tbuckley/cabot-search huggingface dataset:
A phase II trial of durvalumab (MEDI4736) and tremelimumab in metastatic, nontransitional cell carcinoma of the urothelial tract.
Authors: Michal Sarfaty, Irina Ostrovnaya, Min Yuen Teo, Gopa Iyer, Chung-Han Lee, Vanessa Peters, Jennifer Durocher, Ashley Marie Regazzi, Asia S. McCoy, Grace Hettich, Hikmat Al-Ahmadie, Joshua Chaim, Dean F. Bajorin, Jonathan E. Rosenberg, Samuel Aaron Funt
Journal: Journal of Clinical Oncology (2020)

514 Background: Non-transitional cell carcinoma of the urothelial tract (non-TCC) includes several distinct histologies and is associated with a poor prognosis. Prospective data regarding management of patients with metastatic non-TCC is scarce. In this single-arm, phase II study, we assessed the activity and safety of durvalumab and tremelimumab in patients with metastatic non-TCC (NCT03430895). Methods: Eligible patients had unresectable/metastatic non-TCC with ECOG PS 0-1 regardless of prior therapy (except for patients with small cell carcinoma who must have progressed after chemotherapy). Patients received treatment with durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 cycles, then durvalumab 1500 mg IV Q4W for a total treatment duration of 12 months. The primary endpoint was overall response rate by RECIST 1.1. The study was planned as a Simon’s minimax two-stage design, with 13 patients planned for stage 1. If 1 or more responses were seen in stage 1, an additional 14 patients were planned to be accrued for a total of 27. Results: Thirteen patients were treated (median age 57 years; range, 33-76), including 7 (54%) with small cell carcinoma, 3 (23%) with squamous cell carcinoma, and 3 (23%) with adenocarcinoma. 11 patients (85%) had visceral metastases, and 6 patients (46%) had liver metastases. The study was terminated after stage 1 as no responses were seen; 11 patients (85%) had PD and 2 patients (15%) had SD as their best response. Median PFS was 1.8 months (95% CI 1.25, not reached [NR]) with a median follow-up of 6.8 months (range 4.3 – 18.1 months). Median OS was 6.43 months (95% CI 4.36, NR). Grade 3-4 treatment-related adverse events occurred in 31% of patients. Conclusions: In this poor prognosis cohort of patients with non-TCC, no responses were seen with durvalumab and tremelimumab. Immune correlative studies to help determine mechanisms of resistance will be presented. Novel therapeutic strategies are urgently needed for patients with metastatic non-TCC. Clinical trial information: NCT03430895.
Safety and outcome of stereotactic body radiation therapy (SBRT) with rectal hydrogel spacer for prostate cancer.
Authors: Lily Chen, Ang Gao, Bhavani S. Gannavarapu, Aurelie Garant, Neil Bipinchandra Desai, Michael Ryan Folkert, Chul Ahn, Claus G. Roehrborn, Yair Lotan, Robert D. Timmerman, Raquibul Hannan
Journal: Journal of Clinical Oncology (2020)

