tbuckley/cabot-search huggingface dataset:
Disruption of the eIF4F translation initiation complex as a determinant of diffuse large B-cell lymphoma responsiveness to enzastaurin (LY317615.HCl) and its primary metabolite (LY326020).
Authors: Jeremy Richard Graff, Ann M McNulty, Chad A Dumstorf, Stephen H Parsons, Bruce W Konicek, Chad A Hall
Journal: Journal of Clinical Oncology (2012)

8082 Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL patients at high risk of relapse following R-CHOP therapy. In a phase 2 DLBCL study, 4 of 55 treated patients were progression- free after prolonged, continuous oral enza therapy with 3 of these 4 confirmed as complete responders (Robertson et al., JCO, 2007). The molecular mechanism for this differential response is unclear. Methods: In clinical trials, Enza yields 2-4 µM total circulating drug, comprised of ~50% enza, ~50% primary metabolite, LY326020. We therefore evaluated the sensitivity of a DLBCL cell panel representing both Activated B Cell (ABC) and Germinal Center (GC) subtypes to enza and LY326020. Gene expression analyses, western blotting to explore intracellular signaling and mRNA cap analogue co-capture assays were used to identify the critical effectors of drug sensitivity. Results: For the first time, we show the profound biological activity of LY326020, the primary metabolite that accounts for ~ 50% of circulating drug in patients. Like Enza, though more potently, LY326020 inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant cells, enza and LY326020 reduced phosphorylation of numerous proteins in the PI3K-AKT-TOR pathway (e.g. pGSK3β ser9 ) in a dose and time-dependent manner. However, only sensitive DLBCL cells showed reduced 4EBP1 ser65 phosphorylation. Accordingly, we show a dose and time-dependent increase in 4EBP1: eIF4E binding. This increase is most pronounced by LY326020. Moreover, cells selected for resistance to enza show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to the pro-apoptotic effects of enza and LY326020. Conclusions: These data demonstrate that sensitivity of DLBCL to both enza and LY326020 is critically dependent upon 4EBP1 modulation and subsequent disruption of the eIF4F translation complex. Moreover, these data are the first to show the potent biologic activity of LY326020, the primary metabolite of enza that accounts for ~50% of total circulating drug in patients and in preclinical models.
QIM20-123: Utilization of a Distress Screening Tool in an Inpatient Hematopoietic Stem Cell Transplant Unit
Authors: Ivana Espinosa, Christina Pozo- Kaderman, Maritza Alencar, Jessica MacIntyre, Lisa Merheb, Elise James, Abby-Gail Solomon, Michelle Rodriguez Diaz, Sophie Torrents, Maria Rueda- Lara
Journal: Journal of the National Comprehensive Cancer Network (2020)
Hepatocellular carcinoma diameter and blood platelet levels in a large cohort of Chinese patients in Taiwan.
Authors: Brian I. Carr, Chih-Yun Lin, Sheng-Nan Lu
Journal: Journal of Clinical Oncology (2013)

e15157 Background: Cirrhosis is often associated with thrombocytopenia and predisposes to HCC. Platelets are known to produce several HCC growth factors. Methods: A cohort of 4,139 Chinese HCC patients from Taiwan was interrogated for baseline clinical, tumor and liver function characteristics in relation to blood platelet counts. Results: Trichotomization of the cohort by tumor size after log-linearization, revealed significant relationships of tumor size to blood platelet, AFP and GGTP levels. Patients with higher platelets had larger tumors, more tumor nodules and higher AFP and GGTP levels than those with lower platelet levels. 80% of patients with larger tumors had normal platelet counts, compared to 50% of patients with smaller tumors. Analysis of the cohort according to platelet sub-sets, revealed significant relationships of platelet counts to tumor size and AFP levels. By Spearman’s correlation coefficient, platelet counts correlated moderately with tumor size (rho=0.411), but weakly with tumor numbers, PVT, AST or AFP levels. Sub-set analysis of the cohort according to platelet levels showed that 38% of patients had thrombocytopenia and they had the smallest tumors, lowest tumor numbers, lowest percent with PVT and lowest AFP levels. Conclusions: There was a significant correlation between HCC size and blood platelet counts; patients with larger tumors had higher platelet levels.
Beyond the burn: Studies on the physiological effects of flamethrowers during World War II
Authors: David W. Van Wyck
Journal: Military Medical Research (2020)

