tbuckley/cabot-search huggingface dataset:
Observational Study of Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (Egfr-Tki) in Activating Egfr Mutation-Positive (Egfrm+) Advanced or Recurrent Non-Small-Cell Lung Cancer (Nsclc) After Radiological Progression to First-Line Therapy with Egfr-Tki
Authors: Y. Yamane, H. Sakai, F. Kurimoto, J. Sudo, H. Tsuzuki, S. Takahashi, Y. Hosomi, C. Tanai, K. Yoh, Y. Goto, Y. Ohashi, H. Kunitoh
Journal: Annals of Oncology (2014)
Insulin resistance, hyperinsulinemia, and obesity-associated hypertension.
Authors: M W Brands, J E Hall
Journal: Journal of the American Society of Nephrology (1992)

Recent work to elucidate the cause of obesity-associated hypertension has focused on insulin resistance and hyperinsulinemia. A significant amount of epidemiologic and correlational evidence suggests a link between these factors and obesity-associated hypertension, and acute insulin infusion studies have revealed renal, neural, and cardiovascular effects of this hormone that, if maintained chronically, could cause hypertension. However, correlations and acute effects may not reliably predict a chronic cause-and-effect relationship, and the fundamental question of whether chronic increases in plasma insulin concentration per se can produce a sustained increase in arterial pressure has not been completely resolved. Recent studies designed to address this question directly have found no evidence of a hypertensive effect of insulin in normal dogs, or in dogs with a 70% reduction in kidney mass and given a high sodium intake. Chronic hyperinsulinemia also did not potentiate the pressor effects of angiotensin II or norepinephrine. In fact, hyperinsulinemia caused significant reductions in total peripheral vascular resistance in dogs and a decrease in arterial pressure. Furthermore, induction of insulin resistance in dogs made obese by being fed a high-fat diet eliminated the decrease in peripheral vascular resistance during chronic insulin infusion but did not uncover a pressor effect of hyperinsulinemia. In contrast, insulin infusion for up to 7 days produced a sustained increase in arterial pressure in rats. Although the mechanism for this pressor response is unknown, these data indicate either that there are major species differences in the chronic blood pressure response to insulin or that specific, presently unknown, conditions must exist in order for insulin to raise blood pressure. Also, it is not clear whether humans respond more like rats or dogs with respect to blood pressure changes during chronic hyperinsulinemia. However, it is apparent that obesity hypertension is probably much too complex to be ascribed to insulin resistance and hyperinsulinemia alone.
Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer
Authors: Noël J.-M. Raynal, Justin T. Lee, Youjun Wang, Annie Beaudry, Priyanka Madireddi, Judith Garriga, Gabriel G. Malouf, Sarah Dumont, Elisha J. Dettman, Vazganush Gharibyan, Saira Ahmed, Woonbok Chung, Wayne E. Childers, Magid Abou-Gharbia, Ryan A. Henry, Andrew J. Andrews, Jaroslav Jelinek, Ying Cui, Stephen B. Baylin, Donald L. Gill, Jean-Pierre J. Issa
Journal: Cancer Research (2016)

Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer.
Identification and Validation of Lymphovascular Invasion as a Prognostic and Staging Factor in Node-Negative Esophageal Squamous Cell Carcinoma
Authors: Qingyuan Huang, Kongjia Luo, Chun Chen, Geng Wang, Jietian Jin, Min Kong, Bifeng Li, Qianwen Liu, Jinhui Li, Tiehua Rong, Haiquan Chen, Lanjun Zhang, Yuping Chen, Chengchu Zhu, Bin Zheng, Jing Wen, Yuzhen Zheng, Zihui Tan, Xiuying Xie, Hong Yang, Jianhua Fu
Journal: Journal of Thoracic Oncology (2016)
Randomized, phase II study of biweekly versus weekly paclitaxel/carboplatin (PC) for the treatment of advanced non-small cell lung cancer: A Japan-Korea collaborative clinical trial
Authors: K. Takayama, Y. Kim, M. Ichiki, S. Kim, K. Inoue, S. Yang, M. Kawasaki, M. Jung, S. Tokunaga, K. Kim, Y. Nakanishi
Journal: Journal of Clinical Oncology (2008)

