tbuckley/cabot-search huggingface dataset:
Effect of baseline medications on response to immunotherapy in hepatocellular carcinoma.
Authors: Tomi Jun, Sirish Dharmapuri, Thomas Urban Marron, Max W. Sung, Celina Ang
Journal: Journal of Clinical Oncology (2020)

484 Background: Immunotherapy (IO) response rates in advanced hepatocellular carcinoma (HCC) are less than 20%. The microbiome has been shown to mediate IO response in experimental models, and clinical studies have observed that antibiotics, especially prior to IO initiation, are associated with reduced IO response. We reasoned that commonly prescribed antacid medications, such as proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs), which are known to influence the microbiome, may also influence IO response. Methods: This is a retrospective chart review-based study of 95 patients with advanced HCC treated with IO at a single academic medical center. The primary outcome was overall survival (OS). The secondary outcome was overall response rate (ORR). The primary predictors were antibiotic or antacid exposure in the 60 days prior to IO. A secondary predictor was antibiotic or antacid exposure in the 30 days prior to IO. Results: The cohort was predominantly male (84%), was racially diverse (31% White, 23% Black, 23% Asian, 13% Hispanic), and had a median age of 65 years. There were 49 deaths with a median follow up of 0.96 years. The most common underlying liver diseases were HCV (49%), HBV (31%), and NASH (11%). The majority of patients had cirrhosis (80%), with a median Child Pugh score of 6. Within 60 days before IO, 25 patients received antibiotics, 40 received PPIs and 5 received H2RAs. Most patients receiving antibiotics also received a PPI (92%). The median duration of antibiotics was 5 days. Neither antibiotic nor antacid exposure within 60 or 30 days prior to IO was significantly correlated with OS in univariate or multivariate analyses, nor were they correlated with ORR. Conclusions: No significant associations between baseline exposure to antibiotics and antibiotics and OS or ORR were identified in this single-institution study. Larger observational studies or mechanistic studies are needed to clarify interactions between medications, the microbiome, and IO response. [Table: see text]
DNA-damage repair deficiency (dDDR) and response to nanoliposomal irinotecan (nal-IRI) in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Sameeha Rau, Andrea P. Espejo Freire, Gretel Terrero, Manisha Jayandra Patel, Benjamin Woodress Rush, Caio Max Sao Pedro Rocha Lima, Peter Joel Hosein
Journal: Journal of Clinical Oncology (2020)

731 Background: Chemotherapy is the standard of care for patients with mPDAC but there are no biomarkers to aid in treatment selection. Nal-IRI with 5-fluorouracil/folinic acid (FUFA) improves survival over FUFA in the second-line treatment of mPDAC. Nal-IRI is a topoisomerase inhibitor and its action produces DNA damage leading to cell death. We hypothesize that tumors with dDDR, a process that is altered in a subset of patients with PDAC, may be more sensitive to the effects of nal-IRI. Methods: Utilizing the IRB-approved pancreas cancer databases at the University of Miami and Wake Forest University, we identified patients with mPDAC treated with nal-IRI and FUFA who had germline and/or somatic mutation testing. We conducted a retrospective chart review to extract demographic and clinical characteristics including treatments received, response, and survival. Results: Among 31 patients identified, the median age was 66y and 47% were female. Nine patients had a DDR mutation; 6 germline and 3 somatic. Median progression-free survival (PFS) in patients with any germline or somatic DDR mutation was 3.2m vs 3.9m for those without (log-rank p = 0.7). When restricted to germline DDR mutations only, the median PFS was not reached with germline dDDR vs 4m for those without (log-rank p = 0.22). Presence of dDDR was associated with a higher clinical benefit rate (CBR = partial response + stable disease); a DDR mutation was present in 36% of patients who showed clinical benefit vs 15% in those without clinical benefit (p = 0.21). Conclusions: DDR mutations appear to define a subset of patients with mPDAC who may be more sensitive to nal-IRI and FUFA. The PFS and CBR were numerically but not statistically superior, especially in patients with germline DDR mutations. Larger data sets and longer follow-up are needed to confirm this trend.
HRT: doctors demand talks with government to tackle “chaos” of shortages
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Years of hormone replacement therapy (HRT) shortages in the UK have left patients, clinicians, and pharmacists distressed, according to three representative bodies.