Abstract Flamethrowers are widely considered one of warfare’s most controversial weapons and are capable of inflicting gruesome physical injuries and intense psychological trauma. Despite being the last of the major combatants in World War II (WWII) to develop them, the United States military quickly became the most frequent and adept operator of portable flamethrowers. This gave the U.S. military ample opportunity to observe the effects of flamethrowers on enemy soldiers. However, while most people in modern times would consider immolation by flamethrower to be an unnecessarily painful and inhumane way to inflict casualties, immolation was, at one point during World War II (WWII), referred to as “mercy killing” by the U.S. Chemical Warfare Service (CWS). This mischaracterization arose from a series of first-hand accounts describing what were believed to be quick, painless, and unmarred deaths, as well as from a poor and incomplete understanding of flamethrower lethality. As a result, indirect mechanisms such as hypoxia and carbon monoxide poisoning were generally absent from accounts of the flamethrower’s fatal effects. It was not until several years after flamethrowers were introduced to the frontlines that the CWS and National Defense Research Committee (NDRC) conducted a series of tests to better understand the physiological and toxicological effects of flamethrowers. This article examines how the initial absence of scientific data on the physiologic effects of flamethrowers led to an inaccurate understanding of their lethality, and bizarre claims that one of history’s most horrific instruments of war was considered one of the more “humane” weapons on the battlefield.
Introducing a new scoring system based on HER2/neu, p53 oncogenes results and mammographic findings for prediction of tumor grade in breast cancer
Authors: M. Guity, M. Mokri, M. Shakiba, M. Atri
Journal: Journal of Clinical Oncology (2006)

10687 Background: During recent years, several oncogenes have been introduced in relation to breast cancer including her2 and P53. These are related with initiation, degree of progression, invasion and prognosis of breast cancer. In this research the rate of positivity of these oncogenes in 150 patients with invasive ductal carcinoma is introduced and the correlation of the results of a new scoring system comprised of mammograms, P53 and her2 with the tumor grade is assessed. Methods: 150 cases of invasive ductal carcinoma of a private clinic were chosen. The diagnosis of cancer and its grade was confirmed by pathology. All patients underwent mammography befor surgery and the results were classified according to BIRADS system to benign (groups of I and II in BIRADS): Score I, suspicious (group III in BIRADS): Score II and malignant (groups of IV and V in BIRADS): score III. P53 and her2 presence were assessed by immunohistochemical studies and the results were classified as negative (score I) and positive (score II). The final score of each patients was calculated by adding scores of all three studies (P53, her2, mammography) which ranged between 3 to 7. Results: The average age of the patients was 48.2 + 11.2 years; most of them were between 30–50 years old. Three had benign mammograms (2%), 81 had suspicious (54%) and 66 had malignant findings (44%). We showed positive P53in 59 (39%), positive her2 in 69 (46%) and high grade tumor in 77 (51%) patients. On scoring, 2 patients gained 3 (1.3%), 36 scored 4 (24%), 53 patients received 5 (35.3%), 37 reached 6 scores (24.7%) and 22 patients received 7 scores (14.7%). Placing scores 3 and 4 in one group and scores 5–7 in another, the sensitivity and negative predictive value of the system for high grade tumors reached 97.7% and 89.5% respectively. By placing scores 3–6 in one group and score 7 in another, the specificity and positive predictive value of the system reached to 100%. Conclusions: The results of mammography, P53 and her2 seems to have a good correlation with tumor grade, meaning when all three parameters are positive, the patients’ tumor is almost always high grade. No significant financial relationships to disclose.
Conflict of interest disclosure in off-label oncology clinical trials.
Authors: Blair Billings Irwin, Amy Pickar Abernethy, Bradford Richard Hirsch
Journal: Journal of Clinical Oncology (2012)

