tbuckley/cabot-search huggingface dataset:
Effect of scheduled second therapeutic endoscopy on peptic ulcer rebleeding: a prospective randomised trial
Authors: P W Y Chiu
Journal: Gut (2003)

<b>Aim:</b> Recurrent bleeding after initial haemostasis is an important factor that directly relates to the outcome in the management of peptic ulcer bleeding. Conflicting reports have been published concerning the effectiveness of scheduled second therapeutic endoscopy on ulcer rebleeding. We investigate the use of scheduled second endoscopy with appropriate therapy on peptic ulcer rebleeding. <b>Methods:</b> From August 1999 to January 2001, we prospectively randomised patients who had endoscopically confirmed bleeding peptic ulcer with stigmata of acute bleeding, visible vessel, or adherent clot into two groups. Endoscopic therapy was standardised to initial epinephrine injection and subsequent heater probe application. The study group (n = 100) received scheduled second endoscopy 16–24 hours after initial haemostasis, and further therapy was applied if endoscopic stigmata persisted, as above. The control group (n = 94) were observed closely. Those patients that developed rebleeding in either group underwent operation if further endoscopic therapy failed. Outcome measures included ulcer rebleeding, transfusion, duration of stay, and mortality. <b>Results:</b> After initial endoscopic haemostasis, 194 eligible patients were randomised into two groups. Thirteen patients in the control group developed recurrent bleeding within 30 days while five patients in the study group sustained recurrent bleeding (p = 0.0314) (relative risks 0.33, 95% confidence interval 0.1–0.96). The number of patients that required surgery for recurrent bleeding was six in the control group and one in the study group (p = 0.05). There was no difference in duration of hospital stay, transfusion, or mortality between the two groups. <b>Conclusions:</b> A scheduled repeat endoscopy with appropriate therapy 16–24 hours after initial endoscopic haemostasis reduces the number of cases of recurrent bleeding.
Can Chemotherapy Be Discontinued in Unresectable Metastatic Colorectal Cancer? The GERCOR OPTIMOX2 Study
Authors: Benoist Chibaudel, Frédérique Maindrault-Goebel, Gérard Lledo, Laurent Mineur, Thierry André, Mostepha Bennamoun, May Mabro, Pascal Artru, Elisabeth Carola, Michel Flesch, Olivier Dupuis, Philippe Colin, Annette K. Larsen, Pauline Afchain, Christophe Tournigand, Christophe Louvet, Aimery de Gramont
Journal: Journal of Clinical Oncology (2009)

Purpose This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. Patients and Methods Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). Results Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. Conclusion The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.
Hydatid disease of the heart: Report of five cases and review of the literature
Authors: G. Calamai, A. M. Perna, A. Venturini
Journal: Thorax (1974)

<b>Calamai, G., Perna, A. M., and Venturini, A. (1974).</b><i>Thorax</i>, <b>29</b>, 451-458. <b>Hydatid disease of the heart: report of five cases and review of the literature.</b> The world literature on the surgical treatment of echinococcosis of the heart is reviewed. Few cases are surgically treated, although the disease has been known for a long time. Localization to the liver and lungs is the most frequent. Cardiopulmonary bypass techniques make possible surgical treatment of hydatid cyst of the heart. The present paper is concerned with five cases operated upon between 1959 and 1969, three males and two females, their ages ranging from 13 to 46 years. A preoperative diagnosis was made in each case. One case was operated upon under cardiopulmonary bypass. The need for cardiopulmonary bypass on a stand-by basis is emphasized. The localization of the hydatid cyst was in the left ventricular wall (three cases), right ventricular wall (one case), and multiple (one case). The frequency of cardiac echinococcosis ranges between 0·5% and 2% according to various authors. Diagnosis is achieved with the aid of laboratory tests, radiology, and angiography; but the presence of the disease must be suspected in all patients who come from endemic areas. Surgical therapy is mandatory. Due to the growth characteristics of the cyst itself, the danger of damaging the ventricular wall at operation is increased; thus it is essential to have cardiopulmonary bypass facilities immediately available.
Intensity-Modulated Chemoradiotherapy Aiming to Reduce Dysphagia in Patients With Oropharyngeal Cancer: Clinical and Functional Results
Authors: Felix Y. Feng, Hyungjin M. Kim, Teresa H. Lyden, Marc J. Haxer, Francis P. Worden, Mary Feng, Jeffrey S. Moyer, Mark E. Prince, Thomas E. Carey, Gregory T. Wolf, Carol R. Bradford, Douglas B. Chepeha, Avraham Eisbruch
Journal: Journal of Clinical Oncology (2010)

