tbuckley/cabot-search huggingface dataset:
Left Ventricular Assist Devices in Patients With Active Malignancies
Authors: Ilana Schlam, Andy Y. Lee, Song Li, Farooq H. Sheikh, Raja Zaghlol, Binaya Basyal, Christopher Gallagher, Ezequiel Molina, Claudius Mahr, Richard K. Cheng, Ana Barac
Journal: JACC CardioOncology (2021)

There are limited data to guide oncology and cardiology decision-making in patients with a left ventricular assist device (LVAD) and concurrent active malignancy. The goal of this study was to describe cancer treatment approaches, complications, and survival among patients with active cancer on LVAD support in 2 tertiary heart failure and oncology programs. In this retrospective cohort study, LVAD databases were reviewed to identify patients with a cancer diagnosis at the time of or after LVAD implantation. We created a 3:1 matched cohort based on age, sex, etiology of cardiomyopathy, LVAD implant strategy, and INTERMACS profile stratified by site. Kaplan-Meier analysis and Cox proportional hazards models were used to compare survival between patients with cancer and non-cancer comparators. Among 1,123 patients who underwent LVAD implantation between 2005 and 2019, 22 patients with LVADs with active cancer and 66 matched non-cancer comparators were identified. Median age was 62 years (range 41 to 73 years); 50% of patients with cancer were African-American, and 27% were women. Prostate cancer, followed by renal cell cancer and hematologic malignancies were the most common diagnoses. There was no significant difference in unadjusted Kaplan-Meier median survival estimates from the time of LVAD placement between patients with cancer (3.53 years; 95% confidence interval [CI]: 1.41 to 5.33) and non-cancer comparators (3.03 years; 95% CI: 1.83 to 5.26; log-rank P = 0.99). In Cox proportional hazard models, cancer diagnosis as a time-varying variable was associated with a statistically significant increase in death (hazard ratio: 2.05; 95% CI: 1.03 to 4.12; P = 0.04). Patients with cancer had less gastrointestinal bleeding compared with matched non-cancer comparators (P = 0.016). Other complications were not significantly different. Our study provides initial feasibility and safety data and set a framework for multidisciplinary team management of patients with cancer and LVADs.
Oncologist management of NTRK fusion-positive NSCLC improves after virtual patient simulation participation.
Authors: Michelle Arielle Worst, Brittany Cain, Tipp Nelson, Jacob Cohen, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2021)

e23008 Background: Although relatively rare, neurotrophic receptor tyrosine kinase (NTRK) fusions, represent a clinically relevant subgroup of NSCLC that can derive benefit from targeted therapies. Relatively quick and durable responses have been achieved with these targeted therapies in advanced NSCLC and intracranial activity has also been observed. The objective of this study was to determine if an online, virtual patient simulation (VPS)-based continuing medical education (CME) intervention improved performance of oncologists in using appropriate strategies to diagnose and manage patients with NTRK fusion-positive advanced NSCLC. Methods: The CME intervention consisted of two patient cases presented in a VPS platform that allowed learners to order lab tests, diagnoses and treatments in a manner matching the scope and depth of actual practice. Clinical decisions made by the learners using open field entries within an EHR interface were analyzed and, after each decision, tailored clinical guidance (CG) was provided based on current evidence and expert recommendation. Learner decisions were collected post-CG and compared with each user’s baseline (pre-CG) data using a McNemar’s test to determine P values. Results were then aggregated for the two cases based on clinical decisions and stratified by practice setting. The activity posted July 31, 2020; data were collected through December 1, 2020. Results: Overall significant improvements were seen after CG in clinical decisions made by oncologists in both the community and academic settings [reported as % absolute improvement (% correct pre-CG vs % correct post-CG); P value]. Conclusions: This analysis demonstrated that VPS that immerses and engages oncologists in an authentic and practical learning experience can significantly improve evidence-based clinical decisions related to the diagnosis and management of patients with NTRK fusion-positive advanced NSCLC. Despite the improvements, additional educational activities are needed to address any residual gaps and further increase oncologists’ ability in this clinical setting.[Table: see text]
Use of a high-sensitivity anti-Mullerian hormone (AMH) assay to determine ovarian function after chemotherapy for early breast cancer.
Authors: Florian Clatot, Kelsey Thomas, Matteo Lambertini, Nathalie Olympios, Orianne Duhamel, Anne Perdrix, Richard Anderson
Journal: Journal of Clinical Oncology (2021)

