tbuckley/cabot-search huggingface dataset:
Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.
Authors: G J Creemers, C J Gerrits, J H Schellens, A S Planting, M E van der Burg, V M van Beurden, M de Boer-Dennert, M Harteveld, W Loos, I Hudson, G Stoter, J Verweij
Journal: Journal of Clinical Oncology (1996)

Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer.Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses.The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia.Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.
Blockade of Human P2X7 Receptor Function With a Monoclonal Antibody
Authors: G. Buell, I.P. Chessell, A.D. Michel, G. Collo, M. Salazzo, S. Herren, D. Gretener, C. Grahames, R. Kaur, M.H. Kosco-Vilbois, P.P.A. Humphrey
Journal: Blood (1998)
Abstract 16659: Importance of Both Hypothermia and Early Reperfusion on Limiting Myocardial Infarct Size After Ventricular Fibrillation Cardiac Arrest and Acute Coronary Occlusion
Authors: Karl B Kern, Joseph Hanna, Hayley Young, Chiu-Hsieh Hsu, Mathias Zuercher
Journal: Circulation (2014)

Introduction: The post resuscitation ECG is unreliable in identifying acutely occluded culprit coronary arteries. AHA/ACCF 2013 STEMI guidelines strongly recommend (Class 1) early coronary reperfusion for the STEMI post cardiac arrest patient, combined with hypothermia if the patient is comatose, but make no comment about those without ST segment elevation on their post arrest ECG. Cohort studies have shown that 1/3 of all post cardiac arrest patients without ST elevation also have an acutely occluded coronary. However, some have suggested that early coronary angiography is not needed for the post resuscitated without ST elevation. Hypothesis: The early use of hypothermia and reperfusion are both useful for minimizing myocardial infarct size after cardiac arrest. Methods: The study utilized 20 swine (35±5kg). The animals were randomly assigned (2X2 study design) to one of four treatment groups: A) + Hypothermia & + Reperfusion; B) No Hypothermia & + Reperfusion; C)+ Hypothermia & No Reperfusion; D) No Hyp...
Late radiation injury in preoperative chemoradiotherapy
Authors: Yutaka Takahashi, Ei Miyamoto, Takuya Terashi, Hiroshi Hamakawa
Journal: European Respiratory Journal (2012)

Background:   Preoperative chemoradiotherapy (CRT) seems to increase survival rates in advanced non-small cell lung cancer. In the evaluation of this strategy, overall survival (OS) and early complications are generally referred. However, the influence of induction CRT remains controversial. Therefore, the aim of this study is to investigate late radiation injury.    Methods:   From 1996 to 2010, 167 patients treated with major lung resections after CRT (139 lobectomy, 24 pneumonectomy, 3 wedge resection, and 1 segmentectomy) were enrolled. They were treated with platinum-based regimens and had 40 Gy delivered to the primary tumors, hilum and mediastinum. The postoperative condition of residual lungs was assessed in 142 cases.    Results:   72 patients died. Of 72, 49 died of lung cancer, 17 died of other disease, and 5 died of postoperative complications (operative mortality was 3.0%). Of other disease death, 3 aspergillosis and 2 idiopathic pulmonary fibrosis were related to induction therapies. The 5-year OS rates of p-stage 0, 1a, 1b, 2a, 2b, 3a and 3b/4 were 72.0%, 80.5%, 68.2%, 55.6%, 46.9%, 30.5% and 0%, respectively. The 5-year OS rates of p-N0, N1, and N2 were 69.5%, 50.7% and 22.0%, respectively. In 142 cases assessed postoperative condition of residual lungs, 27(19.0%) mild fibrosis, 5(3.5%) severe fibrosis, 37(26.1%) shrinkage, and 9(6.3%) cavity/dead space formation occurred. Radiation injury appeared when residual normal lung was irradiated.    Conclusions:   Preoperative CRT increased survival rate in patients who achieved p-N0, but was associated with higher rates of pneumonectomy and operative mortality. Radiation might affect postoperative devastation in residual lungs. This therapy should be performed cautiously.
Abstract 9607: Factors Associated With Cognitive Deficits in Heart Failure Differ by Gender
Authors: Barbara Riegel, Susan Pressler
Journal: Circulation (2013)

