tbuckley/cabot-search huggingface dataset:
Bicalutamide with or without metformin for biochemical recurrence in prostate cancer patients (BIMET-1).
Authors: Marijo Bilusic, Matthew R. Zibelman, Pooja Ghatalia, Susan Wroblewski, Ravi Amrit Madan, Fatima Karzai, William L. Dahut, James L. Gulley, Elizabeth R. Plimack, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2020)

85 Background: Metformin (MET) may play a role as an anti-proliferative and anti-carcinogenic agent. Epidemiological studies have demonstrated that MET is associated with decreased prostate cancer (PCa) incidence, including decreased PCa specific mortality in diabetic men with PCa. Preclinical studies have shown synergistic effect of MET with bicalutamide, thus prompting this clinical trial evaluating the combination (NCT02614859). Methods: This was an open label, randomized, phase II trial of pts with biochemically recurrent PCa, PSA doubling time 3-9 months, normal testosterone, and BMI &gt; 25. Pts were randomized (2:1) either to MET 1000 mg twice daily orally or observation for initial 8 weeks. Bicalutamide 50 mg orally daily was added to both arms after 8 weeks. Total duration of treatment was 32 weeks. The primary objective was to determine number of pts with undetectable PSA ( &lt; 0.2 ng/mL) at the end of study with key secondary objectives of evaluating PSA declines of ≥ 85%, PSA responses to MET alone and safety. An early stopping rule for futility was set at 39 pts, but due to slow accrual, an unplanned interim analysis was undertaken. Results: 28 patients were randomized between December 2015 and September 2019. Treatment was well tolerated with no dose reductions or treatment discontinuation. No Grade 3 treatment-related adverse events were observed. Conclusions: PSA responses were seen in 50% pts with MET monotherapy after 8 weeks. Although well tolerated, there was no difference in PSA at 32 weeks between the two arms. The trial will be stopped early due to poor accrual and inability to achieve its primary endpoint. Ongoing larger studies of MET in PCa (STAMPEDE) will define it’s utility in prostate cancer. Clinical trial information: NCT02614859. [Table: see text]
Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity
Authors: Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano
Journal: Journal of Clinical Investigation (2020)

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate RORγt. Specific loss of PRMT5 in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the CD4+ Th cell life cycle and invariant NK (iNK) T cell development and CD8+ T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORγt agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.
Sixth Immunotherapy of Cancer conference (ITOC): advances and perspectives—a meeting report
Authors: Catarina Pinto, Michael Bergmann, Daria Briukhovetska, Volkmar Nuessler, Mario Sznol, Michael von Bergwelt-Baildon, Sebastian Kobold
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunotherapy has moved to the forefront of cancer treatment, illustrated by the accelerating pace of novel therapy approvals. In this complex environment, scientists rely on cutting edge conferences to stay informed. The Immunotherapy of Cancer (ITOC) conference was established jointly with the Society of the Immunotherapy of Cancer to bring the European researchers together. In its sixth edition, the ITOC conference has recently been held in Vienna, Austria.
BCG shortage: Reassessing the clinical viability of Bacillus Calmette-Guerin (BCG) after reconstitution.
Authors: Nathan Brooks, Supriya Nagaraju, Justin T. Matulay, Xiang-Yang Han, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2020)