552 Background: It is now well established that AMH can indicate the extent of chemotherapy-induced damage on the ovarian reserve. Very low AMH levels in women after chemotherapy for early breast cancer (eBC) may indicate treatment-induced premature ovarian failure (POI), but the evidence to implement its routine clinical use remains limited. Methods: AMH was measured (Roche cobas autoanalyser) in 197 women aged 40-45 years at diagnosis treated with anthracycline/cyclophosphamide/taxane based chemotherapy for eBC, with no previous endocrine therapy and no subsequent aromatase inhibitor exposure or ovarian suppression. 76% were ER positive and received tamoxifen. The primary objective was to assess the relationships between AMH levels at 6 months after chemotherapy (AMH6) with subsequent ovarian function at 30 months. This included accuracy of prediction of loss of ovarian function at 30 months (E30) after chemotherapy by AMH levels at 6 months (AMH6) and the value of other endocrine/clinical factors pretreatment and at 6 months. Multivariate analysis was performed with data were split into 70% training and 30% testing sets with results reported for model performance on the test set. Results: AMH fell from a median of 0.62 (IQR 0.21-1.31) ng/ml pretreatment to become undetectable ( &lt; 0.01ng/ml) in 137 (70%) of women at 6 months. AMH showed very little recovery, being undetectable in 115 women at 18 months and 119 at 30 months. In those with detectable AMH at 30 months, it remained very low, median 0.07ng/ml, max 0.82ng/ml but nevertheless it reflected ovarian function. Thus median estradiol at 30 months (E30) was 50 pmol/l (IQR 34-68) in women with undetectable AMH at that time, vs 313 pmol/l (IQR 102-1052) in the 80 women with detectable AMH. AMH at 6 months was predictive of ovarian function at 30 months, as E30 was 56 pmol/l (IQR 40-104) in women with undetectable AMH6 vs 258pmol/l (IQR 69-780; p &lt; 0.0001) in women with detectable AMH6, and the positive predictive value (PPV) of AMH being undetectable at 6 months and remaining so at 30 months was 77%. Random forest analysis identified BMI as a non-endocrine predictive factor of E30. Using a stringent cutoff of ≤50pmol/l (13.6 pg/ml) and adding 1:9 weighting to improve PPV gave a test validated PPV of 79.0% while maintaining AUC at 83.7% for prediction of E30. Other classifiers performed less well than random forests. Conclusions: Measurement of AMH at 6 months after chemotherapy has predictive value for later ovarian function, and combining this with other endocrine and baseline data improves discriminative ability. This approach indicates the potential role of multivariate analysis based on AMH measured shortly after chemotherapy to helping optimise subsequent endocrine therapy.
Over the counter H2 receptor antagonists
Authors: A C Douds, J D Maxwell, J R B Cooper
Journal: BMJ (1994)

Improvements in living standards, particularly arising from more disposable income * Environmental improvements-for example, housing, roads * Reduction in tobacco consumption * Improvements in education and communication * Better, more effective, and easier access to health services Futuret * High standards of living and lower unemployment rates * Decline of tobacco consumption * Better health services delivering more effective treatments * Education, to include change in behaviour to reduce risk factors
Early-onset stage II/III colorectal adenocarcinoma in the IDEA database: Treatment adherence, toxicities, and outcomes from adjuvant fluoropyrimidine and oxaliplatin.
Authors: Elisa Fontana, Jeffrey P. Meyers, Alberto F. Sobrero, Timothy Iveson, Anthony Frank Shields, Julien Taieb, Takayuki Yoshino, Ioannis Souglakos, Elizabeth Catherine Smyth, Florian Lordick, Markus H. Moehler, Andrea Harkin, Roberto Labianca, Jeffrey A. Meyerhardt, Thierry Andre, Takeharu Yamanaka, Ioannis Boukovinas, Axel Grothey, Irit Ben-Aharon, Qian Shi
Journal: Journal of Clinical Oncology (2021)

