tbuckley/cabot-search huggingface dataset:
Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
Authors: Lijun Liao, Kai Markus Schneider, Eric J C Galvez, Mick Frissen, Hanns-Ulrich Marschall, Huan Su, Maximilian Hatting, Annika Wahlström, Johannes Haybaeck, Philip Puchas, Antje Mohs, Jin Peng, Ina Bergheim, Anika Nier, Julia Hennings, Johanna Reißing, Henning W Zimmermann, Thomas Longerich, Till Strowig, Christian Liedtke, Francisco J Cubero, Christian Trautwein
Journal: Gut (2019)

There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC).Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments.Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO).
Authors: Thomas Powles, James M. G. Larkin, Poulam Patel, Begoña Pérez-Valderrama, Alejo Rodriguez-Vida, Hilary Glen, Fiona Thistlethwaite, Christy Ralph, Gopalakrishnan Srinivasan, Maria Jose Mendez-Vidal, Wing-Kin Liu, Aaron Prendergast, Laura Vosper, Kelly Mousa, Cristina Suárez
Journal: Journal of Clinical Oncology (2019)

545 Background: Metastatic papillary renal cancer (PRC) has poor outcomes and there is need for new treatments. There is a strong rationale for investigating MET and PD-L1 inhibition in this disease. In this study, we investigate savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Methods: This single arm phase I/II trial explored durvalumab and savolitinib at starting doses of 1500mg Q4W and 600mg OD respectively, with a 4wk savolitinib run-in. Treatment naïve or previously treated patients with metastatic PRC were included. Response rate (RR) (RECIST v1.1) was the primary endpoint. Progression free survival (PFS), tolerability (CTCAE v4) and overall survival were secondary endpoints. Biomarkers were explored from archived tissue. Results: Dose escalation work identified a dose of durvalumab of 1500mg Q4W and savolitinib 600mg OD to take forward to phase II. Between Jan 2017 and Jul 2018, 42 patients were enrolled at this dose. 1 patient did not receive study treatment. The following analyses were performed on the remaining 41 patients. 12% of patients did not receive the combination (3 PD, 1 death, 1 PS deterioration). The median follow up was 8.9 months (95% CI: 6.9-10.9 months). IMDC good, intermediate and poor risk disease occurred in 29% (n=12), 63% (n=26), and 7% (n=3) patients respectively. Overall RR was 27% (11/41), while median PFS was 3.3 months (95% CI: 1.5-NR months). RR and median PFS in the previously untreated cohort (N=28) were 29% (8/28) and 12.0 months (95% CI: 1.5-NR months) respectively. Grade 3/4 toxicity occurred in 15 patients. Discontinuation for toxicity occurred in 3 patients, all due to liver toxicities. Biomarker work including PD-L1 and MET expression will be included in the analysis. Conclusions: The combination of savolitinib and durvalumab appears safe and associated with clinical activity in PRC. Clinical trial information: NCT02819596.
Quality of life (QOL) as a predictor of clinical outcome in patients (pts) with head and neck cancer (HNC).
Authors: Arun Sendilnathan, Ayham Deeb, Robert Bach, Rishi Agarwal, Changchun Xie, Farah Kaval, Courtney Robinson, Kelly Guthrie, Sue Dupuy, Trisha Michel Wise-Draper, John Charles Morris, Michelle Lynn Mierzwa, Bradley Joseph Huth, Kevin P. Redmond, William Barrett, Yash Patil, Keith Wilson, David J. Adelstein, Keith Casper, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2015)

