tbuckley/cabot-search huggingface dataset:
A New Tachyarrhythmia in a 60-Year-Old Woman
Authors: Ari J. Bennett, Spencer Carter, Jose A. Joglar
Journal: Circulation (2019)

ECG CHALLENGEA 60-year-old woman with a history of hypertrophic obstructive cardiomyopathy, paroxysmal atrial fibrillation, and metastatic rectal cancer presented to the emergency department with new-onset respiratory distress.Her home medications included, among others, metoprolol and digoxin, both of which had recent dose increases after a hospitalization complicated by atrial fibrillation with rapid ventricular response.In the emergency department, the patient was normotensive and tachypneic with hypoxia that resolved with supplemental oxygen.Her laboratory tests were significant for elevated troponin T (0.13 ng/mL, normal<0.01),N-terminal pro b-type natriuretic peptide (40 001 pg/mL, normal<300), and creatinine (1.42 mg/dL, baseline=0.7).Her electrolytes, hemogram, and thyroid-stimulating hormone were normal.The admission ECG is shown in Figure 1A.Given frequent rhythm changes noted on telemetry after intravenous diuresis and continuation of her home medications, a repeat ECG was ordered (Figure 1B).What is the rhythm during each recorded ECG; what is the most likely diagnosis; and what is the next best step in management?Please turn the page to read the diagnosis.
Predictors of suicide risk in adolescent and young adults (AYA) with cancer.
Authors: Jeremy Howard Lewin, Kate Thompson, Donovan Moncur, Sam Mancuso
Journal: Journal of Clinical Oncology (2019)

11519 Background: Whilst AYA accounts for a small proportion of annual cancer cases, the complexity of this subgroup places them at a disproportionately high risk of psychological distress and poor mental health. This study aimed to identify patient and disease characteristics associated with suicide in AYA patients. Methods: A retrospective analysis of AYA (aged 15-39) between the years 1973 to 2015 from the Surveillance, Epidemiology, and End Result Research database were included. A training and test set were used to develop a model predicting suicide. The SMOTE sampling algorithm was used for the training set due to severe class imbalances. A random forest model was trained with 10 clinical features (cancer subtype, age, sex, race, marital status, diagnostic year, number of in situ/malignant tumours, chemotherapy, surgery, and radiation therapy) with recursive feature elimination (RFE) via 10-fold cross validation. Results: There were 139,394 AYA included with 974 (0.7%) having a documented suicide or self/inflicted injury yielding an incidence of 1499 suicides / 100,000 person years. The standardized mortality ratio (SMR) for AYA was 34.4 (95% CI: 32-37)(Aged 15-24: 47.4 (39-57); Aged 25-39: 32.3 (29-35)). Suicide rates increased over time (1973-1980: SMR = 18.0 (15-22); 2001-2015: SMR = 127.0 (102-155)). Univariate analyses observed high rates of suicide in: females (43.8 (38-51)); single/unknown relationship status (47.1 (42-52)); “other” race (85.2 (52-132)) and by cancer type: leukaemia (77.1 (42-129)), soft tissue sarcoma (73.7 (57-94)), unspecified malignancy (71.0 (9-256)) and brain (63.6 (43-91)). We randomly assigned AYAs to a training set (n = 97,576) and test set (n = 41,818), stratified by cause of death. All 10 clinical features were retained with RFE. The prediction model achieved an AUC of 0.59, accuracy of 0.78, sensitivity of 0.40 and specificity of 0.78. Conclusions: Risk of suicide in AYA is high compared to normative data, further heightened in females, single/unknown relationship and certain tumour subtypes. The prediction model performed poorly, potentially related to the exclusion of mental health variables, which are not collected by the SEER dataset. Our findings suggest that dedicated psychosocial supports and targeted mental health assessments are critical components of care for AYA.
Computational Segmentation and Classification of Diabetic Glomerulosclerosis
Authors: Brandon Ginley, Brendon Lutnick, Kuang-Yu Jen, Agnes B. Fogo, Sanjay Jain, Avi Rosenberg, Vighnesh Walavalkar, Gregory Wilding, John E. Tomaszewski, Rabi Yacoub, Giovanni Maria Rossi, Pinaki Sarder
Journal: Journal of the American Society of Nephrology (2019)

