tbuckley/cabot-search huggingface dataset:
Standardized and compliant bio-informatics pipeline for neoepitope analysis in oncology clinical trials
Authors: N. Masloboeva-Siwach, S. Ribi, H. Lempiäinen, T. Rujan, M. Flesch
Journal: Annals of Oncology (2018)

Background: Several novel and highly promising immunotherapeutic approaches are now in development, such as vaccination with synthesized long peptides or vaccines that encode relevant neoepitope sequences, as well as activated T cell therapies that recognize neoepitopes. Neoantigens (aka neoepitopes) are derived from tumor-specific somatic mutations accumulated during cancer progression. The discovery of patient specific high affinity neoepitopes is challenging, as several genomics attributes of the tumor and germline cells need to be measured and integrated to derive accurate predictions. Most of the existing bio-informatics pipelines for neoepitope prediction are complex sets of command line scripts that are complicated to operate, difficult to run efficiently on cloud or High-Performance Computing (HPC) environments and difficult to validate for the use of clinical trials and submissions. Methods: We established a bio-informatics pipeline that allows calling of somatic variants, the estimation of the expression levels of the mutated proteins and the calling of patient specific MHC genotypes from paired tumor-normal tissue samples. The information can be used for predicting and selecting the most specific patient neoepitopes. We have ensured that the pipeline can run directly on most scalable cloud and HPC environments. The pipeline also includes the required regulatory features so that it can be used in clinical trials, and the results can be directly submitted to regulatory authorities. Results: We present the automated neoepitope prediction pipeline and show that it includes all compliance features required for operating in regulated clinical environments. We also demonstrate the scientific validation of the pipeline by reproducing and confirming the results from a published medical case of a metastatic breast cancer patient that was successfully treated with tumor-infiltrating lymphocytes (TILs) reactive against 4 patient specific mutated proteins. Conclusions: We provide a standardized bio-informatics pipeline for neoepitope prediction that can be automated, runs highly efficient on the most scalable HPC environments and can be validated to support clinical trials and decisions. Legal entity responsible for the study: Genedata AG. Funding: Has not received any funding. Disclosure: N. Masloboeva-Siwach: Employee of Genedata Inc. S. Ribi, H. Lempiäinen, T. Rujan: Employee of Genedata AG. M. Flesch: Employee of Genedata GmbH.
Cardiovascular Hospitalization in Patients Treated with Dasatinib or Nilotinib in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients in Routine Clinical Practice
Authors: Michael J. Mauro, Clara Chen, Jorge E. Cortes, Carlo Gambacorti-Passerini, Ginny P Sen, Srikanth Gajavelli, Catherine Davis, Mauricette Michallet
Journal: Blood (2018)
Endoscopic lithotripsy for right intrahepatic bile duct stone through endoscopic ultrasound-guided hepaticogastrostomy
Authors: Koichiro Mandai, Koji Uno, Kenjiro Yasuda
Journal: Endoscopy (2018)

Treatment for intrahepatic bile duct (IHBD) stones remains a challenge. Although endoscopic ultrasound (EUS)-guided antegrade treatment for biliary stones has been reported recently [1] [2], this method is indicated for stones in the common bile duct or left IHBD. For right IHBD stones, percutaneous transhepatic biliary drainage-guided treatment is usually performed. Herein, we describe an endoscopic treatment procedure for right IHBD stones through an EUS-guided hepaticogastrostomy (HGS) route.
Pulmonary hypertension in chronic lung disease and hypoxia
Authors: Steven D. Nathan, Joan A. Barbera, Sean P. Gaine, Sergio Harari, Fernando J. Martinez, Horst Olschewski, Karen M. Olsson, Andrew J. Peacock, Joanna Pepke-Zaba, Steeve Provencher, Norbert Weissmann, Werner Seeger
Journal: European Respiratory Journal (2018)

Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged.
The Role of Hepatitis B Surface Antigen in Nucleos(t)ide Analogues Cessation Among Asian Patients With Chronic Hepatitis B: A Systematic Review
Authors: Jiaye Liu, Tao Li, Li Zhang, Aiqiang Xu
Journal: Hepatology (2018)

