tbuckley/cabot-search huggingface dataset:
Prognostic relevance of neutrophil to lymphocyte ratio (NLR) before anti-PD1 therapy in metastatic melanoma patients.
Authors: Daniel Vilarim Araujo, Rafael Vanin de Moraes, Victor Aurelio Ramos Sousa, Mauro Daniel Spina Donadio, Aline Fusco Fares, Helano C. Freitas, Vladmir C. Lima, Milton Jose Barros
Journal: Journal of Clinical Oncology (2017)

e21045 Background: Biomarkers to select the patients most likely to benefit from checkpoint inhibitors are urged. NLR is a simple way of measuring systemic inflammation and is an independent predictor of survival before Anti-CTLA4 therapy. We hypothesized if NLR is also a predictor of survival before Anti-PD1 therapy. Methods: We performed a retrospective review of the medical records of all consecutive metastatic melanoma patients who received Nivolumab treatment from January/2014 – February/2017, including 53 patients prospectively collected from an Expanded Access Program. Of 86 patients, 83 patients were included for demographic and efficacy analysis, and 74 had information about baseline pre-treatment NLR. We analyzed NLR as a continuous variable and categorised ≥ 5 vs. &lt; 5. Kaplan-Meier method was used for survival analysis. Long-rank test compared categories and Cox proportional hazards regression model was used to assess the prognostic significance of baseline NLR in univariate and multivariable analysis. Results: Median PFS for the entire population was 6,407 months (3,28 – 9,52) and median OS was not reached (NR) with a median FU of 10,74 months. The median NLR ratio was 3,11 (0,87 – 19). 18 patients (24,3%) had a ≥ 5 NLR vs. 56 (75,7%) &lt; 5. Median PFS for NLR ≥ 5 was: 2,3 (1,75 – 2,84) vs. 12,02 (5,11 – 18,93) for &lt; 5 (HR = 3,11; IC95% 1,52 – 6,27; p = 0,001). Median OS ≥ 5: 3,05 (2,06 – 4,04) vs. NR for &lt; 5 (HR = 5,88; IC95% 2,60 – 13,29; p = 0,001). NLR categorised remained statistically significant in multivariate analysis for PFS and NLR as a continuous variable remained statistically significant for both PFS and OS in multivariate analysis (Table 1). Conclusions: Baseline NLR is a rapid, simple, and cost-free predictor of survival before Anti-PD1 therapy. These results should be validated in a larger cohort of patients. [Table: see text]
Oval Cells Contribute to Fibrogenesis of Marginal Liver Grafts under Stepwise Regulation of Aldose Reductase and Notch Signaling
Authors: Xiao-Bing Liu, Chung-Mau Lo, Qiao Cheng, Kevin Tak-Pan Ng, Yan Shao, Chang-Xian Li, Sookja K Chung, Irene Oi Lin Ng, Jun Yu, Kwan Man
Journal: Theranostics (2017)

Background and Aims: Expanded donor criteria poses increased risk for late phase complications such as fibrosis that lead to graft dysfunction in liver transplantation. There remains a need to elucidate the precise mechanisms of post-transplant liver damage in order to improve the long-term outcomes of marginal liver grafts. In this study, we aimed to examine the role of oval cells in fibrogenic development of marginal liver grafts and explore the underlying mechanisms. Methods: Using an orthotopic rat liver transplantation model and human post-transplant liver biopsy tissues, the dynamics of oval cells in marginal liver grafts was evaluated by the platform integrating immuno-labeling techniques and ultrastructure examination. Underlying mechanisms were further explored in oval cells and an Aldose reductase (AR) knockout mouse model simulating marginal graft injury. Results: We demonstrated that activation of aldose reductase initiated oval cell proliferation in small-for-size fatty grafts during ductular reaction at the early phase after transplantation. These proliferative oval cells subsequently showed prevailing biliary differentiation and exhibited features of mesenchymal transition including dynamically co-expressing epithelial and mesenchymal markers, developing microstructures for extra-cellular matrix degradation (podosomes) or cell migration (filopodia and blebs), and acquiring the capacity in collagen production. Mechanistic studies further indicated that transition of oval cell-derived biliary cells toward mesenchymal phenotype ensued fibrogenesis in marginal grafts under the regulation of notch signaling pathway. Conclusions: Oval cell activation and their subsequent lineage commitment contribute to post-transplant fibrogenesis of small-for-size fatty liver grafts. Interventions targeting oval cell dynamics may serve as potential strategies to refine current clinical management.
Sixty seconds on . . . semaglutide
Authors: Nigel Hawkes
Journal: BMJ (2017)

