tbuckley/cabot-search huggingface dataset:
Mutational analysis using next-generation DNA sequencing in platinum-resistant muscle-invasive bladder cancer.
Authors: Arash Samiei, Pritam Tayshetye, Angela Sanguino, Ralph Miller, John Lyne, Jeffrey Cohen, Shifeng Mao
Journal: Journal of Clinical Oncology (2019)

e16006 Background: Platinum-resistant muscle-invasive bladder cancer (prMIBC) is the main cause of bladder cancer mortality. Recent advances in next-generation DNA sequencing (NGS) has allowed characterization of the molecular landscape of MIBC. Yet, the correlation between the molecular alteration and the poor outcome of prMIBC is still lacking. This study aims to explore the potential genetic alterations in this group of patients. Methods: A retrospective study of prMIBC patients that had NGS molecular profiling at a single center from November 2014 to October 2018 was conducted. The prMIBC was defined as patients who had a significant residual disease or disease progression following cisplatin-based chemotherapy in a neoadjuvant or metastatic disease setting. NGS was performed on formalin-fixed paraffin-embedded tissue samples through commercial companies. Results: A total of 17 prMIBC with the median age of 65 [51-74] years old were included in this study. At the end of the study, 8 patients were alive and 9 deceased. A total of 58 mutations were identified. 7 of the 58 genes were mutated in ≥20% of cases: TP53 (65%), TERT promoter -124C &gt; T (59%), ARID1A (35%), CDKN2A/B (30%), RB1 (24%), PIK3CA (24%), and FLCN (20%). Less frequent mutations (12% each) include MDM2, AKT2, KDM6A, SMARCA4, FGF3, FGF4, BRCA2, STAG2, and CCNE1 genes. Analysis of the mutations revealed key pathways including TP53/cell cycle pathway altered in 82%, PI-3K/mTOR pathway in 71%, Telomere regulation in 59%, SWI/SNF complex in 35% and histone modification in 24% of cases. Conclusions: Among patients with prMIBC, mutations in the p53/cell cycle pathway are the most common findings. Genetic alteration involving the PI-3K/mTOR pathway is frequently associated with prMIBC, which could provide an important lead for a predictive model and targeted intervention. Interestingly, the TERT promoter -124C &gt; T mutation is a very common molecular alteration in prMIBC that has not been reported before. Telomere regulation may play a role in contributing to platinum-resistance in bladder cancer. Further elucidation of the molecular landscape in prMIBC on a larger scale would help to establish a molecular model to predict platinum-response in MIBC.
Epidemiology, prevalence and national trends of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) in hospitalized US patients between 2002-2014.
Authors: Ahmed Elkafrawy, Hasan F. Othman, Samia Asif, Leen Al-Sayyed, Anuj Shrestha
Journal: Journal of Clinical Oncology (2019)

e15616 Background: cHCC-CCA represents a rare type of primary liver cancer that was first identified in 1949. The aim of this study is to evaluate epidemiology, clinical outcomes and national trends of cHCC-CCA in hospitalized US patients using the Nationwide Inpatient Sample database (NIS). Methods: NIS database was inquired to identify patients with HCC between 2002 and 2014 using ICD9-CM codes. Patients with HCC were classified into two groups, one group with cholangiocarcinoma (CCA) and the other group without CCA. SPSS version 25 was used for statistical analysis. Results: We identified 525,699 patients with HCC between 2002-2014. Of them, 2,158 patients (0.4%) had CCA. In the cHCC-CCA group, 87.8% of the patients were above 50 years old, 58.1% were male, 63.7% were Caucasian, and 10% were African American. Mortality in patients hospitalized with cHCC-CCA was 8.5% compared to 11.1% in patients with HCC (OR 0.74, 95% CI 0.64-0.86, P &lt; 0.0001). Mortality in cHCC-CCA patients decreased from 19.1% in 2002 to 7.9% in 2014. The median length of stay (LOS) in patients with cHCC-CCA was 6 days compared to 4 days in patients with HCC (P &lt; 0.0001). Median LOS for patients with cHCC-CCA was unchanged between 2002 and 2014. The median hospitalization cost of charge in cHCC-CCA patients was 41,012 USD compared to 28,371 USD in HCC patients. In the cHCC-CCA group, it increased from 17,243 USD in 2002 to 37,234 USD in 2014. Only 0.9% of patients with cHCC-CCA underwent liver transplantation compared to 3.5% of HCC patients (OR 0.26, 95% CI (0.17-0.41), P &lt; 0.0001). Conclusions: Prevalence of cHCC-CCA was 0.4% of patients with HCC during the study period. cHCC-CCA was unexpectedly associated with less mortality; possibly because of limitations in comparison due to the smaller number of patients compared to HCC alone. cHCC-CCA was also associated with lower rates of liver transplantation but more prolonged LOS and higher hospitalization cost of charge compared to HCC patients. In the same period, mortality decreased in cHCC-CCA patients and cost of charge increased while prevalence and LOS were unchanged. Further studies are needed to evaluate and understand cHCC-CCA as a separate entity.
Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) <i>(</i>Alliance A021202<i>)</i>.
Authors: Emily K. Bergsland, Michelle R. Mahoney, Timothy R. Asmis, Nathan Hall, Priya Kumthekar, Michael L. Maitland, Donna Niedzwiecki, Andrew B. Nixon, Eileen Mary O'Reilly, Lawrence Howard Schwartz, Jonathan R. Strosberg, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2019)