In actual clinical practice, infinite nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B virus (HBV) infection is unrealistic. The most commonly used endpoint is suppression of HBV DNA to undetectable levels with normalization of alanine aminotransferase. However, this criterion for cessation of treatment is associated with various incidences of virological and clinical relapse. Recent studies suggest that decreasing the hepatitis B surface antigen (HBsAg) level at the end of treatment (EOT) to an appropriate cut-off value appears to be a practicable and attainable cessation criterion. We performed a systematic review to explore the optimal cut-off value of HBsAg at EOT for the cessation of NAs treatment. Eleven studies with 1,716 patients were included in this review. When the HBsAg levels at EOT were <100 IU/mL and >100 IU/mL, the respective off-therapy virological relapse rates were 9.1%-19.6% (range) and 31.4%-86.8% (range) at ≥12 months off therapy, regardless of hepatitis B e antigen (HBeAg) status; the respective off-therapy clinical relapse rates were 15.4%-29.4% (range) and 48.1%-63.6% (range) at ≥12 months off therapy, regardless of HBeAg status; and the respective off-therapy HBsAg loss rates were 21.1%-58.8% (range) and 3.3%-7.4% (range) for HBeAg-negative patients at ≥39 months off therapy. Conclusion: Cessation of long-term NAs therapy before HBsAg seroclearance in patients with chronic hepatitis B is a feasible alternative to indefinite treatment. An HBsAg level <100 IU/mL at EOT seems to be a useful marker for deciding when to discontinue NAs therapy. However, regular monitoring is required after the cessation of NAs treatment, and long-term outcomes must be further evaluated.
The Emergent Course of Bipolar Disorder: Observations Over Two Decades From the Canadian High-Risk Offspring Cohort
Authors: Anne Duffy, Sarah Goodday, Charles Keown-Stoneman, Paul Grof
Journal: American Journal of Psychiatry (2018)

Objective: The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis. Methods: Parent bipolar disorder was confirmed by the best-estimate procedure and lithium response by research protocol. High-risk offspring (N=279) and control subjects (N=87) were blindly assessed, annually on average, with the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version or the Schedule for Affective Disorders and Schizophrenia–Lifetime version. DSM-IV diagnoses were confirmed using the best-estimate procedure in blind consensus reviews. Cumulative incidence and median age at onset were determined for lifetime syndrome- and symptom-level data. Mixed models assessed the association between parent and offspring course. A multistate model was used to estimate the clinical trajectory into bipolar disorder. Results: The cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years (range, 12.4 to 30.3). The clinical course of the affected parent was associated with that of the affected child. Depressive episodes predominated during the early bipolar course, especially among offspring of lithium responders. Childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively, and depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. The best-fit model of emerging bipolar disorder was a progressive sequence from nonspecific childhood antecedents to adolescent depression to index manic or hypomanic episode. Subthreshold sleep symptoms were significantly associated with transition from well to non-mood disorder, and psychotic symptoms in mood episodes were significantly associated with transition from unipolar to bipolar disorder. Conclusions: Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence. Childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.
Application of the Test-Negative Design to General Laboratory Submissions
Authors: Danuta M. Skowronski, Gaston De Serres
Journal: JAMA Pediatrics (2018)

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Complaints against doctors fell by 8% in 2017
Authors: Clare Dyer
Journal: BMJ (2018)

Complaints about doctors to the General Medical Council are falling and more cases are being resolved without a full investigation, the latest annual report from the regulator shows.1

Numbers of complaints were down 8% in 2017 (from 8228 in 2016 to 7541) and reduced by 13% over the five years from 2012 to 2017 (from 8664 to 7541). Referrals from employers went down by 46% (from 604 in 2012 to 328 in 2017) in part because of GMC work …
The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases
Authors: Monica S. Thakar, Larisa Broglie, Brent Logan, Andrew Artz, Nancy Bunin, Lauri M. Burroughs, Caitrin Fretham, David A. Jacobsohn, Alison W. Loren, Joanne Kurtzberg, Caridad A. Martinez, Shin Mineishi, Adam S. Nelson, Ann Woolfrey, Marcelo C. Pasquini, Mohamed L. Sorror
Journal: Blood (2018)
Comparison of Antibiotic Prescribing for Pediatric Community-Acquired Pneumonia in Children’s and Non-Children’s Hospitals
Authors: Alison C. Tribble, Rachael K. Ross, Jeffrey S. Gerber
Journal: JAMA Pediatrics (2018)

