with 90% of mice showing a survival benefit as compared to 30% of mice with the tri-therapy involving the traditional E7LP 'liquid' vaccine.C + P is commonly used to treat cervical cancer patients and its combination with E7/E6 vaccination is currently being tested in a phase I/II trial (NCT02128126).Our data suggests that new vaccine formulations combined with local immunostimulation and standard-of-care chemotherapy have promise to further benefit patients with HPV-associated cancer.
Association of leisure time physical activity with breast cancer risk and breast cancer sub-types in Nigerian women.
Authors: Galya Bigman, Sally Nneoma Adebamowo, Elima Enaji Jedy-Agba, Izuchukwu Benerdin Achusi, Clement Adebayo Adebamowo
Journal: Journal of Clinical Oncology (2019)

e13085 Background: The association between physical activity and breast cancer has not been studied among Nigerian women and in particular by breast cancer sub-types. Therefore are studies aims are to examine the association between leisure time physical activity (LTPA) and breast cancer in Nigerian women and to examine the association between LTPA and estrogen receptor positive (ER+), triple negative breast cancer (TNBC+), Luminal A breast cancer in Nigerian women. Methods: We enrolled 739 newly diagnosed primary invasive breast cancer and 739 age-matched controls in Nigeria from 01/2014 to 07/2016. This analysis is restricted to the 40% of cases for whom we have complete ER, TNBC and Luminal-A data and their matched controls. We derived the average amount of time per week spent on LTPA over the past one year using a modified Nurses’ Health Study II PA questionnaire. LTPA was calculated from the total metabolic equivalent (METs) assigned for each reported physical activity hour/week (i.e. walking, cycling, and dancing). We examined LTPA by comparing participants who attained the WHO physical activity recommendations of at least 150 minutes of moderate-intensity or/and 75 minutes of vigorous-intensity aerobic activity weekly with those who did not. We used conditional logistic regression to estimate the adjusted Odds Ratio (OR) of LTPA and overall as well as subtypes of breast cancer. Results: The mean (SD) age of cases was 41.6 (9.1) and controls was 43.9 (11.8) years. Women who attained the WHO physical activity recommendations had 43% decreased risk of breast cancer (OR = 0.57 95% CI:0.42-0.77) compared with those who did not, after controlling for demographic, anthropometric and fertility related factors. LTPA was also associated with reduced risk of breast cancer subtypes by 41% for ER+, 59% for TNBC+ and 59% for Luminal A. Conclusions: Physical activity is associated with reduced risk of breast cancer overall and by subtypes in Nigerian women.
Adverse events following the use of immune checkpoint inhibitors: An analysis of the WHO VigiAccess database.
Authors: Nikita Nikita, Ralph Zinner, Jennifer Maria Johnson, Natasha Ghosh, Melissa Wilson, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2019)

e13118 Background: Immune checkpoint inhibitors (ICIs), especially ipilimumab (ipi) and nivolumab (nivo), have received approvals from the U.S. Food and Drug Administration for the treatment of multiple tumor types. These medications have shown great promise in the treatment of several malignancies but are associated with immune-related adverse events. This study was undertaken to better understand the patterns of adverse events following different ICIs. Methods: We used the World Health Organization (WHO) Vigiaccess Database, the largest adverse events reporting database, to identify, summarize, and report adverse drug events (AE) attributed to ipi and nivo. The database contains reports for ipi beginning in 2008 and for nivo beginning in 2012. We manually extracted the data from the database and conducted Chi-square tests to examine the difference in occurrence of AEs in various organ systems between patients receiving ipi and nivo. The five most common organ systems affected by AE associated with ipi and nivo were identified. Results: AEs were reported in 15,504 ipi users and 21,306 nivo users. Ipi users reported significantly higher AEs in gastrointestinal system compared to nivo users (p &lt; 0.0001). Conversely, nivo users reported significantly higher AEs in respiratory disorders (p &lt; 0.0001), skin and subcutaneous tissue organ systems (p = 0.0001), and neoplasms benign, malignant and unspecified (p &lt; 0.0001) compared to ipi users. Conclusions: To our knowledge this is the largest study on reported AEs following ipi and nivo. The patterns of treatment-related AEs differed significantly for these two immune checkpoint inhibitor therapies. Further studies are required to guide treatment selection.[Table: see text]
An algorithmic approach to deriving line of therapy in a real-world data set for non-small cell lung cancer (NSCLC).
Authors: Chhaya Shadra, James Lin Chen, Cheryl D. Cho-Phan, Aradhana Ghosh, Jonathan Hirsch
Journal: Journal of Clinical Oncology (2019)

