tbuckley/cabot-search huggingface dataset:
Leukemic transformation among 1306 patients with primary myelofibrosis: risk factors and development of a predictive model
Authors: Rangit R. Vallapureddy, Mythri Mudireddy, Domenico Penna, Terra L. Lasho, Christy M. Finke, Curtis A. Hanson, Rhett P. Ketterling, Kebede H. Begna, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Journal: Blood Cancer Journal (2019)

Among 1306 patients with primary myelofibrosis (PMF), we sought to identify risk factors that predicted leukemic transformation (LT) in the first 5 years of disease and also over the course of the disease. 149 (11%) LT were documented; patients who subsequently developed LT (n = 149), compared to those who remained in chronic phase disease (n = 1,157), were more likely to be males (p = 0.02) and display higher circulating blasts (p = 0.03), ASXL1 (p = 0.01), SRSF2 (p = 0.001) and IDH1 (p = 0.02) mutations. Logistic regression analysis identified IDH1, ASXL1 and SRSF2 mutations, very high-risk karyotype, age > 70 years, male sex, circulating blasts ≥ 3%, presence of moderate or severe anemia and constitutional symptoms, as predictors of LT in the first 5 years of diagnosis. Time-to-event Cox analysis confirmed LT prediction for IDH1 mutation (HR 4.3), circulating blasts ≥ 3% (HR 3.3), SRSF2 mutation (HR 3.0), age > 70 years (HR 2.1), ASXL1 mutation (HR 2.0) and presence of moderate or severe anemia (HR 1.9). HR-based risk point allocation resulted in a three-tiered LT risk model: high-risk (LT incidence 57%; HR 39.3, 95% CI 10.8-114), intermediate-risk (LT incidence 17%; HR 4.1, 95% CI 2.4-7.3) and low-risk (LT incidence 8%). The current study provides a highly discriminating LT predictive model for PMF.
Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice
Authors: Minjie Shen, Feifei Wang, Meng Li, Nirnath Sah, Michael E. Stockton, Joseph J. Tidei, Yu Gao, Tomer Korabelnikov, Sudharsan Kannan, Jason D. Vevea, Edwin R. Chapman, Anita Bhattacharyya, Henriette van Praag, Xinyu Zhao
Journal: Nature Neuroscience (2019)
Significant Strain Variation in the Mutation Spectra of Inbred Laboratory Mice
Authors: Beth L Dumont
Journal: Molecular Biology and Evolution (2019)

Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood. Here, I use high-quality whole genome sequences from 29 inbred laboratory mouse strains to explore the root causes of strain variation in the mutation spectrum. My analysis leverages the unique, mosaic patterns of genetic relatedness among inbred mouse strains to identify strain private variants residing on haplotypes shared between multiple strains due to their recent descent from a common ancestor. I show that these strain-private alleles are strongly enriched for recent de novo mutations and lack signals of widespread purifying selection, suggesting their faithful recapitulation of the spontaneous mutation landscape in single strains. The spectrum of strain-private variants varies significantly among inbred mouse strains reared under standardized laboratory conditions. This variation is not solely explained by strain differences in age at reproduction, raising the possibility that segregating genetic differences affect the constellation of new mutations that arise in a given strain. Collectively, these findings imply the action of remarkably precise nucleotide-specific genetic mechanisms for tuning the de novo mutation landscape in mammals and underscore the genetic complexity of mutation rate control.
Rare subtypes of pancreatic cancer: Clinical outcomes and implications for clinical trial enrollment.
Authors: John David, Richard Tuli, Nicholas Nissen, Jun Gong, Alexandra Gangi, Veronica Placencio-Hickok, Gillian Gresham, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2019)

