tbuckley/cabot-search huggingface dataset:
Abstract 19234: A Short Term Premorbid High Fat Diet Disrupts Cardiac Leptin Signaling, Impairs Glucose Metabolism and Increases Morbidity and Mortality with Myocardial Infarction
Authors: Kenneth McGaffin, Keith Yester, William Witham
Journal: Circulation (2012)

Introduction A habitual high fat diet (HFD) contributes to obesity, and increases morbidity in cardiovascular disease (CVD), whereas the effects of a short-term HFD on CVD outcomes are unknown. This study was performed to test the hypothesis that a short term premorbid HFD disrupts cardiac leptin signaling, impairs glucose metabolism and exacerbates morbidity and mortality with myocardial infarction (MI). Methods/Results Lean, 12 week old male C57BL/6 mice were provided either a HFD (60% fat calories; n=24) or regular chow (RC) (16% fat calories; n=24) for 7 days. Equal number of mice from each dietary group were then randomly assigned to experimental MI or sham procedure, and maintained on RC until study completion at 7 days. Echocardiography and cardiac catheterization were performed on all surviving mice, and hearts were examined for biochemical and histologic measures of cardiac injury, and oxidative metabolism. Results are presented as mean ± SEM with statistical comparisons by t-test, or log-rank Mantel-Cox test (for survival). Groups of sham mice were not significantly different from each other in any measured outcome. However, with MI, a HFD increased mortality (41 vs 19%), cardiac dysfunction (fractional shortening 23±1 vs 29±1% and ejection fraction 24±2 vs 36±2%), and cardiac dilation (end diastolic dimension 4.6±0.1 vs 3.9±0.1mm and volume 56.6±1.3 vs 44.3±2.5uL); all p&lt;0.05. A HFD also increased post-MI cardiac TUNEL positive cells (11.3±0.5 vs 4.1±0.3%; p&lt;0.05) and oxidative stress by thiobarbituric reactive substances (6.8±0.2 vs 4.2±0.3 nMol/ml malondialdehyde equivalents; p&lt;0.05). These worse indices of cardiac injury were associated with a 89±3% reduction in cardiac ObR expression, and a corresponding 86±17% reduction in signal transducer and activator of transcription-3 activation by Western blot (both p&lt;0.05). Finally, post-MI decreases in pyruvate dehydrogenase activity (65±12%), glut4 mRNA (83±2%) and glucose oxidation (69±11%) were seen in hearts from premorbid HFD mice, whereas a 88±9% increase in fatty acid oxidation occurred (all p&lt;0.05). Conclusions These data suggest that a short-term premorbid HFD impairs cardiac leptin signaling and glucose metabolism, and exacerbates morbidity and mortality outcomes in MI.
Does the addition of adjuvant intraoperative postdissection tumor bed chemotherapy during GI neuroendocrine tumor debulking benefit patients?
Authors: Yi-Zarn Wang, Aman Chauhan, Robert A Ramirez, Melissa A Stevens, J Philip Boudreaux, Eugene Woltering, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2015)