76 Background: Ultra-hypofractionated radiotherapy delivered using stereotactic body radiotherapy (SBRT) is a cost-effective treatment for localized prostate cancer. Optimal dosing remains unclear, as commonly used 30-40Gy/5fx regimens appear to overestimate hypofractionation’s control benefits. Here, we report the largest experience of 45Gy/5Fx of SBRT for prostate cancer patients treated with hydrogel peri-rectal spacer (‘hydrogel’). Methods: An IRB-approved retrospective protocol was used to conduct a registry search identifying all patients with prostate cancer who received 45Gy/5Fx between 2015-2019 with hydrogel. Genitourinary (GU) and gastrointestinal (GI) toxicities were defined using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. The ASTRO-Phoenix failure definition of Nadir+2 ng/mL was used for biochemical failure. Results: We analyzed 250 low (9.2%), intermediate (85.2%), and high-risk (5.6%) prostate cancer patients with a median follow-up of 9.9 months (range: 0-45.7 months). Acute GU and GI grade ≥ II toxicities were noted in 15.2% and 7.2% of patients, respectively. Late GU grade II and III toxicities occurred in 24.0% and 1.2% of patients, respectively, while late GI grade II and III toxicities occurred in 4.0% and 0.4% of patients, respectively. In patients (N=44) with follow-up &gt;2 years, late GU and GI grade III toxicities occurred in 4.55% and 2.27% of patients, respectively. A significant correlation was noted for acute GI and GU toxicity predicting the respective late GI and GU toxicity (p-value &lt; 0.001 for both). Physician-reported Grade ≥ II new onset erectile dysfunction was 17.2%. A gradual decline in prostate-specific antigen with a mean nadir of 0.04 (95% CI: [0.018, 0.067]) at 36 months was noted. The actuarial freedom from biochemical failure was 96.33% at 3 years. Overall survival was 94.09% at 3 years with no deaths attributed to prostate cancer. Conclusions: SBRT treatment of 45Gy/5Fx with hydrogel is well tolerated with GU/GI toxicities comparable to those reported for conventional fractionation. Although short, the 3-year biochemical control rate is encouraging. Longer follow-up and prospective evaluation are warranted.
Pollen Food Allergy Syndrome in Black and White Children with Food Allergies in the FORWARD Study
Authors: Susan Fox, Aame Andy-Nweye, Mahboobeh Mahdavinia, Mary Tobin, Perry Catlin, Annika Chura, Amal Assa'ad, Adam Robinson, Iman Abdikarim, Amaziah Coleman, Hemant Sharma, Jacqueline Pongracic, Olivia Negris, Jialing Jiang, Lucy Bilaver, Christopher Warren, Jamie Fierstein, Pamela Newmark, Alexandria Bozen, Ruchi Gupta
Journal: Journal of Allergy and Clinical Immunology (2020)
High risk of microscopic colitis after <i>Campylobacter concisus</i> infection: population-based cohort study
Authors: Hans Linde Nielsen, Michael Dalager-Pedersen, Henrik Nielsen
Journal: Gut (2020)

Objective Microscopic colitis (MC) encompasses the two histopathological distinct entities of collagenous colitis (CC) and lymphocytic colitis (LC). In this Danish population-based cohort study, we examined the risk of MC following stool culture with Campylobacter concisus , C. jejuni , non-typhoidal Salmonella or a culture-negative stool test. Design We identified patients with a first-time positive stool culture with C. concisus , C. jejuni , non-typhoidal Salmonella or negative stool test, from 2009 through 2013 in North Denmark Region, Denmark, and matched each with 10 population comparisons. All subjects were followed up until 1 March 2018 using Systematised Nomenclature of Medicine codes from The Danish Pathology Register for incident diagnoses of CC and LC. We computed risk and adjusted HRs with 95% CIs for MC among patients and comparisons. Results We identified 962 patients with C. concisus , 1725 with C. jejuni , 446 with Salmonella and 11 825 patients with culture-negative stools. The MC risk and HR versus comparisons were high for patients with C. concisus (risk 6.2%, HR 32.4 (95% CI 18.9 to 55.6)), less for C. jejuni (risk 0.6%, HR 3.7 (95% CI 1.8 to 7.7)), low for Salmonella (risk 0.4%, HR 2.2 (95% CI 0.5 to 10.8)) and for patients with negative stool testing (risk 3.3%, HR 19.6 (95% CI 16.4 to 23.4)). After exclusion of the first year of follow-up, the HRs were 9.3 (95% CI 4.1 to 20.1), 2.2 (95% CI 0.9 to 5.4), 1.3 (95% CI 0.2 to 11.1) and 5.6 (95% CI 4.6 to 7.2), respectively. Conclusion A high risk of MC was observed following C. concisus in stools. Further studies are needed to elucidate any underlying biological mechanisms.
Abstract 14149: Trends in Community Acquired and Health Care Associated Infective Endocarditis: A 21-Year Statewide Study
Authors: Abel E Moreyra, Sasha-ann East, Mihir Trivedi, Stavros Zinonos, John B Kostis, Nora M Cosgrove, Javier Cabrera, William J Kostis
Journal: Circulation (2018)

Hypothesis: Changes in guidelines have not altered the incidence of infective endocarditis (IE). However, the profile of the microorganisms causing IE has changed. Methods: Using the Myocardial Inf...
How to become a neurosurgeon
Authors: Jacqui Wise
Journal: BMJ (2020)

