tbuckley/cabot-search huggingface dataset:
CYP3A-inducing antiepileptics decrease sorafenib exposures: Results of a phase II study in adults with recurrent glioblastoma.
Authors: S. Gururangan, J. J. Vredenburgh, A. Desjardins, K. Peters, J. E. Herndon, R. E. McLendon, D. Janney, H. S. Friedman, D. A. Reardon
Journal: Journal of Clinical Oncology (2010)

2089 Background: Sorafenib, an oral inhibitor of VEGFR-2, Raf, PDGFR, c-KIT and Flt-3, has established activity against renal cell carcinoma and hepatocellular carcinoma, and has recently demonstrated promising activity for lung and breast cancer. Recently, a variety of protracted dosing schedules of temozolomide have been evaluated as a strategy to further enhance its antitumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase II trial of this regimen among patients with recurrent glioblastoma. Methods: Adult patients with GBM at any recurrence after standard temozolomide chemoradiotherapy received sorafenib administered at 400 mg twice daily and continuous daily temozolomide dosed at 50 mg/m2. Assessments were performed after every other cycle. The primary endpoint was progression-free survival at 6 months (PFS-6) and the secondary end points were radiographic response, overall survival (OS) and safety. Sorafenib pharmacokinetics were assessed on days one and 28 of cycle one. Results: Of 32 enrolled patients, twelve (38%) were on CYP3-A inducing antiepileptics (EIAEDs), seventeen (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-plantar erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic analyses revealed no differences between patients on day 1 regardless of EIAED status, but significantly lower exposures on day 28 for patients on EIAEDs (p = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. Conclusions: Our study confirms that sorafenib can be safely administered with daily temozolomide, but this regimen has limited antitumor activity among recurrent GBM patients. Coadministration of EIAEDs can lower sorafenib exposures in this population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Validation of the 30-Day Postoperative Mortality Standard and Its Relevance
Authors: Kamal M. F. Itani
Journal: JAMA Surgery (2016)

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The impact of short periods of match congestion on injury risk and patterns in an elite football club
Authors: Chris Carling, Alan McCall, Franck Le Gall, Gregory Dupont
Journal: British Journal of Sports Medicine (2015)

Background The effect of fixture congestion on injury rates and patterns has received scarce attention in elite football and existing investigations have not accounted for player rotation or examined the temporal distribution and potential cause of injuries. Aim To prospectively investigate the epidemiology of injury during short periods of fixture congestion in a professional football club. Methods Over a six-season period, exposure time and injury data were compared in the same players (n=25 (14 individuals)) when participating in two frequently occurring short congested fixture cycles in comparison to match-play outside these cycles. (1) two successive matches separated by an interval totalling ≤3 days calculated immediately from the end of play in match 1 to the beginning of play in match 2; (2) three successive matches separated by ≤4-day intervals starting the day immediately after each match. Results In two-match congestion cycles, incidence rate ratios (IRR) showed that there was a higher risk of injury in the final 15 min of play in the second match in comparison to match-play outside the cycles (IRR: 3.1 (95% CI 1.1 to 9.3), p=0.0400). A greater risk of injury overall (IRR: 2.0 (95% CI 1.1 to 3.8), p=0.0345) and in the first-half of play (2.6 (1.1 to 6,5), p=0.0386), and risk of ankle sprains (10.4 (95% CI 1.9 to 57.9), p=0.0068) and non-contact injuries due to a ‘change in direction’ (IRR: 7.8 (1.3 to 46.8), p=0.0243) were observed in the final match of three-match congestion cycles in comparison to match-play outside the cycles. Conclusions Injury rates and patterns were affected in the same elite football players when competing in short congested fixture cycles in comparison to match-play outside the cycles.
Abstract 13253: Race, Exercise Training and Outcomes in Chronic Heart Failure
Authors: Robert J Mentz, Vera Bittner, Aijing Z Starr, Jerome L Fleg, Gordon Moe, Ann M Swank, Meredith Fitz-Gerald, Anil Nigam, Andrew Kao, Anekwe Onwuanyi, William E Kraus, David J Whellan, Stephen J Ellis, Christopher M O'Connor
Journal: Circulation (2012)

