tbuckley/cabot-search huggingface dataset:
A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study.
Authors: Ghassan K. Abou-Alfa, Stephen Lam Chan, Junji Furuse, Peter R. Galle, Robin Kate Kelley, Shukui Qin, Jon Armstrong, Annie Darilay, Gordana Vlahovic, Alejandra Negro, Bruno Sangro
Journal: Journal of Clinical Oncology (2018)

TPS4144 Background: Thus far, sorafenib remains the standard of care for first line systemic therapy in patients with advanced HCC but patient prognosis and quality of life (QOL) continues to be poor. HCC may be responsive to immunotherapy due to higher expression of immunosuppressive cells and upregulation of CTLA-4 and PD-1 immune checkpoints (Gao et al 2009, Hato et al 2014, Pardee & Butterfield 2012). Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are also associated with upregulation of regulatory T cells and PD-L1/PD-1 expression (Miroux et al 2010, Pardee & Butterfield 2012). Blockade of PD-L1/PD-1 or CTLA4 immune checkpoints demonstrated clinical benefit in HCC as monotherapy. In preclinical studies, combination of anti-PD-L1 and anti-CTLA-4 antibodies enhanced anti-tumour activity compared to monotherapy, indicating that the two pathways are non-redundant (Stewart, et al). Early clinical data from a phase I/II trial combining anti-PD-L1 and CTLA-4 (NCT02519348) demonstrated safety and a durable objective response rate (ORR) of 18%, prompting study expansion. Methods: HIMALAYA (NCT03298451) is the first randomized, open-label, multicenter, phase 3 study to assess the efficacy and safety of D+T combination therapy versus sorafenib in the first-line treatment of patients with unresectable, histologically-confirmed HCC. Patients will be randomized to arms evaluating D monotherapy, D+T combination therapy, or sorafenib monotherapy. Patients will be stratified according to macrovascular invasion (yes versus no), etiology of liver disease (HBV versus HCV versus others), and performance status (ECOG 0 vs 1). The primary endpoint for this study is overall survival (OS). Secondary endpoints include ORR, duration of response, disease control rate, progression-free survival, and time to progression according to RECIST v1.1 using investigator assessments. Safety and health-related QoL will also be assessed. Clinical trial information: NCT03298451.
Endogenous DNA damage in peripheral blood lymphocytes (PBLs) in patients with metastatic urothelial carcinoma (MUC).
Authors: Patrik Palacka, Zuzana Sestakova, Katarina Kalavska, Katarina Rejlekova, Katarina Gasparova, Zuzana Sycova-Mila, Michal Chovanec, Jana Obertova, Daniela Svetlovska, Michal Mego, Miroslav Chovanec
Journal: Journal of Clinical Oncology (2018)

e16511 Background: First-line cisplatin-based chemotherapy is used as a standard treatment of patients with MUC. DNA damage represents one of the most important factors contributing to its toxicity. The objective of this prospective study is to evaluate the prognostic value of DNA damage level in PBLs from MUC patients before treatment with first-line chemotherapy. Methods: PBLs isolated from 25 consecutive MUC (22 bladder) patients (17 men) were included into this study. Karnofsky index < 80% was present in 12 patients, 14 of them had visceral metastases. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. Results: At the median follow-up 9.6 months, 19 patients progressed (76.0%) and 13 patients (52.0%) died. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 6.37 ± 0.45. Patients with DNA damage levels higher than the mean had better progression free survival (HR = 1.91, 95% CI 0.78-4.71) and overall survival (HR = 2.53, 95% CI 0.85-7.52) compared to patients with DNA damage levels lower than the mean. Conclusions: These data suggest that endogenous DNA damage levels in PBLs from MUC patients may serve as a prognostic marker early identifying patients with poor outcome.
Real world experience and biomarkers of nivolumab in dutch advanced renal-cell carcinoma patients.
Authors: Saskia Lisa Verhaart, Carla M.L.- Van Herpen, Sjoukje Oosting, Astrid Van Der Veldt, Susanne Osanto, Maureen J.B. Aarts, Danny Houtsma, Frank P.J. Peters, Gerard Groenewegen, Axel Bex, Sasja F. Mulder, Loes M. Pronk, Metin Tascilar, Paul Hamberg, Maartje Los, Gerard Vreugdenhil, Marco Polee, Albert J. Ten Tije, John B. A. G. Haanen, Alfonsus Johannes Maria van den Eertwegh
Journal: Journal of Clinical Oncology (2018)