Pathologists use visual classification of glomerular lesions to assess samples from patients with diabetic nephropathy (DN). The results may vary among pathologists. Digital algorithms may reduce this variability and provide more consistent image structure interpretation.We developed a digital pipeline to classify renal biopsies from patients with DN. We combined traditional image analysis with modern machine learning to efficiently capture important structures, minimize manual effort and supervision, and enforce biologic prior information onto our model. To computationally quantify glomerular structure despite its complexity, we simplified it to three components consisting of nuclei, capillary lumina and Bowman spaces; and Periodic Acid-Schiff positive structures. We detected glomerular boundaries and nuclei from whole slide images using convolutional neural networks, and the remaining glomerular structures using an unsupervised technique developed expressly for this purpose. We defined a set of digital features which quantify the structural progression of DN, and a recurrent network architecture which processes these features into a classification.Our digital classification agreed with a senior pathologist whose classifications were used as ground truth with moderate Cohen's kappa κ = 0.55 and 95% confidence interval [0.50, 0.60]. Two other renal pathologists agreed with the digital classification with κ1 = 0.68, 95% interval [0.50, 0.86] and κ2 = 0.48, 95% interval [0.32, 0.64]. Our results suggest computational approaches are comparable to human visual classification methods, and can offer improved precision in clinical decision workflows. We detected glomerular boundaries from whole slide images with 0.93±0.04 balanced accuracy, glomerular nuclei with 0.94 sensitivity and 0.93 specificity, and glomerular structural components with 0.95 sensitivity and 0.99 specificity.Computationally derived, histologic image features hold significant diagnostic information that may augment clinical diagnostics.
Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial
Authors: Jeffrey A Cohen, Giancarlo Comi, Krzysztof W Selmaj, Amit Bar-Or, Douglas L Arnold, Lawrence Steinman, Hans-Peter Hartung, Xavier Montalban, Eva Kubala Havrdová, Bruce A C Cree, James K Sheffield, Neil Minton, Kartik Raghupathi, Vivian Huang, Ludwig Kappos
Journal: The Lancet Neurology (2019)
P14.122 Integrin α5 is a poor prognostic factor in patients with glioblastoma treated by the Stupp protocol
Authors: N Etienne-Selloum, J Prades, D Bello Roufai, F El Azumi, M Boone, H Sevestre, S Trudel, A Coutte, C Desenclos, J Constans, B Chauffert, M Dontenwill
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness through preclinical studies and genomic analysis of several cohorts of patients. However, protein expression data are still missing to confirm this hypothesis. Our aim was to investigate the prognostic value of integrin α5 protein expression level in GBM. MATERIAL AND METHODS We retrospectively determined the protein expression level of integrin α5 using immunochemistry in tumors from patients treated in 6 French centers. Paraffin sections of GBM were labeled by immunofluorescence and analyzed by confocal microscopy. The corresponding clinical and survival data have been identified and analyzed. The primary end-point was overall survival (OS). RESULTS Out of 297 patients newly diagnosed with GBM between 2006 and 2013, 152 met the inclusion criteria (scheduled for initial treatment with the Stupp protocol, age &gt; 18 years) and 95 tumor samples were suitable for immunohistochemical analysis. The median age is 58 years, (64 men, 34 women). Most of patients received macroscopic (43%) or partial (36%) surgery. In univariate analysis using the Log Rank test, high integrin α5 expression level was associated with poor prognosis (PFS: hazard ratio (HR) = 1,696, p=0,0355; OS: HR=1,598, p = 0,0508). Corresponding median OS were 15,6 versus 19,2 months. Similarly, OS was significantly reduced with age (&gt; 60 years), lower resection degree, higher RPA (recursive partitioning analysis) score and non-methylated MGMT (O-6-methylguanine-DNA methyltransferase) promoter. In the subgroup of patients who received the full initial protocol (temozolomide treatment together with radiotherapy and later as adjuvant treatment; n=58) mean OS was strongly reduced when integrin α5 expression level was high (15,6 versus 22,8 months, p=0,0162) suggesting an impact of integrin signaling on temozolomide response in GBM. CONCLUSION Our study validates for the first time that the high protein level expression of α5 integrin is associated with poor prognosis in GBM. It also confirms its potential as a therapeutic target and its likely role in resistance to temozolomide as previously shown in preclinical study.
Two cases of multidrug-resistant Neisseria gonorrhoeae related to travel in south-eastern Asia, France, June 2019
Authors: Thibaut Poncin, Manel Merimeche, Aymeric Braille, Mary Mainardis, Cécile Bebear, Hervé Jacquier, Béatrice Berçot
Journal: Eurosurveillance (2019)

