tbuckley/cabot-search huggingface dataset:
Postdisaster Pharmacy Needs
Authors: Bridget Kuehn
Journal: JAMA (2018)

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IgG4-Related Disease Simulating Carcinoma Colon With Diffuse Peritoneal Carcinomatosis on 18F-FDG PET/CT
Authors: Shelvin Kumar Vadi, Ashwin Singh Parihar, Rajender Kumar, Harmandeep Singh, Bhagwant Rai Mittal, Amanjit Bal, Saroj Kumar Sinha
Journal: Clinical Nuclear Medicine (2018)

IgG4-related disease (IgG4-RD) continues to be a diagnostic challenge and a great mimicker of malignancies. We report here a case of young man who presented with subacute intestinal obstruction with initial imaging and clinical features suggestive of carcinoma colon. F-FDG PET/CT showed diffuse peritoneal carcinomatosis pattern typically seen with abdominal malignancies. However, the histopathology and the raised IgG4 levels diagnosed it to be IgG4-RD. Although F-FDG PET/CT has typical patterns corresponding to the multisystemic involvement of IgG4-RD, the index case did not show any such findings.
Prognostic markers in triple-negative breast cancer (TNBC): The role of androgen receptor, e-cadherin, and Ki67.
Authors: Giuseppina Rosaria Rita Ricciardi, Barbara Adamo, Valeria Barresi, Antonio Ieni, Tindara Franchina, Michele Caruso, Alessandra Zacchia, Carmine Fazzari, Giovanni Tuccari, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2015)

1089 Background: TNBC represents a group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. However, TNBC is clinically and biologically heterogeneous and no clear prognostic biomarker has been identified. We evaluated the prognostic value of various clinical-pathological variables, including androgen receptor (AR), E-cadherin (CDH1) and Ki67. Methods: This is an observational, retrospective study of 99 patients (pts) with TNBC diagnosed during 2000-2010 in two Italian hospitals. All pts received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) of the primary tumors was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ≥ 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as > 14% positive tumor cells. Cox proportional hazard univariate and multivariable models were used to evaluate the associations of each variable with relapse-free survival (RFS) and overall survival (OS). Distribution of samples within groups was compared using a Chi-square test. Results: Median age was 61 years (range 33-83). The majority of tumors were ductal (n = 85, 85.8%), node-negative (n = 49, 58.3%), grade 3 (n = 66, 66.7%) and showed high Ki67 (n = 74, 74.7%). The distribution of tumor stage was I (n = 32, 32.3%), II (n = 37, 37.4%), III (n = 30, 30.3%). AR, CDH1 expression was found in 17.1% and 50.5% of the cases. Only 26.6% of AR-positive cases were grade 3 compared with 68.2% of grade 3 in AR-negative cases (p =0.01). At median follow-up of 62.0 months (range 3.0-118.0), 95 pts were evaluable for RFS and OS. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly associated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status and grade. Conclusions: Our findings support the potential prognostic value of molecular biomarkers such as CDH1 that might be useful to classify subgroups of TNBC.
FDA names and shames branded pharma companies that obstruct generics development
Authors: Owen Dyer
Journal: BMJ (2018)

The US drug regulator has launched a website that identifies branded drug companies that it says shirk legal and ethical requirements to share their products with generics makers in an effort to slow the development of rival products.1

“No patients should be priced out of medicines they need to support their health,” said the Food and Drug Administration’s commissioner, Scott Gottlieb. “At the FDA, we’re taking steps across a broad range of areas to improve new and generic drug competition as a way to improve access and affordability. Among these efforts, we’re especially focused on addressing tactics we sometimes hear …
Global Burden of Multiple Myeloma
Authors: Andrew J. Cowan, Christine Allen, Aleksandra Barac, Huda Basaleem, Isabela Bensenor, Maria Paula Curado, Kyle Foreman, Rahul Gupta, James Harvey, H. Dean Hosgood, Mihajlo Jakovljevic, Yousef Khader, Shai Linn, Deepesh Lad, Lorenzo Mantovani, Vuong Minh Nong, Ali Mokdad, Mohsen Naghavi, Maarten Postma, Gholamreza Roshandel, Katya Shackelford, Mekonnen Sisay, Cuong Tat Nguyen, Tung Thanh Tran, Bach Tran Xuan, Kingsley Nnanna Ukwaja, Stein Emil Vollset, Elisabete Weiderpass, Edward N. Libby, Christina Fitzmaurice
Journal: JAMA Oncology (2018)