4572 Background: Although nivolumab, a programmed death 1 inhibitor, has been approved as a second line treatment for advanced renal-cell carcinoma (RCC) in Europe since 2016, its real-world experience is currently unknown. Methods: Efficacy, toxicity and potential biomarkers (histology, performance score, lactate dehydrogenase [LDH], eosinophils, neutrophils and lymphocytes) of nivolumab were retrospectively evaluated in Dutch RCC patients, who were consecutively registered in a national database between March 2016 and May 2017. Results: Data of 264 patients in 24 hospitals was analyzed. Twenty-one (9%), 122 (49%) and 104 (42%) patients were categorized in favorable, intermediate and poor MSKCC risk groups, respectively. Median overall survival (OS) was 18.7 months (95% CI, 13.7 – 23.7) and time to treatment failure (TTF) 6.0 months (95% CI, 5.1 – 6.8). Overall, 46 grade 3 or 4 adverse events (AEs) in 39 patients (15%) and two nivolumab related deaths were reported. After a median follow-up of 12.3 months, 78% (38 of 49) of responding patients had an ongoing response. Clear-cell histology patients had a median OS of 17.6 months (95% CI, 14.6 – 20.6) and TTF of 5.6 months (95% CI, 4.8 – 6.3) while non-clear-cell histology patients had a median TTF of 3.3 months (95% CI, 1.4 –5.1). Patients with a WHO performance score ≤ 1 had a better OS and TTF as compared to patients with a performance score of ≥ 2; median OS 18.7 months (95% CI, not estimable) vs. 5.4 months (95% CI, 1.2 – 9.6) and TTF 6.0 months (95% CI, 5.0 – 6.9) vs. 2.4 months (95% CI, 1.5 – 3.3). In patients with normal baseline LDH, median OS was not estimable and median TTF 6.7 months (95% CI, 5.2 – 8.2), while a decreased efficacy (median OS 9.7 months (95% CI, 7.5 – 11.9) and TTF 2.9 months (95% CI, 2.1 – 3.6) was observed in patients with elevated LDH at baseline. An increase in absolute eosinophil count between week 0 and 8 was related to improved OS (HR = 0.41; 95% CI, 0.23 – 0.73, P = 0.003) and TTF (HR = 0.65; 95% CI, 0.46 – 0.92, P = 0.015). Conclusions: In this real-world population, efficacy and safety of nivolumab are comparable to the results reported in the pivotal phase III trial. Remarkably, increase in eosinophil count during treatment with nivolumab predicts improved efficacy and survival.
The Ethics of Smart Pills and Self-Acting Devices: Autonomy, Truth-Telling, and Trust at the Dawn of Digital Medicine
Authors: Craig M. Klugman, Laura B. Dunn, Jack Schwartz, I. Glenn Cohen
Journal: The American Journal of Bioethics (2018)

Digital medicine is a medical treatment that combines technology with drug delivery. The promises of this combination are continuous and remote monitoring, better disease management, self-tracking, self-management of diseases, and improved treatment adherence. These devices pose ethical challenges for patients, providers, and the social practice of medicine. For patients, having both informed consent and a user agreement raises questions of understanding for autonomy and informed consent, therapeutic misconception, external influences on decision making, confidentiality and privacy, and device dependability. For providers, digital medicine changes the relationship where trust can be verified, clinicians can be monitored, expectations must be managed, and new liability risks may be assumed. Other ethical questions include direct third-party monitoring of health treatment, affordability, and planning for adverse events in the case of device malfunction. This article seeks to lay out the ethical landscape for the implementation of such devices in patient care.
Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes.
Authors: Jessica Ribeiro Gomes, Raphael Brandao Moreira, Matheus Bongers Alessandretti, Marcelo Rocha De Sousa Cruz
Journal: Journal of Clinical Oncology (2017)

e23166 Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.
P01.011 Fluorescence diagnosis with 5 ALA and noncontrast ASL-perfusion in the planning of brain gliomas surgery
Authors: S Goryaynov, A Batalov, N Zakharova, I Pronin, A Baev, E Pogosbekyan, L Fadeeva, D Chelushkin, A Potapov
Journal: Neuro-Oncology (2018)