e17088 Background: HNC pts suffer from symptoms of their disease and side effects of standard treatments that can significantly impact their QOL. There is paucity of data regarding impact of symptoms and QOL on subsequent oncologic and functional outcome in patients treated on standard therapy. Methods: We utilized self-reported EORTC-30 and EORTC-35 questionnaires, which are validated for cancer pts and HNC pts respectively. These include cancer specific and general symptoms (SX), function (FX), and global health status (GHX)measures. Pts were requested to fill out surveys at baseline, 3, 6, and 12 months (mos). Nutritional, functional and oncologic outcome were collected through a retrospective chart review. Results: A total of 161 pts were evaluated; predominantly male (70%), white (91%), squamous cell (86%), good PS(0-1) (75%). Median age 59 y (26-92). T3-T4 ( 36%), N1-3( 42%), p16 +( 24%). Common sites were oral cavity (36%), oropharynx (26%), larynx/hypopharynx (21%). Radiation and chemotherapy delivered in 70% and 36% pts. FX and SX scales along with nutrition, social contact, and total EORTC-35 score worsened by 3 mos (p ≤ 0.05). GHX worsened by 6 mos ( p 0.03) Early recurrence correlated with worse SX scale, FX, or nutrition scores at baseline ( p ≤ 0.01) or GHX at 6 mos ( p 0.00) . Poor nutrition, poor eating skills, and low total EORTC-35 score predicted early recurrence ( HR 2.5, 2.2, 1.9, respectively, p ≤ 0.04) Higher mortality also correlated with worse baseline SX scale, nutrition, and overall EORTC 30 measure ( p ≤ 0.04) By 3 mos poor SX predicted mortality ( HR = 4.46,p = 0.04) In addition, baseline poor score for nutrition, swallow, social eating, social contact and overall EORTC-35, all predicted future feeding tube dependence. (p ≤ 0.04) Interestingly, physician estimated performance status did not correlate with patient reported QOL. Conclusions: QOL and nutrition status assessment is feasible during routine outpatient HNC pts visit. These measures are able to predict pts at risk for feeding tube dependence, early recurrence and death. Additional studies need to address if early interventions to improve QOL and nutrition status will translate into better oncologic outcome.
Ovarian carcinosarcoma share similar molecular profile as ovarian serous carcinoma but not endometrial carcinosarcoma.
Authors: Haider Mahdi, Joanne Xiu, Sandeep K. Reddy, Robert Debernardo
Journal: Journal of Clinical Oncology (2015)

5560 Background: Ovarian carcinosarcomas (OCS) are rare and aggressive malignancies with limited treatment options. It is unclear if this uncommon type of cancer shares similar molecular changes as endometrial carcinosarcoma (ECS) or serous ovarian carcinoma (SOC). We compared the molecular profile of a cohort of OCS to that of SOC and ECS to explore the potential overlap in treatment paradigms. Methods: 110 OCS, 141 ECS and 1587 SOC were evaluated using a commercial multiplatform profiling service (CARIS Life Sciences, Phoenix, AZ). Specific testing performed included a combination of gene sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH or FISH). Results: TP53 was the most commonly mutated gene in all three malignancies with 76.4 % of OCS, 68.8 % of ECS and 69% of SOC. Alteration of PI3K/AKT/mTOR and MAPK pathways were noted to be similar in OCS and SOC but was less frequently altered than ECS including mutation in PIK3CA (7.6% and 2.3% vs. 22.2%, p < 0.001), FBXW7 (0% and 0.6% vs.12.1%, p < 0.001), PTEN (3.7% and 0.8% vs. 12%, p < 0.001) and KRAS (5.2% and 5.0% vs. 13.5%, p < 0.001). For homologous recombination pathway, SOC and ECS were more likely to have BRCA1 (20% and 18% vs. 9%) and BRCA 2 mutations (18% and 27% vs. 12%) than OCS. However, the differences were not statistically significant. No difference in alteration of RB, NOTCH, angiogenesis and FGFR pathways was noted among the three cohorts. Estrogen (14.6% and 25.1% vs. 53.1%, p < 0.001) and androgen receptors (18.8% and 12.2% vs. 32.4%, p < 0.001) were expressed less frequently in OCS and ECS than SOC respectively. On the other hand, expression of progesterone receptors was more frequent in in OCS and SOC than ECS (26.5% and 30.5% vs. 20.9%, p < 0.001). Conclusions: While ovarian carcinosarcoma and uterine carcinosarcoma are histologically similar, we reveal that OCS share molecular changes similar to that of SOC. Both OCS and SOC have significantly lower activity of PI3K/AKT/mTOR, MAPK pathways and higher progesterone receptors expression than ECS. Treatment with regimens that are active in ovarian serous could be considered when treating patients with ovarian carcinosarcoma.
Influence of strong antioxidant supplementation on the level of oxidative DNA damage/oxidative stress in head and neck cancer patients undergoing radiotherapy.
Authors: Pawel Szymanski, Piotr Blaszczyk, Anna Bak, Radoslaw Sitarz, Katarzyna Indrak, Krzysztof Roszkowski
Journal: Journal of Clinical Oncology (2015)