Multiple myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality. A comprehensive description of the global burden of MM is needed to help direct health policy, resource allocation, research, and patient care.To describe the burden of MM and the availability of effective therapies for 21 world regions and 195 countries and territories from 1990 to 2016.We report incidence, mortality, and disability-adjusted life-year (DALY) estimates from the Global Burden of Disease 2016 study. Data sources include vital registration system, cancer registry, drug availability, and survey data for stem cell transplant rates. We analyzed the contribution of aging, population growth, and changes in incidence rates to the overall change in incident cases from 1990 to 2016 globally, by sociodemographic index (SDI) and by region. We collected data on approval of lenalidomide and bortezomib worldwide.Multiple myeloma mortality; incidence; years lived with disabilities; years of life lost; and DALYs by age, sex, country, and year.Worldwide in 2016 there were 138 509 (95% uncertainty interval [UI], 121 000-155 480) incident cases of MM with an age-standardized incidence rate (ASIR) of 2.1 per 100 000 persons (95% UI, 1.8-2.3). Incident cases from 1990 to 2016 increased by 126% globally and by 106% to 192% for all SDI quintiles. The 3 world regions with the highest ASIR of MM were Australasia, North America, and Western Europe. Multiple myeloma caused 2.1 million (95% UI, 1.9-2.3 million) DALYs globally in 2016. Stem cell transplantation is routinely available in higher-income countries but is lacking in sub-Saharan Africa and parts of the Middle East. In 2016, lenalidomide and bortezomib had been approved in 73 and 103 countries, respectively.Incidence of MM is highly variable among countries but has increased uniformly since 1990, with the largest increase in middle and low-middle SDI countries. Access to effective care is very limited in many countries of low socioeconomic development, particularly in sub-Saharan Africa. Global health policy priorities for MM are to improve diagnostic and treatment capacity in low and middle income countries and to ensure affordability of effective medications for every patient. Research priorities are to elucidate underlying etiological factors explaining the heterogeneity in myeloma incidence.
Multiregion sequencing of penile cancer to reveal distinct patterns of heterogeneous actionable mutations.
Authors: Simon Rodney, Miljana Tanic, James Barrett, Webster Philomena Amy, Patricia de Winter, Wei Shen Tan, Pramit Khetrapal, Liqin Dong, Sheida Rezaee, Alex Freeman, Raj Nigam, Peter Malone, Asif Muneer, Stephan Beck, Andrew Feber, John D Kelly
Journal: Journal of Clinical Oncology (2017)

4518 Background: Penile cancer is a rare but mutilating disease. Due to its rarity few studies have investigated the molecular oncogenic changes. There is a huge need to improve the poor outcome of metastatic disease by advancing the standard practice of platinum based therapies. Treatment based on actionable mutations and the potential of immunotherapies may improve clinical outcomes. We present the first analysis of intra-tumour heterogeneity within penile cancer. Methods: Tissue samples, greater than 80% purity, were collected from four spatially distinct tumor regions together with matched normal and metastatic tissue. Deep whole exome sequencing was performed on the resulting 48 samples from eight patients. Mutations were called by using Mutect2 and annotated with Annovar. Copy number changes were estimated using Sequenza and phylogenetic trees created using pyclone. Results: A mean of 650 single nucleotide variants and insertion/deletion events were discovered per tumor sample. Extensive intra-tumor heterogeneity was found with a wide range of different predicted subclonal architectures. Two distinct patterns were noted: either the acquisition of mutations by the lymph node metastasis was an early event with a lower mutational load, or it was a later event with a high mutational load. In the two instances where patients were negative for human papillomavirus infection, the lymph node metastasis evolved at a later date. However in 5/6 cases of HPV infection, an early subclone developed which potentially led to the lymph node metastasis. Driver mutations in p53, cMET or FAT1 were found to be truncal early events in 80% of cases. Actionable mutations in PIK3CA and EGFR were found to be subclonal in two further samples. Conclusions: There is extensive intra- and inter-tumour heterogeneity within penile cancer. The main truncal drivers in penile cancer are cMET, FAT1 and p53. Samples infected with human papillomavirus appeared to have a distinct signature in terms of both copy number changes and clonal architecture. Actionable mutations PIK3CA and EGFR were found to be subclonal in origin. This may have profound effects on the clinical utility of targetable treatments such as tyrosine kinase inhibitors.
Abstract 20409: Myocardial Flow Reserve Is Impaired In Systemic Sarcoidosis
Authors: Brett W Sperry, Balaji K Tamarappoo, Laura Young, Richard Brunken, Manuel Cerqueira, Rory Hachamovitch
Journal: Circulation (2016)