We report two cases of multidrug-resistant Neisseria gonorrhoeae urogenital infection with ceftriaxone resistance in a heterosexual couple in south-western France who were successfully treated with a single, high dose of intramuscular ceftriaxone (1 g). Whole genome sequencing of isolate F91 identified MLST13871, NG-MAST1086, NG-STAR233. Patient history revealed the isolate F91 was most likely acquired during a trip to Cambodia and belongs to the successful multidrug-resistant FC428 Asian clone.
Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer
Authors: Connie Kang, Sohita Dhillon, Emma D. Deeks
Journal: Drugs (2019)

Trifluridine/tipiracil (Lonsurf®) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and tipiracil, a thymidine phosphorylase inhibitor. Trifluridine/tipiracil has recently been granted an additional indication in the USA for the treatment of metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have been previously treated with at least two systemic treatment regimens, and has received a positive opinion for this indication in the EU. In the large pivotal phase III TAGS trial, trifluridine/tipiracil plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) compared with placebo plus BSC in this patient group. Progression-free survival (PFS) and the disease control rate were also improved with trifluridine/tipiracil relative to placebo. Health-related quality of life was not adversely affected by the addition of trifluridine/tipiracil to BSC and time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status was significantly delayed. The most common adverse events were mainly haematological (neutropenia, leucopenia and anaemia) and gastrointestinal (nausea, vomiting and diarrhoea), and were generally manageable with dosage modifications and/or supportive care. Adverse events ≥ Grade 3 were most frequently haematological in nature. Thus, trifluridine/tipiracil provides a valuable and much needed treatment option for patients with metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed on at least two prior therapies.
CD3 bispecific antibody–induced cytokine release is dispensable for cytotoxic T cell activity
Authors: Ji Li, Robert Piskol, Ryan Ybarra, Ying-Jiun J. Chen, Jason Li, Dionysos Slaga, Maria Hristopoulos, Robyn Clark, Zora Modrusan, Klara Totpal, Melissa R. Junttila, Teemu T. Junttila
Journal: Science Translational Medicine (2019)

T cell-retargeting therapies have transformed the therapeutic landscape of oncology. Regardless of the modality, T cell activating therapies are commonly accompanied by systemic cytokine release, which can progress to deadly cytokine release syndrome (CRS). Because of incomplete mechanistic understanding of the relationship between T cell activation and systemic cytokine release, optimal toxicity management that retains full therapeutic potential remains unclear. Here, we report the cell type-specific cellular mechanisms that link CD3 bispecific antibody-mediated killing to toxic cytokine release. The immunologic cascade is initiated by T cell triggering, whereas monocytes and macrophages are the primary source of systemic toxic cytokine release. We demonstrate that T cell-generated tumor necrosis factor-α (TNF-α) is the primary mechanism mediating monocyte activation and systemic cytokine release after CD3 bispecific treatment. Prevention of TNF-α release is sufficient to impair systemic release of monocyte cytokines without affecting antitumor efficacy. Systemic cytokine release is only observed upon initial exposure to CD3 bispecific antibody not subsequent doses, indicating a biological distinction between doses. Despite impaired cytokine release after second exposure, T cell cytotoxicity remained unaffected, demonstrating that cytolytic activity of T cells can be achieved in the absence of cytokine release. The mechanistic uncoupling of toxic cytokines and T cell cytolytic activity in the context of CD3 bispecifics provides a biological rationale to clinically explore preventative treatment approaches to mitigate toxicity.
Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis
Authors: Hamzah Abu-Sbeih, Lauren Nicholas Herrera, Tenglong Tang, Mehmet Altan, Anne-Maria P. Chaftari, Pablo C. Okhuysen, Robert R. Jenq, Yinghong Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The gut microbiome impacts the efficacy of immune checkpoint inhibitor (ICI) therapy and the development of ICI-mediated diarrhea and<b>/</b>or colitis (IMDC). Antibiotic therapy,especially that with anaerobic activity, has profound effects on the gut microbiome. Therefore, we sought to assess the effect of antibiotics on the development of IMDC. <h3>Methods</h3> Patients who received ICI therapy from January 2016 to January 2018 were examined retrospectively. A Cox regression model was used to assess factors associated with overall survival. <h3>Results</h3> A total of 826 patients were included. Of these patients, 51.6% received inhibitors of programmed cell death protein-1 or its ligand, 32.0% received inhibitors of cytotoxic T-lymphocyte-associated antigen-4, and 16.5% received a combination of the two. IMDC occurred in 52.5% of the patients after a median of 8 weeks. Overall, 569 patients (68.9%) received antibiotic therapy. Antibiotic use at any time was associated with reduced IMDC occurrence and recurrence rates but also with frequent hospitalization and intensive care unit admission for IMDC as well as increased IMDC severity. Compared with patients who received antibiotic therapy only before ICI therapy initiation, those receiving it after ICI had a higher IMDC rate and more often needed immunosuppressive therapy and hospitalization for IMDC. Antibiotics with anaerobic activity were included in 51% of the antibiotic therapy regimens and were associated with increased immunosuppressant use, hospitalization, intensive care unit admission for IMDC, and severe IMDC grades. Forty-one patients received empiric prophylactic antibiotic therapy at IMDC onset. These patients more often needed immunosuppressive therapy, intravenous steroids, and infliximab/vedolizumab; had more frequent and longer hospitalization for IMDC and higher IMDC grades; and more frequently had IMDC recurrence than did patients who did not receive antibiotic therapy at the time of IMDC symptom onset. <h3>Conclusions</h3> Whereas antibiotic therapy appeared to be protective against IMDC onset, use of antibiotics, especially those with anaerobic activity, after ICI therapy was associated with increased risk of severe IMDC.
FitFirms: A wellness option for oncology trainees.
Authors: Bhavana Pathak, Ann M. Eapen, Jason A. Zell
Journal: Journal of Clinical Oncology (2019)

