tbuckley/cabot-search huggingface dataset:
Big data in IBD: big progress for clinical practice
Authors: Nasim Sadat Seyed Tabib, Matthew Madgwick, Padhmanand Sudhakar, Bram Verstockt, Tamas Korcsmaros, Séverine Vermeire
Journal: Gut (2020)

IBD is a complex multifactorial inflammatory disease of the gut driven by extrinsic and intrinsic factors, including host genetics, the immune system, environmental factors and the gut microbiome. Technological advancements such as next-generation sequencing, high-throughput omics data generation and molecular networks have catalysed IBD research. The advent of artificial intelligence, in particular, machine learning, and systems biology has opened the avenue for the efficient integration and interpretation of big datasets for discovering clinically translatable knowledge. In this narrative review, we discuss how big data integration and machine learning have been applied to translational IBD research. Approaches such as machine learning may enable patient stratification, prediction of disease progression and therapy responses for fine-tuning treatment options with positive impacts on cost, health and safety. We also outline the challenges and opportunities presented by machine learning and big data in clinical IBD research.
Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial
Authors: Ida Pernicova, Stephen Kelly, Sharon Ajodha, Anju Sahdev, Jonathan P Bestwick, Plamena Gabrovska, Olufunso Akanle, Ramzi Ajjan, Blerina Kola, Marietta Stadler, William Fraser, Mirjam Christ-Crain, Ashley B Grossman, Costantino Pitzalis, Márta Korbonits
Journal: The Lancet Diabetes & Endocrinology (2020)
Broad immune activation underlies shared set point signatures for vaccine responsiveness in healthy individuals and disease activity in patients with lupus
Authors: Yuri Kotliarov, Rachel Sparks, Andrew J. Martins, Matthew P. Mulè, Yong Lu, Meghali Goswami, Lela Kardava, Romain Banchereau, Virginia Pascual, Angélique Biancotto, Jinguo Chen, Pamela L. Schwartzberg, Neha Bansal, Candace C. Liu, Foo Cheung, Susan Moir, John S. Tsang
Journal: Nature Medicine (2020)
Radiotherapy (RT) guided by ultra‐small superparamagnetic iron oxide (USPIO)-contrast MRI staging for patients with advanced or recurrent prostate cancer.
Authors: Yun Rose Li, Michael J. Dattoli, Jelle Barentsz, Mack Roach
Journal: Journal of Clinical Oncology (2020)

218 Background: Aggressive treatment of oligometastatic PC may prolong survival in selected patients. USPIO-contrast MRI is potentially more sensitive in detecting early lymph node (LN) metastases than PET. Methods: This retrospective study explores the safety and utility of USPIO-guided RT in 69 patients with advanced/recurrent PC treated at 2 US institutions. All USPIO-MRIs were completed at RadboudUMC and interpreted by expert radiologists. Age, Stage, Gleason score, PSA, prior therapy, duration of androgen-deprivation (ADT), cause of death, details of RT, and adverse events (AEs) were collected by chart review. Biochemical recurrence (BCR) was defined as PSA Nadir plus 2.0 (RT) or PSA&gt;0.2 (radical prostatectomy, RP). Patients received external beam radiation (RT) to involved nodal basins (+/-prostate/prostate bed) with either a simultaneous integrated or sequential boost to USPIO(+) nodes. All patients received &gt;6 months of ADT. Overall (OS) and BCR free-survival (BCRFS) were calculated using Cox-PH models in R. Results: Between 2007-18, 69 patients with de novo or recurrent PC were found to have USPIO(+) LNs and received USPIO-guided RT; median age was 62. The majority of patients presented after BCR following RP (N=28), definitive RT (N=27) or RP and post-op RT (N=6). Prior to USPIO-MRI, 20/69 patients had cN1 disease based on abdominal-pelvic CT/MRI, Bone Scan, Prostascint-scan, and F18 Choline, Axumin or PSMA PET/CT. The mean(median)USPIO(+) LNs was 5.2(3) Range=[1-32]. Patients had (+)pelvic (95%), para-aortic (43%), and/or peri-rectal LNs (19%). At median follow up of 29.5(44.6) Range=[5-127] months, OS was 58/69 (84%) and 11/11 patients died of PC. At last follow up, 40 patients remained BCR-free (BCRFS not reached). The median time to BCR (N=29) was 25.9 months after USPIO-guided RT. For patients with follow-up imaging, recurrences were predominantly out-of-field (outside of elective LN fields or in osseous sites). No patients experienced &gt;CTCAE grade 2 AEs. Conclusions: In this cohort of 69 patients with predominantly recurrent PC, USPIO-directed RT was well-tolerated, feasible and resulted in encouraging biochemical control rates.
105P Antiproliferative Effect of New Lignan from Abies Sibirica on Hormone-Dependent Breast Cancer Cells in Vitro
Authors: O.S. Zhukova, A.M. Shcherbakov, L.V. Fetisova, M.V. Kiselevskii, N.E. Nifantiev
Journal: Annals of Oncology (2012)
Rules on isolation rooms for suspected covid-19 cases in GP surgeries to be relaxed
Authors: Zosia Kmietowicz
Journal: BMJ (2020)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Rules on isolation rooms for suspected covid-19 cases in GP surgeries to be relaxed Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Non-prostate cancer malignancies detected by 18F-Fluciclovine PET/CT.
Authors: Andrew R. Barsky, Grace S. Ahn, Austin A. Pantel, Neha Vapiwala
Journal: Journal of Clinical Oncology (2020)