Purpose To assess clinical and functional results of chemoradiotherapy for oropharyngeal cancer (OPC), utilizing intensity-modulated radiotherapy (IMRT) to spare the important swallowing structures to reduce post-therapy dysphagia. Patients and Methods This was a prospective study of weekly chemotherapy (carboplatin dosed at one times the area under the curve [AUC, AUC 1] and paclitaxel 30 mg/m 2 ) concurrent with IMRT aiming to spare noninvolved parts of the swallowing structures: pharyngeal constrictors, glottic and supraglottic larynx, and esophagus as well as the oral cavity and major salivary glands. Swallowing was assessed by patient-reported Swallowing and Eating Domain scores, observer-rated scores, and videofluoroscopy (VF) before therapy and periodically after therapy through 2 years. Results Overall, 73 patients with stages III to IV OPC participated. At a median follow-up of 36 months, 3-year disease-free and locoregional recurrence-free survivals were 88% and 96%, respectively. All measures of dysphagia worsened soon after therapy; observer-rated and patient-reported scores recovered over time, but VF scores did not. At 1 year after therapy, observer-rated dysphagia was absent or minimal (scores 0 to 1) in all patients except four: one who was feeding-tube dependent and three who required soft diet. From pretherapy to 12 months post-therapy, the Swallowing and Eating Domain scores worsened on average (± standard deviation) by 10 ± 21 and 13 ± 19, respectively (on scales of 0 to 100), and VF scores (on scale of 1 to 7) worsened from 2.9 ± 1.5 (mild dysphagia) to 4.1 ± 0.9 (mild/moderate dysphagia). Conclusion Chemoradiotherapy with IMRT aiming to reduce dysphagia can be performed safely for OPC and has high locoregional tumor control rates. On average, long-term patient-reported, observer-rated, and objective measures of swallowing were only slightly worse than pretherapy measures, representing potential improvement compared with previous studies.
Fas (CD95/Apo-1)–Mediated Damage to Ventricular Myocytes Induced by Cytotoxic T Lymphocytes From Perforin-Deficient Mice
Authors: Bella Felzen, Mark Shilkrut, Hadar Less, Israel Sarapov, Gila Maor, Raymond Coleman, Richard B. Robinson, Gideon Berke, Ofer Binah
Journal: Circulation Research (1998)