445 Background: Pancreatic cancer subtypes such as adenosquamous (AS) and squamous cell carcinoma (SCC) are rare and poorly understood. Treatment recommendations are extrapolated from pancreatic adenocarcinoma (AC) and these patients are often included in AC clinical trials. Herein, we describe clinical outcomes and inclusion of these subtypes in AC clinical trials. Methods: The National Cancer Database (NCDB) was queried to identify patients with AC, AS, and SCC between 2004 and 2014. Overall survival was evaluated using Kaplan-Meier methodology and multivariable (MVA) cox regression models were fit to identify differences in survival outcomes between subtypes adjusted by baseline demographic and clinical variables. ClinicalTrials.gov was interrogated to identify inclusion of AS and/or SCC in contemporary PA clinical trials. Results: We identified 115,061 patients with pancreatic cancer. Median age was 69 (range 18 – 90) and median follow up was 54 months (95% CI 53 – 55). Age, sex, median income, education, comorbidities, race, and stage were significantly associated with overall survival (OS). OS by subtype compared to AC: AS HR of 0.98 (p = 0.59) and SCC HR 1.29 (p &lt; 0.001). OS by subtype and stage compared to AC: stage I/II, AS HR of 0.98 (p = 0.59), SCC HR 1.44 (p = 0.001); stage III, AS HR of 1.32 (p = 0.02) and SCC HR 1.48 (p = 0.01); stage IV, AS HR of 1.1 (p = 0.06), SCC HR 1.2 (p = 0.06). Data from 283 phase II or III interventional trials completed between 2008-2018 were exported from clinicaltrials.gov. The majority of trials listed did not specify inclusion or exclusion of AS or SCC subtypes. Conclusions: This is the largest report of clinical outcomes in rare subtypes of pancreatic cancer. SCC and to a lesser extent, AS, have worse OS compared to AC. It is unclear how rare pancreatic cancer subtypes are handled in the inclusion and analysis of clinical trial data and how this may impact enrollment and survival outcomes.[Table: see text]
Chaplaincy for the 21st century: tackling a complex mosaic of agnosticism and provisional beliefs
Authors: Alistair B Appleby
Journal: BMJ (2019)

Patients deserve spiritual or existential care from someone they trust and feel connected with. In this respect, some patients may prefer a spiritual carer who is not religiously categorised. But isn’t the religious/secular categorisation of spiritual care providers itself problematic?1

Doctors frequently encounter patients who do not regularly attend religious services or affiliate …
Feasibility of Shockwave Coronary Intravascular Lithotripsy for the Treatment of Calcified Coronary Stenoses
Authors: Todd J. Brinton, Ziad A. Ali, Jonathan M. Hill, Ian T. Meredith, Akiko Maehara, Uday Illindala, Alexandra Lansky, Matthias Götberg, Nicolas M. Van Mieghem, Robert Whitbourn, Jean Fajadet, Carlo Di Mario
Journal: Circulation (2019)
Clinical Outcomes in Patients with Persistent Asthma (PA) by Attainment of Healthcare Effectiveness and Data Information Set (HEDIS) Measures: Stratification by Medication Management (MM) and/or Asthma Medication Ratio (AMR) Attainment
Authors: Aimee Near, Huan Huang, Rinat Ariely, Michael DePietro, Miao Jiang, Alberto Batista, Karthik Ramakrishnan, Giselle Mosnaim
Journal: Journal of Allergy and Clinical Immunology (2019)
Duodenal neuroendocrine tumors: Somewhere between the pancreas and small bowel?
Authors: Adriana Carolina Gamboa, Yuan Liu, Mohammad Yahya Zaidi, Rachel M Lee, Maria C. Russell, Kenneth Cardona, Shishir K. Maithel
Journal: Journal of Clinical Oncology (2019)

377 Background: While small sub-2 cm pancreatic neuroendocrine tumors (NETs) are often observed given their indolent behavior, small bowel NETs are routinely resected with a regional lymphadenectomy regardless of size given their malignant potential. Considering this variability, our aim was to define the natural history of duodenal (D-NETs) and determine the role of resection. Secondary aim was to define clinicopathologic factors associated with overall survival (OS) in pts who undergo resection. Methods: All pts in the National Cancer Database (2004-14) diagnosed with non-metastatic, non-functional D-NETs were included. Local resection (LR) was defined as local excision, polypectomy, or excisional biopsy. Anatomic resection (AR) was defined as removal with radical surgery. Tumor size was divided into three categories (&lt; 1 cm, 1-2 cm, ≥ 2 cm). Propensity score weighting analysis was used to create balanced cohorts between resection and no-resection pts; this was maintained in all three size categories. Primary endpoint was OS. Results: Among 5,502 pts, median age was 65 yrs; 52% were male. Median f/u was 51 mos. Median tumor size was 0.8 cm. Resection was performed in 72% (n = 3954) of which 61% were LR and 39% were AR. At least one lymph node (LN) was retrieved in 25% of pts, of which 44% had LN metastasis. 74% had negative margins. Resection and no-resection cohorts were propensity score weighted for age, gender, race, Charlson-Deyo score, and tumor grade, all of which were independently associated with OS on MV Cox regression analysis, thus creating balanced cohorts. Resection was associated with improved median OS compared to no-resection (MNR vs 94 mos, p &lt; 0.01); this persisted for all three size categories (&lt; 1 cm: MNR vs 194 mos; 1-2 cm: MNR vs 56 mos; &gt; 2 cm: MNR vs 90 mos; all p &lt; 0.01). Subset analysis of each size cohort who underwent resection showed that neither type of resection, LN retrieval, LN positivity, or margin status was associated with OS (all p &gt; 0.05). Conclusions: All pts with non-metastatic non-functional D-NETs should be considered for resection regardless of tumor size. Given their lack of prognostic value, the type of resection and extent of LN retrieval should be tailored to the patient’s clinical picture and safety profile.
Hepatitis B Virus–Specific T Cells as a Biomarker for Discontinuation of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B
Authors: Yongjun Tian, Jing‐hsiung James Ou
Journal: Hepatology (2018)