6041 Background: Off-label prescribing of anti-cancer targeted therapies is increasingly prevalent. Post-regulatory evidence and reporting requirements for reimbursement for off-label oncologic indications are less stringent than the threshold for United States Food and Drug Administration registration. What are the prevalence, reliability, and predictors of conflict of interest (COI) and funding disclosure statements in published reports of studies of cancer targeted therapies conducted in the post-regulatory setting? Methods: As a part of a federally-funded systematic review, manuscripts were included in the analysis if they were used to support one of 19 indications for cancer targeted therapies that were off-label but reimbursable according to authoritative compendia in 2006 or before. Studies were categorized according to trial design, trial results, average impact factor of journals, and the presence of COI and funding disclosure statements. Results: Sixty-nine studies were included in the systematic review. Prevalence of COI and funding disclosures was low, at 33% and 58%, respectively; time trends showed some improvement between 2002 to 2007, but only 60% of studies had disclosures by 2007. Predictors of COI disclosure were publication in high impact factor journals (p&lt;0.001), large study sample size (p=0.001), enrollment exclusively in the US (p=0.04), and study of the targeted therapy in combination with other agents as opposed to the study drug alone (p=0.03). Studies with multiple sites were more likely to include a funding disclosure statement (p=0.01). Conclusions: There is need for more consistent disclosure of potential sources of bias in COI and funding statements in studies of off-label indications for anti-cancer targeted therapies.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of patients with brain metastases (BM) from renal cell cancer (RCC).
Authors: David Naskhletashvili, Vera Gorbunova, Mark Bychkov, Ali Bekyashev, Vladislav Karahan, Vladimir Aloshin, Zoya Michina, Sergey Medvedev, Evgeny Prozorenko, Alla Markovich
Journal: Journal of Clinical Oncology (2013)

e15546 Background: About 2–11% of all patients (pts) with RCC develop BM, leading to a poor prognosis and a median survival of &lt;6 months after whole brain radiotherapy. The role of targeted therapy in the management of BM is controversial. This study was designed to evaluate EGFR TKIs in RCC pts with BM. Methods: eligible pts had confirmed RCC and BM (≥1 lesion of ≥10mm diameter) aged &gt;18 years with ECOG performanse status (PS) of 0–2. From June 2009 to January 2013, 11 pts with RCC and BM were enrolled in this study. 10 pts (91%) had extracranial metastases. 6 pts received sunitinib (50mg/day, 4 weeks, every cycle), 4 pts received sorafenib (800 mg/day) and 1 patient received pazopanib (800 mg/day) until radiologically-verified progressive disease. The primary endpoints were objective response rate (ORR) - complete and partial response in the brain and in the extracranial lesions, progressive-free survival (PFS) and overall survival. Demographics were: median age - 59 years (range 44–74 years); male/female - 10/1; PS 1/2 - 7/4; previously treated/untreated - 10/1; number of BM: ≤3/&gt;3 - 6/5. Previous treatment: nephrectomy – 10 pts (91%), cytokines – 6 pts (54,5%), targeted therapy (before BM) – 4 pts (36,4%). Local control of BM: previous neurosurgery – 2 pts (18,2%), radiosurgery – 4 pts (36,4%), previous neurosurgery + radiosurgery – 2 pts (18,2%). Results: ORR in the brain was 27,3% (3 partial responses). All partial responses in the brain achieved in patients who received targeted therapy and radiosurgery. Stable disease in the brain was 54,5% (6 pts). 1 patient with stable in the brain received targeted therapy and radiosurgery, 5 pts received targeted therapy. ORR in the extracranial lesions was 20% (2 partial responses). Stable disease in the extracranial lesions was 50% (5 pts). The median of PFS was 6 months. The median of overall survival was 10 months. Conclusions: surgery and radiotherapy, including radiosurgery, must be considered as optimal local treatment for pts with RCC and BM. Targeted drugs have demonstrated their ability to achive a clinical and X-ray verified objective effect (as stabilization in most cases) in treating of pts with disseminated RCC and BM.
BODY MASS INDEX AND LEFT VENTRICULAR FUNCTION OF ACUTE CORONARY SYNDROME SURVIVORS: DATA FROM THE TRACE-CORE COHORT
Authors: Khanh-Van Tran, Matthew W. Parker, Adedotun Ogunsua, Darleen Lessard, Catarina Kiefe, David McManus, Gerard P. Aurigemma
Journal: Journal of the American College of Cardiology (2020)
Zoledronic acid for hormone-naive prostate cancer with bone metastasis.
Authors: Masahiro Nozawa, Isao Hara, Kazuhiro Nagao, Hideyasu Matsuyama, Hirotsugu Uemura
Journal: Journal of Clinical Oncology (2013)