Abstract —Cytotoxic T lymphocytes (CTLs) that infiltrate the heart are important immune effectors implicated in heart transplant rejection, myocarditis, and other cardiomyopathies. To investigate the mechanism(s) underlying CTL damage to the myocardium through activation of the Fas receptor (Fas/CD95/Apo-1) by the Fas ligand, we explored the interaction between peritoneal exudate CTLs (PELs), derived from perforin gene–knockout (P−/−) mice, and murine ventricular myocytes. Fas expression on isolated ventricular myocytes was demonstrated immunohistochemically. Action potentials, [Ca 2+ ] i transients, and contractions of myocytes conjugated to P−/− PELs or treated with the apoptosis-inducing anti-Fas monoclonal antibody Jo2 were recorded. Action potential characteristics of nonconjugated myocytes and myocytes conjugated with P−/− PELs were, respectively, as follows: V m , −73.2±1.5 and −53.6±6.4 mV (mean±SEM); action potential amplitude, 117.9±3.9 and 74.3±21.2 mV; and action potential duration at 80% repolarization, 17±6 and 42±13 milliseconds (all P &lt;.05). P−/− PELs also induced early and delayed afterdepolarizations as well as arrhythmogenic activity. Diastolic [Ca 2+ ] i increased during the cytocidal interaction with P−/− PELs, from a fluorescence ratio of 0.82±0.05 (n=7) to 1.98±0.09 (n=13) ( P &lt;.05). All of the effects caused by P−/− PELs were reproduced by incubating the myocytes with Jo2. Heparin (50 μg/mL), an antagonist of inositol trisphosphate (IP 3 )–operated sarcoplasmic reticulum Ca 2+ channels, or U-73122 (2 μmol/L), a phospholipase C inhibitor, but not the inactive agonist U-73343, prevented Fas-mediated myocyte dysfunction. Additionally, intracellular application (through the patch pipette) of the active IP 3 analogue, inositol 1,4,5-trisphosphate, but not the inactive analogue, inositol 1,3,4-trisphosphate, caused electrophysiological changes resembling those resulting from P−/− PELs and Jo2, suggesting that CTL-induced Fas-based myocyte dysfunction is mediated by IP 3 . We conclude that a Fas-based perforin-independent mechanism of CTL action can account for the immunopathology seen in the allotransplanted heart, myocarditis, and dilated cardiomyopathy.
Protein Kinase A Effects of an Expressed <i>PRKAR1A</i> Mutation Associated with Aggressive Tumors
Authors: Elise Meoli, Ioannis Bossis, Laure Cazabat, Manos Mavrakis, Anelia Horvath, Sotiris Stergiopoulos, Miriam L. Shiferaw, Glawdys Fumey, Karine Perlemoine, Michael Muchow, Audrey Robinson-White, Frank Weinberg, Maria Nesterova, Yianna Patronas, Lionel Groussin, Jérôme Bertherat, Constantine A. Stratakis
Journal: Cancer Research (2008)

Abstract Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G&amp;gt;T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1αΔ184-236 (R1αΔ6)]. We compared in vitro R1αΔ6 with wild-type (wt) R1α. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1α and mutant (mt) R1α; we observed by confocal microscopy R1α tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (Cα). Introduction of the R1αΔ6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1α protein in wt-R1α– and R1αΔ6-transfected cells but the former also exhibited discrete aggregates of R1α that bound Cα; these were absent in R1αΔ6-transfected cells and did not bind Cα at baseline or in response to cyclic AMP. Other changes induced by R1αΔ6 included decreased nuclear Cα. We conclude that R1αΔ6 leads to increased PKA activity through the mt-R1α decreased binding to Cα and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. [Cancer Res 2008;68(9):3133–41]
The Effect of Comorbid Illness and Functional Status on the Expected Benefits of Intensive Glucose Control in Older Patients with Type 2 Diabetes: A Decision Analysis
Authors: Elbert S. Huang, Qi Zhang, Niren Gandra, Marshall H. Chin, David O. Meltzer
Journal: Annals of Internal Medicine (2008)