Background: In 2005 Bennett proposed a conceptual model of cognitive deficits (CD) in heart failure (HF). The purpose of this study was to test the model and to identify if results differ by gender. Methods: Data from 280 HF patients were analyzed using generalized linear modeling to predict CD measured as the number of neuropsychological tests on which participants scored in the abnormal range. Five tests (Trail-Making Tests A and B, Digit Symbol-Substitution, Probed-Recall Memory, Letter Number Sequencing) were used; the number on which subjects scored below their age-based norm was used as the measure of CD (0-5 range). Predictors entered into the model were age, sex, education, Charlson Comorbidity score, hypertension (yes/no), depression measured with the PHQ-9, HF type (systolic/mixed or diastolic), HF etiology (ischemic/nonischemic), ejection fraction, NYHA functional class, duration since diagnosis, and number of medications taken daily. Only oxygen saturation proposed in the original model was unavailable. Results: Overall, the model was adequate to describe CD but several of the variables were poor predictors so the model was rerun separately in men (n=180, mean age 63±12.3, 33% black) and women (n=100, mean age 60±12.7, 36% black). In men the model fit well (p=0.005) but not in women (p=0.969). In men the best indicators of CD were older age, less education, and poor functional class; these variables explained 36.3% of the variance in CD. In women, a new model was proposed that focused on behavior (smoking, drinking, exercise, medication adherence, taking vitamins, body weight, sleep hygiene), symptoms (NYHA functional class, sleep quality, fatigue, daytime sleepiness, depression), and social support. Demographic characteristics of age and education were included, as these are known to predict CD. In women the best predictors of CD were older age, lower medication adherence, worse NYHA functional class, and less social support. These 4 variables explained 55.9% of the variance in CD in women. When the new model was tested in men, only NYHA class was associated with CD, explaining 1.5% of the variance. Conclusion: Different factors are associated with cognitive decline in men and women. Different interventions targeting CD may be needed.
The impact of diabetes mellitus and obesity on pathologic complete response rate of neoadjuvant chemoradation for gastroesophageal cancer: A retrospective review.
Authors: J. K. Boyd, D. R. Jones, B. Kozower, C. Lau, H. K. Sanoff
Journal: Journal of Clinical Oncology (2010)

e14627 Background: Five year survival for patients treated with trimodality therapy for esophageal cancer remains a dismal 25%- 35%. Pathologic complete response (pCR) predicts better outcomes. Diabetes (DM) and obesity are increasingly recognized as mediators of cancer risk and outcomes, perhaps through the interplay of insulin resistance/hyperinsulinemia and the insulin and insulin-like growth factor receptors. We sought to determine the influence of DM and body mass index (BMI) on the rate of pCR in patients treated with neoadjuvant chemoradiotherapy (CRT) for esophageal and gastroesophageal junction cancers. Methods: Patients were identified from a prospectively collected database of patients undergoing esophagectomy at the University of Virginia from 2002-2009. Patients with squamous cell (SC) or adenocarcinomas (AC) of the esophagus or GE junction that received neoadjuvant CRT within 6 months of esophagectomy were eligible. Patients were considered to have pCR if there was no evidence of viable tumor in the resected specimen. Patients with microscopic residual disease were classified as not having a pCR. Bivariate statistics were used to compare pCR by DM, insulin use, and BMI. Results: Of the 122 pts, 19 (16%) had DM, 6 were insulin dependent. Median age was 60 years (range 22-83) years, 82% male, 93% Caucasian, 3% African- American. Histology was 83% AC (n = 101),15% SC (n = 18). The rate of pCR was similar in patients with and without DM (36% vs. 31%, p = 0.62). pCR rates for insulin-dependent and non-insulin- dependent DM were 67% vs. 29%, p = 0.2. The rate of pCR among patients with BMI > or = 30, 33%, was similar to that of non-obese patients, BMI < 30, 26%, p = 0.5. Conclusions: Despite previous reports of reduced pCR in diabetics treated with neoadjuvant therapy, we found no association between diabetes or obesity and pCR. There was a suggestion that among diabetics, patients using insulin did particularly well. Future work will focus on the role of glucose control in CRT responses. No significant financial relationships to disclose.
Imatinib versus interferon-α (IFN-α) plus ara-c for patients with newly diagnosed chronic-phase (CP) chronic myeloid leukemia (CML) from the Mexican Institute of Social Security (IMSS) perspective: 72 months number needed to treat (NNT) to achieve a complete cytogenetic response (CCyR)
Authors: A. A. Erazo-Valle, K. A. Nacho-Vargas, J. Guzman-Caniupan, L. Zapata-Sanchez, G. Salinas-Escudero, R. Rivas-Bocanegra, E. Baez, J. Athie-Rubio, W. Feng
Journal: Journal of Clinical Oncology (2008)