19124 Background: We previously reported that a biweekly PC therapy produced an objective response rate (ORR) of 35.1% and overall survival of 11.9 months in the chemonaive advanced NSCLC patients (pts) with a more favorable toxicity profile than every 3 week regimen. In the current study, we conducted the Japan-Korea international clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC to select the suitable therapy for Asian. Methods: Chemonaive PS0–2 pts with IIIB/IV NSCLC were randomly assigned to biweekly regimen (paclitaxel 135mg/m2 and carboplatin AUC 3 at d1, d15) or weekly regimen (paclitaxel 90mgm2 at d1, d8, d15 and carboplatin AUC 6 at d1). Results: In total 212 pts, 140 pts from Japan and 72 pts from Korea were enrolled between Feb 2005 and May 2007. 101 pts and 109 pts were assigned to biweekly and weekly regimen, respectively. Clinical background in both groups did not show any difference. Analysis was performed on the 207 assessable pts. ORRs are 31.6% (B) and 40.4% (W) in total, and the results were similar in Japan and Korea. ORRs are 29.7% (B) and 39.4% (W) in Japan, and 35.3% (B) and 42.1% (W) in Korea. In both countries, weekly regimen showed the better response rate compared with biweekly regimen. The most common toxicity was neutropenia in both countries. In Japan, hematological toxicities with grade 3 and more were 57.8% (B) and 69.0% (W), and non-hematological toxicities were 25.0% (B) and 14.1% (W). In Korea, hematological toxicities with grade 3 and more were 29.4% (B) and 36.8% (W), and non-hematological toxicities were 5.9% (B) and 5.3% (W). The toxicities seemed to be mild in Korea than Japan. Conclusions: Weekly PC therapy is well torelated and showed promising efficacy data in advanced NSCLC pts compared with biweekly regimen. No significant financial relationships to disclose.
Soft tissue sarcoma
Authors: N Eastley, P N Green, R U Ashford
Journal: BMJ (2016)

#### What you need to know A 45 year old woman presented to her general practitioner several times over nine months with a gradually enlarging, hard lump in her anterior thigh. An ultrasound scan showed a solid intramuscular mass in the anterior compartment of her thigh, prompting a two week wait referral to the regional sarcoma diagnostic clinic. Magnetic resonance imaging showed a large, heterogeneous intramuscular mass. Core biopsy confirmed a high grade soft tissue sarcoma, and staging computed tomography showed lung metastases. The patient underwent chemotherapy for metastatic disease, followed by resection of her primary tumour, but her disease relapsed and she died 16 months after diagnosis. Soft tissue sarcoma is a heterogeneous group of malignancies. They account for 1% of cancers and have a five year survival of approximately 50%. They can occur at any age (although more than 65% occur in people aged over 50 years1) and in any part of the body. #### How common are soft tissue sarcomas?
Detection of Pancreatic Cancer–Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance
Authors: Paul T. Winnard, Santosh K. Bharti, Marie-France Penet, Radharani Marik, Yelena Mironchik, Flonne Wildes, Anirban Maitra, Zaver M. Bhujwalla
Journal: Cancer Research (2016)

The dire effects of cancer-induced cachexia undermine treatment and contribute to decreased survival rates. Therapeutic options for this syndrome are limited, and therefore efforts to identify signs of precachexia in cancer patients are necessary for early intervention. The applications of molecular and functional imaging that would enable a whole-body "holistic" approach to this problem may lead to new insights and advances for diagnosis and treatment of this syndrome. Here we have developed a myoblast optical reporter system with the purpose of identifying early cachectic events. We generated a myoblast cell line expressing a dual tdTomato:GFP construct that was grafted onto the muscle of mice-bearing human pancreatic cancer xenografts to provide noninvasive live imaging of events associated with cancer-induced cachexia (i.e., weight loss). Real-time optical imaging detected a strong tdTomato fluorescent signal from skeletal muscle grafts in mice with weight losses of only 1.2% to 2.7% and tumor burdens of only approximately 79 to 170 mm(3). Weight loss in cachectic animals was also associated with a depletion of lipid, cholesterol, valine, and alanine levels, which may provide informative biomarkers of cachexia. Taken together, our findings demonstrate the utility of a reporter system that is capable of tracking tumor-induced weight loss, an early marker of cachexia. Future studies incorporating resected tissue from human pancreatic ductal adenocarcinoma into a reporter-carrying mouse may be able to provide a risk assessment of cachexia, with possible implications for therapeutic development.
Abstract 17423: The Cardioprotective MitoKrATPr Channel - Unmasked
Authors: D. Brian Foster, Alice S Ho, Jasma Rucker, Anders O Garlid, Ling Chen, Agnieszka Sidor, Keith D Garlid, Brian O'Rourke
Journal: Circulation (2012)