442 Background: Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. The only treatment for potential cure and durable results is resection with extensive debulking. However, even with the most elegant surgical dissection/resection, macro and microscopic residual disease at the tumor resection bed remains a distinctive possibility. We hypothesize that local application of 5-florouracil (5-FU) within tumor bed would eliminate the microscopic residual disease post operatively. Methods: Surgical records of 188 consecutive patients who underwent extensive cytoreductive surgeries for stage IV, small bowel NETs with boggy mesenteric lymphadenopathy between 2003-2012 were reviewed. 85 Patients who had 5-Florouracil saturated gelfoam strips secured into their mesenteric resection defects served as the study group (n=85) with one hundred three patients who did not receive such intra-operative chemotherapy as the control (n=103). Survival from the time of diagnosis, postoperative morbidity and mortality between the two groups were collected and compared. Results: Mortality rates at immediate, 30, 60 and 90 days post operative period were 3; 0; 1; 0; and 0; 2; 0; 4 respectively for study and control group. Minor complications (Clavien-Dindo Grade I and II) at 30, 60 and 90 day postoperative period were 12; 0; 1 and 12; 5; 5 respectively. Major complications (Grade III and IV) at the same time intervals were 2; 0; 2 and 2; 3; 2 for study and control groups. Most of all, the mean survival from time of histological diagnosis for the study patients was 210 months (17.5 years) as compared to 177 months (14.7 years) for the control group with a difference of 33 months (2.75 years). Conclusions: Intra-operative tumor resection bed chemotherapy is a safe adjuvant without any discernible toxicity. Furthermore, it might provide survival benefit to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery without additional procedure related complications.
Phase I study of ON 01910.Na by 3-day continuous infusion (CI) in patients (pts) with advanced cancer
Authors: T. Ohnuma, S. Y. Cho, J. Roboz, J. D. Jiang, D. Lehrer, L. Silverman, J. D. Schwartz, E. P. Reddy
Journal: Journal of Clinical Oncology (2006)

13137 Background: The benzyl styryl sulfone analog ON 01910.Na is a novel anticancer agent that inhibits mitotic progression and induces apoptosis; it has activity against most human cancer cells in vitro and against a broad spectrum of human xenografts in mice. Cell kill effects are exposure time-dependent in vitro. After 3d exposure 200 nM ON 01910.Na killed &gt; 90% of Daudi lymphoma cells, whereas 40-fold higher drug concentration killed only 50% of cells after 24h exposure. Dogs that received CI of 325 mg/kg/d ×3 failed to reach MTD. Methods: Starting dose 50 mg/m 2 /d as a 72 hr CI was 1/10 th MTD of rats’ daily dose given × 28 d. Treatment cycles were repeated every 2 wks until progressive disease, intolerable toxicity, or withdrawal of consent. Dose was escalated by Fibonacci progression in single pts until grade 2 toxicity when cohorts of 3 are to be studied. Volunteers may be retreated at a higher dose if tolerated by a preceding naïve subject. Results: One man and four women (61–77 yrs) have been studied in 21 cycles in 5 mos as of 1/10/06. Doses of 50, 100, 150 and 250 mg/m 2 /d × 3 have been given for 1 to 10 cycles. Grade 1 granulocytopenia (2/4 pts with carcinoma) indicates biologic activity. Grade 1 fatigue (3/5) was less than in prior chemotherapy regimens. No grade 2 toxicity has yet occurred. Cumulative toxicity has not been seen. Two pts have had stable disease 6+ and 22+ wks. After deproteinization with acetonitrile, plasma or serum samples were measured by mass spectrometry. At 100 mg/m 2 /d steady state levels were 730 nM after the 1st cycle and 1190 nM after the 4th cycle. Drug levels were maximal at 3 to 6 h despite CI suggesting induction of a metabolizing pathway. Levels fell precipitously at the end of infusion on the 1 st cycle but a low level persisted in one pt for 48h after the major drop in the 4 th cycle, suggesting drug accumulation. Conclusion: Levels effective in vitro have been obtained in vivo by CI without limiting toxicity. Hints of activity already seen suggest that this compound has clinical promise. This phase I study continues. [Table: see text]
Gemcitabine (G) plus carboplatin (C) at AUC 5 demonstrates reduced grade 4 thrombocytopenia rate compared to AUC 5.5 in first line therapy of patients with advanced stage NSCLC
Authors: J. Treat, C. P. Belani, J. Schiller, M. J. Monberg, J. Cunneen, R. Chen, Z. Ye, C. K. Obasaju
Journal: Journal of Clinical Oncology (2006)