e17004 Background: Because of the many controversies concerning the consumption of antioxidants during the treatment of cancer, herein we decided to ascertain whether the supplementation of strong antioxidant (Beta vulgaris) in irradiated head and neck cancer patients would influence parameters which describe oxidative stress/DNA damage and the clinical effects of therapy. Methods: 41 patients with head and neck cancer (T3-4 N1 M0) were divided into two subgroups: I/supplementation chips from beetroot (n = 19) and II/control group (n = 22). Patients were treated by radiotherapy: Total dose of 70 Gy/35 fractions. Acute reactions were measured using the Dische scale. Total survival times in individual subgroup patients were estimated. Spot urine samples and blood were collected before the treatment and supplementation, 7 days and 14 days after beginning the radiotherapy and 1 day after the last irradiation. Daily excretion of 8-oxoGua and 8-oxodG in urine and the level of 8-oxodG in leukocytes of peripheral blood of patients were analyzed. All the previously mentioned modifications were analyzed using techniques involving high performance liquid chromatography/electrochemical detection (HPLC/EC) or HPLC/gas chromatography and mass spectroscopy (GC-MS). Results: The supplementation with Beta vulgaris during radiotherapy did not have any influence on the values of the urinary oxidative stress markers 8-oxo-Gua and 8-oxo-dG or on the amount of 8-oxo-dG in cellular DNA at particular time points of measurement, in the examined subgroups of patients. Results also suggest that with irradiated patients supplementation of Beta vulgaris does not worsen survival times (36.8 vs 26.1 months; p = 0.37), intensification of acute radiation reactions is reduced. Conclusions: Definite confirmation of the presented results, being a part of the implemented project, requires recruitment of a much more numerous group of patients and a long follow-up, which would allow for correlating the results of the analyses with clinical effects. An attractive group, indicated in such studies, includes patients with malignancies, treated radically with a good prognosis.
Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System
Authors: Nicolas Massaly, Bryan A. Copits, Adrianne R. Wilson-Poe, Lucia Hipólito, Tamara Markovic, Hye Jean Yoon, Shiwei Liu, Marie C. Walicki, Dionnet L. Bhatti, Sunil Sirohi, Amanda Klaas, Brendan M. Walker, Rachael Neve, Catherine M. Cahill, Kooresh I. Shoghi, Robert W. Gereau, Jordan G. McCall, Ream Al-Hasani, Michael R. Bruchas, Jose A. Morón
Journal: Neuron (2019)
Preoperative trial of neoadjuvant abiraterone plus or minus cabazitaxel: Early results.
Authors: Jaime Omar Herrera-Caceres, Hanan Goldberg, Aaron Richard Hansen, Srikala S. Sridhar, Robert James Hamilton, Antonio Finelli, Alexandre Zlotta, Anthony M. Joshua, Neil Eric Fleshner
Journal: Journal of Clinical Oncology (2019)