10537 Background: Burnout in oncologists has been rising over the past decade. Burnout leads to poor patient outcomes and poor physician health. Younger oncologists are at higher risk for burnout. The Firm System was designed by Victor McKusick at the Johns Hopkins hospital in 1975 to integrate faculty and trainees into clinical and psychologically supportive cohorts. Here we describe an adapted Firm System called the FitFirms, which focused on social connectivity and altruistic service as means to combat burnout in oncology trainees. Methods: We divided the Hematology and Oncology Division of an academic Comprehensive Cancer Care center into four cohorts of faculty-fellow teams called FitFirms. Each FitFirm was named after a notable local or national female leader in the field of cancer medicine—The Henrietta Lacks Firm, The Jane Wright Firm, The Padmini Iyer Firm, and The Rita Mehta Firm. The faculty and fellows interacted on an at-minimum quarterly basis in casual social events and/or community service-oriented events for 15 months. The social events included group dinners, bowling, paint and game nights. The service events included participation in 5K walk/run fundraiser for our institution’s cancer center and support of a National Cancer Survivors Day event for US Veterans. A didactic discussion series was created to explore concepts of resiliency, work-life balance, and the role of art in medicine—mentored by faculty across the spectrum of oncologic disciplines (Surgical Oncology, Gynecologic Oncology, Palliative Care, and Health Communication). The Maslach Burnout Inventory survey was used to survey the oncology trainees before and after the interventions. Results: Nine pre-intervention surveys were collected with 78% of trainees describing themselves as on the burnout spectrum of feeling either ineffective, overextended, disengaged, or burned out (22% engaged). After 15 months, 10 post-intervention surveys were collected in which 60% of trainees described themselves on the burnout spectrum (40% engaged). Conclusions: The FitFirms are a novel system using social capital to reduce the problem of burnout in oncology trainees by engaging in social connectivity and altruistic service through faculty-mentored, historically-named divisional cohorts.
Interpreting CD4 Counts in a Patient With HIV
Authors: Sarath Nath, Sridesh Nath, Susana Lazarte
Journal: JAMA Internal Medicine (2019)