7130 Background: GC is a commonly used regimen in first-line therapy of advanced stage NSCLC. Various dosing of carboplatin in the GC regimen produces different toxicity profiles. This report summarizes three recent large clinical trials, including the Coalition Trial, using GC regimens that had comparable efficacy to other modern doublets. Methods: Three trials using GC as first-line treatment for advanced NSCLC with recent best response and toxicity data were selected. Pt populations were similarly defined, including measurable or evaluable Stage IIIB (with pleural effusion) or IV disease. All utilized similar 21-d regimens of G 1000 mg/m 2 d 1,8 and C AUC 5.5 or 5.0 d1. Results: Despite a grade 4-thrombocytopenia rate of 12% in Trial 1 (Coalition) there was no difference in serious bleeding events compared to the other arms (paclitaxel/carboplatin and paclitaxel/gemcitabine). Discussion: In these three trials, 1126 pts with advanced NSCLC were treated with first-line GC. This database of 743 patients assessed for safety suggests that GC AUC 5 results in a 4.7% (95% CI: 3.3–6.5%) grade 4-thrombocytopenia rate with similar anti-tumor efficacy. The regimen of G 1000 mg/m 2 on d1, 8 with C AUC 5 on d1 of a 21-d cycle may be optimal for treatment of advanced NSCLC. [Table: see text] [Table: see text]
The possibility of molecular targeted therapy in patients with pulmonary large cell neuroendocrine carcinoma.
Authors: A. Iyoda, W. D. Travis, S. X. Jiang, K. Nezu, F. Ogawa, H. Amano, I. Okayasu, V. W. Rusch, H. Yoshimura, Y. Satoh
Journal: Journal of Clinical Oncology (2010)

e21113 Background: The prognosis for patients with large cell neuroendocrine carcinoma (LCNEC) of the lung is very poor. However, the optimal treatment for patients with LCNEC is not decided. Recently, it is reported that molecular targeted therapy is effective for patients with lung carcinoma. In order to improve the prognosis of patients with LCNEC, it is important for us to understand the possibility of molecular targeted therapy for patients with pulmonary LCNEC. In this study, we studied gene amplification, gene mutation and immunohistochemical expression for molecular markers in patients with pulmonary LCNEC, and compared those with patients with pulmonary adenocarcinoma which has already introduced many kinds of molecular target therapies. Methods: We analyzed 13 patients with primary lung carcinoma diagnosed as LCNEC according to the classification of World Health Organization in 1999 and 14 patients with adenocarcinoma, which underwent treatment at Kitasato University Hospital. We evaluated immunohistochemical expression for CD20, c-KIT, human epidermal growth factor receptor type 2 (HER2), and vascular endothelial growth factor (VEGF), gene mutation for epidermal growth factor receptor (EGFR), K-ras and c-kit, and gene amplification using fluorescence in situ hybridization (FISH) for EGFR. Results: In cases with LCNEC, the expressions of CD20, c-KIT, HER2, and VEGF were 0/13 (0%), 10/13 (76.9%), 4/13 (30.8%), and 13/13 (100%).In c-KIT and HER2, there were significant differences between LCNEC and adenocarcinoma (p = 0.0018, c-KIT, and p = 0.0037, HER2). Only 2 cases with LCNEC had strong expression of HER2, although no case with adenocarcinoma had that. Cases with adenocarcinoma had a significantly higher rate of EGFR gene mutation than LCNEC cases did, although there was only 1 mutation of exon 20 of EGFR gene in LCNEC. There is no mutation of K-ras and c-kit and no amplification of EGFR-FISH in cases with LCNEC. Conclusions: In LCNEC, the expressions of c-KIT and VEGF were frequently observed, however, the gene mutation of c-kit was not done. Anti-VEGF treatment is promising for patients with LCNEC, although the treatment for c-KIT was not clear. No significant financial relationships to disclose.
Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial.
Authors: Dong-Wan Kim, Ranee Mehra, Daniel Shao-Weng Tan, Enriqueta Felip, Laura Quan Man Chow, D. Ross Camidge, Johan F. Vansteenkiste, Sunil Sharma, Tommaso De Pas, Gregory J. Riely, Benjamin J. Solomon, Juergen Wolf, Michael Thomas, Martin H. Schuler, Geoffrey Liu, Armando Santoro, Margarida Geraldes, Anthony Boral, Alejandro Javier Yovine, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2014)