98 Background: High-risk prostate cancer (PC) has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy, prior to RP has yet to be defined. The Princess Margaret Cancer Centres’ ACDC study investigates the application of agents used for castration resistant PC in the neoadjuvant setting by comparing the use of abiraterone (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel (CA) prior to RP in 76 high-risk patients. Herein, we report early results and protocol modifications. Methods: This phase II trial will randomize patients to two treatment arms: Arm A (AA/P + LHRH + CA 25 mg/m 2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective is to compare the pathological complete response (CR) between the treatment arms. We present the RP outcomes and safety data for the first 13 participants. Results: Out of 13 randomized participants, 10 completed study procedures and underwent RP. One participant (Arm B) completed study drug treatment, but opted for radiation therapy, while 2 participants (both in Arm B) were discontinued due to hepatoxicity. At RP, 2 participants exhibited CR (1 in each group) and an additional 3 patients exhibited near CR (less than 5% tumor volume). The Table demonstrates patient characteristics, pathologic results and Grade 3 adverse events rates. Of note, 2 patients (both in CA arm) developed post-operative thrombo-embolic events post RP and two experienced febrile neutropenia. Conclusions: Early findings indicate significant tumor response with 50% of patients exhibiting CR or near CR. Reduction in dosage of Cabazitaxel to 20 mg/m2 as well as need for extended post-operative thromboembolic prophylaxis have been implemented. ACDC early outcomes. [Table: see text]
TOP2A-based prognostication in triple negative breast cancer and correlation with basal phenotype.
Authors: Benjamin C. Calhoun, Christopher Lanigan, Brian Rubin, Karen C Mrazeck, Gabriela Rosa, Michael Barnes, Sherry Dean, Bonnie LaFleur
Journal: Journal of Clinical Oncology (2015)

1098 Background: Patients with triple-negative breast cancer (TNBC) are ineligible for endocrine and HER2-trageted therapy and remain at high risk for relapse after treatment. Most TNBC are basal-like (BL) but recent studies identified additional subtypes of TNBC. Immunohistochemistry (IHC) for various markers has been reported to correlate with clinical outcomes, but many studies are based on relatively limited IHC panels. We applied a large IHC-based marker set in a TNBC cohort to evaluate their potential for prognostic and predictive modeling Methods: Archived tissue samples from a prospectively maintained registry of 145 TNBC patients (mean age 57.2 years; median follow up 3.8 years) were used to investigate associations between marker expression and time-to-progression. Progression was defined as local, regional, or distant recurrence. IHC for EGFR, HMWCK (high molecular weight cytokeratin), TOP2A, BCL2, and AR was performed. Simple data imputation was used for missing protein data as complete case analysis (no missing data) resulted in a sample size of 82. Positive was defined as > 10% for AR and > 0% (any staining) for EGFR and HMWCK.TOP2A and bcl2 staining was recorded in 5% increments and optimal cut-points relative to time-to-progression were used to define positivity and negativity. Cox proportional hazard models were used to examine associations between expression and progression. A random forest classification tree approach was used to identify potential co-expression between proteins Results: TNBC expressed HMWCK, EGFR, AR, TOP2A, and BLC2 in 76.6, 86.2, 13.1, 58.6, and 12.4% of cases, respectively. With an optimal derived cutoff of 40%, TOP2A expression was associated with shorter time to progression (HR = 2.01; p = 0.059) while the expression of BCL2 (optimal cut-off: 60%) was not (HR = 0.18; p = 0.087). Sixty-seven (46.2%) cases showed co-expression of HMWCK, EGFR, and TOP2A. TOP2A was consistently correlated with HMWCK (66% agreement in positivity) and c-MET (43% agreement in positivity) per the classification tree Conclusions: Results indicate a potential correlation of TOP2A with the BL phenotype of TNBC and provide a rationale for further investigation into tailored therapy for TNBC.
Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC).
Authors: Shilpa Gupta, Guru Sonpavde, Petros Grivas, Andrea B. Apolo, Elizabeth R. Plimack, Thomas W. Flaig, Noah M. Hahn, Arjun Vasant Balar, Dean F. Bajorin, Matt D. Galsky, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2019)