28 Background: Novel imaging modalities such as 18 F-fluciclovine PET/CT provide additional sensitivity over conventional imaging modalities in the workup of recurrent prostate cancer (PC). The range of published sensitivity and specificity values for 18 F-fluciclovine is broad, however, and NCCN guidelines note the scan’s high false-positive rate. Prior case reports have described incidental detection of non-PC using this modality, including melanoma, oropharyngeal, pancreatic, penile, liver, and breast cancers. Herein, we surveyed our institutional 18 F-fluciclovine PET/CT results to assess the rate and histologies of incidentally-detected non-PC. Methods: We retrospectively identified consecutive men with PC who underwent 18 F-fluciclovine PET/CT as part of their disease workup. After identifying studies with unequivocal PET-avidity, we assessed for subsequent tissue sampling and/or imaging to confirm a non-PC malignancy. We report these patients’ clinicopathologic data. Results: Three-hundred thirty-six men underwent 18 F-fluciclovine PET/CT for PC at our institution between 6/2017-7/2019. Seven (2%) were found to have non-PC malignancies. The diagnoses were: meningioma (n=3, 43%), non-small cell lung cancer (NSCLC) (n=2, 29%), gastric adenocarcinoma (n=1, 14%), and pancreatic neuroendocrine tumor (n=1, 14%). One of the patients with meningioma underwent resection as a result, while the other two were surveilled by MRI. Both cases of NSCLC were biopsied and resected. Tissue sampling was not performed in the gastric or pancreatic cases, as these patients were already known to have these malignancies. Conclusions: In this large institutional series, we found a low rate (2%) yet broad range of non-PC malignancies incidentally detected by 18 F-fluciclovine PET/CT performed for PC, including diagnoses not previously reported in the literature. Such detection allowed patients to receive definitive management or appropriate surveillance for the non-PC malignancies. These findings underscore the importance of clinical and/or pathological correlation of positive scan results.
Does screening for frailty with the vulnerable elders survey (VES-13) identify older adults with GU malignancy who benefit most from a consultation in a geriatric oncology clinic?
Authors: Naser M. KH. M. S AlQurini, Narhari Timilshina, Rana Jin, Allison Loucks, Arielle Berger, Lindy Romanovsky, Martine Puts, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2020)

209 Background: The VES-13 is a well-studied brief frailty screening tool for ≥ 65 older adults (OAs) in the oncology setting. Vulnerable patients (scoring ≥ 3) are at higher risk for adverse outcomes and will benefit from a Comprehensive Geriatric assessment (CGA) and cancer treatment decision optimization. Whether the VES-13 is effective specifically in patients with Genitourinary (GU) malignancies remains to be established. Primary objective: to determine if the VES-13 can predict which OAs with GU cancer (Bladder, Prostate, Kidney) had subsequent treatment modification after CGA. Secondary objective: to investigate if there is any association between VES-13 score with comorbidity and chemotherapy toxicity prediction tool (CARG). Methods: The VES-13 was administered to consecutive patients referred to the geriatric oncology (GO) clinic from GU site at the Princess Margaret Cancer Centre, Canada. All patients underwent CGA. CGA assess 8 domains including cognition, comorbidities, function, falls risk. Among patients referred for pre-treatment assessment, we examined whether the VES-13 predicted changes in the final treatment plan after CGA. Descriptive statistics were used to describe the VES-13 scores and final treatment impact. Results: From July 2015-October 2019, 77 were included in this analysis. The VES-13 ≥ 3 group were 52/77 (67.5%), and significantly associated with higher comorbidities (P = 0.003) and worse CARG scores (P = 0.005). The final treatment plan was modified in 36/77 (47%). In univariate analysis, the odds ratio (OR) for VES-13 ≥3 was 1.92 (95% CI 0.72-5.12) for change in final treatment, which was not statistically significant likely due to modest sample size. Interestingly in the same univariate analysis, there was a strong association between final treatment plan with falls risk (OR 2.63, 95% CI 1.03-6.72), physical performance (OR 2.51, 95% CI 0.98-6.45) and cognition (OR 3.95, 95% CI 1.19-13.19). Conclusions: The VES-13 identified vulnerable GU patients who will benefit from CGA and may predict treatment optimization by identifying patients at higher risk of chemotherapy toxicity and higher comorbidity.
SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist
Authors: Antony J Porcino, Larissa Shamseer, An-Wen Chan, Richard L Kravitz, Aaron Orkin, Salima Punja, Philippe Ravaud, Christopher H Schmid, Sunita Vohra
Journal: BMJ (2020)