8003^ Background: ALK+ NSCLC is sensitive to crizotinib (CRZ) but patients (pts) invariably progress. Ceritinib (LDK378) is a novel ALK inhibitor (ALKi) more potent than CRZ in enzymatic and cell-based assays and CRZ-resistant animal models. Prior results from this Phase I study (ASCEND-1) established a MTD of 750 mg/d. Methods: Adult pts with advanced ALK+ cancers received oral ceritinib q.d. After MTD determination, pts were enrolled to expansion groups: ALKi pretreated (PT) NSCLC; ALKi naive NSCLC; non-NSCLC diseases. Results are reported for all NSCLC pts receiving ceritinib at the recommended dose (750 mg/d). Results: 255 pts from 11 countries were treated at 750 mg/d. 246 pts had ALK+ NSCLC, with 4.5 months' median follow-up; of these, 67% had received ≥2 anticancer therapies; ORR was ≥60% in each subgroup of pts with 0, 1, 2, and 3 prior anticancer regimens. 83 pts were ALKi naïve. All 163 ALKi PT pts had received CRZ – 78% as their last prior therapy – and 92% had progressive disease on prior ALKi. Investigator efficacy assessments are presented for 180 NSCLC pts who received first dose of ceritinib ≥18 wks prior to cut-off (2 Aug 2013). Of all 255 pts, the most common AEs were diarrhea (84%), nausea (77%), vomiting (57%), fatigue (36%), and ALT increased (36%). The most common Grade 3/4 AEs were ALT increased (21%), and AST increased (8%). Ceritinib treatment is ongoing for 58% of pts. During the dosing period dose reductions occurred in 133 pts (52.2%), all due to an AE. Only 24 (9.4%) pts discontinued ceritinib due to an AE. Conclusions: Ceritinib 750 mg/d has rapid, durable and high antitumor activity in ALK+ NSCLC pts, regardless of prior treatment with ALKi, providing effective treatment in this pt population. Clinical trial information: NCT01283516. Endpoint ALKi PT N=121 ALK naive N=59 All N=180 ORR, n (%) [95% CI] 67 (55.4%) [46.1, 64.4] 41 (69.5%) [56.1, 80.8] 108 (60.0%) [52.4, 67.2] DOR (Median [95% CI]) 7.4 mos [5.4, 10.1] NEa [5.6, NE] 9.7 mos [6.9, 11.4] Time to first response (Median [min, max]) 6.1 wks [4.6, 24.1] 6.1 wks [3.0, 24.1] 6.1 wks [3.0, 24.1] PFS (Median [95% CI]) 6.9 mos [5.4, 8.7] NEb [6.7, NE] 7.0 mos [6.2, 10.1] Abbreviation: NE, not estimable. a DOR rate at 12 mos: 71.1% (95% CI: 49.8, 84.6). b PFS rate at 12 mos: 58.1% (95% CI: 41.6, 71.5).
Are baseline performance status and line of chemotherapy administration important for palliation of metastatic non-small cell lung cancer (NSCLC) with chemotherapy?
Authors: H. S. Bozcuk, B. Dalmis, M. Samur, B. Savas, M. Ozdogan, M. Artac, M. Yildiz
Journal: Journal of Clinical Oncology (2004)