Neurosurgery involves the assessment, diagnosis, and surgical management of disorders of the nervous system.A career in neurosurgery is demanding but very rewarding.The first step to becoming a neurosurgeon is to complete a medical degree followed by two years of foundation training.During this time, it's important to try to get the right exposure and experience, including, if possible, getting involved in research or audit.Try to find a consultant neurosurgeon to be your mentor.Towards the end of foundation training, applications for neurosurgical training posts can be made.In the UK this process is hosted by Yorkshire and the Humber Deanery. 1 All applicants have to sit the multi-specialty recruitment assessment (MSRA)-a computer based assessment designed to test knowledge and skills as well as professional capabilities and decision making.Applications are made through Oriel online recruitment. 2 Applications usually open in November with shortlisting, MSRA, and interviews occurring in the following January.Offers tend to be made in March.
The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle invasive bladder cancer: A single-arm prospective study.
Authors: Hiroaki Matsumoto, Kazuhiro Nagao, Sho Ozawa, Masahiro Samoto, Junichi Mori, Ryo Inoue, Yoshiaki Yamamoto, Seiji Yano, Hiroshi Hirata, Tomoyuki Shimabukuro, Hideyasu Matsuyama
Journal: Journal of Clinical Oncology (2020)

516 Background: Radical cystectomy is still the standard treatment for muscle-invasive bladder cancer (MIBC), while the patients with MIBC are not always appropriate candidates due to multiple comorbidities. We establish novel treatment strategy by trimodal treatment. Methods: The regimen was gemcitabine 300 mg/m 2 , and cisplatin 30mg/m 2 in day 1 and concomitant irradiation 2Gy/Fr, 5 fraction per week. Irradiation was administered to whole pelvis up to 30Gy, then boost to true pelvis until total 48Gy to 54Gy. Extensive transurethral resection (TURBT) was performed and we confirmed pathological stage ≥T2. TURBT was also performed after chemoradiotherapy to evaluate the pathological response to treatment. This study was approved in our institutional review board (ID: H23-89) and the information was opened on UMIN (ID: UMIN000006363). We analyzed their treatment efficacy and survival. Results: The patients were 29 men and 9 women, median age was 76.5 y.o. and median follow up was 23 months (1 - 112). Clinical stage T2, T3, T4, N1 and N2 were 23, 10, 5, 4, 2 cases, respectively. The 2- and 5-year metastatic-free survival (MFS), bladder-recurrence free survival (bRFS), cancer-specific survival (CSS), and overall survival (OS) rates after treatment were 91.7 and 84.0%, 59.7 and 42.6%, 87.3 and 87.3%, and 87.3 and 81.8%, respectively. Salvage cystectomy was performed 3 patients and they were still alive. CR rate was 78.9% and overall response rate was 92.1%. cT stage and valiant histology was not associated with treatment response. The patients achieved CR had significant good prognosis in CSS (p=0.0149) and OS (p=0.0149) compared with non-responders. In cox hazard model, CR achievement was significant prognostic factors for OS (p =0.0015, HR 6.804e+26, 95% CI 56.94-1.631e+86). Patients were able to receive 3 to 5 cycle GC radiation and any grade 3 or more adverse event was 7 (18.4%) cases. no treatment related death was recorded. Conclusions: In selected patients, GC radiation for MIBC may provide good oncological outcomes as bladder preservation strategy.
Phase II trial of definitive radiotherapy with leuprolide and enzalutamide in high-risk prostate cancer.
Authors: Claire Marie de la Calle, Albert Chang, Ghezal Rashid, Anthony C. Wong, Alice Choi, Felix Y Feng, Alexander R. Gottschalk, Paul Lawrence Menzel, Peter Carroll, Hao Gia Nguyen
Journal: Journal of Clinical Oncology (2020)