Tian, Yongjun Ph.D.; James Ou, Jing‐hsiung Ph.D.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information
Long-Term Effects of Finasteride on Prostate Cancer Mortality
Authors: Phyllis J Goodman, Catherine M Tangen, Amy K Darke, M Scott Lucia, Leslie G Ford, Lori M Minasian, Howard L Parnes, Michael L LeBlanc, Ian M Thompson
Journal: New England Journal of Medicine (2019)

Effects of Finasteride on Prostate Cancer MortalityTo the Editor: One man in nine will receive a diagnosis of prostate cancer during his lifetime.We previously reported the results of the Prostate Cancer Prevention Trial, in which 18,882 men were randomly assigned to receive finasteride or placebo for 7 years.The study's primary end point -the prevalence of prostate cancer during the 7 years of the trial -was met: the risk of prostate cancer with finasteride was 24.8% lower than the risk with placebo. 1 Paradoxically, the risk of high-grade cancer (Gleason score of 7 to 10) was higher with finasteride, a finding that led to recommendations against the use of finasteride for the prevention of prostate cancer.Subsequent trials showed that finasteride improved detection of prostate cancer and highgrade prostate cancer by improving the performance characteristics of the prostate-specific antigen (PSA) test, digital rectal examination, and the prostate biopsy.These biases could explain the paradox, but the questions of whether the greater number of high-grade prostate cancers could have led to diminished survival or to an increase in prostate cancer mortality persisted. 2n 2013, we addressed the first of these questions, finding similar survival rates in the two treatment groups of the Prostate Cancer Prevention Trial. 3 To address the second question, participants with a potentially valid Social Security number, whether last known to be alive or previously deceased, were submitted to the National Death Index in December 2014.Deaths from prostate cancer were reviewed by an end-point review committee.The cumulative incidence of death from prostate cancer was calculated, including all participants who underwent randomization, with deaths due to a cause other than prostate cancer classified as a competing risk.(For details, see the Supplementary Appendix, available with the full text of this letter at NEJM.org.)
Abstract 18893: Long-term Burden of Coarctation of the Aorta: A Contemporary Review of 842 Patients Up to the Seventh Decade of Life
Authors: Melissa G Lee, Sonya Babu-Narayan, Claudia Montanaro, Aleksander Kempny, Anselm Uebing, Yves d'Udekem, Michael Gatzoulis
Journal: Circulation (2017)

Introduction: Reports suggest 25% mortality within 30 years from repair of coarctation of the aorta (CoA). We aimed to examine the long-term outcome after CoA repair in a contemporary cohort. Metho...
A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism
Authors: Jonathan M. Davis, Ilea Heft, Stephen W. Scherer, James M. Sikela
Journal: American Journal of Psychiatry (2019)

The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population.The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview-Revised. The authors then combined data from previous studies (N=524) for final analyses.A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, NBPF1 and NBPF14 (R2=6.2%). Associations were preferentially found in multiplex versus simplex families.The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.
Adipose stromal vascular fraction and regenerative therapy in SSc: response to the article by Magalon <i>et al</i>
Authors: Paola Di Benedetto, Paola Cipriani, Piero Ruscitti, Vasiliki Liakouli, Roberto Giacomelli
Journal: Annals of the Rheumatic Diseases (2019)