534 Background: To address the current worldwide shortage of BCG, the AUA and SUO recommend reducing the dose to 1/3rd vial and enabling 3 patients to be treated in one setting. The manufacturer states that BCG must be used immediately after reconstitution, despite literature in the bacteriological world suggesting that M. Bovis might be viable for longer than a few hours. Herein we sought to study the viability of BCG after re-constitution at time points relevant to clinical practice. Methods: TICE BCG from separate lots was reconstituted per the manufacturer’s guidance and stored at 4 °C without light exposure. At predetermined time points, BCG was inoculated on Selective Middlebrook 7H11 agar in triplicate and incubated at 37°C with 5% CO2. M. smegmatis served as a positive control and un-inoculated media was incubated for 2 weeks as a negative control. CFUs were assessed between 3 and 4 weeks from plating. Acid-fast staining confirmed the presence of BCG. Data was analyzed as the mean of replicated experiments and compared to the reference (Time 0) using Student’s T-tests. Results: No significant difference in CFUs was observed for BCG between 0 and 8 hours after reconstitution (Table). Colony forming units significantly declined starting 24 hours after reconstitution, though the magnitude of this difference was less than 10 fold (which falls within the range of CFUs listed for the vial by manufacturer). Viability remained constant for both lots analyzed. Conclusions: Given the recurrent shortages of BCG, split dosing may become a clinical necessity. This often presents logistic quandaries since the manufacturer recommends each vial must be used within 2 hours. We have shown that the viability of TICE BCG is unaltered at least 8 hours after reconstitution and only begins to decline at 24 hours after reconstitution. This should allow pharmacists and physicians administering BCG more leeway in scheduling patients for split dose therapy. [Table: see text]
<i>FGFR2/3</i> genomic alterations (GA) in cell-free (cf)DNA from patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Lesli Ann Kiedrowski, Roby Antony Thomas, Nicholas J. Vogelzang, Guru Sonpavde, Sumati Gupta, Theodore Stewart Gourdin, Bishoy Morris Faltas, Rebecca Nagy, Richard B. Lanman, Petros Grivas
Journal: Journal of Clinical Oncology (2020)

565 Background: Erdafitinib is approved in pts with aUC with relevant FGFR2/3 GA. BLC2001 trials in pts with activating FGFR2/3 mutations reported 40% ORR to erdafitinib (49% for those with single nucleotide variants [SNVs] and 16% with fusions), 39% stable disease rate, and potentially reduced response to anti-PD-L1. Genomic profiling with plasma cfDNA next-generation sequencing (NGS) is increasingly used to identify targetable GA in pts with advanced solid tumors and presents a minimally invasive option for identification of FGFR2/3 GA. Methods: Genomic data from the Guardant360 database were queried from clinical results released from 10/19/15 - 8/28/19 for clinical samples submitted with diagnoses of aUC or related diagnoses (e.g. bladder cancer, renal pelvis carcinoma). All assays included FGFR2/3 fusions and complete sequencing of all critical exons harboring sensitizing FGFR2/3 SNVs. Results: 1349 results from 1096 unique pts were identified. Somatic GA were identified in 1192 tests (88%) from 997 pts. Fusions and/or nonsynonymous SNVs in FGFR2/3 were identified in 201 pts (20%); 141 pts (14%) had at least one characterized activating FGFR2/3 GA. Of 34 pts (3.4%) with FGFR3 fusions, partners included TACC3 (32), JAKMIP1 (1), and TNIP2 (1). Overall, most SNVs identified in FGFR3 were predicted to be activating (103/125, 82%) whereas in FGFR2 most were variants of uncertain significance (VUS; 62/72, 86%). Of 89 unique variants (59 in FGFR2, 30 in FGFR3), 19 (21%) were activating mutations (7 in FGFR2, 12 in FGFR3). The most common activating SNVs in FGFR3 were S249C (58 pts), Y373C (20) and R248C (10), and in FGFR2 was N549K (4). VUS in both genes were individually uncommon (no VUS recurring in &gt;3 pts). Median copy number-adjusted clonality of SNVs in FGFR3 was higher than those in FGFR2 (0.80 vs 0.20); this remained true when limiting to only characterized activating mutations (0.84 vs 0.17). Conclusions: cfDNA NGS analysis identifies fusions and a broad spectrum of SNVs in FGFR2/3, including heterogeneous subclonal mutations, at a rate similar to reported tissue testing. cfDNA is a minimally invasive option for pts with aUC to assess candidacy for erdafitinib and clinical trials.
The Molecular and Epigenetic Mechanisms of Innate Lymphoid Cells (ILCs) Memory and its Relevance for Asthma
Authors: Mukesh Verma, Lidia Michalec, Anand Sripada, Nathan Dyjack, Magdalena Gorska, Max Seibold, Brian O'Connor, Richard Martin
Journal: Journal of Allergy and Clinical Immunology (2020)
Long-term outcomes of patients with locally advanced bladder cancer that underwent intra-arterial chemotherapy with/without radiotherapy for organ preservation.
Authors: Tomohiro Matsuo, Yasuyoshi Miyata, Kensuke Mitsunari, Kojiro Ohba, Hideki Sakai
Journal: Journal of Clinical Oncology (2020)

