tbuckley/cabot-search huggingface dataset:
Comparison of Biologics and Oral Treatments for Plaque Psoriasis
Authors: April W. Armstrong, Luis Puig, Avani Joshi, Martha Skup, David Williams, Junlong Li, Keith A. Betts, Matthias Augustin
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> The clinical benefits of novel treatments for moderate to severe psoriasis are well established, but wide variations exist in patient response across different therapies. In the absence of head-to-head randomized trials, meta-analyses synthesizing data from multiple studies are needed to assess comparative efficacy among psoriasis treatments. <h3>Objective</h3> To estimate the relative short-term and long-term efficacy of biologics and oral agents for the treatment of moderate to severe psoriasis. <h3>Data Sources</h3> A systematic literature review was conducted on December 4, 2017, and updated on September 17, 2018. The Embase, MEDLINE, and Cochrane Central Register databases were included. <h3>Study Selection</h3> Phase 2, 3, or 4 randomized clinical trials of treatments licensed by the US Food and Drug Administration and the European Medicines Agency for adults with moderate to severe psoriasis with data on Psoriasis Area and Severity Index assessment of 75%, 90%, and 100% reductions (PASI 75, 90, and 100) at 10 to 16 weeks (short-term efficacy) or 44 to 60 weeks (long-term efficacy) from baseline. <h3>Data Extraction and Synthesis</h3> Data were extracted based on the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. A bayesian network meta-analysis was conducted to estimate short-term PASI response rates; to account for variation across trials, an ordinal model that adjusted for reference arm response was implemented. The long-term PASI rates were estimated via a traditional meta-analysis. <h3>Main Outcomes and Measures</h3> PASI 75, 90, and 100 response rates at 10 to 16 weeks and 44 to 60 weeks from baseline. <h3>Results</h3> Sixty trials meeting all inclusion criteria were included. At weeks 10 to 16, the highest PASI 90 rates were seen with risankizumab-rzaa (71.6%; 95% credible interval [CrI], 67.5%-75.4%), brodalumab (70.8%; 95% CrI, 66.8%-74.6%), ixekizumab (70.6%; 95% CrI, 66.8%-74.6%), and guselkumab (67.3%; 62.5%-71.9%). At weeks 44 to 60, the treatments with the highest PASI 90 rates were risankizumab-rzaa (79.4%, 95% CI, 75.5%-82.9%), guselkumab (76.5%; 95% CI, 72.1%-80.5%), brodalumab (74.0%; 95% CI, 69.3%-78.1%), and ixekizumab (73.9%; 95% CI, 69.9%-77.5%). Findings were consistent for short-term and long-term PASI 75 and 100 responses. <h3>Conclusions and Relevance</h3> This study provides an assessment of the comparative efficacy among treatments for moderate to severe plaque psoriasis. The meta-analysis suggests that brodalumab, guselkumab, ixekizumab, and risankizumab-rzaa were associated with the highest PASI response rates in both short-term and long-term therapy.
Correlation of tumor mutation with efficacy in patients with gastric cancer who received nivolumab and ramucirumab combination therapy.
Authors: Izuma Nakayama, Hirokazu Shoji, Hiroki Hara, Taito Esaki, Nozomu Machida, Kengo Nagashima, Kazunori Aoki, Kazufumi Honda, Daisuke Takahari, Takahiro Miyamoto, Narikazu Boku, Ken Kato
Journal: Journal of Clinical Oncology (2020)

413 Background: Nivolumab (Nivo) plus ramucirumab (Ram) showed promising efficacy in the second-line chemotherapy for advanced gastric cancer (AGC) in NIVORAM study with the 44% of objective response rate (ORR) and 38.6% of 6-month progression free survival (PFS) rate. We investigated the correlation of tumor mutation load and efficacy. Methods: Patients received Nivo (3mg/kg, Q2W) in combination with Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. Tissue samples were collected before the treatment, and analyzed for tumor mutation load using Oncomine Tumor Mutation Load Assay. Efficacy included ORR, overall survival (OS), PFS and duration of response. OS and PFS curves were estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazards model. Results: By the data cut off of December 15, 2018, the median follow duration on therapy was 13.7 month. Thirty AGC pts who obtained tissue sample were analyzed. Median tumor mutation load (TML) was 6.755 mutation/Mb (range 0.84-19.67). Higher TML (cut-off median) related to better tendency of efficacy with ORR (40.0% vs 20.0%), PFS (5.32 vs 2.33 months) and OS (18.1 vs 10.6 months). 6-month PFS rate was better in TML higher group (48%) compared to TML lower group (18%). In multivariate analysis, higher TML showed 2.030 of hazard ratio (95% CI; 0.849-4.855, p-0.112) for PFS, and 1.915 (95% CI; 0.578-6.343, p=0.287) for OS. Conclusions: The patients with higher tumor mutation load have a better tendency for OS and PFS, among AGC patients who received Nivo and Ram combination therapy. Clinical trial information: NCT02999295.
Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: Experience of a tertiary Asian center.
Authors: Kennedy Ng, Lawrence Wen Jun Wong, Su Pin Choo, David Wai-Meng Tai, Sze Huey Tan, Andrea Jing Shi Ang, Joycelyn Jie Xin Lee
Journal: Journal of Clinical Oncology (2020)