3517 Background: Incidence of early-onset colorectal cancer (eoCRC, age &lt; 50) is steadily increasing. Decisions on adjuvant treatment (adjTx) regimen and duration should consider tx adherence, toxicity (tox) and expected outcomes in a population with life-expectancy longer than late onset CRC (loCRC, age ≥ 50). Methods: Individual patient data from stage II/III patients (pts) from 6 randomised trials in the IDEA database were used to compare characteristics, tx adherence, and adverse events of eoCRC to loCRC. To reduce the confounder of non-cancer-related deaths due to age/co-morbidities, time-to-recurrence (TTR) and cancer-specific survival (CSS) were compared by stratified Gay k-sample test. 5-year cancer-specific mortality (CSM) rate were estimated by adjusted cumulative incidence function. 3-year relapse-free survival (RFS) rate were compared by stratified and adjusted COX models. Results: Out of 16,349 pts included, 1564 (9.6%) were eoCRC. Compared to loCRC, eoCRC had lower percent of male pts (51% vs 57%, p &lt; 0.01) better performance status (PS0 86% vs 80%, p &lt; 0.01), similar T stage distribution (% T1-3/T4: 76/24 vs 77/23, p = 0.97), higher rate of N2 disease (24% vs 22%, p &lt; 0.01), more likely to complete pre-planned duration of adjTx (83.2% vs 78.2%, p &lt; 0.01) and received a higher tx intensity especially with 6 month tx (mean oxaliplatin dose intensity 75% vs 72%, p &lt; 0.01; capecitabine 85% vs 78%, p &lt; 0.01; 5FU 85% vs 82% p &lt; 0.01). Gastrointestinal tox was more common in eoCRC (any grade nausea 58% vs 45%, p &lt; 0.01; any grade vomiting 22% vs 16%, p &lt; 0.01); haematological tox was more frequent in loCRC (62% vs, 69%, p = &lt; 0.01); any grade neuropathy rate was similar (75%). Significant interaction was found between age and T stage for TTR (p = 0.04). Clinical outcome estimates and comparisons are shown in Table. Notably, high risk stage III (T4/N2) eoCRC had significantly lower 3-y RFS rate (54% vs 64%, HR adj 0.74, p &lt; 0.01). Conclusions: eoCRC have better tx adherence than loCRC, as expected. While in high risk stage II and low risk stage III, cancer-specific outcomes are not different, in high risk stage III young age is negatively prognostic and associated with significantly higher relapse rate and risk of CRC death; this is despite a higher administered adjTx-intensity, suggesting a more aggressive disease biology. Clinical trial information: NCT00749450 (SCOT); NCT00646607 (TOSCA); NCT01150045 (CALGB/SWOG 80702); NCT00958737 (IDEA France) [Table: see text]
Development and validation of an unfolded protein response-related gene signature to predict overall survival in HNSCC.
Authors: Jun Chen, Bei Zhang
Journal: Journal of Clinical Oncology (2021)