e18099 Background: Real World Data (RWD) is being used for outcomes research and regulatory submissions. A key variable needed to understand treatment outcomes is Line of Therapy (LoT). However, LoT is generally not captured in RWD sources such as electronic health records (EHR) or claims data, and is typically derived using manual abstraction. To determine whether an automated approach to LoT derivation is possible, we created an algorithm and applied it to patients (pts) in the Syapse Learning Health Network. Methods: We selected confirmed NSCLC pts from 4 health systems in the RWD set, verifying diagnosis using ICD-9/10/O3 topography and morphology codes. We analyzed the EHR-derived medication list using a regimen-independent algorithm that classified antineoplastic drugs (AD), as defined by ATC L01, into LoT. Within each LoT, we compared the top 80% of AD prescribed (by volume of pts) to the LoT as indicated on each drug’s FDA label. We then used descriptive statistical summaries to outline the alignment between automated algorithmic results and indicated usage within that LoT. Results: In a set of 10,842 NSCLC pts, a total of 106 unique AD were prescribed in the first line as identified by our algorithm, and 13 drugs were prescribed as first line for 80% of the pts. Of those, 9 (69%) of those are indicated for first line, 3 are not indicated for NSCLC, and 1 is indicated for a subsequent NSCLC line, per FDA labels. 82 unique AD were prescribed in the second line as identified by our algorithm, and 15 drugs were prescribed as second line for 80% of the pts. Of those, 11 (73%) are indicated for treatment/continuation therapy for recurrent, advanced or metastatic disease, 3 are not indicated for NSCLC, and 1 is indicated for first line NSCLC per FDA labels. 36 unique AD were prescribed in subsequent line as identified by our algorithm, and 18 drugs were prescribed as subsequent line for 80% of the pts. Of those, 12 (67%) are indicated for treatment of recurrent, advanced or metastatic disease or subsequent systemic therapy, 5 are not indicated for NSCLC and 1 is indicated for first line per FDA labels. Conclusions: An automated algorithmic approach for deriving lines of therapy may be a viable solution to scalably calculate LoT in RWD sets. A deeper analysis using statistical sensitivity and specificity assessment of such algorithms is needed to validate the potential of an algorithmic approach.
Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study
Authors: Meng Zhu, Kuanfeng Xu, Yang Chen, Yong Gu, Mei Zhang, Feihong Luo, Yu Liu, Wei Gu, Ji Hu, Haixia Xu, Zhiguo Xie, Chengjun Sun, Yuxiu Li, Min Sun, Xinyu Xu, Hsiang-Ting Hsu, Heng Chen, Qi Fu, Yun Shi, Jingjing Xu, Li Ji, Jin Liu, Lingling Bian, Jing Zhu, Shuang Chen, Lei Xiao, Xin Li, Hemin Jiang, Min Shen, Qianwen Huang, Chen Fang, Xia Li, Gan Huang, Jingyi Fan, Zhu Jiang, Yue Jiang, Juncheng Dai, Hongxia Ma, Shuai Zheng, Yun Cai, Hao Dai, Xuqin Zheng, Hongwen Zhou, Shining Ni, Guangfu Jin, Jin-Xiong She, Liping Yu, Constantin Polychronakos, Zhibin Hu, Zhiguang Zhou, Jianping Weng, Hongbing Shen, Tao Yang
Journal: Diabetes Care (2019)

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified &amp;gt;60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85–0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.
Impact of PET-imaging during treatment planning on outcome in meningioma patients.
Authors: Stephanie E Combs, Hanna Fischer, Theresa Voglhuber, Christian Diehl, Chistoph Straube, Igor Yakushev, Kerstin Kessel
Journal: Journal of Clinical Oncology (2019)

e13542 Background: Modern radiotherapy (RT) techniques such as IMRT combined with IGRT increased safety and precision over the years. However, during treatment planning, the definition of the planning target volume (PTV) remains challenging, and differentiation between healthy tissue, i.e., meninges, post-operative changes, and residual tumor can be difficult using MR and CT imaging alone. In this study, we evaluated the impact of additional PET-imaging on local control (LCR) and overall survival (OS). Methods: We analyzed 351 patients with primary RT of meningiomas treated between 1996 and 2018 and divided the cohort into low-grade (n = 283) and high-grade (n = 68) cases. All patients were treated with fractionated stereotactic radiotherapy (FSRT) with a median dose of 54.0 Gy and a median single dose of 1.8 Gy. A radiation oncologist delineated PTV based on diagnostic CT and MRI and, if available, additional PET-imaging. We used only PET-images acquired within 50 days before RT. In our clinic, PET-planned meningioma treatment started in 2000 with Methionine (2001-2010), between 2004 and 2011 F-18 FET tracer was used, and since 2011 only 68Ga-Dotanoc/Dotatoc PETs are acquired. This study is registered under the open science framework: DOI 10.17605/OSF.IO/RYX9D. Results: Median follow-up was 6.9 years (95%-KI: 6.3-7.4). For low-grade meningiomas, mean OS was 15.5 years (95%-KI: 14.7-16.2) and mean PFS was 15.7 years (95%-KI: 14.9-16.6); for high-grade cases, median OS was 13.8 years (95%-KI: 10.4-17.1), and median PFS was 8.9 years (95%-KI: 6.4-11.4). PET imaging had a significant impact on OS (p = 0.030) and PFS (p = 0.023) for low-grade meningiomas; however, in the multivariate analysis (with the prognostic factors age, gender, PTV, Karnofsky index, and time from resection to RT), it remained only significant for LCR. For high-grade cases, PET-imaging had no influence. Conclusions: PET-imaging improves the detection of tumor cells, especially during treatment planning. It showed a significant influence on OS and LCR. Further analyses will investigate the influence of PET regarding, e.g., residual tumor tissue, tumor size, and establish cut-off values for which tumors additional PET-imaging might be beneficial. With the further prognostic a weighted scoring system will be developed for prognostic assessment. [Table: see text]