In response to the shortages, caused by ongoing manufacturing and supply problems, the British Menopause Society, the Faculty of Sexual and Reproductive Healthcare (FSRH), and the Royal College of Obstetricians and Gynaecologists (RCOG) have written to the health secretary Matt Hancock, calling for a new working group to tackle the problem.

The bodies …
The Use of Benralizumab in the Treatment of Near-Fatal Asthma: A New Approach
Authors: Sanjay Ramakrishnan, James R. Camp, Bavithra Vijayakumar, Frances M. Hardinge, Matilda L. Downs, Richard E. K. Russell, Ian D. Pavord, Mona Bafadhel
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Abstract 16129: Apolipoprotein E (apoe) Gene Polymorphisms Modulate Postprandial Lipemia in Response to a Mediterranean Dietary Intervention: Cordioprev Study
Authors: Francisco Gomez-Delgado, Jose David Torres-Peña, Isabel Perez-Corral, Elena Yubero-Serrano, Antonio Camargo, Andreea Corina, Juan Francisco Alcala-Diaz, Jose Lopez-Miranda, Pablo Perez-Martinez, Javier Delgado-Lista
Journal: Circulation (2018)

Introduction: Exacerbated postprandial lipemia (ePPL) is considered as an emergent risk factor related with cardiovascular disease (CVD). Several factors among which stand out diet composition and ...
The impact of mismatch repair status to the preoperative staging of local colon cancer: Implications for clinical management.
Authors: Torben Hansen, Emilie Erbs, Natacha D. Trabjerg, Soeren Rafael Rafaelsen, Jan Lindebjerg, Lars Henrik Jensen
Journal: Journal of Clinical Oncology (2020)

16 Background: Computed tomography (CT) scan is standard in preoperative local staging of colon cancer. Tumours with a deficient mismatch repair (dMMR) system are characterised by unique clinical and pathophysiologic aspects that may impact on the accuracy of the preoperative CT staging. Methods: Data from the Danish Colorectal Cancer Group national clinical database addressing a cohort of patients operated for stage I-III colon cancer in 2010-15 was analysed. The analyses of MMR status had been conducted consecutively through means of immunohistochemistry. All CT scans were blindly assessed by a certified radiologist. Results: Data from 590 patients, operated at a specialised cancer centre were available for analyses. A dMMR phenotype was detected in 135 (22.9%) of the patients. The overall correlation of the clinical and pathological T-category was significant for both groups. There was inferior correlation between cN and pN (p &gt; 0.05) in pMMR cancers with a higher degree of over-staging assessed by CT-scan, compared to a significant correlation between cN and pN stage in pMMR cancers (p &lt; 0.01). Of the 91 dMMR tumours judged node-positive by the preoperative CT scan, 59 (64.8%) showed no sign of metastatic involvement at the postoperative assessment. Conclusions: The accuracy of preoperative CT lymph node staging in colon cancer seems to differ depending on MMR status and may impact the clinical management including the neoadjuvant setting.
Prognostic value of modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ration (NLR) after curative resection for gastric cancer.
Authors: Yusuke Shimodaira, Sachie Koike, Yusuke Takahashi, Masao Okada, Kaori Hayashibara, Yasushi Sekino, Masahiro Sakon, Manabu Takata, Hitoshi Seki, Yasuhiro Munakata
Journal: Journal of Clinical Oncology (2020)