Introduction:  Myocardial inflammation or scarring in patients with cardiac sarcoidosis may be associated with impaired myocardial blood flow (MBF). We sought to investigate MBF and flow reserve (MFR) in patients with sarcoidosis and compare results to controls.   Methods:  A single-center retrospective cohort analysis was performed in patients with systemic sarcoidosis and FDG- positron emission tomography (FDG-PET) findings of inflammation or scar without obstructive coronary artery disease (CAD) who underwent dynamic rest-stress (Rb-82 with 0.4mg regadenoson) PET-myocardial perfusion imaging (PET-MPI) from 2007-2015 and compared to controls without CAD or active disease known to be associated with low MBF. 4DM software was used to calculate MBF and MFR in a 17-segment model. Multiple linear regression was used to assess the association between MFR and sarcoidosis after adjusting for age, sex, hypertension, hyperlipidemia, body mass index, diabetes, and ejection fraction.   Results:  We identified 16 patients with extra-cardiac sarcoidosis and positive FDG-PET (age 52.6±10.6 years, EF 48.7±14%, JMHW positive 63%) and 31 controls (age 57.7±10.8 years, EF 59.5±10.8%). There were 5 patients with sarcoidosis with low MFR defined as    Conclusions:  Global MFR is reduced in patients with systemic sarcoidosis as compared to controls after adjusting for confounding variables.
Subscribing to Your Patients — Reimagining the Future of Electronic Health Records
Authors: Katherine Choi, Yevgeniy Gitelman, David A. Asch
Journal: New England Journal of Medicine (2018)

As compared with other digital transformations, clinicians' engagement with EHRs seems limited and effortful. Hospital-based clinicians, for instance, must still go to the chart to check on their patients. What if they could instead subscribe to Ms. Jones in room 328?
Abstract 17002: Deficient cMyBP-C Protein Expression During Early Cardiac Differentiation Underlies Human Hypertrophic Cardiomyopathy Cellular Phenotypes in Disease Specific Human Es Cell Derived Cardiomyocytes
Authors: Andre Monteiro da Rocha, Guadalupe Guerrero-Serna, Adam Helms, Carly Luzod, Sergey Mironov, Mark Russell, Jose Jalife, Sharlene M Day, Gary D Smith, Todd J Herron
Journal: Circulation (2016)