Randomised clinical trials are the preferred method for establishing average intervention effects for groups. Using key methodological elements of these trials, n-of-1 trials provide rigorous evidence of intervention effects for individuals. N-of-1 trials are particularly useful for situations where randomised clinical trials are not always feasible or appropriate, such as for individuals with rare diseases, comorbid conditions, or using concurrent treatments. N-of-1 trials enhance precision when intervention effects are heterogeneous between individuals. Here, we describe an extension to the SPIRIT (standard protocol items: recommendations for interventional trials) guideline, SPENT (SPIRIT extension for n-of-1 trials), to improve the completeness and transparency of n-of-1 trial protocols. SPENT is also aligned with the CONSORT (consolidated standards of reporting trials) extension for n-of-1 trials (CENT). The guideline development group followed the development strategy for reporting guidelines endorsed by the EQUATOR Network. SPENT began with a systematic review for n-of-1 protocol recommendations. After analysis to identify possible SPENT items, a three round Delphi process was implemented, with international participation involving researchers, patient advocates, and other stakeholders. This was followed by in-person meetings and email discussion of the SPENT group to achieve consensus. SPENT has 14 extension items specific to n-of-1 trials, a checklist for n-of-1 trial protocol abstracts, and additional guidance for eight SPIRIT items where trialists could encounter issues specific to n-of-1 trials. This paper describes the rationale and development process, and provides examples and explanations for each SPENT checklist item.
Therapeutic switch from omalizumab to mepolizumab in patients with uncontrolled severe eosinophilic asthma: treatment effect by exacerbations in previous year and maintenance use of OCS
Authors: Mark Liu, Bradley Chipps, Xavier Muñoz, Gilles Devouassoux, Miguel Bergna, Steven Smith, Frank Albers, Robert Price, Jay Azmi, Dmitri Galkin, Kenneth Chapman
Journal: Journal of Allergy and Clinical Immunology (2020)
Phase III study of perioperative pembrolizumab (pembro) plus cystectomy versus cystectomy alone in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-905.
Authors: Matt D. Galsky, Andrea Necchi, Neal D. Shore, Fred Witjes, Kijoeng Nam, Eric Sbar, Blanca Homet Moreno, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2020)