295 Background: Several biomarkers based on serum chemistry have been reported to be associated with the prognosis of several types of cancers. This retrospective study aimed to investigate the prognostic value of preoperative mGPS and NLR after curative resection for gastric cancer. Methods: A total of 295 patients who underwent curative gastrectomy for primary gastric cancer at our institution from January 2013 to December 2017 were enrolled in this study. The mGPS was calculated by CRP and Alb using standard thresholds ( &gt; 0.5 mg/dL for CRP and &lt; 3.5 g/dL for Alb). The NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. The survival curves of patients stratified by each parameter were plotted by the Kaplan-Meier method and compared by log-rank test. Multivariate Cox proportional hazards regression models were used to select parameters independently correlated with prognosis. Results: The median follow-up time was 36.7 months, and 29 patients died during follow-up. The estimated 5-year survival rate was 83.1%. Results from the univariate analyses showed mGPS2 (CRP &gt; 0.5 mg/dL and Alb &lt; 3.5 g/dL) was associated with poor survival while NLR and NLRc was not (P &lt; 0.001, P = 0.506, and P = 0.423, respectively). In the multivariate analyses, the mGPS2 was identified as an independent predictive factor for OS in gastric cancer patients after curative resection (HR: 2.624; 95% CI: 1.058-6.505; P = 0.037). Conclusions: Preoperative mGPS2 was associated with worse survival after curative resection of gastric cancer patients. Based on our study, those with mPGS2 may be warranted to receive additional therapy or nutritional support to acquire better survival.
Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.
Authors: Katherine Anne Johnson, Philip Emmerich, Kristina A. Matkowskyj, Dustin A. Deming
Journal: Journal of Clinical Oncology (2020)

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p &lt; 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p &lt; 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.
A dual receptors-targeting and size-switchable “cluster bomb” co-loading chemotherapeutic and transient receptor potential ankyrin 1 (TRPA-1) inhibitor for treatment of triple negative breast cancer
Authors: Yashi Wang, Sheng Yin, Lin Mei, Yiliang Yang, Shanshan Xu, Xuan He, Mou Wang, Man Li, Zhirong Zhang, Qin He
Journal: Journal of Controlled Release (2020)
A prospective trial of elemental enteral feeding in patients with pancreatic cancer cachexia (PANCAX-1).
Authors: Andrew Eugene Hendifar, Gillian Gresham, Haesoo Kim, Michelle Guan, Jar-Yee Liu, Brian Minton, Diane Bhuiyan, Ruby Langeslay, Andre Rogatko, Jun Gong, Veronica Placencio-Hickok
Journal: Journal of Clinical Oncology (2020)

726 Background: Unintentional weight loss affecting &gt; 85% of pancreatic cancer (PC) patients contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Optimal treatment approaches have not been developed. We hypothesize that peptide-based enteral nutritional support in cachectic advanced PC patients, receiving palliative chemotherapy, results in improved weight, lean body mass (LBM), and hand-grip strength. Methods: Pancreatic adenocarcinoma patients with cachexia (&gt; 5% unintentional weight loss within the previous 6 months) were provided a jejunal tube peptide-based diet for 3 months. Primary outcome was weight stability (0.1kg/BMI unit decrease). Secondary outcomes included changes from baseline in LBM, bone mineral density (BMD), total body fat mass (BFM), handgrip strength, physical activity (Fitbit), and CA19-9 and CRP. Planned interim analysis was performed after 14 patients completed treatment. Results: From 31 consenting patients, 16 were evaluable for the primary outcome. Patients receiving enteral therapy were 39% male, median age 69 (Range: 41 to 89 years), and 74% ECOG 1. A summary of change in outcomes at 3 months from baseline is shown in Table. The primary endpoint of weight stability in 10 (62.5%) patients was met, thus completing study. Overall survival was 6.5 months (n=31) and 9.9 months for evaluable patients (n=16). Weight stability was statistically associated with LBM (Pearson’s correlation: 0.87, p&lt;0.001), but not survival (HR: 0.94, 95% CI 0.32, 2.83, p=0.92). Conclusions: Peptide-based enteral feeding resulted in weight stability and improvements in lean body mass and physical function. Further randomized trials assessing nutritional support in advanced patients are warranted. NIH/NCATS Grant # UL1TR000124. Clinical trial information: NCT02400398 . [Table: see text]
Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): Pooled results from two phase III studies (REACH and REACH-2).
Authors: Masatoshi Kudo, Richard S. Finn, Manabu Morimoto, Kun-Ming Rau, Masafumi Ikeda, Chia-Jui Yen, Peter R. Galle, Josep M. Llovet, Bruno Daniele, Ho Yeong Lim, Kun Liang, Kenta Shinozaki, Chunxiao Wang, Reigetsu Yoshikawa, Paolo Abada, Ryan C. Widau, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2020)