559 Background: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real-world data on efficacy and safety however is lacking, more so when used in patients who fall out of standard clinical trial criteria. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our centre who received at least one dose of an ICI between May 2015 - June 2018. Data cutoff was 31 Dec 2018. Responses were evaluated using RECIST v1.1 criteria. Results: 114 patients fulfilled inclusion criteria. Median age was 66 years and 88.6% were male. 96.5% had an ECOG PS of 0 – 1. 64.9% received an ICI within a clinical trial setting. 62.3% received monotherapy ICI. 19.6% of patients had Child-Pugh B disease on initiation of ICI, and 69.3% had an ALBI Grade of 2. 50.0% were known to have hepatitis B and 11.4% had hepatitis C. Baseline HBV VL ranged from undetectable to 8210000 IU/mL. 30.7% received prior systemic treatment, most commonly sorafenib (82.9%). Over a median follow-up duration of 5.7 months (0.03 - 42.4), ORR was 18.4%, and disease control rate (DCR) was 51.8%. Median PFS was 2.6 months (1.7 - 3.9), and median OS was 13.9 months (7.0 - 16.2). 5 patients (23.8%) had response duration of more than 18 months. 35.1% received further systemic therapy after ICI. On multivariable analyses, age ≥ 65 years, higher albumin level and lower bilirubin level were associated with increased OS. 68.0% of patients experienced adverse events (AEs) of any grade, 12.0% of these being grade 3 - 4. No grade 5 adverse events were observed. Use of antiviral therapy was associated with a lower risk of hepatic AEs (p = 0.04) whilst high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AEs. Conclusions: In the real-world setting, responses and adverse event profiles to ICI use are comparable to those observed in clinical trials despite a more heterogenous population base. The expansion of indications for ICI use in advanced HCC beyond current approvals warrants greater study.
Sustained-release Griffithsin nanoparticle-fiber composites against HIV-1 and HSV-2 infections
Authors: Kevin M. Tyo, Amanda B. Lasnik, Longyun Zhang, Mohamed Mahmoud, Alfred B. Jenson, Joshua L. Fuqua, Kenneth E. Palmer, Jill M. Steinbach-Rankins
Journal: Journal of Controlled Release (2020)
Abstract 15240: Effect of Change in Temperature and Hospital Admissions for Cardiovascular Disease: A Nationwide Study From the Japanese Registry of All Cardiac and Vascular Diseases
Authors: Kihei Yoneyama, Takumi Higuma, Kanaka Teramoto, Mika Watanabe, Yuki Ishibashi, Masaki Izumo, Yasuhiro Tanabe, Tomoo Harada, Yoshihiro J Akashi
Journal: Circulation (2019)

Introduction: It is known that temperatures affect incident of cardiovascular diseases, but there is limited information how cardiovascular hospitalizations are affected by changes in temperatures....
Adenovirus-Antibody Complexes Contributed to Lethal Systemic Inflammation in a Gene Therapy Trial
Authors: Suryanarayan Somanathan, Roberto Calcedo, James M. Wilson
Journal: Molecular Therapy (2020)