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) &lt; 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.
Intratumoral and subcutaneous injection of HVJ-E (GEN0101) for metastatic castration-resistant prostate cancer: Open-label, phase I, dose escalation study.
Authors: Kazutoshi Fujita, Yasutomo Nakai, Taigo Kato, Atsunari Kawashima, Takeshi Ujike, Akira Nagahara, Motohide Uemura, Ryoichi Imamura, Koji Okihara, Osamu Ukimura, Tsuneharu Miki, Yasufumi Kaneda, Norio Nonomura
Journal: Journal of Clinical Oncology (2019)

e16511 Background: Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E (GEN0101). Methods: Patients with CRPC who were resistant to standard of care or could not receive standard of care were eligible. GEN0101 was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a modified 3+3 dose-escalation design to determine the recommended dose of GEN0101. The primary end points were to evaluate safety and tolerability of GEN0101 and determine the recommended dose. The secondary end points were to analyze antitumor effect and tumor immunity. The study is registered at UMIN Clinical Trials Registry, number UMIN000017092. Results: Of the 9 patients treated, 3 received 30,000mNAU of GEN0101 and 6 received 60,000mNAU. There were no dose-limiting toxicities, and the recommended dose of GEN0101 was defined as 60,000mNAU. Radiographically, one patient had stable disease and 2 had progressive disease in the low-dose group, and 5 patients had stable disease and one had progressive disease in the high-dose group. Four patients in high dose group had reductions in lymph node metastasis after 2 treatment cycles. Final PSA increase rates in high-dose group were more suppressed than those in low-dose group. NK cell activity was enhanced in 2 patients (66%) in low-dose group and 5 patients (83%) in high-dose group, Serum interleukin-6, and IFN-γ levels were not affected by GEN0101 treatment. Conclusions: Intratumoral and subcutaneous injections of GEN0101 were well tolerated and feasible. Antitumor effect in lymph node metastasis were observed in CRPC patients. It is necessary to test whether the treatment with GEN0101 improves the survival of CRPC patients. Clinical trial information: UMIN000017092.
Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: A prospective, randomized, open label, single-center trial.
Authors: Tao Ma, Xueli Bai, Qichun Wei, Shunliang Gao, Bingfeng Huang, Wei Chen, Ji Wang, Tingbo Liang
Journal: Journal of Clinical Oncology (2019)