Background: Physicians are uncertain about when to pursue intensive glucose control among older patients with diabetes. Objective: To assess the effect of comorbid illnesses and functional status, mediated through background mortality, on the expected benefits of intensive glucose control. Design: Decision analysis. Data Sources: Major clinical studies in diabetes and geriatrics. Target Population: Patients 60 to 80 years of age who have type 2 diabetes and varied life expectancies estimated from a mortality index that was validated at the population level. Time Horizon: Patient lifetime. Perspective: Health care system. Intervention: Intensive glucose control (hemoglobin A1c [HbA1c] level of 7.0) versus moderate glucose control (HbA1c level of 7.9). Outcome Measures: Lifetime differences in incidence of complications and average quality-adjusted days. Results of Base-Case Analysis: Healthy older patients of different age groups had expected benefits of intensive glucose control ranging from 51 to 116 quality-adjusted days. Within each age group, the expected benefits of intensive control steadily declined as the level of comorbid illness and functional impairment increased (mortality index score, 1 to 26 points). For patients 60 to 64 years of age with new-onset diabetes, the benefits declined from 106 days at baseline good health (life expectancy, 14.6 years) to 44 days with 3 additional index points (life expectancy, 9.7 years) and 8 days with 7 additional index points (life expectancy, 4.8 years). A similar decline in benefits occurred among patients with prolonged duration of diabetes. Results of Sensitivity Analysis: With alternative model assumptions (such as Framingham models), expected benefits of intensive control declined as mortality index scores increased. Limitations: Diabetes clinical trial data were lacking for frail, older patients. The mortality index was not validated for use in predicting individual-level life expectancies. Adverse effects of intensive control were not taken into account. Conclusion: Among older diabetic patients, the presence of multiple comorbid illnesses or functional impairments is a more important predictor of limited life expectancy and diminishing expected benefits of intensive glucose control than is age alone.
Transplantation for primary biliary cirrhosis: Retrospective analysis of 400 patients in a single center
Authors: Raquel F. Liermann Garcia, Christian Evangelista Garcia, Paul McMaster, James Neuberger
Journal: Hepatology (2001)

Orthotopic liver transplantation (OLT) is an effective treatment for patients with advanced primary biliary cirrhosis (PBC). We have conducted a retrospective analysis of 400 consecutive patients transplanted for PBC between 1983 and 1999. Mean follow–up was 56 months. The proportion of patients grafted for PBC fell progressively, from 35% in 1990 (n = 80) to 21% in 1999 (n = 111); comparison of patients grafted in the 2 decades showed that the median age increased from 53 to 56 years and the median serum bilirubin at transplantation fell from 270 μmol/L to 132 μmol/L. The overall actuarial patient and graft survival at 1, 5, and 10 years is 83%, 78%, and 67% and 82%, 75%, and 61%, respectively. The net gain in 5–year survival compared with predicted survival in the absence of transplantation fell from 37% (range, 82%–90%) to 16% (range, 91%–99%). Multiple organ failure (16.1%) and sepsis (9.6%) were the major causes of early deaths ( &lt;6 months). Recurrent PBC, diagnosed on allograft histology, was found in 68 (17%) patients, at a mean time of 36 months. We were unable to identify any pretransplantation donor or recipient factor, which identified those patients at risk of recurrence, although recurrence was much earlier and more frequently seen in patients receiving tacrolimus ( P = .04). PBC remains a good indication for liver transplantation, with excellent survival rates. The age at transplantation increased although patients tended to be grafted earlier. Survival rates have increased although there is a reduction in the survival benefit. Recurrence may be common, but does not seem to affect medium–term graft survival.
Problems With the Interpretation of Pharmacoeconomic Analyses
Authors: Suzanne R. Hill, Andrew S. Mitchell, David A. Henry
Journal: JAMA (2000)

ContextPharmacoeconomic analyses are being used increasingly as the basis for reimbursement of the costs of new drugs. Reports of these analyses are often published in peer-reviewed journals. However, the analyses are complex and difficult to evaluate.ObjectiveTo describe the nature of problems encountered in the evaluation and interpretation of pharmacoeconomic analyses used as a basis for reimbursement decisions.Data SourcesAll major submissions to the Department of Health and Aged Care (DHAC) by the pharmaceutical industry for funding made under the Australian Pharmaceutical Benefits Scheme. Specifically, the DHAC's database of submissions that were received between January 1994 and December 1997 were reviewed.Study SelectionOf a total of 326 submissions, 218 had serious problems of interpretation and were included in the analysis. The nature of the serious problems reviewed were classified as estimates of comparative clinical efficacy, comparator issues, modeling issues, and calculation errors.Data ExtractionAll submissions in the DHAC's database were reviewed and data were extracted if both the DHAC evaluators and technical subcommittee considered problems to have a significant bearing on the decisions of the parent committee.Data SynthesisOf a total of 326 submissions, 218 (67%) had significant problems and 31 had more than 1 problem. Of the 249 problems identified, 154 (62%) related to uncertainty in the estimates of comparative clinical efficacy, and 71 (28.5%) related to modeling issues, which included clinical assumptions or cost estimates, used in the construction of the economic models. There were 15 instances of disagreement over the choice of comparator, and serious calculation errors were found on 9 occasions. Overall, 159 problems (64%) were considered to be avoidable.ConclusionsSignificant problems were identified in these pharmacoeconomic analyses. The intensive evaluation process used in the Australian Pharmaceutical Benefits Scheme allowed for identification and correction of pharmacoecomomic analysis problems, but the resources that are required may be beyond the capacity of many organizations, including peer-reviewed journals.
ADAM17 mediates OSCC development in an orthotopic murine model
Authors: Fernando Moreira Simabuco, Rebeca Kawahara, Sami Yokoo, Daniela C Granato, Lucas Miguel, Michelle Agostini, Annelize ZB Aragão, Romênia R Domingues, Isadora L Flores, Carolina CS Macedo, Ricardo Della Coletta, Edgard Graner, Adriana Franco Paes Leme
Journal: Molecular Cancer (2014)