Introduction:  Mutations of cardiac sarcomere genes have been identified to cause hypertrophic cardiomyopathy (HCM), but the molecular mechanisms that lead to cardiomyocyte hypertrophy and risk for sudden death are uncertain.   Hypothesis:  Stem cell (hESC)-derived cardiomyocytes (hESC-CMs) are a useful tool to study human HCM disease mechanisms at play during human cardiac differentiation  in vitro .   Methods:  Control or HCM specific hESC-CMs were generated using monolayer and cytokine based differentiation. Cardiomyocytes were stained against α-actinin for determination of sarcomere organization and cell size. Additionally, samples were collected during the time course of cardiac differentiation for protein expression analysis. Differentiated cardiomyocytes were purified with SIRPα-2 mediated magnetic separation for generation of cardiac monolayers for electrophysiological phenotype analysis.   Results:  HCM-specific hESC-CMs displayed hallmark aspects HCM including sarcomere/myocyte disarray (Figure1a), hypertrophy (Figure 1b) and impaired calcium impulse propagation (Figure 1c). During cardiomyocyte differentiation, expression of  MYBPC3  in HCM ESC-CMs temporally lagged behind control hESC-CMs but by day 30 post differentiation was similar to control ESC-CMs (Figure 2a). Gene transfer of full-length  MYBPC3  during early cardiac differentiation (Figure 2b) prevented sarcomere disarray (Figure 2c), hypertrophy (Figure 2d) and improved calcium impulse propagation in HCM hESC-CMs (Figure 2e).   Conclusions:  These findings point to the critical role of  MYBPC3  during sarcomere assembly in cardiac myocyte differentiation and suggest developmental influences of  MYBPC3  truncating mutations on the mature hypertrophic phenotype.
Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives
Authors: Gantumur Battogtokh, Yeon Su Choi, Dong Seop Kang, Sang Jun Park, Min Suk Shim, Kang Moo Huh, Yong-Yeon Cho, Joo Young Lee, Hye Suk Lee, Han Chang Kang
Journal: Acta Pharmaceutica Sinica B (2018)

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.
Abstract 19498: Race-Specific Impact of Atrial Fibrillation Risk Factors in Blacks, Hispanics, and Whites in an Electronic Medical Record
Authors: Timothy L Shih, Benjamin Romer, Mohammed Al-Yafi, Birju Rao, Brandon Chalazan, Mark McCauley, Henry Huang, William Galanter, Dawood Darbar
Journal: Circulation (2016)

Introduction:  Cohort studies have shown that despite a greater burden of traditional risk factors, atrial fibrillation (AF) is less common among non-whites than whites for unclear reasons. However, the role of race-specific influences of medical factors and outcomes related to AF in African Americans (AA), Hispanic-Latino (HL), Asian (AS), or Caucasian (C) has not been examined in an electronic medical record (EMR).   Hypothesis:  To test the hypothesis that race-specific risk factors play an important role in the etiology and outcome of patients with AF using an EMR.   Methods:  Using the UIC EMR, 3607 patients with an ICD-9 CM 427.3 for AF were identified over a 7 year period (2008-2015). Multivariate analysis of variance was used to compare incidence of AF risk factors with subgroup analysis. Risk factors were identified from ICD-9 CM: hypertension (HTN), diabetes mellitus (DM), stroke/TIA, smoking, COPD, vascular disease, obstructive sleep apnea (OSA). Manual review of EMR was performed in 171 of the 3607 patients to validate both AF diagnosis and CHA 2 DS 2 -VASC score (CVS).   Results:  Total hospitalizations: 39.6% (AA); 29.9% (C); 10.7% (HL); 2.4% (AS); and 17.4% (Other). AA and HL were more likely to have HTN as compared with C and AS (85% & 84% vs. 76% & 74%; P 0.05).   Conclusion:  Patterns of AF risk factors varied between ethnicities. Non-whites hospitalized with AF were more likely to have HTN, vascular disease, stroke, and smoking history than whites. Our findings support the role of the EMR in delineating the role of ethnic-specific risk factors in the etiology of AF.
The impact of preoperative dexamethasone on long-term survival following surgery for colorectal cancer.
Authors: Stephen Thomas McSorley, Bo Khor, Campbell SD Roxburgh, Paul G. Horgan, Donald C McMillan
Journal: Journal of Clinical Oncology (2018)

644 Background: Steroids given at the induction of anaesthesia are associated with a reduction in the magnitude of the postoperative systemic inflammatory response and fewer complications following elective surgery for colorectal cancer (McSorley et al. Ann Surg Oncol 2017;24(8):2104-2112). The present study examined their impact on survival. Methods: Patients who underwent elective surgery, with curative intent, for stage I-III colorectal cancer at a single centre between 2008 and 2016 were included. Data on preoperative dexamethasone was obtained from anaesthetic records, and its impact on cancer specific (CSS) and overall survival (OS) assessed using Cox regression in an unmatched (n=556) and a propensity score matched cohort (n=276) (Table 1). Results: After excluding postoperative mortalities (n=3), there were 98 deaths (18%), with 57 (10%) due to cancer. Of those alive at censoring, the median follow up was 47 months (range 16-110). In the unmatched cohort, there was no significant association between dexamethasone and CSS (HR 0.90, 95% CI 0.52-1.53, p=0.688) or OS (HR 0.95, 95% CI 0.63-1.43, p=0.804). In the propensity score matched cohort, there was no significant association between dexamethasone and CSS (HR 1.18, 95% CI 0.55-2.53, p=0.668) or OS (HR 1.21, 95% CI 0.67-2.17), p=0.532). Conclusions: These results suggest that whilst preoperative steroids are associated with improved short term outcomes following surgery for colorectal cancer, they have no negative effect on long term outcomes. [Table: see text]
Abstract 16578: Sudden Death is Less Common in Young Competitive Athletes Than in Non-athletes: But We Systematically Screen Only Athletes
Authors: Barry Maron, Tammy S Haas, Emily R Duncanson, Ross F Garberich, Andrew M Baker, Shannon Mackey-Bojack
Journal: Circulation (2015)

Background: Screening competitive athlete populations for cardiovascular disease is a topic of considerable interest, due to the highly visible sudden deaths (SDs) occurring in young people predominantly with genetic and/or congenital diseases. Media attention to these events may have created the skewed impression that SDs in high school and college students occur almost exclusively in athletes. We address here the important question of whether SDs due to cardiovascular diseases in fact occur largely in competitive athletes, compared to the frequency of such events in young people who are not engaged in sports. Methods: Case records of the Hennepin County (Minneapolis) Medical Examiner were interrogated to identify SDs, age 14-23 years, 2000 to 2014. The number of Hennepin County high school/college students who were competitive athletes (or non-athletes) was estimated from publicly available data sources. Results: Twenty-seven SDs were identified, including 3 individuals who were athletes, either with hypertrophic cardiomyopathy (HCM), a structurally normal heart, or anomalous origin of the left main coronary artery from the right aortic sinus. The other 24 deaths were in young people not involved in organized sports, including: 4 each with HCM or arrhythmogenic right ventricular cardiomyopathy, and 5 with coronary artery disease. Ratio of SDs in non-athletes to athletes was 24 to 3 or 8:1. Incidence of non-athlete SDs over 946,889 person-years was 1:39,454, i.e., 3-fold greater than that for SDs in competitive athletes over 361,841 person-years, i.e., 1:120,614. Conclusion: Cardiovascular SDs are less frequent in competitive athletes than in non-athletes. These data underscore a major (ethical) limitation inherent in confining cardiovascular screening to trained athletes, as is the current practice in the U.S. and elsewhere.
On-Demand versus Maintenance Inhaled Treatment in Mild Asthma
Authors: Stephen C. Lazarus
Journal: New England Journal of Medicine (2018)

U.S. and international guidelines for the treatment of mild persistent asthma recognize three distinct goals of therapy: to relieve and control symptoms, to prevent exacerbations, and to reduce loss of lung function, with minimal side effects.1,2 Short-acting beta-agonists (SABAs), such as albuterol and terbutaline, achieve the first goal, because they relieve symptoms rapidly. Long-acting beta-agonists (LABAs) provide symptom control for 12 to 24 hours, but beta-agonists offer only symptom relief. Accordingly, inhaled glucocorticoids are recommended for the other goals of therapy. Inhaled glucocorticoids reduce the incidence and severity of symptoms, prevent exacerbations, and reduce airway remodeling — effects that are . . .
The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma
Authors: Leo Rasche, Edgardo J. Angtuaco, Terri L. Alpe, Grant H. Gershner, James E. McDonald, Rohan S. Samant, Manoj Kumar, Rudy Van Hemert, Joshua Epstein, Shayu Deshpande, Ruslana Tytarenko, Shmuel Yaccoby, Jens Hillengass, Sharmilan Thanendrarajan, Carolina Schinke, Frits van Rhee, Maurizio Zangari, Brian A. Walker, Bart Barlogie, Gareth J. Morgan, Faith E. Davies, Niels Weinhold
Journal: Blood (2018)