To study blood flow in brain gliomas using the ASL-perfusion to predict 5-ALA intraoperative fluorescence in glioma surgery. The study group included 149 patients (76 women, 73 men aged from 12 to 75, avg. 44 ± 15 years) with primary supratentorial gliomas: 40 - low-grade (WHO grade I-II) and 109 - high-grade (42- WHO grade III, 67 - WHO grade IV). Patients were examined on a 3T MRI-scanner. The pseudo-continuous ASL (pcASL) technique was used to determine tumor blood flow (TBF). TBF was normalized regarding intact white matter (nTBFmax).In 57 of 149 patients tumor resection was performed using fluorescence-guided technology with 5-ALA. All diagnoses were confirmed histopathologically. Mean nTBFmax in the low-grade glioma group was 1.61 ± 0.76. In the group of high-grade gliomas nTBFmax was 8.51 ± 5.53. nTBFmax in the groups of low- and high-grade gliomas was significantly different (p <0.001).The sensitivity of this technique in the differential diagnosis of low-grade and high-grade gliomas was 89%, specificity was 87.5%, AUC - 0.955, сutoff - 2.4. We found a significant difference in nTBFmax between fluorescent and non-fluorescent gliomas (p <0.05).The sensitivity and specificity of pcASL in predicting intraoperative fluorescence in gliomas was 74% and 73%, accordingly, AUC - 0.716, сutoff - 3.3. pcASL is a reliable quantitative technique for the differential diagnosis between low- and high-grade gliomas. pcASL can be used in predicting intraoperative fluorescence in gliomas.The study was supported by Russian Foundation for Basic Research (grant № 18-315-00384).
Access to oncological care in patients with breast and lung cancer treated at public and private hospitals in Buenos Aires, Argentina.
Authors: Gonzalo Recondo, Cesar Cosacow, Hernan J Cutuli, Luciano Cermignani, Samanta Straminsky, Alejandro M Naveira, Martin Pitzzu, Gabriela Antares De Ronato, Gabriela Nacuzzi, Gonzalo Taetti, Santiago Corsico, Giuliana Colucci, Mabel Berrueta, Ezequiel Garcia Elorrio
Journal: Journal of Clinical Oncology (2018)

e18640 Background: Timely access to oncological care is a determinant factor to provide adequate treatment of patients with cancer. We describe the time elapsed from the first consultation to the diagnosis and treatment of patients with breast and lung cancer treated with chemotherapy at public and private hospitals in Buenos Aires, Argentina. Methods: Patients over 18 years old with lung or breast cancer diagnosis and treated with chemotherapy were included. Clinical and epidemiological data were collected. We used the Kaplan-Meier estimator to study the time elapsed between the first consultation to diagnosis and from diagnosis to treatment initiation and the log Rank test to compare both groups. Results: A total of 168 patients with breast cancer and 100 patients with lung cancer were included between June 2016 and September 2017. In patients with breast cancer, the median time (Q1-Q3) elapsed between the diagnosis and treatment was 76 days (64-86) in public hospitals and 60 days (52- 65) in private hospitals (p = 0.0001). In the subgroup of patients treated in the adjuvant and neoadjuvant setting, median time was 130 (109-159) versus 64 (56-73) days (p < 0.0001) and 57 days (49 - 75) versus 26 (16 - 41) respectively (p = 0,0002). There were no significant differences in the time from first consultation to diagnosis between public and private hospitals. In patients with lung cancer, median (Q1-Q3) time from the first consultation to diagnosis was 86 days (69-116) in public hospitals and 48 (33-61) days in private hospital. Time from diagnosis to treatment was 71 days (60-83) and 31 days (24-39), respectively (p = 0.0002). In the subgroup of patients treated in the adjuvant, neoadjuvant and with chemoradiation therapy the median time from diagnosis to treatment was 83 (64-99) vs 22 (14-37) days (p < 0.0091) and in patients treated with metastatic disease, 63 days (49 - 75) and 33 (16 - 41) days (p = 0,0002). Conclusions: There are significant disparities in the access to treatment with chemotherapy for patients with breast and lung cancer between public and private hospitals in Buenos Aires. Social, economic, educational factors and disease patterns differ substantially between both systems.
Phase I study of afatinib and radiotherapy (RT) with or without temozolomide (TMZ) in newly diagnosed glioblastoma (GB).
Authors: Frank Saran, Liam Welsh, Allan James, Catherine McBain, Rao Gattamaneni, Sarah Jefferies, Fiona Harris, Agnieszka Cseh, Karine Pemberton, Jennifer Schaible, Shaun Bender, Michael Brada
Journal: Journal of Clinical Oncology (2018)