studies of early CP intervention starting at 6 months of age have been ongoing since 2013.A limitation to the generalizability of our findings may be that 3 clinical trials of early CP motor interventions have been ongoing since 2013.Administration of magnesium is a resource-intensive intervention that is not without risks.Given our findings, the role of magnesium for fetal neuroprotection may need reevaluation at the national level.Physicians should evaluate the longterm impact of clinical interventions, a mandate not unique to magnesium trials for prevention of CP.Many industries have developed lean thinking tools, such as the plan-do-checkadjust cycle, that can drive evaluation of health care recommendations adopted following large randomized trials.
Predictive score using clinical and blood biomarkers in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy
Authors: A. Prelaj, S.E. Rebuzzi, P. Pizzutilo, M. Montrone, F. Pesola, V. Longo, V. Lapadula, F. Cassano, P. Petrillo, D. Bafunno, N. Varesano, V. Lamorgese, A. Mastrandrea, D. Ricci, A. Catino, G. Domenico
Journal: Annals of Oncology (2018)

Background: Despite the overall survival (OS) benefit, only 18-20% of aNSCLC patients respond to immune-checkpoint inhibitors (ICI) as second-line therapy with a median progression-free survival (mPFS) of 2-4 months. The identification of predictive and prognostic biomarkers to select patients most likely to respond to ICI is greatly needed in guiding clinical practice. Methods: We conducted a retrospective monocentric analysis of 154 aNSCLC patients receiving single-agent Nivolumab or Pembrolizumab as second-line (68%) and >3rd line (32%). We collected complete blood cell count at baseline and evaluated LDH, absolute neutrophil count (ANC), lymphocyte count (ALC), monocyte count (AMC) and eosinophil count (AEC) and their ratio such as neutrophil-lymphocyte ratio (NLR), derived-NLR (dNLR) and lymphocyte-monocyte ratio (LMR). Univariate and multivariate analyses were performed to identified indipendent predictors factors for immunotherapy (using Kaplan–Meier and Cox Progression analyses). Results: The multivariate analysis on clinical factors showed the negative predictive role of ECOG PS 2 and liver metastasisand the positive predicitive role of smoking status. The multivariate analysis for PFS showed the negative predictive role of higher ANC (>6000/mL) and LDH (>400 mg/dl) and positive predictive role of higher ALC (>2200/mL). Also, according to stepwise regression analyses, NLR>4 playsa negative predictive and prognostic role at baseline. Finally, five predictive clinical and blood biomarkers at baseline (smoking status, ECOG PS, liver metastases, LDH and NLR), were used to create a predictive score for immunotherapy. Three predictive groups were defined as high, intermediate and low with a mPFS of 10.2 vs 4.9 vs 1.7 months respectively (HR 4.18 95% IC 2.64–6.62, p < 0.001).Table6PPredictive FactorAssessmentPointECOG PS0-1 20 1Smoking (pack-years)> 43 < 430 1Liver metastasesNo Yes0 1LDH (mg/dl)< 400 > 4000 1NLR< 4 > 40 1Predictive groups (Points): 1 = 0 2 = 1-2 3 = 3-5PFS (months): 10.2 4.9 1.7HR 4.18 95% IC (2.64 – 6.62) p < 0.001 Open table in a new tab Conclusions: In advanced NSCLC patients treated with second-line immunotherapy, the identification of five and predictive clinical and blood biomarkers at baseline, combined in a predictive score, may help identify patients most likely to benefit from immunotherapy. Legal entity responsible for the study: Clinical Cancer Center Giovanni Paolo II, Bari, Italy. Funding: Has not received any funding. Disclosure: G. Domenico: Advisory board: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Abstract P092: Adolescent and Young Adult Women Have Low Cardiovascular Disease Awareness
Authors: Holly C Gooding, Courtney Brown, Caterina Stamoulis, Anna C Revette, Sarah D DeFerranti
Journal: Circulation (2018)