Intra-arterial administration of an adenovirus serotype 5 (Ad5) vector in a gene therapy trial caused lethal, systemic inflammation in subject 019 with ornithine transcarbamylase deficiency. This unanticipated inflammatory response was absent in another subject receiving the same vector dose and in 16 subjects receiving lower vector doses. We hypothesized that an immune memory to a previous natural adenovirus infection enhanced the immune response to high-dose systemic Ad5 vector, causing the exaggerated immune response in subject 019. To investigate this, we found that rabbit polyclonal sera to Ad5 and pooled human immunoglobulin (Ig) inhibited Ad5 vector transduction of non-immune cells in vitro, but enhanced transduction and activation of human dendritic cells (DCs). Sera from approximately 7% of normal human subjects and 50% of patients treated topically with Ad5 vectors enhanced Ad5 transduction and activation of DCs, apparently from formation of Ig-Ad5 immune complexes and binding to DCs through FcγR. Subject 019's blood substantially increased Ad5-vector activation of human DC primary cultures at levels exceeding those from normal subjects. Although this study is based on one event in a single subject, the results implicate a pre-existing humoral immune response to Ad5 in the lethal systemic inflammatory response that occurred in subject 019.
Comparing five-weekly S-1 plus cisplatin with tri-weekly capecitabine plus cisplatin in patients with HER2-negative recurrent gastric cancer after S-1 adjuvant therapy or chemotherapy naïve advanced gastric cancer: A pooled analysis of HERBIS-2 (OGSG 1103) and HERBIS-4A (OGSG 1105) trials.
Authors: Jin Matsuyama, Hisato Kawakami, Kazumasa Fujitani, Yusuke Akamaru, Shigeyuki Tamura, Shunji Endo, Yutaka Kimura, Youichi Makari, Takao Tamura, Naotoshi Sugimoto, Daisuke Sakai, Toshimasa Tsujinaka, Masahiro Goto, Yukinori Kurokawa, Toshio Shimokawa, Taroh Satoh
Journal: Journal of Clinical Oncology (2020)

379 Background: HERBIS-2 trial was a phase II trial where S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) were compared in recurrent HER2 negative gastric cancer (GC) patients with recurrence free interval (RFI) by S-1containing adjuvant of ≥ 6 months. We performed pooled analyses of HERBIS-2 and HERBIS-4A trial where SP and XP were compared in chemotherapy-naive HER2 negative gastric cancer (GC) patients as these trials being identical. Methods: Both HERBIS-2 and 4A trials, patients were randomly assigned to receive either SP (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/ m 2 on day 8, every 5 weeks) or XP (capecitabine 1,000 mg/m 2 twice daily for 14 days plus cisplatin 80 mg/m 2 on day 1, every 3 weeks). Results: In HERBIS-2 which was s closed early due to poor accrual, SP ( N= 10) tended to confer a better overall survival (OS) compared with XP ( N= 9)[18.7 (95%CI, 2.8 – NR) months vs.13.4 (95% CI, 5.2 – 31.3) months; hazard ratio (HR), 0.443 (95% CI, 0.156 – 1.258); P= .117]. In pooled analyses with HERBIS-2 and 4A, SP ( N= 50) vs. XP ( N = 51) showed longer progression free survival (6.4 vs.5.1 months; HR, 0.666; P= .62), OS (14.8 vs. 10.6 months; HR, 0.695; P= .099), time to treatment failure (4.6 vs. 3.6 months; HR, 0.668; P= .045), and higher disease control rate (86.4% vs. 68.1%, P= .149). Subgroup analysis revealed that OS benefit in SP arm compared to XP arm was significantly larger if the patient having PS of 0 [HR, 0.554 (95% CI, 0.309 to 0.959; interaction P= .035], or the tumor arising from upper area of stomach [HR, 0.266 (95% CI, 0.070 to 0.731); interaction P= .013] or harboring differentiated type cancer [HR, 0.433 (95% CI, 0.228 to 0.822); interaction P= .011], respectively. Conclusions: Our data suggest the use of SP in the 1 st line setting in HER2 negative advanced or recurrent GC with RFI by S-1 adjuvant of ≥ 6 months. Pooled analyses further suggest SP as the standard 1 st line chemotherapy for HER2 negative AGC irrespective of S-1 adjuvant in Japan. Clinical trial information: UMIN000006755/UMIN000006105.
Feasibility of 6 months of maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck (HNC).
Authors: Christiane Matuschek, Edwin Boelke, Jürgen Debus, Claus Belka, Stephan Welz, Michael Henke, Thomas Wendt, Christian Ohmann, Petra Stegmaier, Michael Bamberg, Thomas Wiegel, Volker Budach, Joerg Schipper, Wilfried Budach
Journal: Journal of Clinical Oncology (2012)

e16033 Background: The prognosis for HNC patients (pts) after surgical treatment and adjuvant chemoradiation (CRT) is unsatisfactory in case of close resection margin &lt;5 mm (CM) or extra capsular extent at the lymph nodes (ECE). Therefore we conducted a multicenter phase II study to investigate the toxicity and efficacy of adjuvant radiotherapy (RT) in combination with concurrent cisplatin, 5- fluorouracil (5FU), and cetuximab (CTX) followed by maintenance therapy with CTX for 6 months. Here, we present the preliminary results on feasibility and toxicity. Methods: HNC pts after primary surgery were eligible for the study, if a CM or ECE was detected. Cisplatin [20 mg/m2 d1-5 and d29-33] and 5-FU (CI 600 mg/m 2 d1-d5 + d29-33) were given concurrently to postoperative RT using an integrated boost IMRT-technique (1.8/2.0/2.2Gy QD) to a total dose of 61.6 Gy. CTX started 7 days prior CRT with a loading dose of 400 mg/m 2 followed by weekly CTX (250 mg/m2) during CRT. Maintenance CTX started after completion of CRT plus CTX with 500 mg/m² every 2 weeks over a 6-month period. Results: 55 of 80 planned pts (46 male, 9 female, mean age 55.6, range 29-70 years) have finished CRT, 50 are evaluable for toxicity. Concurrent CRT plus CTX was associated with grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reaction outside the radiation portals in 46%, 28%, and 14% of pts, respectively. One toxic death occurred (peritonitis at day 57). CTX was terminated in 10% of all pts (allergic reactions) after the first application. In 22% of all pts CTX was discontinued during the last 2 weeks or at the end of CRT. Of those pts embarking on maintenance therapy, 80% were still on CTX after 3 and 63% after 5 months. 48% completed 6 months maintenance therapy. Conclusions: Adjuvant CRT in combination with CTX followed by maintenance CTX is feasible with toxicity in the expected range. Compliance to maintenance CTX was satisfactory during the first 3-5 months.
Minimizing reflux after peroral endoscopic myotomy: navigational pocket technique
Authors: Rintaro Hashimoto, Kenneth J. Chang
Journal: Endoscopy (2020)

Peroral endoscopic myotomy (POEM) is an established and effective treatment for patients with achalasia. However, post-POEM reflux is a common complication [1]. POEM with posterior approach enables better scope positioning and has similar efficacy to the anterior approach [2]. The gastric oblique muscles are contiguous with the circular muscles of the distal esophagus and important for preventing gastroesophageal reflux [3]. These muscle fibers are routinely encountered and easily disrupted on the posterior approach, which may increase the frequency of post-POEM reflux [4]. The oblique muscle fibers are most sparse along the lesser curvature [3]. A POEM strategy that minimizes disruption of the oblique muscles while maintaining the posterior approach may attenuate post-POEM reflux.
Single institutional analysis of resectable pancreatic cancer.
Authors: Jeff Wiisanen, Patrick Navin, Moustafa El Khatib, William R Bamlet, Sean P. Cleary, Robert R. McWilliams, Mark J. Truty, Thanh P. Ho, Mindy L. Hartgers, Siddhartha Yadav, Amit Mahipal
Journal: Journal of Clinical Oncology (2020)

706 Background: In recent years, there has been a shift towards neo-adjuvant treatment (NAT) of non-metastatic pancreas cancer in the hopes of improving negative margin rate, lymph node negativity, recurrence and survival. Even patients deemed resectable based on NCCN criteria are receiving NAT but data for these patients remains limited. This current study evaluated the outcomes of patients diagnosed with resectable pancreatic adenocarcinoma. Methods: Patients were retrospectively identified through the Mayo Clinic, Rochester SPORE pancreatic cancer registry as well as search of the electronic medical record via Advanced Cohort Explorer from May 2011 to 2016. Baseline demographics, tumor characteristics, treatments rendered, and outcomes were collected. Variables were analyzed for association with recurrence from time of surgery and survival from time of diagnosis using Kaplan-Meier curves and Cox proportional hazards regression. Results: A total of 520 patients with resectable pancreatic adenocarcinoma were identified. 72 patients received upfront chemotherapy with 44 (61.1%) proceeding to surgical resection. 62 patients received upfront chemotherapy followed by radiation with 33 (53.2%) proceeding to surgical resection. 12 patients received upfront radiation alone with 7 (58.3%) proceeding to surgical resection. 374 patients did not receive any NAT with 293 (78.3%) proceeding to surgical resection. In total, 377 (72.5%) went to resection. Median time to recurrence from surgery was 27.7 months vs. 21.7 months for NAT and upfront resection, respectively (HR 0.87, 95% CI 0.60-1.72, p = 0.48). Median overall survival from diagnosis for those receiving NAT was 40.6 months vs. 24.7 months for those receiving upfront resection (HR 0.62, 95% CI 0.41-0.92, p = 0.02). Conclusions: This study shows an approximate 16 month improvement in overall survival of patients receiving upfront NAT for resectable pancreatic adenocarcinoma. This might be due to a better selection of patients. It also highlights that not all patients with resectable cancer undergo resection. Further studies are warranted to identify why resectable patients are not proceeding to resection and which specific NAT approaches benefit patients the most.
Clinical outcomes of FOLFIRINOX and gemcitabine-nab-paclitaxel for metastatic pancreatic cancer in the real-world setting.
Authors: Fabio Franco, Jose Ignacio Martin Valades, David Marrupe, Juan Carlos Camara, David Gutierrez Abad, Ana Lopez-Alfonso, Brezo Martinez-Amores, Ana Leon, Mar Perez, Ignacio Juez, Alicia Hurtado, Ana Ruiz-Casado
Journal: Journal of Clinical Oncology (2020)