ADAM17 is one of the main sheddases of the cells and it is responsible for the cleavage and the release of ectodomains of important signaling molecules, such as EGFR ligands. Despite the known crosstalk between ADAM17 and EGFR, which has been considered a promising targeted therapy in oral squamous cell carcinoma (OSCC), the role of ADAM17 in OSCC development is not clear. In this study the effect of overexpressing ADAM17 in cell migration, viability, adhesion and proliferation was comprehensively appraised in vitro. In addition, the tumor size, tumor proliferative activity, tumor collagenase activity and MS-based proteomics of tumor tissues have been evaluated by injecting tumorigenic squamous carcinoma cells (SCC-9) overexpressing ADAM17 in immunodeficient mice. The proteomic analysis has effectively identified a total of 2,194 proteins in control and tumor tissues. Among these, 110 proteins have been down-regulated and 90 have been up-regulated in tumor tissues. Biological network analysis has uncovered that overexpression of ADAM17 regulates Erk pathway in OSCC and further indicates proteins regulated by the overexpression of ADAM17 in the respective pathway. These results are also supported by the evidences of higher viability, migration, adhesion and proliferation in SCC-9 or A431 cells in vitro along with the increase of tumor size and proliferative activity and higher tissue collagenase activity as an outcome of ADAM17 overexpression. These findings contribute to understand the role of ADAM17 in oral cancer development and as a potential therapeutic target in oral cancer. In addition, our study also provides the basis for the development of novel and refined OSCC-targeting approaches.
Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
Authors: Yuli Lin, Nana Peng, Jianping Li, Hongqin Zhuang, Zi-Chun Hua
Journal: Molecular Cancer (2013)

Urokinase (uPA) and its receptor (uPAR) play an important role in tumour growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Targeting the excessive activation of this system as well as the proliferation of the tumour vascular endothelial cell would be expected to prevent tumour neovasculature and halt tumour development. The amino terminal fragment (ATF) of urokinase has been confirmed effective to inhibit the proliferation, migration and invasiveness of cancer cells via interrupting the interaction of uPA and uPAR. Triptolide (TPL) is a purified diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic anticancer activity of TPL and ATF in various solid tumour cells.Using in vitro and in vivo experiments, we investigated the combined effect of TPL and ATF at a low dosage on cell proliferation, cell apoptosis, cell cycle distribution, cell migration, signalling pathways, xenograft tumour growth and angiogenesis.Our data showed that the sensitivity of a combined therapy using TPL and ATF was higher than that of TPL or ATF alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle arrest, and inhibition of uPAR-mediated signalling pathway contributed to the synergistic effects of this combination therapy. Furthermore, using a mouse xenograft model, we demonstrated that the combined treatment completely suppressed tumour growth by inhibiting angiogenesis as compared with ATF or TPL treatment alone.Our study suggests that lower concentration of ATF and TPL used in combination may produce a synergistic anticancer efficacy that warrants further investigation for its potential clinical applications.