8175 Background: Although chemotherapy improves quality of life (qol) in patients with metastatic NSCLC, factors interacting with the change in qol remain unclear. Methods: 50 metastatic NSCLC patients starting 1st or 2nd line chemotherapy were prospectively evaluated. EORTC QLQ-C30 questionnaires were completed thrice during the 1st 2 cycles. Chemotherapy toxicity was graded according to the SWOG toxicity scale. The effect of chemotherapy (time) and its interaction with ECOG ps (=1 or 2) and line of chemotherapy administration on EORTC QLQ-C30 subscales were evaluated with Repeated Measures ANOVA models. Results: There have been significant changes with chemotherapy in some aspects of qol. Interestingly, both ps and line of chemotherapy administration (chemo) interacted with the change in insomnia scale (P=0.035 and 0.049, respectively), and line of chemotherapy administration with the change in fatigue scale (P=0.005). Conclusions: These findings stress the importance of baseline ps and the line and type of chemotherapeutics used for palliation. No significant financial relationships to disclose.
Efficacy of selective JAK inhibition in models of leukemia, lymphoma, myeloma, and JAK2V617F dependent malignancy
Authors: J. S. Fridman, E. Caulder, P. Liu, J. Li, P. A. Scherle, J. Rodgers, J. Redman, G. Hollis, R. C. Newton, K. Vaddi
Journal: Journal of Clinical Oncology (2008)

14564 Background: The increased kinase activity frequently observed in cancer is implicated in tumorigenesis and resistance to therapy. Genetic and epigenetic changes resulting in aberrant activation of the Janus kinase (JAK) family of tyrosine kinases is common in numerous hematological malignancies, including myeloproliferative disorders. As such, JAK inhibition may be a promising therapeutic strategy for the treatment of hematological diseases associated with JAK activation. Methods: Potent (IC50 < 10nM) and selective (∼100-fold against >30 kinases) JAK inhibitors were utilized to treat a number of engineered and spontaneous cancer cell lines derived from hematological malignancies in vitro and in vivo. The impact of JAK inhibition on downstream signaling pathways (e.g. STAT) and growth and survival of malignant cells was evaluated. Results: Constitutively phosphorylated STAT3/5 (pSTAT) was observed in nearly all cell lines tested. JAK inhibitors reduced pSTAT levels by > 80% in most cell lines. In some cell lines (e.g. INA-6, TF-1, BaF3JAK2V617F) viability was reduced by > 90% and was accompanied by apoptosis. Following oral administration of JAK inhibitors, pSTAT levels and tumor growth were inhibited (> 90%) in a mouse xenograft model of multiple myeloma. Moreover, JAK inhibition improved the therapeutic responses to a number of therapeutics in this model. Additionally, we demonstrate that JAK activation, through clinically relevant cytokine signaling pathways, conveys resistance ( > 50 fold) to imatinib in a Bcr-Abl expressing cells. Importantly, we show that this resistance is reversed with JAK inhibition in vitro and in vivo, the latter resulting in increased survival, suggesting this mechanism of resistance is surmountable. Conclusions: Aberrant STAT activation has been observed in a number of hematological malignancies. Here we have shown that selective JAK inhibition is sufficient to reduce pSTAT levels and inhibit the growth and survival of malignant cells. Moreover, we have demonstrated that JAK inhibition restores sensitivity to Abl kinase inhibition in CML cells rendered resistant to treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Incyte Incyte
Randomised Prospective Evaluation of Iron Balance, Chelation Efficiency, Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO.
Authors: Yesim Aydinok, Patricia Evans, Aysen Terzi, Nurten Cetiner, John B. Porter
Journal: Blood (2005)
THE FREQUENCY OF THE RS55705857 RISK ALLELE IS ELEVATED AND SIMILAR IN FAMILIAL AND SPORADIC GLIOMA PATIENTS
Authors: Robert Jenkins, Margaret Wrensch, Thomas Kollmeyer, Georgina Armstrong, Sara Olson, Rose Lai, Daniel Lachance, Ching Lau, Elizabeth Claus, Jill Barnholtz-Sloan, Dora Il'yasova, Joellen Schildkraut, Richard Houlston, Sanjay Shete, Jonine Bernstein, Faith Davis, Ryan Merrell, Christoffer Johansen, Siegal Sadetzki, Beatrice Melin, Melissa Bondy
Journal: Neuro-Oncology (2013)