656 Background: Randomized clinical trials have established new chemotherapeutic standards of care for metastatic pancreatic cancer, namely FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GNP) after demonstrating a significant and relevant increase of overall survival. However, there are some important uncertainties regarding how many patients are candidate to each of the two new regimens in the real life and how is the pattern of use in the elderly population. Methods: This is a retrospective study. Departments of Pharmacy of 7 Spanish hospitals generated the listings of patients (pts) treated in first line with these new regimens (FFX or GNP). Non-metastatic patients were excluded. An exploratory analysis was performed in the elderly population. Results: From Jan 2012 to Dec 2017, a total of 119 pts (M/F 58/42 %) were treated. Med age 63 y (38-83 y), 99% adenocarcinoma. 40% located in the head of pancreas. ECOG 87% 0-1. 89% had liver mets. In the 1st line 49.6% were treated with FFX and 50.4% with GNP. 53% of the pts could receive a 2nd line (82% after FFX 75% after GNP). The median OS was 12 months with no statistically significant differences between both regimens (12,7m for FFX vs 10,2 m for GNP). Elevated Ca 19.9 levels and Neutrophil-Lymphocyte ratio (NLR) increased the risk of death. Patients who received both regimens in first/second line had a median OS longer than 15 months whichever the sequence. 32 patients (27%) were older than 70 yo. 13 (41%) were treated with FFX and 19 (59%) with GNP. The median OS for patients older than 70 was 9.5m versus 12.3m for patients younger than 70. Conclusions: In our setting the use of FFX and GNP for treating metastatic pancreatic cancer is quite similar. Superiority could not be demonstrated for any of the schemes in first-line. Overall survival was determined by basal Ca 19.9 and NLR. Patients receiving both regimens (FFX or GNP) in first/second line whichever the sequence, exhibited the best survival rates. In our series elderly patients had poor survival rates.
Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction
Authors: Augusto A. Litonjua, Vincent J. Carey, Nancy Laranjo, Benjamin J. Stubbs, Hooman Mirzakhani, George T. O’Connor, Megan Sandel, Avraham Beigelman, Leonard B. Bacharier, Robert S. Zeiger, Michael Schatz, Bruce W. Hollis, Scott T. Weiss
Journal: New England Journal of Medicine (2020)

We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze.
NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).
Authors: Jennifer J. Knox, Mairead Geraldine McNamara, Lipika Goyal, Mark Doherty, Christoph Springfeld, Joon Oh Park, Aimery De Gramont, Helena Verdaguer, John Raymond Zalcberg, Daniel H. Palmer, T.R. Jeffry Evans, Paul J. Ross, Juan W. Valle
Journal: Journal of Clinical Oncology (2020)

TPS602 Background: Biliary tract cancer (BTC) carries a poor prognosis and has no approved treatments. Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1 st -line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome key cancer resistance mechanisms associated with gemcitabine. Promising signs of efficacy have been observed with single-agent NUC-1031 in a Phase I study in advanced solid tumors (Blagden et al 2018) and in the Phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg/m 2 on days 1 and 8 of a 21-day cycle for the 1 st -line treatment of advanced BTC. Of 14 patients (pts) enrolled in 2 cohorts (NUC-1031: 625 mg/m 2 and 725 mg/m 2 ), 1 pt achieved a CR and 6 pts achieved PR, giving an unconfirmed ORR of 50% and representing an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D of NUC-1031 in combination with cisplatin is 725 mg/m 2 . The tolerability profile together with robust efficacy signals suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global Phase III study. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus GemCis for 1 st -line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m 2 NUC-1031 + 25 mg/m 2 cisplatin or 1000 mg/m 2 gemcitabine + 25 mg/m 2 cisplatin, administered on days 1 and 8 of a 21-day cycle. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.