Background:  The strength of race as a predictor of outcomes in a contemporary chronic heart failure (HF) population and its interaction with exercise training response remains unexplored.   Methods:  We performed an analysis of HF-ACTION, which randomized 2,331 HF patients with EF    Results:  Of patients with race documented, 62% (N=1426) were white, 33% (N=749) were AA and 5% (N=121) were other. Compared with whites, AAs were younger (median 55 vs. 62 yr), more often female (40% vs. 22%), and less often had ischemic HF (32% vs. 61%), but had a similar EF and creatinine. At baseline, AAs had a lower peak VO2 (raw median 13.2 vs. 15.0 mL/kg/min) and shorter 6-minute walk (raw median 348 vs. 383 meters) despite gender adjustment (both P P =0.032) and CV mortality/HF hosp ( P =0.0002). After multivariable adjustment including education and income level, AA race was associated with increased CV mortality/CV hosp and CV mortality/HF hosp, but not increased mortality ( Table ). There was no significant interaction between race and exercise training on outcomes (all  P >0.5).   Conclusion:  AA race in chronic HF patients with reduced EF was associated with younger age, higher proportion of women and non-ischemic etiology, reduced baseline exercise capacity, and increased CV mortality/CV hosp and CV mortality/HF hosp, but not increased all-cause mortality or a differential response to exercise training on clinical outcomes.
Predictors of pulmonary toxicity in limited-stage (LS) small cell lung cancer (SCLC) patients treated with concurrent chemotherapy (CTX) and high-dose (70 Gy) daily radiotherapy (RT): A pooled analysis of three CALGB studies.
Authors: J. K. Salama, L. Hodgson, H. Pang, M. R. Green, J. J. Urbanic, A. W. Blackstock, J. Crawford, J. Bogart, E. E. Vokes
Journal: Journal of Clinical Oncology (2011)

7078 Background: Predictors of post CTX-RT pulmonary toxicity in LS-SCLC patients are not well defined. Current guidelines are derived from NSCLC regimens, not accounting for the unique biology of SCLC. We analyzed patients on 3 consecutive CALGB LS-SCLC trials to determine factors predicting for post-treatment pulmonary toxicity. Methods: Patients treated on CALGB protocols 39808, 30002, 30206, investigating 2 cycles of newer CTX agents (39808: topotecan, paclitaxel; 30002: paclitaxel, oral etopside, oral topotecan; 30206: cisplatin, irinotecan) followed by concurrent carboplatin/etopside and 70 Gy daily RT were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3-5 pulmonary toxicities following CTX-RT. PFT data were not routinely collected and not included in this analysis. Results: 211 patients were treated, 100 patients (39808 n=9, 30002 n=34, 30206 n=57) were evaluable with RT dose-volume parameters and adverse event data. Patient characteristics were balanced between except for those in 30206 with significantly improved baseline PS. Median overall and progression free survival was 22.6 months (95% CI: 18.5-29.4) and 13.9 months (95% CI: 12.6-16.7), respectively. Three patients experienced post-treatment pulmonary toxicity. No patients experienced grade 4-5 pulmonary toxicity. Patients with post-treatment grade 3 pulmonary toxicity were likely to be older (p=0.09) and have a smaller total lung volume (p=0.05). Furthermore, exposure of larger volumes of lung to lower (median V5=70%, p=0.09, median V10=63%, p=0.07), intermediate (median V20=50%, p=0.04) and high (median V60=25%, p=0.01) doses of RT were all associated with grade 3 pulmonary toxicity, as was larger mean lung RT dose (median 31 Gy p=0.02). Conclusions: Post-treatment pulmonary toxicity following completion of 2 cycles CTX followed by CTX-RT was uncommon. Few events limtied statistical power to draw firm conclusions. Data available suggest that care should be taken to minimize mean lung RT exposure, as well as volumes of low, intermediate and high doses of RT.
More than a lucrative liquid: the risks for adult consumers of human breast milk bought from the online market
Authors: Sarah Steele, Jens Foell, Jeanine Martyn, Andreas Freitag
Journal: Journal of the Royal Society of Medicine (2015)