2036 Background: GB is a malignant primary incurable CNS tumor with poor prognosis. RT + TMZ is standard treatment for newly diagnosed GB suitable for radical treatment. ErbB pathway dysregulation has a role in the pathogenesis of GB and EGFR activation contributes to RT resistance. The irreversible ErbB family blocker afatinib has a manageable safety profile and modest activity in recurrent GB. This Phase I study assessed the feasibility of first-line afatinib + RT ± TMZ in GB. Methods: This 3+3 dose-escalation study enrolled 36 pts with newly diagnosed GB. Treatment was stratified by MGMT promoter methylation status. Pts with promoter methylation received RT + TMZ + afatinib (20, 30, 40 mg/day) for 6 wks (RT period), then afatinib 40 mg/day + TMZ for up to 6 months before afatinib 40 mg/day until progression/undue AEs (maintenance period; Regimen M). As TMZ has limited benefit in pts with unmethylated MGMT, these pts received RT + afatinib then afatinib (Regimen U). Primary endpoint: MTD of afatinib + RT ± TMZ. Secondary endpoints: AEs, ORR, PK. Results: In regimen M, 20 pts (median [range] age: 52.5 [25–66] yrs) were treated for median [range] 151 [6–2340] days (20 mg n = 7; 30 mg n = 6; 40 mg n = 7); of those evaluable for MTD, 1/6, 0/6 and 2/5 had dose-limiting toxicities (DLTs) in the RT period (2 grade [G] 4 thrombocytopenia and 1 G3 vomiting). MTD of afatinib + RT + TMZ was 30 mg/day. In regimen U, 16 pts (53.5 [34–68] yrs) were treated for median [range] 168 [1–397] days (20 mg n = 3; 40 mg n = 13); of those evaluable for MTD, 0/3 and 1/6 had DLTs (1 G3 diarrhea) in the RT period. MTD of afatinib + RT was 40 mg/day. Common treatment-related AEs (TRAEs) are shown in the Table. ORRs were 25% and 6% in regimens M and U, respectively. PK evaluation indicated that combination of afatinib with RT + TMZ had no influence on afatinib exposure. Conclusions: The MTD of afatinib + RT was 30 mg/day with TMZ and 40 mg/day without TMZ. The safety profile of afatinib + RT ± TMZ was as expected, based on the known profiles of the individual agents. Common TRAEs Clinical trial information: NCT00977431. Regimen M (n = 20); n (%) Regimen U (n = 16); n (%) Grade Grade All ≥3 All ≥3 Diarrhea 16 (80) 1 (5) 13 (81) 1 (6) Rash 13 (65) 1 (5) 12 (75) 2 (13) Fatigue 9 (45) 1 (5) 6 (38) 0 Nausea 9 (45) 0 2 (13) 0 Thrombocytopenia 3 (15) 3 (15) 1 (6) 0
A comparison of gefitinib for advanced non-small cell lung cancer patients with different <i>EGFR</i> mutation types.
Authors: Haijun Zhang, Nishant Patel, Pingping Wu
Journal: Journal of Clinical Oncology (2017)