549 Background: Intermediate-stage HCC, as defined as Barcelona Clinic Liver Cancer (BCLC) Stage B, is a heterogeneous disease in terms of liver function and tumor load. REACH (NCT01140347) and REACH-2 (NCT02435433) investigated ramucirumab (RAM) in patients (pts) with HCC after prior sorafenib (SOR), with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: All pts had HCC (BCLC stage C or B disease refractory/not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or Placebo (P) Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was performed. Prognosis of BCLC staging in overall survival (OS) was evaluated by multivariate Cox PH model (adjusted for baseline AFP and treatment (trt) arm); Trt effects in BCLC stage B and C by Cox PH model; median OS/PFS were estimated by Kaplan-Meier method. Objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), and adverse events (AEs) were also reported by BCLC. Liver function was assessed at baseline and prior to each trt with the Albumin-Bilirubin (ALBI) linear predictor. Results: Baseline characteristics were generally balanced between trt arms in each BCLC stage. BCLC staging trended as an independent prognosis factor for OS [B v C; HR = 0.756 (0.546, 1.046)]. A consistent trt benefit for RAM v P was observed across staging (Table). Grade ≥3 AEs were consistent with observations from both individual studies; hypertension was the most frequent grade ≥3 AE. No difference in liver function, as measured by ALBI, was observed between trt arms in either BCLC stage. Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit irrespective of BCLC stage. RAM was well tolerated and did not alter liver function compared to P. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]
Advances in the Evolutionary Understanding of MHC Polymorphism
Authors: Jacek Radwan, Wiesław Babik, Jim Kaufman, Tobias L. Lenz, Jamie Winternitz
Journal: Trends in Genetics (2020)

Proteins encoded by the classical major histocompatibility complex (MHC) genes incite the vertebrate adaptive immune response by presenting peptide antigens on the cell surface. Here, we review mechanisms explaining landmark features of these genes: extreme polymorphism, excess of nonsynonymous changes in peptide-binding domains, and long gene genealogies. Recent studies provide evidence that these features may arise due to pathogens evolving ways to evade immune response guided by the locally common MHC alleles. However, complexities of selection on MHC genes are simultaneously being revealed that need to be incorporated into existing theory. These include pathogen-driven selection for antigen-binding breadth and expansion of the MHC gene family, associated autoimmunity trade-offs, hitchhiking of deleterious mutations linked to the MHC, geographic subdivision, and adaptive introgression.
A phase II study of durvalumab (MEDI4736) (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Benny Johnson, Jane V Thomas, Arvind Dasari, Kanwal Pratap Singh Raghav, Eduardo Vilar Sanchez, Bryan K. Kee, Cathy Eng, Christine Megerdichian Parseghian, Van K. Morris, Robert A. Wolff, Imad Shureiqi, Scott Kopetz, Michael J. Overman
Journal: Journal of Clinical Oncology (2020)