Rationale: Activation of the mitochondrial ATP-sensitive potassium channel (MitoKATP) plays a critical role in cardiac ischemic preconditioning, yet the molecular identity of the channel subunits r...
Abstract P309: Foreclosure Rates During Economic Recession and Cardiovascular Health: Paradoxical Results from the Survey of the Health of Wisconsin
Authors: F. Javier Nieto, Kristen M Malecki, José Antonio Tapia Granados
Journal: Circulation (2014)

Contrary to conventional wisdom, research has shown that economic recessions are associated with decreases in mortality and, conversely, mortality increases during times of economic expansion. Most of these studies are based on unemployment data and few have examined morbidity data as outcomes. The present analyses used data from the 2008-11 waves of the Survey of the Health of Wisconsin (SHOW) to study the association between county rates of foreclosures during the 2009-10 economic recession and cardiovascular health. SHOW is based on a probabilistic statewide sample of adult (21-74 years old, n = 1,643) residents in Wisconsin. The cardiovascular health (CVH) index was defined using a combination of “ideal or intermediate” levels of seven risk factors and health behaviors (body mass index, cholesterol, glucose, diet, physical activity, blood pressure and smoking). Foreclosure rates for the 72 counties of Wisconsin were obtained from commercially available data for the period 2000-2012. Other covariates included Census-based neighborhood socioeconomic status (SES), individual-level SES, and measures of mental wellbeing (using the Depression, Anxiety and Stress Scale, DASS). Of the 1,643 participants, 1.0% had ideal CVH (“ideal” in all 7 metrics) and 25.6% had overall “good” (ideal or intermediate) CVH (at least one “intermediate,” but no “poor” in any of the 7 components). The prevalence of good CVH was higher in younger, white, higher education and income participants, and those living in suburban areas. Participants recruited from counties in the top quartile of foreclosure rates in 2009 (at the peak of the economic recession) had higher prevalence of good CVH. Compared to the lowest quartile, the demographics-adjusted odds ratio of good CVH were 2.0 (95% CL 1.4-2.9), 2.1 (1.4-3.1) and 2.7 (2.8-3.9) for the 2nd, 3rd, and 4th quartile of foreclosure rates, respectively (p-trend=0.003). Additional adjustment of individual/county SES and measures of individuals’ mental health did not materially change these results. These paradoxical associations were not present when using foreclosure data from years preceding the recession as primary exposures (2000-07). In conclusion, county foreclosure rates, a marker of the severity of the 2009 economic recession in local communities, appears to be associated with better cardiovascular health. These results are consistent with previous research linking recessions with better health outcomes. However, interpreting these results as meaning that foreclosures improve health at the individual level might be subject to ecological fallacy. Additional analyses controlling for unmeasured confounders and possible selection biases are needed to further understand the significance of these findings.
HLA-associated multipeptide vaccination in biochemically relapsed prostate cancer patients
Authors: S. Feyerabend, S. Stefanovic, C. Gouttefangeas, M. Widenmeyer, D. Wernet, J. Hennenlotter, J. Bedke, K. Dietz, S. Pascolo, H. Rammensee, A. Stenzl
Journal: Journal of Clinical Oncology (2009)