e16092 Background: The potency of zoledronic acid for hormone-naïve prostate cancer is unclear. We conducted a phase II study to investigate the benefit of administering zoledronic acid concomitant with androgen-deprivation therapy in treatment-naïve prostate cancer patients with bone metastases, in which the primary endpoint was skeleton-related event (SRE)-free survival at 24 months after treatment. Methods: Treatment-naïve male patients with histologically confirmed adenocarcinoma of the prostate and radiologic evidence of bone metastasis were eligible. Treatment consisted of bicalutamide 80 mg administered orally on Day 1 and every day, goserelin acetate 10.8 mg administered subcutaneously on Day 8 and every 12 weeks, and zoledronic acid 4 mg administered intravenously on Day 8 and every four weeks. Results: Between July 2008 and April 2010, a total of 53 patients were enrolled and 52 evaluable. Median age was 72 years (range, 55 - 86). Median primary PSA was 249.4 ng/ml (range, 2.19 –19201). Median follow-up period was 33.3 months. The SRE-free survival rate at 24 months after treatment was 82.7 %. Median time to PSA progression was 25.9 months (95% confidential interval, 17.97-24.43). The score of the extent of bone diseases was stable or decreased in 73 % of the patients at 24 months after treatment. The grade-3 osteonecrosis of the jaw was reported in three patients (5.8 %). Conclusions: Our results suggest the potency of the early introduction of zoledronic acid for prostate cancer patients with bone metastases. Future studies are certainly required to ascertain the most appropriate timing of the commencement of zoledronic acid for patients with bone-metastatic prostate cancer. Clinical trial information: UMIN000007548.
Comparative Pricing of Branded Tenofovir Alafenamide–Emtricitabine Relative to Generic Tenofovir Disoproxil Fumarate–Emtricitabine for HIV Preexposure Prophylaxis
Authors: Rochelle P. Walensky, Tim Horn, Nicole C. McCann, Kenneth A. Freedberg, A. David Paltiel
Journal: Annals of Internal Medicine (2020)

Background: Tenofovir alafenamide–emtricitabine (F/TAF) was recently approved as a noninferior and potentially safer option than tenofovir disoproxil fumarate–emtricitabine (F/TDF) for HIV preexposure prophylaxis (PrEP) in the United States. Objective: To estimate the greatest possible clinical benefits and economic savings attributable to the improved safety profile of F/TAF and the maximum price payers should be willing to pay for F/TAF over generic F/TDF. Design: Cost-effectiveness analysis. Data Sources: Published literature on F/TDF safety (in persons with and those without HIV) and the cost and quality-of-life effects of fractures and end-stage renal disease (ESRD). Target Population: Age-stratified U.S. men who have sex with men (MSM) using PrEP. Time Horizon: Five years. Perspective: Health care sector. Intervention: Preexposure prophylaxis with F/TAF versus F/TDF. Outcome Measures: Fractures averted, cases of ESRD averted, quality-adjusted life-years (QALYs) saved, costs, incremental cost-effectiveness ratios (ICERs), and maximum justifiable price for F/TAF compared with generic F/TDF. Results of Base-Case Analysis: Over a 5-year horizon, compared with F/TDF, F/TAF averted 2101 fractures and 25 cases of ESRD for the 123 610 MSM receiving PrEP, with an ICER of more than $7 million per QALY. At a 50% discount for generic F/TDF ($8300 per year) and a societal willingness to pay up to $100 000 per QALY, the maximum fair price for F/TAF was $8670 per year. Results of Sensitivity Analysis: Among persons older than 55 years, the ICER for F/TAF remained more than $3 million per QALY and the maximum permissible fair price for F/TAF was $8970 per year. Results were robust to alternative time horizons and PrEP-using population sizes. Limitation: Intermittent use and on-demand PrEP were not considered. Conclusion: In the presence of a generic F/TDF alternative, the improved safety of F/TAF is worth no more than an additional $370 per person per year. Primary Funding Source: National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, National Institute of Mental Health, and Massachusetts General Hospital Executive Committee on Research.
Synchronous primary ovarian and endometrial cancer in recent years: Changes in recent years.
Authors: Maria Creselda deLeon, Giuseppe Del Priore, Deleep Gudipudi
Journal: Journal of Clinical Oncology (2013)