e20544 Background: The aim of this study was to compare the efficacy and toxicity of gefitinib as first or second line therapy for advanced non-small cell lung cancer (NSCLC) patients with positive exon 21 (L858R) or exon 19 deletion mutation. Methods: We retrospectively analyzed the clinical data of 60 endothelial growth factor receptor ( EGFR) mutated advanced lung adenocarcinoma patients from July 2011 to November 2015, who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death. Results: At the time of last follow-up visit, 1 death had occurred. Among the 59 patients who remained survival, 17 patients progressed. Overall, the median progression-free survival (mPFS) was 10 months (95% confidence interval (CI): 7.53–12.46 months, p &lt; 0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in first line therapy than that in second line therapy: in first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58–14.41 months, p &lt; 0.05); in the second line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31–12.68 months, p &lt; 0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted mPFS was significantly longer for patient with exon 19 deletion than that with positive exon 21in both first line therapy and second line therapy. The most common Grade 1 or 2 adverse events included rash (76.6%), abnormal liver function (60%), dry skin (48.3%), diarrhoea (46.6%), fatigue (40%) and paronychia (33.3%) etcetera in non-haematological toxicity, whereas anemia(33.3%), leukocytopenia (20%) etcetera were included in haematological toxicity. Conclusions: Patients with NSCLC who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in first line therapy than that in second line therapy when treated with gefitinib. And EGFR mutation types may influence the response to gefitinib therapy.
P01.036 Treatment of Glioblastoma - improvements over two decades at a single centre
Authors: M Eriksson, M Johansson, T Bergenheim, M Sandström
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a rapidly progressing tumour with a short overall survival. The treatment of GBM has evolved over the last decades and is today multimodal including surgery with maximal tumour resection followed by radiotherapy and chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single centre. 244 patients treated for GBM 2005 - 2015 has been included in a tissue bank with tumour tissue and/or blood samples. A clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment. Survival was also studied for all 571 patients in our region diagnosed with GBM between 1995 and 2015. The overall median survival for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995–1996 and 2010–2015, respectively (p<0.05). The two-year survival for the same time periods improved from 7.4% to 17.8% (p<0.01). After the introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased survival was noted. The implementation of intraoperative 5-aminolevulinic acid did, in patients that underwent tumour resection, increase the number of total tumour resections (≥95%) from 32.6% to 54.1% (p<0.001). Positive prognostic factors were young age, good performance status, absence of diabetes or metabolic disease, total tumour resection and completion of postoperative radiochemotherapy. The results of this study are in line with earlier results regarding survival and prognostic factors. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.
Follow the TRAIL: Understanding the etiology of persistent fatigue following radiation therapy.
Authors: Leorey N Saligan, Kristin Dickinson, Alexandra Espina, Li Rebekah Feng
Journal: Journal of Clinical Oncology (2016)

10113 Background: Fatigue is a distressing side effect of cancer therapy. Emerging evidence suggests immunological involvement in the pathogenesis of chronic fatigue (CF) related to radiation therapy (RT) for cancer. We hypothesize that changes in immunological markers underlie chronic fatigue symptoms in men with non-metastatic prostate cancer (NM-PC) patients who have previously received localized external beam RT (EBRT). Methods: A sample of 34 men with NM-PC scheduled to receive EBRT were followed at baseline and one year following EBRT completion. Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F) was administered to measure fatigue levels. Blood was drawn at baseline and one year after EBRT. Plasma cytokine levels were determined using the Bio-Rad Bio-Plex Cytokine Assay Kits. Gene expression profiles were determined using microarray analysis and analyzed using Partek Genomics Suite 6.6 as well as Ingenuity Pathway Analysis. Results: At one year after EBRT completion, 34% of subjects continued to experience persistent fatigue, defined as a decrease in FACT-score of 3 points or greater from baseline. One year following EBRT, microarray analysis revealed 44 genes that were differentially expressed between the CF and non-fatigue (NF) groups. The main disease networks identified by pathway analysis of the differentially expressed genes are related to cancer pathophysiology. Further, there was an increase in gene expression levels of the decoy receptor TRAIL-R3in the CF group. Interestingly, the ligand of this decoy receptor, TRAIL, is significantly higher in the plasma of CF subjects compared to NF subjects. Conclusions: Concomitant upregulation of TRAIL and its decoy receptor suggest that fatigue may be more than just a distressing side effect of cancer treatment. Instead, fatigue symptoms may serve as a behavioral indicator of the underlying disease status in cancer patients.
TCT-318 Impact of coronary artery disease and prior coronary artery bypass grafting on patients undergoing transcatheter aortic valve replacement
Authors: Toby Rogers, Quan Zou, Rebecca Torguson, Petros Okubagzi, Itsik Ben-Dor, Vinod Thourani, Lowell Satler, Ron Waksman
Journal: Journal of the American College of Cardiology (2018)