574 Background: We previously reported efficacy and safety of intra-arterial chemotherapy with/without radiotherapy in patients with locally advanced bladder cancer. However, there was no data on long-term outcomes, such as organ preservation, subsequently metastasis, and survival of such therapy. In this study, we investigated outcomes of intra-arterial chemotherapy with/without radiotherapy in these patients for long term periods. Methods: In this study, we investigated 129 patients who treated with intra-vesical chemotherapy (n = 50) and intra-arterial chemotherapy and radiotherapy (n = 79). There was no significant difference on age at diagnosis, gender, grade, and T stage between these two groups. Mean/median follow up periods in intra-vesical chemotherapy (n = 50) and intra-arterial chemotherapy with radiotherapy was 86.5/101 and 107.7/122 months. Results: Rates of bladder preservation in intra-arterial therapy and intra-arterial therapy with radiotherapy are 66.0 and 82.3%, respectively (P = 0.035), and Kaplan-Meier survival curves showed that intra-arterial therapy with radiotherapy had better than intra-arterial therapy (P = 0.007). On the other hand, subsequently metastasis-free survival rates in intra-arterial therapy with radiotherapy was significantly better than those with intra-arterial therapy (P = 0.037). Regrading cause-specific survival, the survival period in intra-arterial therapy with radiotherapy was significantly better than that in intra-arterial therapy (P &lt; 0.001). In addition, even if radical cystectomy was performed, the survival rates after the operation in intra-arterial therapy with radiotherapy was significantly better than that in intra-arterial therapy (P = 0.002). There was no sever complication at late phase (over 5 years). Conclusions: Our results showed that intra-arterial therapy with radiotherapy showed better outcomes of bladder preservation, subsequently metastasis, and survival. In addition, in patients locally advanced bladder cancer received radical cystectomy, intra-arterial therapy with radiotherapy had better prognosis compared to intra-arterial therapy.
Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: Analysis of the STAR TOR registry.
Authors: Michael Moran, Marcus Hubbe, Michael Rink, Lothar Bergmann, Arne Strauss, Stephan Bernhardt, Marianne Schmid, Martin Boegemann, Katrin Schlack
Journal: Journal of Clinical Oncology (2020)

628 Background: Metastatic renal cell carcinoma (mRCC) treatment is partly informed by risk group. The two most commonly used prognostic models, the International Metastatic RCC Database Consortium (IMDC) and the Memorial Sloan-Kettering Cancer Center (MSKCC), stratify patients (pts) into favorable (0 risk factors [RFs]), intermediate (1–2 RFs) or high risk (≥3 RFs) groups. This study examined real-world outcomes according to IMDC and MSKCC RFs in sunitinib-treated pts with mRCC. Methods: Data were extracted on 19 June 2019 from a large, prospective German multicenter registry (STAR-TOR). Only pts with sufficient data for risk stratification by IMDC and MSKCC were included in this analysis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of RFs on survival was assessed using Cox’s regression analysis and the chi square test. Results: According to IMDC or MSKCC, 16.7% and 15.3%, 26.2% and 30.8%, 18.7% and 24.7%, and 38.5% and 29.2 of pts had 0, 1, 2 and ≥3 RFs, respectively. In IMDC intermediate pts, only &lt; 1 year diagnosis to therapy (24.8%) was the most common RF; in MSKCC intermediate pts, &lt; 1 year diagnosis to therapy with low hemoglobin (19.9%) were the most common. OS was not significantly different for pts with 0 vs 1 (p = 0.24), or 2 vs ≥3 (p = 0.16) IMDC RFs, but was significant according to MSKCC RFs (0 vs 1, p = 0.04; 2 vs ≥3, p &lt; 0.01). OS was significantly longer for pts with 1 vs 2 RFs for IMDC (p = 0.03) and MSKCC (p = 0.04), but PFS was not (IMDC, p = 0.29; MSKCC, p = 0.12). OS was significantly longer for 0 vs 2, 0 vs ≥3, and 1 vs ≥3 RFs for IMDC and MSKCC RFs (all comparisons, p &lt; 0.01). Similar results were observed for PFS with the exception of 0 vs 1 IMDC RF (p = 0.01). Conclusions: The intermediate risk group appears to be heterogeneous. OS for pts with 1 RF may align with the favorable risk group and pts with 2 RFs may align with the poor risk group.[Table: see text]
Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
Authors: Alisson C. Cardoso, Nicholas T. Lam, Jainy J. Savla, Yuji Nakada, Ana Helena M. Pereira, Abdallah Elnwasany, Ivan Menendez-Montes, Emily L. Ensley, Ursa Bezan Petric, Gaurav Sharma, A. Dean Sherry, Craig R. Malloy, Chalermchai Khemtong, Michael T. Kinter, Wilson Lek Wen Tan, Chukwuemeka G. Anene-Nzelu, Roger Sik-Yin Foo, Ngoc Uyen Nhi Nguyen, Shujuan Li, Mahmoud Salama Ahmed, Waleed M. Elhelaly, Salim Abdisalaam, Aroumougame Asaithamby, Chao Xing, Mohammed Kanchwala, Gonçalo Vale, Kaitlyn M. Eckert, Matthew A. Mitsche, Jeffrey G. McDonald, Joseph A. Hill, Linzhang Huang, Philip W. Shaul, Luke I. Szweda, Hesham A. Sadek
Journal: Nature Metabolism (2020)
Comparison of the performance of risk scoring systems for tumor bleeding in patients with inoperable gastric cancer
Authors: Young-Il Kim, Il Ju Choi, Jong Yeul Lee, Chan Gyoo Kim, Hark Kyun Kim, Young Lee Park
Journal: Endoscopy (2020)