THE FREQUENCY OF THE RS55705857 RISK ALLELE IS ELEVATED AND SIMILAR IN FAMILIAL AND SPORADIC GLIOMA PATIENTS
Deleterious effect of cyclosporins on the ischemic kidney in the rat and the protection by the calcium antagonist verapamil.
Authors: A Ar'Rajab, I J Dawidson, R B Harris, W J Mileski, J T Sentementes
Journal: Journal of the American Society of Nephrology (1994)

Cyclosporine A (CsA) nephrotoxicity has been suggested to be aggravated in the presence of ischemia, as occurs after renal transplantation. Cyclosporine G (CsG) may be less nephrotoxic than CsA. This study evaluated in the rat (1) the effect of CsA and CsG on blood flow and the function of the kidney subjected to 60 min of warm ischemia and (2) the protective effect of the calcium antagonist verapamil (VP). After left nephrectomy, ischemia was induced in the right kidney by the clamping of the kidney pedicle for 60 min, which resulted in a significant increase in serum creatinine (SCr) to 2.30 +/- 0.25 mg/dL by Day 1 with 25% mortality by Day 7. The administration of CsA or CsG (20 mg/kg i.v. daily for 7 days) after 60 min of renal ischemia significantly increased SCr and mortality compared with ischemia alone. In another set of experiments, 60 min of warm ischemia was applied to the right kidney and RBF was measured in both kidneys with a laser Doppler flowmeter. Blood flow in the ischemic kidney returned to the preischemic level by 15 min after the removal of the vascular clamp in the control animals. In contrast, in animals treated with CsA, a significant decrease in RBF was seen in both kidneys; however, blood flow in the ischemic kidney was significantly lower than that in the nonischemic kidney. CsG also decreased RBF in both kidneys, although in the left (nonischemic) kidney, RBF remained significantly higher with CsG than with CsA.(ABSTRACT TRUNCATED AT 250 WORDS)
Oncologists' attitudes towards recommending exercise to cancer patients: A Canadian national survey
Authors: L. W. Jones, K. S. Courneya, C. Peddle, J. R. Mackey
Journal: Journal of Clinical Oncology (2004)

8138 Background: Preliminary research suggests that exercise may be a beneficial supportive therapy for cancer patients and that oncologists may play an important role in promoting exercise to their patients. In the present study, we examined oncologists' attitudes towards recommending exercise to cancer patients during treatment. Methods: Using a national survey, 659 practicing medical and radiation oncologists in Canada listed in the Canadian Medical Directory and Royal College of Physicians and Surgeons directory (2002–2003) were sent a brief questionnaire. Results: The response rate was 46% (281/610). Overall, the majority of oncologists agreed that exercise was beneficial (62.0%), important (55.8%) and safe (63.1%) for cancer patients during treatment. Moreover, 43.1% reported that they tried to recommend exercise to their patients when appropriate while oncologists' actually reported recommending exercise to 28% of their patients in the past month. Independent predictors of providing an exercise recommendation were oncologists' intention (β=.42; p<.001) and perceived ability to recommend exercise (β=.15; p=.009), and their evaluation of their patients' perceived approval of providing exercise advice (β=.15; p=.024). Analyses also indicated significant differences between oncologists with younger, female, and medical oncologists generally having more favorable attitudes towards exercise for cancer patients. Conclusions: Oncologists have a favorable attitude toward recommending exercise to cancer patients although several important barriers may prevent oncologists' from providing exercise advice to their patients. Further research is required evaluating the effectiveness of interventions and strategies designed to improve oncologist's confidence and ability to advise their patients on exercise during oncology consultations. No significant financial relationships to disclose.