So it seems. A study of 28 obese people in Leeds found that they lost an average of 5 kg and cut food intake by nearly a quarter when treated with semaglutide, an antidiabetes drug being developed by Novo Nordisk.1

There are lots more data. Documents submitted to the US Food and Drug Administration by the company show …
Abstract 11929: Simultaneous Assessment of Myocardial Viability With 18F-fluorodeoxyglucose Uptake and Late Gadolinium Enhancement by PET/MRI
Authors: Atsuro Masuda, Takayoshi Yamaki, Hiroyuki Kunii, Takeyuki Nanbu, Takamitsu Hara, Hitoshi Kubo, Hiroshi Ito, Seiichi Takenoshita, Yasuchika Takeishi
Journal: Circulation (2016)

Introduction: Both 18F-fluorodeoxyglucose (FDG) PET and late gadolinium enhancement on cardiac MRI (LGE-CMR) have been utilized for myocardial viability evaluation. However, the association between...
Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial
Authors: Piero Ferolla, Maria Pia Brizzi, Tim Meyer, Wasat Mansoor, Julien Mazieres, Christine Do Cao, Hervé Léna, Alfredo Berruti, Vincenzo Damiano, Wieneke Buikhuisen, Henning Grønbæk, Catherine Lombard-Bohas, Christian Grohé, Vincenzo Minotti, Marcello Tiseo, Javier De Castro, Nicholas Reed, Gabriella Gislimberti, Neha Singh, Miona Stankovic, Kjell Öberg, Eric Baudin
Journal: The Lancet Oncology (2017)
The Right Place at the Right Time: Medical Oncology Outpatients' Perceptions of Location of End-of-Life Care
Authors: Amy Waller, Rob Sanson-Fisher, Nicholas Zdenkowski, Charles Douglas, Alix Hall, Justin Walsh
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Helping people achieve their preferred location of care is an important indicator of quality end-of-life (EOL) care. Using a sample of Australian medical oncology outpatients, this study examined (1) their preferred location of EOL care; (2) their perceived benefits and worries of receiving care in that location; (3) the percentage who had discussed preferences with their doctor and/or support person; and (4) whether they wanted their doctor to ask them where they wanted to die. Methods: Adults with a confirmed diagnosis of cancer were approached between September 2015 and January 2016 in the waiting room of an Australian oncology outpatient clinic. Consenting participants completed a home-based pen-and-paper survey indicating preferred location of care, perceived benefits and worries of that location, whether they had discussed preferences with their doctors, and whether they were willing to be asked about their preferences. Results: A total of 203 patients returned the survey (47% of those eligible). Less than half preferred to be cared for at home (47%), 34% preferred a hospice/palliative care unit, and 19% preferred the hospital. Common benefits and worries associated with locations included perceived burden on others, familiarity of environment, availability of expert medical care, symptom management, and likelihood of having wishes respected. More patients had discussed preferences with their support persons (41%) than doctors (7%). Most wanted a doctor to ask them about preferred location of care (87%) and thought it was important to die in the location of their choice (93%). Conclusions: Patients were willing to have clinicians to ask them where they wanted to die, although few had discussed their preferences with doctors. Although home was the most preferred location for many patients, the overall variation suggests that clinicians should adopt a systematic approach to eliciting patient preferences.
Tdap Vaccination Coverage During Pregnancy — Selected Sites, United States, 2006–2015
Authors: Stephen Kerr, Carla M. Van Bennekom, Jennifer L. Liang, Allen A. Mitchell
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during the third trimester of each pregnancy to provide protection to newborns, who are at risk for pertussis-related morbidity and mortality (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University (the Birth Defects Study) has recorded data on vaccinations received during pregnancy since 2006. Among 5,606 mothers of infants without structural birth defects in this population (control group), <1% had received Tdap vaccine before 2009. By 2012, the percentage of mothers of infants in the control group (control infants) who had received Tdap increased to approximately 9%, and then in 2013 and continuing through 2015, increased markedly, to 28% and 54%, respectively. As the prevalence of maternal Tdap vaccination increased, so did the proportion of pregnant women who received Tdap in the third trimester, as recommended (94%-100% from 2010 to 2015). The vast majority of Tdap vaccinations (96%) were received in a traditional health care setting (e.g., the office of the woman's obstetrician or primary care physician or her prenatal clinic). Increasing vaccination coverage during pregnancy could help reduce the impact of pertussis on infant morbidity and mortality.
Prophylactic salpingectomy with delayed oophorectomy (PSDO): Feasibility study in women with BRCA mutations.
Authors: Denise R Nebgen, Laura L. Holman, Jean Hurteau, Elizabeth Keeler, Gary B. Chisholm, Charlotte C. Sun, Karen H. Lu
Journal: Journal of Clinical Oncology (2016)