Background The Glasgow – Blatchford bleeding score (GBS) and admission and full Rockall scores are widely used risk scoring systems to stratify risk and determine the need for intervention in patients with upper gastrointestinal bleeding. We evaluated the performance of these risk scoring systems in patients with gastric cancer and tumor bleeding. Methods This retrospective study included patients with inoperable gastric cancer who presented with tumor bleeding at the National Cancer Center, Korea, between 2001 and 2015. The GBS, and admission and full Rockall scores were calculated. Primary outcome was the performance of the risk scoring systems in predicting the need for urgent interventions (endoscopic therapy, transarterial embolization, and surgery). The risk factors associated with urgent intervention were analyzed. Results Of 357 patients with tumor bleeding, 118 (33.1 %; 116 endoscopic therapy, 2 trans-arterial embolization) required urgent intervention. The full Rockall score was better at predicting the need for urgent intervention (area under the receiver operating characteristic curve = 0.78; P &lt; 0.001) than the GBS (0.56) and admission Rockall score (0.56). Hemostatic intervention was not performed in patients with a full Rockall score ≤ 6 (103 patients, 28.9 %). On multivariate analysis, endoscopic stigmata of recent hemorrhage of Forrest classes Ia – IIb were significant factors associated with urgent intervention. Conclusions The full Rockall score was superior to the GBS and admission Rockall score in predicting the need for urgent intervention for tumor bleeding. Thus, endoscopic evaluation is required to determine the need for urgent intervention in patients with gastric cancer and tumor bleeding.
Relative Reductions in Attack Rate With Prophylactic Berotralstat (BCX7353) in Subjects with Hereditary Angioedema (HAE): Responder Analysis from the APeX-2 Study
Authors: William Lumry, Marcus Maurer, Bruce Zuraw, Aleena Banerji, Marc Riedl, Douglas Johnston, Emel Aygoren-Pursun, Joshua Jacobs, Richard Gower, H. James Wedner, Karl Sitz, Markus Magerl, Melanie Cornpropst, Jennifer Elder, Heather Iocca, Eniko Nagy, Sharon Murray, Philip Collis, William Sheridan, Sandra Christiansen
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 13387: LDL Reductions Below 70 mg/dL Enhance the Effects of a Statin, β-Blocker and RAS Inhibitors on Endothelial Nitric Oxide Bioavailability In Vitro
Authors: R. P Mason, Hazem Dawoud, Samuel C Sherratt, Tadeusz Malinski
Journal: Circulation (2018)