e18033 Background: Genomic expression profiles have enabled the classification of head and neck squamous cell carcinoma (HNSCC) into molecular sub-types and provide prognostic information, which have implications for the personalized treatment of HNSCC beyond clinical and pathological features. Methods: Gene-expression profiling was identified in TCGA- HNSCC (n = 492) and validated with the Gene Expression Ominibus (GEO) dataset(n = 270) for which RNA sequencing data and clinical covariates were available. A single-sample gene set enrichment analysis (ssGSEA) algorithm were used to quantified the levels of various hallmarks of cancer. And LASSO Cox regression model was used to screen robust prognostic biomarkers to identify the best set of survival-associated gene signatures in HNSCC. Statistical analyses were performed using R version 3.4.4. Results: We identified unfolded protein response as the primary risk factor for survival（cox coefficient = 17.4 [8.4-26.3], P &lt; 0.001）among various hallmarks of cancer in TCGA- HNSCC. And unfolded protein response ssGESA scores were significantly elevated in patients who died during follow up (P = 0.009). Kaplan-Meier analysis showed that patients with low ssGSEA scores of unfolded protein response exhibited better OS (HR = 0.69, P = 0.008). And we established an unfolded protein response-related gene signature based on lasso cox. We then apply the unfolded protein response -related gene signature to classify patients into the high risk group and the low risk group with the cutoff of 0.18. Adjusted for stage，age，gender, our signature was an independent risk factor for overall survival in TCGA cohorts (HR = 0.39 [0.28-0.53],P = &lt; 0.001). In external independent cohorts, similar results were observed. In the validation cohort GEO65858, the patients with high unfolded protein response score showed longer survival (HR = 0.62 [0.38-1.0], P = 0.049). And adjusted for stage，age，HPV state, the multivariate cox regression analysis showed that unfolded protein response-related gene signature exhibited an independent risk prediction for overall survival in 270 patients with HNSCC (HR = 0.57 [0.35-0.94], P = 0.026). Conclusions: By analyzing the gene-expression data with bioinformation approach, we developed and validated a risk prediction model with unfolded protein response -related expression scores in HNSCC, which have the potential to identify patients who could have better overall survival.
Reimagining pilocytic astrocytomas in the context of pediatric low-grade gliomas
Authors: Till Milde, Fausto J Rodriguez, Jill S Barnholtz-Sloan, Nirav Patil, Charles G Eberhart, David H Gutmann
Journal: Neuro-Oncology (2021)

Abstract Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.
Evaluating the Prevention Benefit of HCV Treatment: Modeling the SToP‐C Treatment as Prevention Study in Prisons
Authors: Aaron G. Lim, Jack Stone, Behzad Hajarizadeh, Marianne Byrne, Georgina M. Chambers, Natasha K. Martin, Jason Grebely, Gregory J. Dore, Andrew R. Lloyd, Peter Vickerman
Journal: Hepatology (2021)

Background and Aims Between 2014 and 2019, the SToP‐C trial observed a halving in HCV incidence in four Australian prisons following scale‐up of direct‐acting antiviral (DAA) therapy. However, the contribution of HCV treatment to this decline is unclear because the study did not have a control group. We used modeling to consider this question. Approach and Results We parameterized and calibrated a dynamic model of HCV transmission in prisons to data from each SToP‐C prison on incarceration dynamics, injecting drug use, HCV prevalence trends among prison entrants, baseline HCV incidence before treatment scale‐up, and subsequent HCV treatment scale‐up. The model projected the decrease in HCV incidence resulting from increases in HCV treatment and other effects. We assessed whether the model agreed better with observed reductions in HCV incidence overall and by prison if we included HCV treatment scale‐up, and its prevention benefits, or did not. The model estimated how much of the observed decrease in HCV incidence was attributable to HCV treatment in prison. The model projected a decrease in HCV incidence of 48.5% (95% uncertainty interval [UI], 41.9‐54.1) following treatment scale‐up across the four prisons, agreeing with the observed HCV incidence decrease (47.6%; 95% CI, 23.4‐64.2) from the SToP‐C trial. Without any in‐prison HCV treatment, the model indicated that incidence would have decreased by 7.2% (95% UI, −0.3 to 13.6). This suggests that 85.1% (95% UI, 72.6‐100.6) of the observed halving in incidence was from HCV treatment scale‐up, with the remainder from observed decreases in HCV prevalence among prison entrants (14.9%; 95% UI, −0.6 to 27.4). Conclusions Our results demonstrate the prevention benefits of scaling up HCV treatment in prison settings. Prison‐based DAA scale‐up should be an important component of HCV elimination strategies.
HGG-08. CREATION OF AN IN VITRO AND IN VIVO MODEL SYSTEM FOR THE STUDY OF H3.1K27M DIPG
Authors: Joseph Lagas, Lihua Yang, Oren Becher, Joshua Rubin
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating pediatric high-grade glioma that occurs in the brainstem with a median survival of less than 1 year. A greater understanding of the early tumorigenic events is essential for the development of effective therapeutics. DIPG is characterized by founder mutations in histone H3, either H3.1K27M or H3.3K27M. These mutations cause global hypomethylation, resulting in aberrant gene expression. Little is known about how this mechanism contributes to tumorigenesis. Interestingly, H3.1K27M DIPG show an increased incidence in females, whereas H3.3K27M DIPG shows no sex difference. This illustrates that the tumorigenic potential of H3.1K27M may be different between the sexes. Few models of DIPG incorporate the study of H3.1K27M despite the fact that it represents a unique opportunity to obtain valuable information on the tumorigenesis of DIPG through the study of the sex difference. Thus, we have created an in vitro and in vivo model system for H3.1K27M DIPG utilizing the RCAS mouse model system. This system utilizes RCAS vectors and a RCAS-ntva transgenic mouse line to deliver specific mutations to nestin expressing cells in the brainstem, including oligodendrocyte progenitor cells (OPCs), the predicted cell of origin. Delivering H3.1K27M, ACVR1 R206H, and PDGFaa at postnatal day 7 produces DIPG-like tumors in vivo, confirmed by H and E staining, between 60–110 days post injection. Additionally, confirmed through immunofluorescence staining, we can isolate a pure population of OPCs via immunopanning and infect them with RCAS vectors in vitro to produce stable expression of H3.1K27M. Introduction of H3.1K27M alone into male and female OPC cultures provides an opportunity to compare the early tumorigenic effects of H3.1K27M between the sexes in vitro. These results demonstrate that we have created an in vitro and in vivo H3.1K27M DIPG model system for the study of sex differences and tumorigenesis in DIPG.
Covid-19: Eight in 10 doctors have experienced moral distress during pandemic, BMA survey finds
Authors: Abi Rimmer
Journal: BMJ (2021)