323 Background: Adding enzalutamide to standard LHRH agonist and primary radiation therapy may improve the outcomes in patients with high-risk prostate cancer. Methods: All patients met at least 2 of the following criteria: stage cT3a/b, PSA≥20 ng/mL, Gleason Grade 8-10, ≥33% core involvement on biopsy; or had pelvic lymph node involvement ≥1cm on CT or MRI. All patients were started on 24 months of leuprolide and enzalutamide and then underwent 5 weeks of IMRT (whole pelvis, 45Gy total) followed by a brachytherapy boost. PSA, Testosterone (T) and basic labs were followed during and after treatment. Primary outcome was to assess the safety, tolerability, and feasibility of the protocol and PSA complete response (PSA-CR, defined as PSA nadir ≤0.3). Secondary outcomes included: time to biochemical recurrence (BCR) and progression free survival (PFS). Results: 16 patients were enrolled, 2 were not eligible and 3 withdrew before starting treatment. Mean age at enrollment was 68.6 years (SD 9.4). Median follow up time was 28.27 months (IQR 27.3 – 29.1 months). Median time to PSA-CR was 4.20 months (IQR 3.47 – 4.87 months). Currently all patients still have PSA-CR (Table), and none have BCR per ASTRO Phoenix criteria. All-cause, any grade adverse events (AE) were reported in all 11 (100%) patients with 4 (36.4%) experiencing grade 3 AE. One (9.09%) treatment related serious AE (seizure) occurred. There were no grade 5 AE (death related to AE). 4 subjects stopped treatment early due to: seizure, myalgias, hematuria and social reasons. Most patients however were able to complete the 24 months of leuprolide and enzalutamide: median treatment duration was 24.0 months (IQR 12.1 – 24.0 months). Conclusions: Most patients were able to tolerate and complete the entire 24 months of treatment as originally planned. Currently no patients have met criteria for PSA recurrence. Will plan to follow up patients until month 36 to help determine true BCR rates and PFS. Clinical trial information: NCT02508636. [Table: see text]
<i>Notes from the Field:</i> Characteristics of Million Hearts Hypertension Control Champions, 2012–2019
Authors: Matthew D. Ritchey, Judy Hannan, Hilary K. Wall, Mary G. George, Laurence S. Sperling
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

The Million Hearts Hypertension Control Champions, a national recognition program, demonstrates that achieving high hypertension control rates is possible across a range of health care settings and among patient populations at high risk for having uncontrolled hypertension.
Platelet RNA as Pan-Tumor Biomarker for Cancer Detection
Authors: Thomas Wurdinger, Sjors G.J.G. In ‘t Veld, Myron G. Best
Journal: Cancer Research (2020)

Blood-based liquid biopsies are considered a screening approach for early cancer detection. Sequencing technologies enable in-depth analyses of nucleic acids, including mutant cell-free (cf) DNA in the plasma. However, in the blood of patients with early-stage cancer the detection level of mutant cfDNA is relatively low, and complicated by the natural presence of noncancer cfDNA mutants attributed to aging-related processes. Consequently, analysis of methylated cfDNA patterns and alternative approaches such as tumor-educated platelets are gaining traction for the detection of early-stage tumors. Here, we dissect the use of platelet RNA as a potential biomarker for the development of early-stage, pan-cancer blood tests.
Physician Prescribing Patterns and Risk of Future Long‐Term Opioid Use Among Patients With Rheumatoid Arthritis: A Prospective Observational Cohort Study
Authors: Yvonne C. Lee, Bing Lu, Hongshu Guan, Jeffrey D. Greenberg, Joel Kremer, Daniel H. Solomon
Journal: Arthritis & Rheumatology (2020)

To identify the extent to which opioid prescribing rates for patients with rheumatoid arthritis (RA) vary in the US and to determine the implications of baseline opioid prescribing rates on the probability of future long-term opioid use.We identified patients with RA from physicians who contributed ≥10 patients within the first 12 months of participation in the Corrona RA Registry. The baseline opioid prescribing rate was calculated by dividing the number of patients with RA reporting opioid use during the first 12 months by the number of patients with RA providing data that year. To estimate odds ratios (ORs) for long-term opioid use, we used generalized linear mixed models.During the follow-up period, long-term opioid use was reported by 7.0% (163 of 2,322) of patients of physicians with a very low rate of opioid prescribing (referent) compared to 6.8% (153 of 2,254) of patients of physicians with a low prescribing rate, 12.5% (294 of 2,352) of patients of physicians with a moderate prescribing rate, and 12.7% (307 of 2,409) of patients of physicians with a high prescribing rate. The OR for long-term opioid use after the baseline period was 1.16 (95% confidence interval [95% CI] 0.79-1.70) for patients of low-intensity prescribing physicians, 1.89 (95% CI 1.27-2.82) for patients of moderate-intensity prescribing physicians, and 2.01 (95% CI 1.43-2.83) for patients of high-intensity prescribing physicians, compared to very low-intensity prescribing physicians.Rates of opioid prescriptions vary widely. Our findings indicate that baseline opioid prescribing rates are a strong predictor of whether a patient will become a long-term opioid user in the future, after controlling for patient characteristics.
Faecal microbial transplantation in IBS: ready for prime time?
Authors: Giovanni Barbara, Gianluca Ianiro
Journal: Gut (2020)