Introduction: In cardiovascular (CV) disease, endothelial cell (EC) dysfunction is evidenced by reduced nitric oxide (NO) bioavailability due to endothelial NO synthase (eNOS) uncoupling. Widely us...
Growth hormone upregulates ANGPTL4 mRNA and suppresses lipoprotein lipase via fatty acids: Randomized experiments in human individuals
Authors: Astrid Johannesson Hjelholt, Esben Søndergaard, Steen Bønløkke Pedersen, Niels Møller, Niels Jessen, Jens Otto L. Jørgensen
Journal: Metabolism (2020)
Patterns of use of chemotherapy with radiotherapy in the treatment of muscle-invasive bladder cancer: Data from the RAIDER randomized trial of adaptive radiotherapy.
Authors: Robert A. Huddart, Rebecca Lewis, Clare Griffin, Roberto Alonzi, Alison Jane Birtle, Ananya Choudhury, Joanne Cresswell, Farshad Foroudi, Shaista Hafeez, Ann Henry, Ben Hindson, Duncan McLaren, Anita Mitra, Ashok Nikapota, Omi Parikh, Yvonne L. Rimmer, Isabel Syndikus, Mohini Anna Varughese, Emma Hall
Journal: Journal of Clinical Oncology (2020)

503 Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Methods: RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Results: To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to &gt;90% of participants and some &lt;50%. Data on NAC and CRS use is available for 249 patients recruited to date is shown in table. Conclusions: In this ongoing clinical trial the majority of patients are receiving NAC and/or CRS. However, uptake is not universal with ~30% of patients not receiving low dose CRS, including some who have received NAC. Clinical trial information: 26779187. [Table: see text]
Multicenter retrospective analysis of patients with metastatic renal cell carcinoma (mRCC) and bone metastases treated with ipilimumab and nivolumab.
Authors: Kunal Desai, Landon Carter Brown, Wei Wei, Kimberly D. Allman, Allison Martin, Laura S. Wood, Shilpa Gupta, Timothy D. Gilligan, Jorge A. Garcia, Chester Kao, Emily Noelle Kinsey, Patrick Healy, Julie Kephart, Michael Roger Harrison, Sundhar Ramalingam, Andrew J. Armstrong, Daniel J. George, Brian I. Rini, Tian Zhang, Moshe Chaim Ornstein
Journal: Journal of Clinical Oncology (2020)

648 Background: Ipilimumab &amp; nivolumab (I+N) followed by nivolumab maintenance is approved as front-line therapy for intermediate and poor-risk metastatic renal cell carcinoma (mRCC). Bone metastases (BM) are present in up to 30% of mRCC patients (pts) and remain a clinical challenge. We present a multicenter experience of mRCC pts with BMs treated with I+N. Methods: Patients with mRCC and bone metastases treated with (I+N) at Duke Cancer Network and Cleveland Clinic were retrospectively reviewed. Patient demographics, tumor histology, IMDC risk stratification, RECIST-defined ORR and adverse events were collected. Fisher’s exact test was used to determine predictors of response (alpha 0.05). Results: Forty-eight pts with mRCC and radiographically confirmed BMs were included in the analysis: 81% male; median age 54 (range: 41-81); 77% clear cell histology; IMDC risk 17%/52%/31% favorable/intermediate/poor, respectively. I+N was used as first-line medical therapy in 63% of pts and ≥ second-line in remaining pts. Best response on I+N per RECIST criteria: objective response rate (ORR) 23% (0% CR); 23% stable disease (SD); 44% progressive disease (PD). Median duration of treatment was 64 days with 27% of pts still on I+N. PD was the most common reason for discontinuation (38%) followed by adverse events (19%). Nearly half of pts (48%) experienced at least one irAE attributed to I+N therapy. None of the factors examined above was significantly associated with response to treatment. Conclusions: I+N has clinical activity and is well tolerated in mRCC pts with bone metastases; however ORR in this population is lower than expected and 44% pts had PD as best response. Therefore, identifying prognostic factors &amp; improving novel therapies for this cohort of patients are priorities, given overall poorer outcomes in this population.