TPS593 Background: Pts with MIBC ineligible for neoadjuvant cisplatin-based chemotherapy who only receive the standard radical cystectomy+pelvic lymph node dissection (RC+PLND) have a high rate of recurrence and poor prognosis. PD-1/PD-L1 inhibition is an effective first-line option for cisplatin-ineligible pts. Neoadjuvant single-agent pembro, a PD-1 inhibitor, has shown activity in pts with MIBC, with a pathologic complete response (pCR) rate of 42% for all pts and 54% for PD-L1 + pts (PURE-01; NCT02736266). Methods: KEYNOTE-905 (NCT03924895) is a randomized phase 3 trial of preoperative pembro plus RC+PLND versus RC+PLND alone in cisplatin-ineligible pts with MIBC. An estimated 610 pts will be enrolled and randomly assigned 1:1 to either neoadjuvant pembro (3 cycles) followed by RC+PLND and adjuvant pembro (14 cycles) or RC+PLND alone and observation. Pembro 200 mg will be administered IV every 3 weeks. Pts in the RC+PLND group will proceed directly to RC+PLND within 8 weeks from randomization. Pts will be stratified by clinical T stage (T2 vs T3 or T4), PD-L1 expression (combined positive score [CPS] ≥10 vs &lt;10), and geographic region (United States vs Europe vs most of world). Adults (≥18 years) ineligible to receive cisplatin with histologically confirmed MIBC (T2-T4aN0M0), clinically nonmetastatic disease (N0M0), and an ECOG PS score of 0-2 are eligible. Previous systemic anticancer therapies for MIBC are not permitted. CT/MRI will be performed before and after cystectomy. Pts disease free after imaging for cystectomy will continue to undergo serial imaging until disease progression or discontinuation from the study; all imaging will be assessed by blinded independent central review. Coprimary end points are pCR (based on central pathology review) and event-free-survival in all pts and in pts with tumor PD-L1 CPS ≥10. Secondary end points are OS, disease-free survival, and pathologic downstaging in all pts and in pts with tumor PD-L1 CPS ≥10, and safety. Exploratory end points include patient-reported outcomes and biomarkers. Accrual began July 24, 2019. Clinical trial information: NCT03924895.
Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice
Authors: Tibor I. Krisko, Hayley T. Nicholls, Curtis J. Bare, Corey D. Holman, Gregory G. Putzel, Robert S. Jansen, Natalie Sun, Kyu Y. Rhee, Alexander S. Banks, David E. Cohen
Journal: Cell Metabolism (2020)
Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Anthony Serritella, Daniel H. Shevrin, Elisabeth I. Heath, James Lloyd Wade, Elia Martinez, Theodore Karrison, Walter Michael Stadler, Russell Zelig Szmulewitz
Journal: Journal of Clinical Oncology (2020)

91 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.
Transcriptome analysis of ankylosed primary molars with infraocclusion
Authors: Annie Tong, Yuh-Lit Chow, Katie Xu, Rita Hardiman, Paul Schneider, Seong-Seng Tan
Journal: International Journal of Oral Science (2020)

Abstract Primary molar ankylosis with infraocclusion can retard dental arch development and cause dental asymmetry. Despite its widespread prevalence, little is known about its molecular etiology and pathogenesis. To address this, RNA sequencing was used to generate transcriptomes of furcal bone from infraoccluded ( n = 7) and non-infraoccluded ( n = 9) primary second molars, all without succeeding biscuspids. Of the 18 529 expressed genes, 432 (2.3%) genes were differentially expressed between the two groups (false discovery rate &lt; 0.05). Hierarchical clustering and principal component analysis showed clear separation in gene expression between infraoccluded and non-infraoccluded samples. Pathway analyses indicated that molar ankylosis is associated with the expression of genes consistent with the cellular inflammatory response and epithelial cell turnover. Independent validation using six expressed genes by immunohistochemical analysis demonstrated that the corresponding proteins are strongly expressed in the developing molar tooth germ, in particular the dental follicle and inner enamel epithelium. The descendants of these structures include the periodontal ligament, cementum, bone and epithelial rests of Malassez; tissues that are central to the ankylotic process. We therefore propose that ankylosis involves an increased inflammatory response associated with disruptions to the developmental remnants of the dental follicle and epithelial rests of Malassez.
FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation–Induced Mitochondrial Oxidative Stress
Authors: Roberto Ronca, Gaia C. Ghedini, Federica Maccarinelli, Antonio Sacco, Silvia L. Locatelli, Eleonora Foglio, Sara Taranto, Elisabetta Grillo, Sara Matarazzo, Riccardo Castelli, Giuseppe Paganini, Vanessa Desantis, Nadia Cattane, Annamaria Cattaneo, Marco Mor, Carmelo Carlo-Stella, Angelo Belotti, Aldo M. Roccaro, Marco Presta, Arianna Giacomini
Journal: Cancer Research (2020)

Abstract Multiple myeloma, the second most common hematologic malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGF) act as proangiogenic and mitogenic cytokines in multiple myeloma. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for multiple myeloma cell survival and progression by protecting multiple myeloma cells from oxidative stress–induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of multiple myeloma cells by inducing mitochondrial oxidative stress, DNA damage, and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-nondegradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the proapoptotic effects due to FGF blockade. These findings were confirmed on bortezomib-resistant multiple myeloma cells as well as on bone marrow–derived primary multiple myeloma cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from patients with high-risk multiple myeloma. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a nonredundant role in multiple myeloma cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for patients with multiple myeloma with poor prognosis and advanced disease stage. Significance: This study provides new insights into the mechanisms by which FGF antagonists promote multiple myeloma cell death.