We read with interest the report by Magalon et al ,1 supporting the use of stromal vascular fraction (SVF) derived from adipose tissue, as an innovative autologous biotherapy for patients affected by systemic sclerosis (SSc). This disease is a complex multisystem disorder, characterised by microvascular damage, dysregulation of innate and adaptive immunity and generalised fibrosis in the skin and multiple organs, lacking a specific therapy. SSc is classified into two subsets: limited cutaneous (lcSSc), in which the skin fibrosis is limited to the extremities (hands, arms and face), and diffuse cutaneous (dcSSc), in which the skin fibrosis progresses more rapidly, affecting the trunk and …
Evaluation of Genetic Variants of ALOX5 and LTC4S In Aspirin-Induced Acute Urticaria/Angioedema
Authors: Jose A. Cornejo-Garcia, James R. Perkins, Raquel Jurado-Escobar, Inmaculada Doña, Esther Barrionuevo, Natalia Pérez-Sánchez, Joan Bartra, María Isidoro-García, Maria Jose Torres Jaén, Cristobalina Mayorga
Journal: Journal of Allergy and Clinical Immunology (2019)
Immunotherapy-specific miRNA Expression Profiles In Spleenic CD4+ T-cells In A Peanut Sensitized Mouse Model Treated With Oral Or Epicutaneous Immunotherapy
Authors: Jörg Tost, Yimin Shen, Elodie Roche, Camille Plaquet, Veronique Dhelft, Lucie Mondoulet, Christian Daviaud, Christophe M. Dupont, Hugh A. Sampson, Vincent Dioszeghy
Journal: Journal of Allergy and Clinical Immunology (2019)
Unmet need in rheumatology: reports from the Targeted Therapies meeting 2018
Authors: Kevin L Winthrop, Michael E Weinblatt, Mary K Crow, Gerd R Burmester, Philip J Mease, Alexander K So, Vivian Bykerk, Ronald F Van Vollenhoven, Maxime Dougados, Jonathan Kay, Xavier Mariette, Joachim Sieper, Fritz Melchers, Bruce N Cronstein, Ethan Shevach, Ferdinand C Breedfeld, Joachim Kalden, Josef S Smolen, Daniel E Furst
Journal: Annals of the Rheumatic Diseases (2019)

To develop a comprehensive listing of the greatest unmet scientific and clinical needs in rheumatology. The 20th annual international Targeted Therapies meeting brought more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of five disease-specific groups with 20–30 experts assigned to each group based on expertise. Specific groups included rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus, connective tissue diseases and a basic science immunology group spanning all of these clinical domains. In each group, experts were asked to consider recent accomplishments within their clinical domain in the last year and update the unmet needs in three categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. While progress was noted among some of previously identified needs, both new needs were identified and themes from prior meetings were re-iterated: the need for better understanding the heterogeneity within each disease, and for identifying preclinical states of disease allowing treatment and prevention of disease in those at risk, and the elusive ability to cure disease. Within the clinical care realm, improved comorbidity management and patient-centred care continue to be unmet needs, and the need for new and affordable therapeutics was highlighted. Unmet needs for new and accessible targeted therapies, disease prevention and ultimately cure remain a priority in rheumatology.
Sixty seconds on . . . medical detection dogs
Authors: Gareth Iacobucci
Journal: BMJ (2019)

In a manner of speaking. As well as being man’s best friend and more than just a Christmas present, there is a growing body of evidence that a dog can be pretty effective in sniffing out illness and disease.

You bet. Last week, results from the biggest study of its kind by the University of Bristol1 found that dogs can be trained to successfully alert people …
Outcomes of Acute Myeloid Leukemia Patients with Indeterminate Day 14 Bone Marrow Results Treated with and without Re-Induction Chemotherapy
Authors: Omer Jamy, Charles Bodine, Rehan Sarmad, Awal Chadha, Pankit Vachhani, Luciano J Costa, Ayman Saad, Nikolaos Papadantonakis, Harry P. Erba, Antonio Di Stasi
Journal: Blood (2018)
Cutaneous adverse reactions in B-RAF positive metastatic melanoma following sequential treatment with B-RAF/MEK inhibitors and immune checkpoint blockade or vice versa. A single-institutional case-series
Authors: Abdul Rafeh Naqash, Danielle M. File, Carolyn M. Ziemer, Young E. Whang, Paula Landman, Paul B. Googe, Frances A. Collichio
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description. <h3>Methods</h3> After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients. <h3>Results</h3> Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1–8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence. <h3>Conclusions</h3> Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution.