tbuckley/cabot-search huggingface dataset:
Competing causes of death in NCIC CTG MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients
Authors: J. Chapman, D. Meng, L. Shepherd, W. Parulekar, J. N. Ingle, H. B. Muss, M. Palmer, C. Yu, P. E. Goss
Journal: Journal of Clinical Oncology (2007)

540 Background: Risk of death from other malignancies (OM) and other causes (OC) than breast cancer (BC) increases with age. Effects of baseline factors on type of death were assessed with competing risks analyses. Methods: In NCIC CTG MA.17, 5,187 women free of recurrent breast cancer after 5 years of tamoxifen were randomized to letrozole (L, 2,593 women) or placebo (P, 2,594 women). The primary endpoint was disease free survival (DFS), and secondary, overall survival (OS). Follow-up was to October 9, 2005: median 3.9 years, range &lt;0.1 to 7.0 years. Effects of competing risks were examined for endpoints of BC, OM, and OC for 11 baseline trial factors: treatment, age, menopausal status, duration of prior tamoxifen, adjuvant radiotherapy, bone fracture, osteoporosis, cardiovascular disease, hormone receptor status, nodal status, adjuvant chemotherapy. Lagakos’ hierarchical method (Lagakos, Appl. Statist. 1978; 27:235–241) was used to test for differential effects of baseline factors on type of death (BC, OM, OC). Results: Rate of censoring was 97.8%, with 256 deaths (BC, 102; OM, 50; OC, 100; unknown, 4). Non-breast cancer deaths accounted for 60% of known deaths; 72%, for those ≥70 years; and 48%, for those &lt;70 years. Two baseline factors differentially affected type of death. Women with cardiovascular disease were more likely to die from OC (p=0.02), while those with osteoporosis were more likely to die of OM (p=0.03). Age and nodal status had directionally similar effects. Older women had shorter survival from all 3 causes of death (p=0.01). Lymph node positivity was associated with worse survival (p=0.003). Conclusions: Extended L provides similar proportional benefit in improving DFS for all ages of women (Muss ref abstract SABCS 2006). However, the magnitude of competing non-breast cancer, and non-treatment related, causes of death needs to be considered more frequently, since with early detection and improved therapies, breast cancer patients may increasingly be expected to survive their disease to die from another cause. The novel association between baseline osteoporosis and other malignancies is being explored quantitatively. No significant financial relationships to disclose.
Small airways and early origins of COPD: pathobiological and epidemiological considerations
Authors: Francesca Polverino, Joan B. Soriano
Journal: European Respiratory Journal (2020)

Until recently, the conceptual model of the natural history of COPD has been greatly focused on an accelerated decline of lung function, which would occur in adult life in susceptible individuals when chronically exposed to environmental noxious agents, such as cigarette smoke and other inhaled gases. However, 25%–45% of all COPD patients worldwide have never smoked [1]. In addition, pre- and peri-natal factors associated with diverse biological mechanisms can determine low lung function in young adults [2–4]. Among these factors, asthma and active and/or passive smoking act synergistically to affect early lung function deficits in young adulthood [5, 6]. The impact of smoke exposure in susceptible smokers is detectable with exposures to as little as 8–10 pack-years, in their late 30 s to early 40 s [7]. Similarly, early onset asthma is observed in 26% of those diagnosed with COPD at a mean age of 37 years, which represents a 20-fold increased risk of adult airway obstruction compared with those without asthma diagnosis [8]. However, what the combined effects of current active smoking and asthma are in a population of young adults is unknown. The role of the small airways and the early origins of airflow limitation <http://bit.ly/35Uaib3>
Abstract P199: A Digital Health Platform For Weight Loss In Metabolic Syndrome: A 6-month Prospective Study In China
Authors: Conor Senecal, Maria Collazo-Clavell, Mariza de Andrade, Lilach O Lerman, Amir Lerman, Francisco Lopez-Jimenez
Journal: Circulation (2020)