451 Background: Patients (pts) with mUC who are ineligible to receive cisplatin have limited treatment options. Pembrolizumab and atezolizumab were approved as 1 st -line therapy in these pts, but their use is now restricted in pts with tumors with high PD-L1 expression, or platinum-ineligible. “Platinum-ineligible” mUC (cisplatin and carboplatin ineligible), remains undefined, and a clear definition is needed for determining treatment and clinical trial eligibility. Methods: We surveyed 56 genitourinary medical oncologists in the US using an online tool consisting of several clinical parameters (Round 1) and based on the responses, we refined the survey (Round 2) and then compiled the responses to generate a consensus definition. Results: Responses were received from 43/56 (77%) of those surveyed in Round 1 and 44/56 (78.5%) in Round 2. Based on the results shown in the Table, we recommend 1 of the following 5 parameters be used to define "platinum-ineligible” mUC: ECOG PS &gt; 3; Cr Cl &lt; 30 ml/min; Peripheral neuropathy &gt; 3; NYHA Heart Failure Class &gt; 3; ECOG PS 2 and Cr Cl &lt; 30 ml/min. Conclusions: “Platinum-ineligible” mUC is a new and undefined category with a substantial definition variability among investigators. Results from consensus definition are proposed for standardization of this mUC category. [Table: see text]
The PAF1c Subunit Cdc73 Is Essential for Hematopoiesis and Displays Differential Gene Regulation in MLL-AF9 Driven Leukemia
Authors: Nirmalya SAHA, James Ropa, Lili Chen, Hsiang-Yu Hu, Maria Mysliwski, Ann Friedman, Ivan Maillard, Andrew G. Muntean
Journal: Blood (2018)
Incidence of hypocalcemia in patients with castration-resistant prostate cancer treated with denosumab: Data from a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab administered every four weeks (q4w) versus every 12 weeks (q12w)—SAKK 96/12 (REDUSE).
Authors: Silke Gillessen, Roger Anton Fredy Von Moos, Stefanie Hayoz, Hanne Hawle, Richard Cathomas, Christian Alexander Rothermundt, Sandro Anchisi, Andreas Mueller, Tobias Wehrhahn, Henning Burmeister, Susanna Stoll, Anna Llado, Markus M. Borner, Augusto Pedrazzini, Urs Sebastian Huber-Tribolet, Pierre Oliver Bohanes, Ralph C. Winterhalder, Andrea Corinne Fuhrer, Corinne Schaer, Arnoud J. Templeton
Journal: Journal of Clinical Oncology (2019)

139 Background: DN given q4w has shown superiority in delaying skeletal related events over q4w zoledronic acid (ZA). Recently it has been demonstrated that ZA q12w is non-inferior to ZA q4w. The objective of REDUSE is to show non-inferiority for DN q12w versus q4w in terms of SSE. Here we present an interim analysis for the secondary endpoint HC. Methods: Patients (pts) with castration resistant prostate cancer (planned N=690) were randomized 1:1 to DN q4w (Arm A) vs q12w (Arm B) after a 16 week induction phase with application q4w. All pts received vitamin D (ViD) 400 U and calcium (Ca) 500 mg daily. Measurement of corrected serum-Ca was mandatory before each DN injection. This interim analysis was performed after 3.5 years of accrual. Men who received ≥ 1 dose of DN were considered evaluable. Results: 383 pts were evaluable. HC occurred in 28.7% during the first 16 weeks (DN q4w for all pts) and 30.2% afterwards. After the induction phase HC occurred in 40.2% in Arm A and in 20.3% in Arm B. Grade 3 (2.1%) and 4 (1.1%) HC were rare, most frequently occurring in the first 16 weeks. After 1 year of treatment, the incidence of HC was lower in both arms (A: 30.8%, B: 18.7%). A clinically relevant difference for HC was noted between the two arms after the induction phase (table). Conclusions: In our trial nearly 30% of all men treated with DN experienced HC in the q4w induction phase despite mandatory supplementation of calcium and ViD and measurement of Ca. This rate was considerably higher than reported in the registration trials of DN (13%). After induction treatment the incidence of HC is considerably lower in the q12w arm compared to q4w. This suggests that DN given q12w has a more favorable long time toxicity profile (HC) compared to DN q4w. Change in HC grade after week 16 (week 1 – 12: DN q4w Arm A+B), thereafter q4w in Arm A and q12w in Arm B. Clinical trial information: NCT02051218. [Table: see text]