e15765 Background: Although adjuvant chemotherapy with gemcitabine has for years been the standard of care for resected pancreatic cancer, the role of adjuvant radiation is still debatable. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II pancreatic cancer. Methods: This single center randomized controlled trial was designed to enroll 512 patients with stage II pancreatic cancer that underwent curative-intended radical resection from a large-volume tertiary pancreatic center in China. Patients were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT (25 Gray in 5 fractions) followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. Interim analysis was planned at the time of 2.5-years’ enrollment. Results: 40 patients were randomly assigned to treatment between Sep 1, 2015, and Mar 31, 2018 (21 to the gemcitabine group and 19 to the gemcitabine plus SBRT group). Of these, one was excluded because of ineligibility and one did not receive any treatment. The median RFS was 12.4 (9.3-15.6) months in the gemcitabine group and 14.7 (9.2-20.1) months in the gemcitabine plus SBRT group ( P= 0.753), with median LRFS of 18.2 (14.6-21.7) months in the gemcitabine group and 13.1 (9.1-16.8) months in the gemcitabine plus SBRT group ( P= 0.333). The median OS was 21.7 (19.5-24.0) months in the gemcitabine group and 16.9 (12.8-20.9) in the gemcitabine plus SBRT group ( P= 0.066). Grade 3 or 4 neutropenia, thrombocytopenia, nausea or vomiting, and liver dysfunction were all comparable between the two groups. Evaluation of data from the first 40 enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence free survival. And because of failure to achieve the accrual target, the trial was terminated prematurely. Conclusions: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II pancreatic cancer. Clinical trial information: NCT02461836.
Phase 1a/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors.
Authors: Jasgit C. Sachdev, Todd Michael Bauer, Sant P. Chawla, Shubham Pant, Amita Patnaik, Zev A. Wainberg, Sandeep P. Inamdar, Neyssa Marina, Stefanie Sun, Maike Schmidt, Hong Xiang, Patricia LoRusso
Journal: Journal of Clinical Oncology (2019)

2529 Background: B7-H4, a transmembrane protein of the B7 family, is a negative regulator of T cell function, expressed at high levels on several cancers, including approximately 50% of breast, ovarian and endometrial cancers. FPA150 is a fully human antibody against B7-H4 that blocks inhibition of T cell activity and has enhanced antibody-dependent cell-mediated cytotoxicity. It is the first therapeutic molecule targeting B7-H4 to enter the clinic. We report preliminary results from an ongoing phase 1a/1b study of FPA150 in advanced solid tumors. Methods: Phase 1a included dose escalation in which B7-H4-unselected patients with advanced solid tumors were treated with FPA150 at doses between 0.01 to 20 mg/kg every three weeks (Q3W) in an accelerated titration followed by 3+3 design and a separate dose exploration cohort in which B7-H4+ (H-score≥100) patients were treated at doses of 3 or 10 mg/kg Q3W with mandatory pre- and on-treatment biopsies. Results: As of 12/31/2018, 24 patients with a median of 3 prior therapies were treated with FPA150, 6 of whom were in the B7-H4+ dose exploration cohort. Seven patients from dose escalation were also retrospectively identified as B7-H4+. Most patients received FPA150 at 3 mg/kg (n=8) or 10 mg/kg (n=6). Median number of doses was 3 (range 1-11). No dose-limiting toxicities or treatment-related serious adverse events were reported, and there were no treatment-related AEs (TRAEs) leading to discontinuation of FPA150. Most TRAEs were Grade 1-2, with diarrhea and fatigue most common (16.7%). Grade 3 TRAE hypertension occurred in 1 patient. FPA150 displayed approximately dose-proportional exposure at doses ≥0.3 mg/kg with half-life of 1-2 weeks. Conclusions: FPA150 monotherapy demonstrated a favorable safety profile and evaluation of anti-tumor activity is ongoing. 20 mg/kg Q3W was selected as the recommended dose. Phase 1b enrollment of FPA150 monotherapy in patients with B7-H4+ breast, ovarian and endometrial cancer began in February 2019. We will present updated safety, PK, and preliminary biomarker and efficacy data. Clinical trial information: NCT03514121.
A patent on the synthesis of arabino‐oligosaccharides for regulation of immune responses in the lung
Authors: Marcus Peters
Journal: Allergy (2019)

Dr. Peters reports grants from Deutsche Forschungsgemeinschaft, grants from Gesellschaft für Pädiatrische Allergologie und Umweltmedizin, during the conduct of the study; In addition, Dr. Peters has a patent WO2017093276A1 issued.
An open label, single-arm, two-stage, multicenter, phase II study to evaluate the efficacy and safety of TLC388 as second-line treatment in subjects with poorly differentiated neuroendocrine carcinomas (TCOGT1Z14).
Authors: Ming-Huang Chen, Wen-Chi Chou, Chin-Fu Hsiao, Yi-Chang Liu, Chiun Hsu, Shan Yanshen, Yi-Ping Hung, Chia-Hsun Hsieh, Chao-Hua Chiu, Ta-Chih Liu, Shih-Feng Cho, Tsang-Wu Liu, Yee Chao
Journal: Journal of Clinical Oncology (2019)