17542 Background: Imatinib mesylate(IM) is the standard of care for CML because it has demonstrated high and durable responses as well as survival advantage over IFN based therapy (Hochhaus, Blood (ASH Annual Meeting Abstracts) 2007.110: 25). Reed et al, estimated the survival for a newly diagnosed CP-CML patient treated with imatinib was 19.07 years vs. 9.09 years with IFN/Ara-C (Reed, Pharmacoeconomics in press). IM has been included in the Mexican National Basic Formulary as first-line agent and as second-line agent after IFN. CCyR has been established as an effective measure for treatment efficacy in CML, furthermore CCyR is associated to prolonged survival on CML patients. In this study, the NNT approach was used to compared IM with IFN/ Ara-C from the Mexican public healthcare system's perspective. Methods: NNT represents the number of patients that need to be treated with a new intervention in order to achieve one additional event, and is a powerful approach that can be used to make sense of numerical results from clinical trials. The NNT was calculated by the inverse of CCyR at 72 months. A key requirement for an NNT analysis is that all outcomes must be considered over similar time periods. The rates of CCyR at 72 months for IM and IFN/Ara-C as first line treatment for CML-CP were obtained from the International Randomized Interferon vs. STI571 (IRIS) Study update. Results: The 72-month CCyR rate for IM was 82% vs. 12% for IFN/Ara-C. The NNT for IM was 15 patient versus 8.33 for IFN plus Ara-C. For every 1.15 patients treated with IM, 1 patient will achieve a CCyR by 72 months. However, in order to achieve a CCyR with IFN plus Ara-C by 72 months, 7.18 more patients need to be treated, a 7.24- fold difference in NNT to achieve a CCyR, favoring IM. Conclusions: The NNT to achieve a CCyR by 72 months with IM is much lower than that with IFN plus Ara-C in newly-diagnosed CP-CML patients. Further analysis including the total cost of treatment (drug cost and cost to treat adverse events) from Mexico will be conducted to assess the cost-effectiveness comparing IM with IFN/Ara-C in CML-CP patients from the IMSS perspective. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis
Phase I/II study of arginine deiminase (ADI-PEG 20) in patients with advanced malignant melanoma (MM)
Authors: P. A. Ott, R. D. Carvajal, N. Pandit-Taskar, A. A. Jungbluth, E. Hoffman, R. Venhaus, L. Pan, L. Old, A. C. Pavlick, J. D. Wolchok
Journal: Journal of Clinical Oncology (2009)