Introduction: Metabolic Syndrome represents a constellation of findings known to increase cardiovascular risk and all-cause mortality and is becoming more frequent in China. Smartphone applications may provide a cost-effective method to engage in weight loss and improve metabolic syndrome components. Methods: Prospective study of changes in weight and metabolic syndrome risk factors at 6 weeks and 6 months using a smartphone application utilizing a wireless scale, meal replacement biscuits and e-coaching in China. All participants had or were at high risk for metabolic syndrome and all interaction was online, without face to face contact. Results: 218 individuals ,55% female, participated. Median weight loss at 6 weeks and 6 months was 7.3kg and 8.4 kg (P&lt;0.001) respectively. At baseline, 60% met a diagnosis of metabolic syndrome this dropped to 38% at 6 weeks (P&lt;0.001) and stayed at 38% at 6 months (P&lt;0.001). At 6 week the prevalence of all components of metabolic syndrome were improved (P&lt;0.05) except HDL. Conclusions: A smartphone weight loss platform that utilizes a wireless scale, meal replacement biscuits and e-coaching was associated with significant weight loss and improvement in several metabolic syndrome components at 6 weeks and 6 months. This program may provide a scalable intervention against metabolic syndrome, especially in developing countries such as China.
An emerging focus on lipids in extracellular vesicles
Authors: Tore Skotland, Krizia Sagini, Kirsten Sandvig, Alicia Llorente
Journal: Advanced Drug Delivery Reviews (2020)

Extracellular vesicles contain a lipid bilayer membrane that protects the encapsulated material, such as proteins, nucleic acids, lipids and metabolites, from the extracellular environment. These vesicles are released from cells via different mechanisms. During recent years extracellular vesicles have been studied as possible biomarkers for different diseases, as biological nanoparticles for drug delivery, and in basic studies as a tool to understand the structure of biological membranes and the mechanisms involved in vesicular trafficking. Lipids are essential molecular components of extracellular vesicles, but at the moment our knowledge about the lipid composition and the function of lipids in these vesicles is limited. However, the interest of the research community in these molecules is increasing as their role in extracellular vesicles is starting to be acknowledged. In this review, we will present the status of the field and describe what is needed to bring it forward.
Triumph and Tragedy of 21st Century Tuberculosis Drug Development
Authors: Guy Thwaites, Payam Nahid
Journal: New England Journal of Medicine (2020)

Since the discovery of the first antituberculosis drugs 75 years ago, the pursuit of a short, effective, and affordable regimen that has acceptable side effects and is capable of curing most patients most of the time has been a major public health priority. Such a "pan-tuberculosis" regimen is seen by many as essential in reducing the global tuberculosis burden.1 The successful development of two new antituberculosis drugs — bedaquiline and pretomanid — represents an important step forward in the pursuit of pan-tuberculosis regimens fit for the 21st century. Conradie and colleagues now report in the Journal that when this all-oral . . .
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin for targeted therapy of mesothelin expressing mesotheliomas, ovarian and pancreatic cancer
Authors: R. Hassan, S. Bullock, A. Premkumar, R. J. Kreitman, H. Kindler, M. Willingham, I. Pastan
Journal: Journal of Clinical Oncology (2007)

3553 Background: Mesothelin, a cell surface glycoprotein, is an attractive candidate for targeted cancer therapy given its limited expression on normal mesothelial cells and high expression in several human cancers including mesothelioma, ovarian and pancreatic cancer. We conducted a phase I study to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of SS1P, a recombinant anti-mesothelin immunotoxin. Methods: SS1P given as a 30 minute intravenous infusion was administered to 34 patients (pts) with advanced mesothelioma (n = 19), ovarian (n = 13) and pancreatic (n = 2) cancer. SS1P was administered every other day (QOD) for 6 doses to 17 pts and then QOD for 3 doses to 17 other pts. Results: The initial cohort of 17 pts received SS1P QOD x 6 doses and the MTD was 18 μg/kg/dose. Dose-limiting toxicity (DLT) included grade 3 urticaria (1 pt) and grade 3 vascular leak syndrome (2 pts). To allow further SS1P dose escalation 17 pts were treated on the QOD x 3 schedule and the MTD was 45 μg/kg/dose. The DLT was grade 3 pleuritis and was seen in 2/2 pts treated at a dose of 60 μg/kg and in 1/9 pts treated at a dose of 45 μg/kg. In all cases the pleuritis resolved completely. No grade 4 toxicity was observed. The most common grade 1/2 toxicities included hypoalbuminemia (21 pts), fatigue (17 pts), fever (9 pts) and edema (9 pts). At the MTD of 45 μg/kg the mean Cmax of SS1P was 483 ng/ml and half-life was 466 minutes. Of the 33 evaluable pts treated, 4 had minor response, 18 had stable disease and 11 had progressive disease. Two pts with stable disease had complete resolution of their ascites. A pt with peritoneal mesothelioma had complete resolution of her abdominal ascites, required no further therapy and died of unrelated causes 5 years after SS1P treatment. In the other pt with ovarian cancer there was resolution of abdominal and pelvic ascites that lasted 6 months. Conclusion: SS1P is well tolerated with pleuritis as the DLT at the highest dose level. Anti-tumor activity was noted in a group of heavily pretreated patients. Based on pre-clinical studies that show marked synergy between SS1P and chemotherapy, phase II clinical trials of SS1P in combination with chemotherapy for the treatment of mesothelin expressing cancers will open in 2007. No significant financial relationships to disclose.
Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD
Authors: Qian Chen, Christopher A. Deister, Xian Gao, Baolin Guo, Taylor Lynn-Jones, Naiyan Chen, Michael F. Wells, Runpeng Liu, Michael J. Goard, Jordane Dimidschstein, Shijing Feng, Yiwu Shi, Weiping Liao, Zhonghua Lu, Gord Fishell, Christopher I. Moore, Guoping Feng
Journal: Nature Neuroscience (2020)
A single institution experience with neuroendocrine tumors
Authors: A. Badari Badari, M. Javle, Y. Pak, T. Khoury, N. Ramnath, J. Gibbs, B. Kuvshinoff, R. Iyer
Journal: Journal of Clinical Oncology (2007)