152 Background: Monotherapy with immune checkpoint blockade (ICB) is ineffective for patients (pts) with MSS mCRC. Novel approaches to modulate the tumor microenvironment (TME) are needed. Here, we investigate whether the combination of trametinib (T) with durvalumab (D) can alter the immune TME by successfully priming and activating T-cells. Methods: An open-label, single center phase II trial with primary endpoint of immune-related response rate for T+D in refractory MSS mCRC pts (NCT03428126). T is 2mg/day orally starting 1 week prior to D, which is given 1500mg intravenously every 4 weeks. Dose de-escalation strategy performed to identify maximum tolerated dose (MTD). Simon 2-stage design utilized with plans to enroll 29 pts into the first stage, requiring response in 2 or more pts to proceed to stage 2 (n = 15). Results: Demographics for 29 treated pts: 48% female, median age 48 years (range 28-75), and median prior therapies was 2 (range 1-5). No grade (G) 4 treatment-related adverse events (TRAE). The most common G3 TRAE included autoimmune hepatitis (14%) and acneiform rash (10%). G1/2 TRAE included acneiform rash (69%), fatigue (24%) and anemia (21%). No fatal TRAE and 4 pts discontinued treatment due to TRAE. 1 of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an ORR of 3.4%. This pt had an ATM E221fs*14 mutation. 7 pts had stable disease (SD) with median time to progression (TTP) of 5.4 mo (range 3.9-9.3 mo). 1 pt remains on active therapy with SD ( &gt; 10 mo). 5 pts (1 PR, 4 SD) demonstrated decrease in total CEA ng/mL (best percentage reduction: 94%, 95%, 42%, 34% and 21.6% respectively). Median TTP for the entire cohort was 3.2 mo (range 1.1-9.3 mo). Consensus molecular subtypes (CMS) were performed on the primary CRC in 23 pts: 12 CMS2, 2 CMS3, and 9 CMS4. 4 SD pts were CMS2, 1 SD pt was CMS4 and the CMS status of the pt with a PR was unknown. Conclusions: The combination of T+D did not meet efficacy criteria to proceed to the second stage of the study. Analysis of 15 paired on-treatment biopsies is ongoing and will be presented. Utilization of CMS characterization in mCRC clinical trials is feasible and may provide an improved biological understanding of treatment activity. Clinical trial information: NCT03428126.
Comparative efficacy of second-line treatments for advanced hepatocellular carcinoma: A network meta-analysis.
Authors: Neehar Parikh, Alexander Marshall, Keith D. Huff, Rachel Savidge, Keith A. Betts, Jinlin Song, Jing Zhao, Muhan Yuan, Richard D. Kim
Journal: Journal of Clinical Oncology (2020)

545 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is often advanced at the time of diagnosis. This study conducted a network meta-analysis (NMA) to assess the comparative efficacy of second-line (2L) immunotherapy and tyrosine kinase inhibitors (TKIs) without biomarker selection for advanced HCC (aHCC), including nivolumab (NIVO) + ipilimumab (IPI), cabozantinib (CABO), regorafenib (REG), and placebo (PBO). Methods: Randomized trials for CABO and REG (CELESTIAL and RESORCE) were identified through a literature review and included in the NMA. NIVO (1mg/kg) + IPI (3mg/kg) (from CHECKMATE-040) was linked into the evidence network through a matching-adjusted indirect comparison (MAIC) vs. the PBO arm of the CELESTIAL trial. The CELESTIAL trial was chosen due to the similar study design and patient population as the CHECKMATE-040 trial. Clinically relevant characteristics were matched, which included age, sex, Barcelona clinic liver cancer stage, Eastern Cooperative Oncology Group status, α-fetoprotein level, and prior treatments. The NMA included CELESTIAL, RESORCE, and the MAIC results. Investigator-assessed ORR and hazard ratio (HR) of overall survival (OS) were compared in the NMA. Results: After matching the baseline characteristics in the MAIC, the ORR of NIVO+IPI was 30.4% and the HR vs. PBO was 0.35. In the NMA, NIVO+IPI had significantly higher ORR (31.2%) compared to TKIs and PBO (REG: 4.8%; CABO: 4.2%; PBO: 1.0%, differences are presented in Table). In addition, NIVO+IPI was associated with significantly prolonged OS vs. TKIs and PBO (HR: NIVO+IPI vs. REG: 0.56; NIVO+IPI vs. CABO: 0.46; NIVO+IPI vs. PBO: 0.35). Conclusions: The NMA showed that NIVO+IPI was associated with significantly higher ORR and prolonged OS compared to TKIs as 2L treatments for aHCC. [Table: see text]