9030 Background: ADI-PEG 20 is an enzyme that degrades arginine, a crucial amino acid central to metabolism and biosynthesis of growth and development of normal and neoplastic cells. Melanoma is auxotrophic for arginine because it lacks argininosuccinate synthetase (ASS), a key enzyme required for synthesis of arginine from citrulline via the urea cycle. This study evaluates the safety and clinical efficacy of ADI-PEG 20 in patients with MM. Methods: Patients with histologically confirmed stage III (unresectable)/ IV cutaneous, uveal or mucosal MM were treated with 40, 80 or 160 IU/m 2 ADI-PEG 20 i.m. weekly for 9 weeks in a phase I setting. In a phase II component, 16–25 pts receiving 160 IU/m 2 will be evaluated for tumor response (TR) by RECIST. Secondary endpoints for all patients included metabolic response by 18 FDG-PET, pharmacodynamics (PD), immunogenicity and ASS tumor expression by immunohistochemistry. Results: As of Nov. 2008, 24 pts were enrolled (40 IU/m 2 , n=6, 80 IU/m 2 , n=6, 160 IU/m 2 , n=12): 14 males, 10 females. Median age: 66 yrs (range 29- 83 yrs). Toxicity consisted primarily of Grade 1/2 adverse events (AE) (injection site pain, myalgia, arthralgia, fatigue, flushing, rash/itch, nausea, diarrhea, hyperuricemia, taste alteration). One dose limiting toxicity (DLT) of G3 arthralgia was observed at 80 IU/m 2 . Two DLTs (G3 seizure and G3 lymphedema) were reported, at 160 IU/m 2 . No grade 4 or 5 AEs were observed. Of 22 patients evaluable for TR, 8 had stable disease (SD) with 2 of these durable for ≥ 6 months. Notably, 3 SD were uveal melanoma. 14 patients had progressive disease. PD analysis showed plasma arginine depletion during study weeks 1–6 regardless of dose. Immunohistochemical ASS expression analysis in tumor tissue: negative= 13 pts, &lt; 5% cells positive= 5 pts. Conclusions: ADI-PEG 20 as a single agent is well tolerated in advanced MM leading to consistent arginine depletion. The extent of clinical activity has yet to be shown. Combination therapy of ADI-PEG20 with other treatments such as pro-apoptotic reagents during the first 6 weeks of ADI-PEG 20 treatment while arginine is depleted could lead to synergistic anti-cancer activity. No significant financial relationships to disclose.
Abstract 18362: Proteomic and Metabolomic Profiling After Ischemia-Reperfusion Injury Reveals Bottlenecks That Underlie Cardioprotection in Hibernating Mammals
Authors: Quintin J Quinones, Qing Ma, Ricardo Henao, Joseph Lucas, Matthias L Riess, James Bain, Christopher B Newgard, Brian M Barnes, Mihai V Podgoreanu
Journal: Circulation (2013)

Introduction: Mammalian hibernation is a natural molecular adaptation to extreme environmental conditions with important applications for perioperative organ protection. We have previously shown in a surgical model of deep hypothermic circulatory arrest (DHCA) robust cardioprotection in hibernating arctic ground squirrels (AGS) compared with Brown Norway rats (Figure). We conducted an integrated proteomic and metabolomic analysis to identify species and season-specific correlates of the cardioprotective phenotype. Methods: Quantitative 5-fraction 2D-LC/LC-MS/MS was used to identify proteins expressed in the myocardium of summer active AGS, winter hibernating AGS, and rats subjected to DHCA followed by 3h or 24h of reperfusion, or sham (n=3-5/group). The complete sets of 5250 peptides for AGS and 8482 peptides for Rat were matched using an ENSEMBL referenced orthology map. Peptides from the same matched protein and species were log-transformed and summarized into protein level profiles by means of principal component analysis. Myocardial levels of 167 metabolites were quantified by MS. Results: Differentially expressed metabolic enzymes or transporters are paired with substrate and product in Table and reported as a ratio of change over baseline by species and hibernation status. Compared to AGS, rats developed metabolic TCA cycle substrate flux bottlenecks at the level of succinate dehydrogenase and malate transporter. Conclusions: Integration of observed changes in protein abundance with metabolic modules identified specific druggable targets for metabolic optimization that underlie the hibernator cardioprotective phenotype.
Reduction of toxicity of interleukin-2 and lymphokine-activated killer cells in humans by the administration of corticosteroids.
Authors: J T Vetto, M Z Papa, M T Lotze, A E Chang, S A Rosenberg
Journal: Journal of Clinical Oncology (1987)