15164 Background: ABSTRACT Introduction: . The aim of this study was to analyze demographic, therapy, tumor and clinical outcomes of all cases of neuroendocrine cancer at a tertiary cancer and determine the the markers that may better correlate with outcomes than histologic grade. Patients and Methods: With IRB approval , 126 charts with a diagnosis of neuroendocrine carcinoma were identified between 1–1-1999 and 1–1-2004. Ninety-five cases were selected on the basis of complete availability of baseline, therapy and at least one time point of followup data. Patient demographics, therapy details, TNM stage, tumor marker and survival data were collected. Tumors were graded as well, moderate and poorly differentiated and by site of origin. We attempted to correlate the outcome with NCAM(neural cell adhesion molecule-CD56) status, which is a homophylic binding glycoprotein to have a role in cell adhesion. Descriptive statistics and frequency tables were used to describe the data and kaplan meier methods were used to estimate the median survival. Results: There were 28 patients with lung primaries, 25 had primaries in the gut (extra pancreatic),11 had pancreatic primaries, 31 cases had unknown primaries or primaries at sites other than the lungs or the gastrointestinal tract. The estimated median survival for the whole sample was 34 months.(95% C I :20,54) and the 2 year survival rate was 55.3 %.The estimated median survival for CD56 positive group was 11 months(95% C.I :3,38) and that for CD 56 unknown group was 36(95% C .I :20,n/a). A significant difference in survival between CD56 positive group and CD56 unknown was found,based on log-rank test&gt;(P=.02). Baseline characteristics were as follows: M:F 48:47; 19 were well differentiated, 4 were moderately differentiated and 36 of 95 tumors were poorly differentiated, the differentiation was not known in 36 cases. Surgery with curative intent was done in 52 of the patients(54.74%) and 52 received (54.74%)t chemotherapy, 4 patients(4.2%) received chemoembolization and 2 patients(2.1%) received local ablative treatments. Conclusion: These data summarize our instutions experience with this rare malignancy. In our data survival was as expected in the literature and further investigation of the CD 56 status of all patients is underway. No significant financial relationships to disclose.
Radiation Treatment, <i>ATM</i>, <i>BRCA1/2</i>, and <i>CHEK2</i>*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer
Authors: Anne S Reiner, Mark E Robson, Lene Mellemkjær, Marc Tischkowitz, Esther M John, Charles F Lynch, Jennifer D Brooks, John D Boice, Julia A Knight, Sharon N Teraoka, Xiaolin Liang, Meghan Woods, Ronglai Shen, Roy E Shore, Daniel O Stram, Duncan C Thomas, Kathleen E Malone, Leslie Bernstein, Nadeem Riaz, Wendy Woodward, Simon Powell, David Goldgar, Patrick Concannon, Jonine L Bernstein
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.
Supplemental Nutrition Assistance Program—Do Not Take the Food Out of Patients’ Mouths
Authors: Kenneth Covinsky, Mitchell Katz
Journal: JAMA Internal Medicine (2020)

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Abstract P235: Racial/ethnic and Geographic Disparities in Cardiovascular Health Among Pregnant Women in The United States
Authors: Yi Zheng, Jiang Bian, Heather Lipkind, Jinying Zhao, Thomas A Pearson, Hui Hu
Journal: Circulation (2020)