Covid-19: Eight in 10 doctors have experienced moral distress during pandemic, BMA survey finds Abi RimmerNearly 80% of doctors say that the term "moral distress" resonates with their experiences of working during the pandemic, and over half say the same for "moral injury," a BMA survey has found.
Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
Authors: Jan C. Brase, Robert F.H. Walter, Alexander Savchenko, Daniel Gusenleitner, James Garrett, Tobias Schimming, Renata Varaljai, Deborah Castelletti, Ju Kim, Naveen Dakappagari, Ken Schultz, Caroline Robert, Georgina V. Long, Paul D. Nathan, Antoni Ribas, Keith T. Flaherty, Boguslawa Karaszewska, Jacob Schachter, Antje Sucker, Kurt W. Schmid, Lisa Zimmer, Elisabeth Livingstone, Eduard Gasal, Dirk Schadendorf, Alexander Roesch
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells. Patients and Methods: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600–mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening. Results: Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months–not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4–38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers. Conclusions: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
HGG-27. HNRNPA1 SPLICED VARIANT SENSITIZATION EFFECT DISCLOSED IN GLIOMA CELLS
Authors: Ajay Yadav
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is aggressive brain tumor. Glioma heterogeneity builds in hypoxic condition due to its intrinsic high apoptosis rate cause to develop a high selection clonal pressure. HnRNPA1 plays a key role in developing glycolytic tumor, shows its high expression exclusively in hypoxic glioma cells. Recently we observed one more spliced variant of hnRNPA1, encoding higher isoform, exclusively abundant in resistant glioma cell lines. Widely around the scientific community HnRNPA1 splice factor family protein was found distinctly regulating resistant glioma phenotype. To support our hypothesis, methodology we perform includes various apoptosis assays to critically understand hnRNPA1 spliced variant dependent pathway in Temozolomide resistant U87 glioma cells. Proteomic based apoptotic array and angiogenic array enable us to visualize selective knock down of hnRNPA1 has dominant role in promoting apoptotic cascade. Additionally, flow cytometry base annexin V-PI staining technique to understand early and late apoptosis was measured in selective hnRNPA1 spliced variant knockdown cells in presence or absence of PI3 kinase inhibitor wortmannin (5 micro molar). Results showed hnRNPA1 higher isoform knock down promotes more apoptosis compare to lower isoform. Interestingly, overexpression of HnRNPA1 higher isoform or lower isoform alone doesn’t promote apoptosis, however is prominently higher apoptosis in Bortezomib treated U87 glioma cells. These both isoforms are presently majorly in gliomas, but somehow for long was not recognized. Conclusion is to explore more related novel finding or therapeutic strategy to target higher isoform of hnRNPA1, using invivo mouse xenograft model.