5134 Background: We conduct a phase I/II monocenter clinical trial using multi peptide vaccination in patients with hormone naive, biochemically relapsed prostate cancer. The synthetic peptides applied are MHC-class I (HLA-A2) and -class II binders for activating CD4+ and CD8+ T- effector cells in vivo. Study endpoints are side effects as well as PSA- and T-cell response. Methods: Patients (pts) with rising PSA after primary curative surgical treatment without metastatic imageable lesions receive 14 peptides emulsified in Montanide ISA51 subcutaneously, combined with one of four T-cell stimulatory adjuvants versus no adjuvant for 18 months (mo) or until progression. PSA doubling time (DT) and clinical performance are monitored. T-cell activity and specifity are assessed with Elispot assay, tetramer staining and intracellular cytokine stainings. Results: 25 out of 35 pts have terminated the study treatment so far. During the vaccination period, geometric mean PSA DT increased from 7.8 mo (range 1.5 - 44.8 mo, 25 pts) to 11.8 months (range 2.2 - 571.3 mo, 24pts) whereas 1 pt showed a decreasing PSA value. Overall 8/25 pts (32%) had a mean rise of PSA DT of 81.6 mo and four of them did not receive any further treatment and were evaluable for follow-up (FU) after peptide vaccination (FU median 16 mo, range 5–33). These four pts raised their mean geometric PSA DT from 8.2 mo prior study treatment to 51.9 mo at treatment end and 52.5 mo at end of FU. PSA progressed unchanged in 10 patients (40%) or increased intermittently only in 4 pts. Two pts had PSA decline or DT increase during FU but not during the treatment period. Four patients (16%) exhibited an allergic reaction CTCAE II°. All pts reacted to at least one of the tumor antigen-derived HLA-class I epitopes after the fourth vaccine injection and up to six peptides were recognized simultaneously by CD8+ T cells in some individuals. Conclusions: Multi peptide vaccination stabilized or slowed down PSA progress in 11 of 25 cases. Stimulation of specific T-cell response is observed. Rise of PSA DT delaying standard treatment up to 33 mo and thus, delaying disease specific mortality is feasible. No significant financial relationships to disclose.
PTEN hamartoma tumor syndrome (PHTS): Clinical characteristics, onco-phenotype, and molecular analysis.
Authors: M. M. Patnaik, S. Khambatta, S. I. Robinson, R. L. Richardson, M. P. Goetz
Journal: Journal of Clinical Oncology (2010)

1510 Background: Germline mutations of the PTEN gene are associated with a spectrum of clinical syndromes such as Cowden's syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and the adult Lhermitte-Duclos disease (LDD). CS is the most common amongst these, and results in an increased risk of benign and malignant tumors. We sought to characterize the malignancies that develop in patients with PHTS. Methods: Patients at the Mayo Clinic Rochester, with a clinical diagnosis of PHTS, CS, BRRS, PS, and LDD were retrospectively identified from 1980 to 2009. Only patients that met the NCCN consortium criteria for diagnosis were included. The onco-pathology and molecular studies were reviewed, and relevant clinical information retrospectively obtained. Results: Forty six(23 M) patients met the consortium criteria for diagnosis of CS or related disorders. 37 had CS (80.4%), 6 had BRRS (13%) and 3 had LDD (6%). 16 of 20 patients tested had detectable genetic abnormalities; 14 missense/nonsense mutations and 2 deletions. Invasive malignancy was documented as follows: thyroid cancer (n = 7, 15%) (6 papillary, 1 follicular), breast (n = 6, 13%) (1 bilateral), renal cell (n = 6, 13%), colon (n = 2), and one each with endometrial and ovarian cancer. Regarding breast malignancies, 5 of 6 (83%) were triple negative (ER-/PR-/HER2-), and 5 of 6 patients had metastatic disease within 2 years of diagnosis. Unique neoplasms included pituitary macroadenoma (1), vaginal adenocarcinoma (1), rectal cancer (1), bronchioalveolar carcinoma (1), breast lymphoma (1), and perineal squamous cell carcinoma (1). 27 patients had benign thyroid lesions (58.6%), 11 had benign breast disease (23%), 9 had tricholemmomas (19.5%), 8 had acral keratoses (17%), 8 had cutaneous papillomas (17%), 4 had meningiomas (8%), 4 had AV malformations (8%) and 2 had colonic ganglioneuromas (4%). Conclusions: Patients with PHTS can present with a diverse oncological spectrum, highlighting the importance of intense surveillance. Breast cancer in PHTS tends to be aggressive, triple negative, with a high rate of metastases. Contrary to published literature, papillary cancers of thyroid occur more commonly than follicular neoplasms. No significant financial relationships to disclose.
A retrospective review of the University Health Network (UHN) multimodal treatment experience with extended resection of pancreatic ductal adenocarcinoma (PDAC) in patients with arterial involvement.
Authors: Amélie Tremblay St-Germain, Adrian Fox, Maja Segedi, Pablo Emilio Serrano Aybar, Paul Scholtz, Martin O'Malley, Ayelet Borgida, Teresa Bianco, Anna Dodd, Monika K. Krzyzanowska, Malcolm Moore, Joon-Hyung J. Kim, Alice Chia-chi Wei, Steven Gallinger, Neesha C. Dhani, Ian M McGilvray
Journal: Journal of Clinical Oncology (2015)