4101 Background: Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are unknown. Camptothecin analogs, like topotecan and irinotecan, are approved chemotherapy in small cell lung cancer (SCLC). NEC is considered to have similar biological behavior to SCLC. The aim of this study was to analyze the efficacy of TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog, in pretreated metastatic NEC patients. Methods: This single-arm, 2-stage, phase 2 clinical trial was conducted at 4 community and academic centers in Taiwan. Patients aged 20 years or older enrolled between July 2015 to May 2018 had confirmed metastatic NEC with prior systemic therapy with etoposide plus cisplatin. Patients received intravenous 40 mg/m 2 of TLC388 on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Results: twenty-three patients with a median age of 61 (range, 44-73) years, including 18 men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, three patients showed a stable disease and no patient a complete or partial remission, resulting in a disease control rate of 15%. Median PFS was 1.8 (95% CI, 0.4-15) months and median OS was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%), respectively. Conclusions: TLC388 shows modest antitumor activity in metastatic NEC. Clinical trial information: NCT02457273.
Gender norms and health: insights from global survey data
Authors: Ann M Weber, Beniamino Cislaghi, Valerie Meausoone, Safa Abdalla, Iván Mejía-Guevara, Pooja Loftus, Emma Hallgren, Ilana Seff, Lindsay Stark, Cesar G Victora, Romina Buffarini, Aluísio J D Barros, Benjamin W Domingue, Devika Bhushan, Ribhav Gupta, Jason M Nagata, Holly B Shakya, Linda M Richter, Shane A Norris, Thoai D Ngo, Sophia Chae, Nicole Haberland, Katharine McCarthy, Mark R Cullen, Gary L Darmstadt, Gary L Darmstadt, Margaret Eleanor Greene, Sarah Hawkes, Lori Heise, Sarah Henry, Jody Heymann, Jeni Klugman, Ruth Levine, Anita Raj, Geeta Rao Gupta
Journal: The Lancet (2019)
Methodological Issues in Determining the Accuracy of Automated Office Blood Pressure Readings for Diagnosing Hypertension
Authors: Anthony O. Etyang
Journal: JAMA Internal Medicine (2019)

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The effect of everolimus on CNS penetration and efficacy of dasatinib in the treatment of <i>PDGFRA</i>-driven glioma.
Authors: Zachary Miklja, Brendan Mullan, Ruby Siada, Stefanie Stallard, Viveka Nand Yadav, Amy Bruzek, Taylor Garcia, Marcia Leonard, Patricia Robertson, Alyssa Paul, Manjunath Pai, Timothy Phoenix, Bernard Marini, Carl Johannes Koschmann
Journal: Journal of Clinical Oncology (2019)

e13508 Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase CNS penetration and efficacy of dasatinib in in vitro and in vivo models as well as in human PDGFRA-driven glioma. Methods: Tumors were generated in mice using an intra-uterine electroporation (IUE) model [introduction of TP53, PDGFRA and H3K27M mutations in pre-natal cortex]. Dose response, synergism studies, P-GP inhibition and pharmacodynamics/pharmacokinetic studies were then performed on in vitro and in vivo models employing this IUE system. A phase 2 trial employing dasatinib and everolimus was established for children with HGG and diffuse intrinsic pontine glioma (DIPG) that contain PDGFRA alterations (NCT03352427). Paired CSF/plasma samples (before and after addition of everolimus) were collected from enrolled patients. Results: Dasatinib effectively treated mouse HGG cells with an IC 50 of 100 nM. Dose-dependent reduction in PDGFRA and pPDGFRA was found. P-gp inhibitor assay confirmed that everolimus strongly blocks P-gp activity at 1 uM (p = 0.0028 vs untreated). Mice treated with dasatinib and everolimus had extended survival as compared to control. Two-hour exposure to everolimus resulted in sub-IC 50 dasatinib concentration in cortex (23 nM) and tumor (65 nM). 24-hour exposure to everolimus resulted in greater cortex (235 nM) and tumor (509 nM) concentrations. Two trial patients, recurrent HGG ( PDGFRA-amplified) and recurrent DIPG ( PDGFRA D842V) respectively, survived 6 months and 9 months (ongoing) after progression, which compares very favorably to historical controls. A paired CSF sample from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. Conclusions: Dasatinib treatment of PDGFRA-driven HGG is improved with everolimus blockade of P-gp and represents a novel route for improving CNS penetration and efficacy of therapies for HGG. Clinical trial information: NCT03352427.