Sarah Steele, Jens Foell, Jeanine Martyn and Andreas Freitag Global Health, Policy and Innovation Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, UK Richford Gate Medical Practice, Richford Street, London W67HY, UK Lifespan, 167 Point Street, Providence, Rhode Island 02903, USA National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK Corresponding author: Sarah Steele. Email: s.steele@qmul.ac.uk
Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear
Authors: Hongbin Yang, Junhua Yang, Wang Xi, Sijia Hao, Benyan Luo, Xiaobin He, Liya Zhu, Huifang Lou, Yan-qin Yu, Fuqiang Xu, Shumin Duan, Hao Wang
Journal: Nature Neuroscience (2016)
Detection of Human Papillomavirus Types 16 and 18 mRNA in Peripheral Blood of Advanced Cervical Cancer Patients and Its Association With Prognosis
Authors: Chih-Jen Tseng, Chia C. Pao, Jen-Daw Lin, Yung-Kuei Soong, Ji-Hong Hong, Swei Hsueh
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To evaluate the feasibility of detecting human papillomavirus E6 (HPVE6) gene mRNA in the peripheral blood of patients with locally advanced cervical cancer, and the relationship of the circulating HPV viral–specific mRNA with clinicopathologic factors and prognosis of locally advanced cervical cancer. PATIENTS AND METHODS: The presence of types 16 and 18 HPVE6 gene mRNA was determined by reverse transcription followed by nested polymerase chain reaction. Thirty-five patients with locally advanced cervical cancer who were positive for HPV type 16 or 18 DNA were included in the study. All patients received external-beam radiation therapy followed by intracavitary brachytherapy. RESULTS: Eighteen (51.4%) of 35 HPV DNA–positive cervical cancer patients had HPV-specific mRNA in their peripheral blood cells, compared with none of 17 HPV DNA–negative cervical cancer patients and none of 12 control volunteers. The presence of HPVE6 gene mRNA in peripheral blood was associated with bulky tumor volume (&gt; 4 cm) and pelvic lymph node metastasis (tumor volume, P = .03; lymph node status, P = .03). After a median follow-up of 22 months, patients who were positive for peripheral-blood HPVE6 gene mRNA had a significantly higher risk of recurrence than those who were negative (10 of 18 v three of 17, P = .02; mean recurrent time, 20.7 months v 12.6 months, P = .02). There was also a statistically significant association of peripheral-blood HPVE6 gene mRNA positivity with distant metastasis (eight of 18 v one of 17; P = .01). CONCLUSION: Results of this study seem to suggest that the presence of HPVE6 gene mRNA in peripheral blood may provide an early marker that identifies patients who are at risk for metastasis.
The uncompensated costs associated with the evaluation and treatment of neutropenia
Authors: E. Calhoun, S. Brown, M. Kozloff, A. Starr, C. Bennett
Journal: Journal of Clinical Oncology (2004)

6120 Background: Febrile neutropenia is a serous complication of chemotherapy which is frequently managed in the outpatient setting. Health care personnel provide many uncompensated services as they coordinate outpatient and home care services for this treatment-related complication. We performed a time and motion study designed to evaluate time spent and associated costs of uncompensated care provided by physicians, nurses, phlebotomists, and medical assistants for outpatient management of cancer chemotherapy-associated febrile neutropenia. Methods: Over a three month period, cancer chemotherapy-associated febrile neutropenia management activities of a small community medical practice were monitored. Tasks were categorized as: consultation/education, documentation, medication administration, test or medication ordering, phone calls, nursing, procedures, after hours follow-up, and miscellaneous. Unit costs were estimated using 2003 practice-specific salary and fringe benefit rates. Results: The results presented represent the time spent on the evaluation and management of neutropenia and related activities over the course of a 5 day work week. Conclusions: Based on the results of this observational study, the time required for coordination of chemotherapy-associated neutropenia management can be considerable, and the associated uncompensated costs to a small community practice can be substantial. For one community oncology practice, treatment and management of neutropenia and related care costs $88,832 of lost time per year. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen; Medimmune Amgen
Abstract 16322: Thiosulfate: A Carrier Molecule of the Protective Effects of Hydrogen Sulfide Against Neuronal Ischemia
Authors: Eizo Marutani, Marina Yamada, Kentaro Tokuda, Kazuhiro Shirozu, Kenjiro Hanaoka, Masao Kaneki, Fumito Ichinose
Journal: Circulation (2014)

Hydrogen sulfide (H 2 S) is an endogenously produced gaseous signaling molecule that exhibits protective effects in various disease models including cardiac arrest and cardiopulmonary resuscitation. Nonetheless, mechanisms and identity of molecules responsible for the neuroprotective effects of exogenous sulfide donor compounds, such as sodium sulfide (Na 2 S), remain incompletely defined. In circulation, reaction with plasma proteins and or oxidation to sulfur oxides maintains free plasma H 2 S levels very low. Free H 2 S levels only transiently increase and quickly return to its baseline after systemic administration of sulfide donor compounds. Thiosulfate is an oxidation product of H 2 S that is relatively stable in blood and tissues. In the current study, we observed that thiosulfate mediates protective effects of Na 2 S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. We also found that systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral IR injury. Beneficial effects of STS, as well as Na 2 S, were associated with marked increase of thiosulfate, but not H 2 S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating “carrier” molecule of beneficial effects of sulfide. Protective effects of thiosulfate are associated with modulation of Erk1/2, and JNK pathways and S-sulfhydration of cleaved caspase-3. Of note, we discovered that a SLC13 family protein, sodium sulfate co-transporter 2 (SLC13A4, NaS-2), facilitates the transport of sulfide or thiosulfate across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of sulfide and thiosulfate. Given that STS is widely used as an antidote and has very low toxicity in humans, these observations suggest that STS represents a novel therapeutic agent for ischemic brain injury.
Abstract 13581: Combined Assessment of N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Troponin T Levels Improves the Prediction of Future Admission for Heart Failure in Outpatients with Hypertension and Preserved Left Ventricular Ejection Fraction
Authors: Shigeru Matsui, Junnichi Ishii, Hiroshi Takahashi, Ryuunosuke Okuyama, Hideki Kawai, Takashi Muramatsu, Hiroyuki Naruse, Sadako Motoyama, Hideo Izawa, Yukio Ozaki
Journal: Circulation (2014)