Life’s Simple 7 (LS7) developed by the American Heart Association (AHA) reframes cardiovascular disease (CVD) into terms of cardiovascular health (CVH). Large disparities in CVH exist in the general population. However, little is known about the CVH status and its disparities among pregnant women. We used data from two nationally representative surveys to assess racial/ethnic and geographic disparities in pregnancy CVH. Racial/ethnic disparities were examined using data from the 1999-2016 National Health and Nutrition Examination Survey (NHANES). Following LS7, each CVH metric was categorized into poor, intermediate, or ideal. Women with ≥ 4 ideal metrics were determined as having ideal pregnancy CVH. Data from the 2001-2017 Behavioral Risk Factor Surveillance System (BRFSS) were used to identify geographic disparities in pregnancy CVH as determined by self-report and categorized into poor or ideal. Women with &gt; 3 poor metrics were considered as having poor pregnancy CVH. Among the 1,310 pregnant women identified from the NHANES, a lower ideal CVH rate was observed among non-Hispanic Blacks (27.6%), while there were small differences among other racial/ethnic groups (non-Hispanic Whites: 40.5%, Hispanics: 39.7%, and others: 34.7%). Comparing with Non-Hispanic Whites, non-Hispanic Blacks had significantly lower odds to meet an ideal CVH (OR: 0.55, 95% CI: 0.31, 0.97) after adjusting for sociodemographic status. A total of 19,259 pregnant women were identified from the BRFSS. Large geographic disparities in poor pregnancy CVH at the state-level were observed with substantial temporal variations, ranging from 11.7% (Vermont, 2001-2006) to 49.8% (Arkansas, 2013-2017). Continuously increasing rates of poor pregnancy CVH were found in 22 states, while only 2 states (i.e. Kentucky and Washington DC) had continuously decreasing rates in 2001-2017. More efforts are warranted to understand and address these large and increasing disparities in pregnancy CVH.
Association of weekly gemcitabine to conformal radiotherapy as organ-sparing strategy in locally advanced or relapsed bladder cancer
Authors: G. Carillio, M. Alì, A. Mazzola, S. Bagnato, A. Todaro, A. D’Agostino, A. Girlando, R. Aiello, G. Fallica, M. Chiarenza, M. Caruso
Journal: Journal of Clinical Oncology (2007)

15570 Background: Radical surgery is considered the only curative option for locally advanced or relapsed bladder cancer. However, the uncertain prognosis of disease and the poor quality of life due to lack of bladder reservoir require further investigation on possible therapeutic approaches. Methods: This trial has been designed for testing safety and activity of dose-escalating gemcitabine associated to concomitant conformal radiotherapy for locally advanced or relapsed bladder cancer. Patients received radiotherapy at 2 Gy per day to reach a total dose of 60 Gy over 6 weeks. Gemcitabine was administered once-a-week as one-hour IV infusion before starting the radiation treatment. The first explored dose of drug was 300 mg/m2 and the escalation was planned through a Fibonacci modified method by subsequent increases of 100 mg/m2 until definition of the dose-limiting toxicity (DLT). The recommended dose for future phase II study was one level inferior to the reached maximum tolerated dose (MTD). Results: Eighteen patients with median age of 72 years entered the study, half of whom affected by locally advanced tumours, the remainders by recurrence after conservative surgery. The majority of the latter initially had pT2 (UICC staging) muscle invasive transitional cell carcinoma. Twelve patients were treated with weekly gemcitabine at 300 mg/m2 without appearance of any DLT. Among the first 3 patients receiving the dose level of 400 mg/m2, one patient had grade 4 neutropenia. Further 3 patients were enrolled for testing the above dose level, but one of them experienced bowel perforation, therefore the established MTD was 400 mg/m2. The recommended dose of weekly gemcitabine was 300 mg/m2. Effectively, we could observe 11 (61%) pathological complete responses (pCR) confirmed by bladder mapping two months after treatment completion. Nine pCR (82%) occurred in the patients with locally advanced therapy-naïve bladder cancer. Patients with conserved bladders had excellent function, without hematuria, urgency or incontinence. Conclusions: The association of weekly gemcitabine to conformal radiotherapy provides a new alternative to radical surgery approach and strongly supports the organ-sparing strategy for locally advanced bladder cancer. No significant financial relationships to disclose.