The urge of deciphering the secrets of gut microbiota has pervaded merely all fields of medicine, including that of functional GI disorders, now called disorders of gut brain interaction (DGBI).1 The concept that gut microbiota could contribute to symptom generation in DGBI, particularly in IBS is not new. Dysbiosis, small intestinal bacterial overgrowth and bacterial fermentation of foods have been suspected for a long time, although never demonstrated with certainty due to methodological limitations.1 Nonetheless, convincing indirect evidence links microorganisms and microbiota to IBS. Indeed, a bout of infection gastroenteritis leads to the development of IBS in 1 in 10 subjects, the so-called postinfection IBS,2 and disruption of the gut ecosystem with systemic antibiotics increases the risk of IBS.3 With the advent of next-generation sequencing technology and bioinformatics, altered microbiota profiles could be finally detected in patients with IBS compared with healthy individuals.1 However, the disappointment that a unifying microbiological hypothesis did not hold true in all patients was just around the corner.4 In addition, the dilemma if the described microbiota changes are consequence rather than cause of gut dysfunction has never been resolved.1 While rigorous mechanistic studies have yet provided a clear rationale for therapeutic intervention, scientists have been tempted to take shortcuts and point directly to microbiota modulation. In IBS, this approach has been somewhat rewarding. Dietary manipulation reducing fermentable substrates for the microbiota (ie, low-FODMAP diets), downregulation of pathobionts and upregulation of beneficial bacteria (eg, lactobacilli and bifidobacteria) with non-absorbable antibiotics or the use of probiotics have shown some degree of improvement of IBS symptoms.5

Faecal microbiota transplantation (FMT) is undoubtedly the most powerful modality available in the hands of physicians to replace …
Double But Not Single-Stranded RNA Exacerbates Allergen-Induced Airway Hyperresponsiveness and Airway Inflammation
Authors: Shigeru Ashino, Katsuyuki Takeda, Hidemitsu Kitamura, Atsushi Kurokawa, Tomohiro Akaba, Mitsuko Kondo, Kiyoshi Takeyama, Etsuko Tagaya, Naoko Yanagisawa, Erwin Gelfand
Journal: Journal of Allergy and Clinical Immunology (2020)
SF3B1 mutations induce R-loop accumulation and DNA damage in MDS and leukemia cells with therapeutic implications
Authors: Shalini Singh, Doaa Ahmed, Hamid Dolatshad, Dharamveer Tatwavedi, Ulrike Schulze, Andrea Sanchi, Sarah Ryley, Ashish Dhir, Lee Carpenter, Suzanne M. Watt, David J. Roberts, Amal M. Abdel-Aal, Sohair K. Sayed, Somaia A. Mohamed, Anna Schuh, Paresh Vyas, Sally Killick, Andriana G. Kotini, Eirini P. Papapetrou, Daniel H. Wiseman, Andrea Pellagatti, Jacqueline Boultwood
Journal: Leukemia (2020)

The myelodysplastic syndromes (MDS) are common myeloid malignancies characterized by ineffective hematopoiesis and blood cytopenias, with patients showing increasing bone marrow blasts with disease progression [1].Mutations in genes involved in pre-mRNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2) are the most common mutations found in MDS, occurring in over 50% of all cases [2-4].There is evidence that some spliceosome components play a role in the maintenance of genomic stability [5].Splicing is a transcription coupled process; splicing factor mutations affect transcription and may lead to the accumulation of Rloops (RNA-DNA hybrids with a displaced single stranded DNA) [6].Mutations in the splicing factors SRSF2 and U2AF1 have been recently shown to increase R-loop formation in leukemia cell lines, resulting in increased DNA damage, replication stress, and activation of the ATR-Chk1 pathway [7,8].SF3B1 is the most frequently mutated
Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain
Authors: Jeroen F.J. Bogie, Elien Grajchen, Elien Wouters, Aida Garcia Corrales, Tess Dierckx, Sam Vanherle, Jo Mailleux, Pascal Gervois, Esther Wolfs, Jonas Dehairs, Jana Van Broeckhoven, Andrew P. Bowman, Ivo Lambrichts, Jan-Åke Gustafsson, Alan T. Remaley, Monique Mulder, Johannes V. Swinnen, Mansour Haidar, Shane R. Ellis, James M. Ntambi, Noam Zelcer, Jerome J.A. Hendriks
Journal: The Journal of Experimental Medicine (2020)

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.