Background: Hypertension is one of the most prevalent cardiovascular diseases and one of the most important causes of heart failure (HF) with preserved left ventricular ejection fraction (LVEF). We prospectively investigated the incremental predictive value of a combination of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), and galectin-3 for HF admission in outpatients with hypertension. Methods: Baseline serum NT-proBNP, hsTnT, and galectin-3 levels were measured in 443 outpatients (mean age, 69.4 years) with hypertension and LVEF ≥ 50%. Using tissue Doppler echocardiography, E/e’ ratio was calculated. Among these patients, 34% had a history of cardiovascular disease, and 46% had a history of diabetes. Results: Galectin-3 levels significantly (p &lt; 0.0001) correlated with E/e’ ratio (r = 0.21) and estimated glomerular filtration rate (eGFR; r = –0.78). During a mean follow-up period of 899 days, there were 40 (9%) HF admissions. Using multivariate Cox regression analysis including 10 clinical, biochemical, and echocardiographic variables, increased NT-proBNP (relative risk, 2.88 per 10-fold increment, p = 0.007) and hsTnT (4.30 per 10-fold increment, p = 0.004) levels, but not ga1ectin-3 levels, were shown to be independent predictors of HF admission. When patients were stratified into four groups according to NT-proBNP levels ≥ a median value of 193.7 pg/mL and/or hsTnT levels ≥ a median value of 14 pg/mL, HF admission rates were 1.1%, 2.1%, 4.3%, and 20%, respectively (p &lt; 0.0001). Furthermore, when NT-proBNP and hsTnT levels were combined, the predictive values for HF admission were increased, as shown by the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI; Table 1). Conclusions: The combined assessment of NT-proBNP and hsTnT levels can improve the prediction of HF admission in outpatients with hypertension.
A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer
Authors: J. A. Konner, K. Fallon, S. Pezzuli, A. Iasonos, P. Sabbatini, M. Hensley, A. Chiang, W. Tew, D. Spriggs, C. Aghajanian
Journal: Journal of Clinical Oncology (2007)

5523 Background: IP Cis plus IV/IP Tax is a standard therapy for optimally debulked ovarian cancer. Bev is a recombinant humanized IgG1 monoclonal antibody directed against vascular endothelial growth factor (VEGF). Activity of Bev against recurrent ovarian cancer has been reported in phase II trials. In this study IP Cis and IV/IP Tax are combined with IV Bev as front-line therapy to assess safety and tolerability. Methods: Patients with optimal (&lt;1 cm residual), FIGO stage II or III, epithelial ovarian, fallopian tube, or peritoneal cancer, acceptable organ function, and KPS = 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev (starting cycle 2): Tax 135 mg/m 2 IV over 3 hours on Day 1, Cis 75 mg/m 2 IP on Day 2, Tax 60 mg/m 2 IP on Day 8, Bev 15 mg/kg IV on Day 1. Extended treatment with Bev is continued every 3 weeks for 17 treatments after chemotherapy is complete. The study will enroll 41 patients. The primary endpoint is safety and tolerability, determined by the proportion of patients who complete the prescribed 6 cycles of cytotoxic chemotherapy without discontinuation and without dose-limiting non-hematologic and non-electrolyte toxicity. A stopping rule will be applied if excessive toxicity is encountered. Results: To date, 8 women have been treated on the study. Median age: 53 (48–59). All 31 planned doses of chemotherapy have been administered in full. One dose of IP Tax was delayed for 2 days due to abdominal pain. One patient had her first dose of Bev delayed for 1 cycle due to surgical wound infection. There have been no toxicities &gt; grade 3. Grade 1/2 toxicities include: fatigue (87.5%); nausea (50%); and hypomagnesemia (37.5%). Grade 3 toxicities per patient: fatigue (12.5%); hyponatremia (25%); hypokalemia (25%); hypertension (12.5%); abdominal pain (12.5%); and neutropenia (12.5%). Of the 5 patients with pretreatment CA125 &gt;35 Units/mL, 4 normalized their value after 1 cycle of chemotherapy and 1 patient normalized after 2 cycles. Conclusions: Preliminary experience suggests that the combination of IV Bev with IP Cis plus IV/IP Tax may be well tolerated. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.