e16554 Background: Patients with synchronous ovarian and endometrial cancer (SOEC) have been shown to have better prognosis when compared to patients with primary ovarian cancer alone; however with the increasing rate of obesity in the United States we hypothesize that this disease has significant characteristic changes compared to 20 years ago. Methods: This is retrospective study of patients with SOEC diagnosed between 1973-2009. We compared patients from 1973-1991 (n=962) to patients diagnosed between 1992-2009 (n=1800) when obesity became &gt;10% of the US population starting in 1992. Using the Surveillance, Epidemiology, and End Results (SEER) registry, we obtained demographic information which included patient ID, primary site of tumor, year of diagnosis, sex, race, age group and survival months. SOEC was defined as diagnosis of ovarian and endometrial cancer within 0-12 months. Results: A query of SEOC yielded 2,762 women between the ages of 13-99 years. When we compared the stage of disease which was described as localized, regional, distant and unstaged, tumor grade and disease incidence, there was no difference found between the two groups. However when the age of diagnosis was compared, it was apparent that patients diagnosed between the years 1992-2009 were diagnosed at an earlier age 41-50 (28%) compared to patients diagnosed in 1973-1991 who were mostly diagnosed between ages 61-70 (31%) (p &lt;0.001). Conclusions: We were able to demonstrate that women with SOEC in recent years are more likely to be diagnosed at an earlier age but that the disease stage, grade and incidence have stayed the same in the past 40 years. The hypothesis then that SOEC may have gone through some characteristic changes in the past 20 years seems plausible especially in the setting of increase incidence of obesity. [Table: see text]
CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow
Authors: Lena Fischer-Riepe, Niklas Daber, Jonas Schulte-Schrepping, Bruna Caroline Véras De Carvalho, Antonella Russo, Michele Pohlen, Josephine Fischer, Achmet Imam Chasan, Marc Wolf, Thomas Ulas, Shirin Glander, Christian Schulz, Boris Skryabin, Andreas Wollbrink, Dipl-Ing, Nadine Steingraeber, Christopher Stremmel, Megan Koehle, Florian Gärtner, Sabine Vettorazzi, Dirk Holzinger, Joachim Gross, Frank Rosenbauer, Monika Stoll, Silke Niemann, Jan Tuckermann, Joachim L. Schultze, Johannes Roth, Katarzyna Barczyk-Kahlert
Journal: Journal of Allergy and Clinical Immunology (2020)
TRANSVALVULAR GRADIENTS AFTER VALVE-IN-VALVE TAVR ARE OVERESTIMATED BY ECHOCARDIOGRAPHY WHEN THE MODIFIED BERNOULLI EQUATION IS UTILIZED
Authors: Yan Yatsynovich, Mohamed Abdel-Aal Ahmed, Aman Gupta, Sung Lee, Thammi Ramanan, Rose Hansen, Gerald Colern, Vijay Iyer
Journal: Journal of the American College of Cardiology (2020)
Neural Insensitivity to the Effects of Hunger in Women Remitted From Anorexia Nervosa
Authors: Walter H. Kaye, Christina E. Wierenga, Amanda Bischoff-Grethe, Laura A. Berner, Alice V. Ely, Ursula F. Bailer, Martin P. Paulus, Julie L. Fudge
Journal: American Journal of Psychiatry (2020)

Objective: Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study’s aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa. Methods: At two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity. Results: Participants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group. Conclusions: Reduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.