1506 Background: Despite the benefits of risk reducing salpingo-oophorectomy (RRSO) for BRCA 1/2 mutation carriers, the adverse effects of surgical menopause on young women are problematic. Mounting evidence suggests the fallopian tube is the site of origin of BRCA-associated ovarian malignancies. However, no data exist to demonstrate whether salpingectomy lowers the risk of developing ovarian cancer (OC) in women with BRCA mutations. We conducted a feasibility study of PSDO to determine patient acceptance, and to evaluate pathology results and sexual function. Methods: Eligibility criteria included pre-menopausal women with BRCA mutations ages 30 to 47 years recruited from 2 academic centers with high risk clinics and gynecologic oncology programs. Patients (pts) chose one of 3 arms: screening, RRSO, or PSDO. Completion oophorectomy is recommended at age 39 for BRCA1 and age 45 for BRCA2 pts. All pts were seen twice yearly with CA125 and transvaginal ultrasound. Quality of life, sexuality, and menopausal questionnaires were administered through REDCap. Results: To date 40 patients have enrolled: n=20 in PSDO arm (median age=36; range 30-43); n=10 in screening arm (median age=37; range 32-43); and n=10 in RRSO arm (median age=44; range 36-47). No pts have undergone completion oophorectomy in the PSDO arm. Of the 40 pts on the study, n=14 (35%) were BRCA1 carriers, and n=26 (65%) were BRCA2 carriers. 20 pts (50%) had a personal history of breast cancer, and 16 pts (40%) had a family history of OC, (2 pts each had 2 family members with OC). No cases of occult OC and 1 serous tubal intraepithelial carcinomas (STICs) in an RRSO pt. 1/30 (3.3%) were seen. Post-operative responses at 6 and 12 months on the Menopausal Rating Scale and Sexual Activity Questionnaire indicate worsening scores for the RRSO group, while scores for the PSDO arm remained unchanged. Conclusions: At present, 40 BRCA pts have enrolled in the PSDO feasibility study with no adverse events. Compared with the RRSO arm, the PSDO arm shows a trends toward preservation of sexual functioning and absence of menopausal symptoms. Our experience suggests PSDO is an acceptable alternative for select BRCA pts. Long term outcome data on larger populations is needed. Clinical trial information: NCT01907789.
GP who had “wholly inappropriate” relations with patient is struck off
Authors: Clare Dyer
Journal: BMJ (2017)

A GP who engaged in a “wholly inappropriate” sexual relationship with a vulnerable patient has been struck off the UK medical register by a High Court judge, after the General Medical Council successfully appealed against a decision to suspend him for 12 months.1

A medical practitioners tribunal suspended Robert Stone, 62, for the maximum 12 months in August 2016. At a review hearing in August 2017 the tribunal decided that his fitness to practise was …
Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice
Authors: Iva Dincheva, Jianmin Yang, Anfei Li, Tina Marinic, Helena Freilingsdorf, Chienchun Huang, B.J. Casey, Barbara Hempstead, Charles E. Glatt, Francis S. Lee, Kevin G. Bath, Deqiang Jing
Journal: American Journal of Psychiatry (2017)

Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.
Interpreting Biomarker Results in Individual Patients With Mild Cognitive Impairment in the Alzheimer’s Biomarkers in Daily Practice (ABIDE) Project
Authors: Ingrid S. van Maurik, Marissa D. Zwan, Betty M. Tijms, Femke H. Bouwman, Charlotte E. Teunissen, Philip Scheltens, Mike P. Wattjes, Frederik Barkhof, Johannes Berkhof, Wiesje M. van der Flier
Journal: JAMA Neurology (2017)

Biomarkers do not determine conversion to Alzheimer disease (AD) perfectly, and criteria do not specify how to take patient characteristics into account. Consequently, biomarker use may be challenging for clinicians, especially in patients with mild cognitive impairment (MCI).
Vigilancia de VIH/Sida en Europa: datos actualizados a finales de 2000
Authors: F F Hamers, J Alix, C Semaille, H Pilkington, A M Downs
Journal: Eurosurveillance (2001)