In order to evaluate the efficacy of dexamethasone (dex) in reducing the toxicity of therapy with lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2), we treated six patients receiving this form of immunotherapy with intravenous (IV) dex, 4 mg every six hours. Compared with a control group of 27 patients not receiving dex with their immunotherapy, these corticosteroid-treated patients were able to tolerate the administration of more IL-2, yet experienced significantly less toxicity. Dyspnea, confusion, fever, mean peak serum creatinine, and bilirubin levels during treatment were significantly reduced in corticosteroid-treated patients, with a corresponding decrease in pruritus in this group as well. Overall weight gain was not different between groups, although a curtailment of weight gain temporally related to dex treatment was seen in some patients. Hematologic side effects, including anemia, eosinophilia, and thrombocytopenia, were not reduced by dex. These results suggest that dex can inhibit at least some of the toxic side effects of LAK cell and IL-2 therapy. Because of the concern that the therapeutic effect may also be abrogated, future studies combining corticosteroids with this form of immunotherapy should be undertaken with caution.
Mechanism of Metformin: A Tale of Two Sites
Authors: Ruisheng Song
Journal: Diabetes Care (2016)

Metformin (dimethylbiguanide) features as a current first-line pharmacological treatment for type 2 diabetes (T2D) in almost all guidelines and recommendations worldwide. It has been known that the antihyperglycemic effect of metformin is mainly due to the inhibition of hepatic glucose output, and therefore, the liver is presumably the primary site of metformin function. However, in this issue of Diabetes Care , Fineman and colleagues (1) demonstrate surprising results from their clinical trials that suggest the primary effect of metformin resides in the human gut.

Metformin is an orally administered drug used for lowering blood glucose concentrations in patients with T2D, particularly in those overweight and obese as well as those with normal renal function. Pharmacologically, metformin belongs to the biguanide class of antidiabetes drugs. The history of biguanides can be traced from the use of Galega officinalis (commonly known as galega) for treating diabetes in medieval Europe (2). Guanidine, the active component of galega, is the parent compound used to synthesize the biguanides. Among three main biguanides introduced for diabetes therapy in late 1950s, metformin (Fig. 1 A ) has a superior safety profile and is well tolerated. The other two biguanides, phenformin and buformin, were withdrawn in the early 1970s due to the risk of lactic acidosis and increased cardiac mortality. The incidence of lactic acidosis with metformin at therapeutic doses is rare (less than three cases per 100,000 patient-years) and is not greater than with nonmetformin therapies (3). Major clinical advantages of metformin include specific reduction of hepatic glucose output, with subsequent improvement of peripheral insulin sensitivity, and remarkable cardiovascular safety, but without increasing islet insulin secretion, inducing weight gain, or posing a risk of hypoglycemia. Moreover, metformin has also shown benefits in reducing cancer risk and improving cancer prognosis (4,5), as well as counteracting the cardiovascular complications …
Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity
Authors: Suneng Fu, Abdullah Yalcin, Grace Y. Lee, Ping Li, Jason Fan, Ana Paula Arruda, Benedicte M. Pers, Mustafa Yilmaz, Kosei Eguchi, Gökhan S. Hotamisligil
Journal: Science Translational Medicine (2015)

New assays that measure endoplasmic reticulum (ER) function and protein folding identify a small molecule, azoramide, that exerts antidiabetic effects.
Progression of chronic renal failure on substituting a ketoacid supplement for an amino acid supplement.
Authors: M Walser, S Hill, L Ward
Journal: Journal of the American Society of Nephrology (1992)

Twelve patients with severe chronic renal failure (average initial GFR, 13 mL/min) were monitored for 4 to 23 months while receiving an essential amino acid supplement and were then switched to a ketoacid supplement for 6 to 40 months, while continuously receiving a very low-protein (0.3 g/kg), low-phosphorus (7 to 9 mg/kg) diet. Urinary urea N excretion indicated that actual dietary protein intake averaged 0.46 g/kg. Progression, estimated as the linear regression slope of radioisotopically determined GFR on time, slowed from -0.46 +/- 0.31 (SD) to -0.24 +/- 0.15 mL/min/month (P = 0.029). Serum urea N, creatinine, phosphate, and uric acid rose significantly as GFR fell; blood pressure, plasma lipids, and urinary urea excretion were unchanged. Urinary 17-hydroxy-corticosteroid excretion decreased 18%, but this change was only marginally significant (P = 0.087). There was no change in plasma or urinary cortisol or urinary aldosterone. Viewed in light of previous evidence that progression seldom slows when treatment remains constant, the results suggest that this ketoacid supplement slows progression by approximately half, compared with an essential amino acid supplement, with no change in diet.