This Teachable Moment describes a man in his 40s with human immunodeficiency virus infection being treated with combination antiretroviral therapy, cutaneous Kaposi sarcoma in remission, and lymphedema of both legs who presented with acute-onset right lower extremity pain, swelling, and erythema.
Multiple Versus Single Arterial Coronary Bypass Graft Surgery for Multivessel Disease
Authors: Zaza Samadashvili, Thoralf M. Sundt, Andrew Wechsler, Joanna Chikwe, David H. Adams, Craig R. Smith, Desmond Jordan, Leonard Girardi, Stephen J. Lahey, Jeffrey P. Gold, Mohammed H. Ashraf, Edward L. Hannan
Journal: Journal of the American College of Cardiology (2019)
OS1.2 Development and Validation of a RNA-Seq Based Prognostic Signature in Neuroblastoma
Authors: J Zhou, H Ma
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Credible prognostic stratification remains a challenge for neuroblastoma (NBL) with variable clinical manifestations. RNA expression signatures might predict the outcomes; notwithstanding, independent cross-platform validation is still rare. MATERIAL AND METHODS expression data were obtained from NBL patients and then analyzed. In TARGET-NBL data, an RNA-based prognostic signature was developed and validated. Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve. Functional enrichment analysis of the RNAs was conducted using bioinformatics methods. RESULTS A total of 1,119 differentially expressed RNAs and 149 prognosis-related RNAs were identified sequentially. Then, in the training cohort, 12 RNAs were identiﬁed as signiﬁcantly associated with overall survival (OS) and were combined to develop a model that stratified NBL patients into low- and high-risk groups. Twelve RNA signature high-risk patients had poorer OS in the training cohort (n = 105, Hazard Ratios (HR)= 0.10 (0.05–0.20), P &lt; 0.001) and in the validation cohort (n = 44, HR = 0.25 (0.09–0.69), P = 0.008). ROC curve analysis also showed that both the training and validation cohorts performed well in predicting OS (12-month AUC values of 0.852 and 0.438, 36-month AUC values of 0.824 and 0.737, and 60-month AUC values of 0.802 and 0.702, respectively). Moreover, these 12 RNAs may be involved in certain events that are known to be associated with NBL through functional enrichment analysis. CONCLUSION This study identiﬁed and validated a novel 12-RNA prognostic signature to reliably distinguish NBL patients at low and high risk of death. Further larger, multicenter prospective studies are desired to validate this model.
Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study
Authors: Vera Golder, Rangi Kandane-Rathnayake, Molla Huq, Hieu T Nim, Worawit Louthrenoo, Shue Fen Luo, Yeong-Jian Jan Wu, Aisha Lateef, Sargunan Sockalingam, Sandra V Navarra, Leonid Zamora, Laniyati Hamijoyo, Yasuhiro Katsumata, Masayoshi Harigai, Madelynn Chan, Sean O'Neill, Fiona Goldblatt, Chak Sing Lau, Zhan Guo Li, Alberta Hoi, Mandana Nikpour, Eric F Morand
Journal: The Lancet Rheumatology (2019)
Irinotecan pharmacogenetics: The influence of pharmacodynamic genes
Authors: J. M. Hoskins, M. Baiget, E. Marcuello, A. Altes, H. L. McLeod
Journal: Journal of Clinical Oncology (2006)

3075 Background: Pharmacogenetic determinants of the disposition of the topoisomerase I (TOP1) poison, irinotecan, appear to predict patient (pt) risk of developing severe toxicity, but do not explain all reported cases of toxicity or tumor response to irinotecan treatment. Proteins encoded by the TOP1, ADPRT, TDP1, CDC45L, NFKB1 and XRCC1 genes abate the cytotoxic action of camptothecins in vitro. Methods: Genetic variation in the drug target, TOP1, and downstream effectors may influence pt outcomes to irinotecan therapy. A retrospective haplotype-association study was undertaken to investigate the hypothesis. The association between common haplotypes of the 6 candidate genes and severe adverse events (Grade 3/4 diarrhea, neutropenia) and tumor response (objective response, overall survival) was examined in 107 advanced colorectal cancer pts treated with irinotecan-based regimens. Haplotype tags (htSNPs) were selected from haplotype cladograms of each gene. Patient DNA was typed for htSNPs using pyrosequencing and haplotype identities estimated using PHASE v.0.9. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. TOP1 IVS4+61 was related to neutropenia incidence (GG&lt;AG&lt;AA, p&lt;0.05) and TDP1 IVS12+79 to objective response (TT&lt;TG&lt;GG, p&lt;0.05). TOP1 IVS4+61 AG+GG survived longer (24.9 months) than AA pts (7.8 months; p&lt;0.005) and ADPRT +852 (A284A) CT+TT pts longer than CCs (p&lt;0.05). More pts with the XRCC1 3/3 diplotype (83%) had an objective response to therapy than pts with other diplotypes (30%, p&lt;0.05). There was a trend towards more ADPRT 2/2s (33%) experiencing severe neutropenia than pts with other diplotypes (13%, p=0.08). No genetic variant influenced diarrhea incidence. Conclusions: This is the first pharmacogenetic investigation of irinotecan pharmacodynamic factors. Our results suggest TOP1 and ADPRT variants may alter a patient’s risk of experiencing neutropenia and TOP1, TDP1, ADPRT and XRCC1 variants may influence tumor response to irinotecan-based therapies. [Table: see text]