447 Background: Involvement of a major artery with PDAC is a criteria of unresectability. Although major vein resection/reconstruction is now accepted in PDAC resection, the feasibility of arterial resection requires investigation. The response to neoadjuvant therapy (NAT) may be a useful tool for identifying appropriate candidates for extended resection. Methods: We retrospectively reviewed the UHN experience of multimodality therapy in patients (pts) with histologically confirmed PDAC and single vessel arterial involvement (superior mesenteric, celiac or hepatic artery) on CT from Jan 2009 to Dec 2013. These pts received NAT prior to being re-assessed for surgery; pts whose disease was either stable or improved were considered for surgery. Baseline imaging was reviewed independently. Postoperative complications were assessed and oncologic outcomes were analysed with Kaplan-Meier method. Results: We identified a cohort of 57 pts of whom 56 received NAT. On reassessment, 26 (46%) had no evidence of disease progression and were considered operable, while 31 had local or distant progression and were deemed inoperable. Of 26 pts proceeding to surgery, 21 (81%) underwent resection and 5 had a palliative procedure. In the resection group, 10 pts required arterial resection/reconstruction to achieve R0. The post-operative mortality at 90-days was 0% and morbidity was 86% with 33% major complications (Clavien-Dindo III-IV). With a median follow-up of 12,1 months, the median survival for the resection group was 18.7 months (95% CI: 11.2-NA) vs. 13.6 months (95% CI: 11.9-18.1) for the non-resection group, P=0.0246. Conclusions: Our results suggest that a multimodal approach including NAT +/- segmental arterial resection/reconstruction, can be considered but with high post-operative morbidity. The encouraging survival rates of pts after extended resection must be balanced with the morbidity of this surgery. Given the poor prognosis of pts with locally advanced PDAC, there is a rationale for prospective evaluation of this approach to identify pts who are most likely to benefit from this aggressive strategy.
Impact of Maternal Oral Contraceptive Pills on Wheeze and Allergic Outcomes in 5-Year-Olds: A Prospective Birth Cohort Study in Japan
Authors: Kiwako Yamamoto-Hanada, Limin Yang, Tetsuo Shoda, Osamu Natsume, Masami Narita, Yukihiro Ohya
Journal: Journal of Allergy and Clinical Immunology (2016)
NHS overspend reaches £2.3bn
Authors: Susan Mayor
Journal: BMJ (2016)

The NHS overspent by £2.26bn (€2.9bn; $3.2bn) in the first three quarters of this financial year (April to December 2015), a report from Monitor and the NHS Trust Development Authority showed.1 The overspend is forecast to reach £2.37bn by the end of March.

The deficit is £622m more than planned for by the health regulators. The planned £1.6bn was reached at the end of the second quarter. Providers were told that the deficit must be kept below £1.8bn.

“This level of deficit is neither sustainable nor affordable …
British Thoracic Society guidelines for home oxygen use in adults: accredited by NICE
Authors: Maxine Hardinge, Joe Annandale, Simon Bourne, Brendan Cooper, Angela Evans, Daryl Freeman, Angela Green, Sabrine Hippolyte, Vikki Knowles, William MacNee, Lynn McDonnell, Kathy Pye, Jay Suntharalingam, Vandana Vora, Tom Wilkinson
Journal: Thorax (2015)

The British Thoracic Society (BTS) Home Oxygen Guideline provides detailed evidence-based guidance for the use of home oxygen for patients out of hospital. Although the majority of evidence comes from the use of oxygen in patients with chronic obstructive pulmonary disease, the scope of the guidance includes patients with a variety of long-term respiratory illnesses and other groups in whom oxygen is currently ordered, such as those with cardiac failure, cancer and end-stage cardiorespiratory disease, terminal illness or cluster headache. It explores the evidence base for the use of different modalities of oxygen therapy and patient-related outcomes such as mortality, symptoms and quality of life. The guideline also makes recommendations for assessment and follow-up protocols, and risk assessments, particularly in the clinically challenging area of home oxygen users who smoke. The guideline development group is aware of the potential for confusion sometimes caused by the current nomenclature for different types of home oxygen, and rather than renaming them, has adopted the approach of clarifying those definitions, and in particular emphasising what is meant by long-term oxygen therapy and palliative oxygen therapy. The home oxygen guideline provides expert consensus opinion in areas where clinical evidence is lacking, and seeks to deliver improved prescribing practice, leading to improved compliance and improved patient outcomes, with consequent increased value to the health service.