Introduction: The American Heart Association (AHA) Go Red for Women campaign has substantially improved awareness of heart disease among adult women over the past fifteen years, as demonstrated by triennial surveys of women ages 25 years and older. Little is known about awareness among younger women, who represent a key time in the life course for primordial prevention. We hypothesized that adolescent and young adult women 15 to 24 years of age would have lower rates of heart disease awareness than women 25 years of age and older. Methods: We assessed awareness of heart disease and prevention efforts among young women ages 15-24 years using the AHA National Women’s Health Study survey. Participants were a random convenience sample of 103 women recruited from the waiting rooms of two clinical practices (one community health center and one academic medical center). We performed statistical comparisons of this cohort to responses from the 2012 AHA National Women’s Health Study survey of 168 women ages 25-34 years using the chi-square test (binary responses). Results: Only 13 (13%) adolescent and young adult women correctly identified heart disease as the leading cause of death in women. This was significantly lower than the rate of awareness of adult women overall in 2012 (56% of 2432) and of women ages 25-34 years (44% of 168) (p&lt;0.001 for both comparisons). Almost half of the young women surveyed in the current study [(n= 44 (43%)] said they were not at all informed about heart disease. While physicians emerged as the preferred source of information about heart disease among participants, the majority [n=64 (62%)] had never spoken to a health care professional about their risk of heart disease. Most young women surveyed worried little [n = 44 (43%)] or not at all [n = 40 (39%)] about heart disease; mood disorders were the most common concern in this age group, followed by sexual health issues. Despite a lack of general awareness about heart disease, many young women did report engaging in activities known to reduce the risk of heart disease, including getting regular exercise [n = 81 (79%)], maintaining healthy blood pressure [n = 76 (74%)], reducing sugar intake [n = 48 (47%)], and losing weight [n = 48 (47%)]. A significantly higher proportion of women ages 15-24 years aimed to maintain a healthy blood pressure and get regular exercise compared to those ages 24-34 (p&lt;0.02), whereas a similar proportion aimed to lose weight and reduce sugar intake (p&gt;0.7). Conclusions: Adolescent and young adult women are largely unaware of heart disease as the leading cause of death in women. As the antecedents of heart disease begin in childhood and adolescence, these findings demonstrate a major unmet need. Given most young women are not worried about heart disease at this life stage, campaigns to promote heart healthy behaviors should underscore the benefits of these prevention behaviors to mood and emotional health.
Long-term Outcomes of Tetralogy of Fallot
Authors: Clayton A. Smith, Courtney McCracken, Amanda S. Thomas, Logan G. Spector, James D. St Louis, Matthew E. Oster, James H. Moller, Lazaros Kochilas
Journal: JAMA Cardiology (2018)

Tetralogy of Fallot (TOF) is a surgically repairable form of cyanotic congenital heart disease. Multicenter data for long-term survival following repair are sparse.To evaluate the long-term transplant-free survival of TOF by surgical strategy adjusted for era and patient characteristics.Retrospective cohort study enriched with data from the National Death Index and the Organ Procurement and Transplantation Network through 2014. Multicenter cohort from the Pediatric Cardiac Care Consortium (PCCC), a large, US-based clinical registry for interventions for congenital heart disease. The cohort included patients with adequate identifiers for linkage with the National Death Index and the Organ Procurement and Transplantation Network who were enrolled in the PCCC registry between 1982 and 2003 and survived surgical repair of simple TOF. Data were analyzed between September 2015 and April 2018.We examined patient-associated and surgery-associated risk factors affecting survival.We analyzed the transplant-free survival during early (<6 years) and late (≥6 years) phase after TOF surgical repair.Of the 3283 patients who survived repair for simple TOF and met the study's inclusion criteria, 56.4% were male and 43.6% were female. Twenty-five-year survival following TOF repair was 94.5%. Multivariable analysis demonstrated increased risk of early mortality with staged repair (HR, 2.68; 95% CI, 1.59-4.49) and non-valve-sparing operation (HR, 3.76; 95% CI, 1.53-9.19). Presence of a genetic abnormality was associated with increased risk of death both in the early (HR, 3.64; 95% CI, 2.05-6.47) and late postoperative phase (HR, 4.41; 95% CI, 2.62-7.44).Long-term survival after simple TOF repair is excellent. Staged repair and non-valve-sparing operations were negatively associated with survival in the early postrepair phase but not the late postrepair phase. These data are important for patients with repaired TOF and their caretakers and may guide surgical strategies for optimizing the long-term outcomes of this population.
RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling
Authors: Zhan Yao, Yijun Gao, Wenjing Su, Rona Yaeger, Jessica Tao, Na Na, Ying Zhang, Chao Zhang, Andrey Rymar, Anthony Tao, Neilawattie M. Timaul, Rory Mcgriskin, Nathaniel A. Outmezguine, HuiYong Zhao, Qing Chang, Besnik Qeriqi, Mariano Barbacid, Elisa de Stanchina, David M Hyman, Gideon Bollag, Neal Rosen
Journal: Nature Medicine (2018)