En la region occidental de Europa, la incidencia de sida disminuyo un 12% en 2000, comparada con la de 1999, mientras que las tasas de nuevos diagnosticos de VIH no presentan una evolucion global clara, aunque aumentan en personas infectadas tras contacto heterosexual, muchas de las cuales son inmigrantes. En la region oriental, las tasas de nuevos diagnosticos de VIH, principalmente en usuarios de drogas por via parenteral, aumentan rapidamente, en particular en Estonia, Letonia y la Federacion Rusa. En la region central, las tasas de sida e infecciones por VIH permanecen bajas.
Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer
Authors: Angela Chou, Danielle Froio, Adnan M Nagrial, Ashleigh Parkin, Kendelle J Murphy, Venessa T Chin, Dalia Wohl, Angela Steinmann, Rhys Stark, Alison Drury, Stacey N Walters, Claire Vennin, Andrew Burgess, Mark Pinese, Lorraine A Chantrill, Mark J Cowley, Timothy J Molloy, Nicola Waddell, Amber Johns, Sean M Grimmond, David K Chang, Andrew V Biankin, Owen J Sansom, Jennifer P Morton, Shane T Grey, Thomas R Cox, John Turchini, Jaswinder Samra, Stephen J Clarke, Paul Timpson, Anthony J Gill, Marina Pajic
Journal: Gut (2017)

Objective Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. Design Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (&gt;500 specimens). Results Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. Conclusion This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
Lung ultrasound and neonatal ARDS: is Montreux closer to Berlin than to Kigali? – Authors' reply
Authors: Daniele De Luca, Anton H van Kaam, David G Tingay, Sherry E Courtney, Olivier Danhaive, Virgilio P Carnielli, Luc J Zimmermann, Martin C J Kneyber, Pierre Tissieres, Joe Brierley, Giorgio Conti, Jane J Pillow, Peter C Rimensberger
Journal: The Lancet Respiratory Medicine (2017)
Data Science in Radiology: A Path Forward
Authors: Hugo J.W.L. Aerts
Journal: Clinical Cancer Research (2017)

Abstract Artificial intelligence (AI), especially deep learning, has the potential to fundamentally alter clinical radiology. AI algorithms, which excel in quantifying complex patterns in data, have shown remarkable progress in applications ranging from self-driving cars to speech recognition. The AI application within radiology, known as radiomics, can provide detailed quantifications of the radiographic characteristics of underlying tissues. This information can be used throughout the clinical care path to improve diagnosis and treatment planning, as well as assess treatment response. This tremendous potential for clinical translation has led to a vast increase in the number of research studies being conducted in the field, a number that is expected to rise sharply in the future. Many studies have reported robust and meaningful findings; however, a growing number also suffer from flawed experimental or analytic designs. Such errors could not only result in invalid discoveries, but also may lead others to perpetuate similar flaws in their own work. This perspective article aims to increase awareness of the issue, identify potential reasons why this is happening, and provide a path forward. Clin Cancer Res; 24(3); 532–4. ©2017 AACR.
Retroviral and Lentiviral Safety Analysis of Gene-Modified T Cell Products and Infused HIV and Oncology Patients
Authors: Katherine T. Marcucci, Julie K. Jadlowsky, Wei-Ting Hwang, Megan Suhoski-Davis, Vanessa E. Gonzalez, Irina Kulikovskaya, Minnal Gupta, Simon F. Lacey, Gabriela Plesa, Anne Chew, J. Joseph Melenhorst, Bruce L. Levine, Carl H. June
Journal: Molecular Therapy (2017)

Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52.8 years to observe one positive RCR/L event, highlighting the unlikelihood of RCR/L development. Additionally, we estimate the median time for lentivirus-modified T cell products to fall below the 1% vector sequence threshold in peripheral or whole blood that would trigger vector integration site analysis. These estimated times are 1.4 months in hematologic malignancies, 0.66 month in solid tumors, and 0.92 month in HIV. Based on these considerable safety data in HIV and oncology and recent Biologics License Applications filed for lentiviral-modified T cell products for hematologic malignancies, this may be an opportune time to re-evaluate the current guidelines for T cell gene therapy product testing and long-term patient monitoring. Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52.8 years to observe one positive RCR/L event, highlighting the unlikelihood of RCR/L development. Additionally, we estimate the median time for lentivirus-modified T cell products to fall below the 1% vector sequence threshold in peripheral or whole blood that would trigger vector integration site analysis. These estimated times are 1.4 months in hematologic malignancies, 0.66 month in solid tumors, and 0.92 month in HIV. Based on these considerable safety data in HIV and oncology and recent Biologics License Applications filed for lentiviral-modified T cell products for hematologic malignancies, this may be an opportune time to re-evaluate the current guidelines for T cell gene therapy product testing and long-term patient monitoring.