A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.     

Outcomes of induction chemotherapy followed by chemoradiation using intensity‐modulated radiation therapy for esophageal adenocarcinoma

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity‐modulated radiation therapy (IMRT) after induction chemotherapy. Forty‐one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan‐Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty‐nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32–85 years). The majority of acute treatment‐related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2–3 pneumonitis (5%) and 5 patients experienced post‐operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2‐year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

Analysis of human platelet glycoproteins IIb-IIIa and Glanzmann's thrombasthenia in whole blood by flow cytometry

Antibodies that bind to human platelet membrane glycoproteins IIb and IIIa were used to develop methods for analyzing platelet membrane components by flow cytometry. Platelets were tentatively identified by their low-intensity light scatter profiles in whole blood or platelet- rich plasma preparations. Identification of this cell population as platelets was verified by using platelet-specific antibodies and fluorescein-conjugated antiimmunoglobulin. Two-parameter analysis of light scatter versus fluorescence intensity identified greater than 98% of the cells in the "platelet" light scatter profile as platelets due to their acquired fluorescence. Both platelet-rich plasma and whole blood were used to study platelet membrane glycoproteins IIb and IIIa on a single cell basis in an unwashed system. Prostacycline was included in these preparations as a precautionary step to inhibit platelet aggregation during analysis. Flow cytometry is a successful technique for rapid detection of platelet membrane defects such as Glanzmann's thrombasthenia. Platelets from Glanzmann's thrombasthenic individuals were readily distinguished from platelets with normal levels of glycoprotein IIb and IIIa and from platelets with glycoprotein levels characteristic of heterozygote carriers of this disorder. This technique provides a sensitive tool for investigating platelet functional defects due to altered expression or deficiency of platelet surface proteins.     

Évaluation du bullying scolaire (harcèlement scolaire) chez les adolescents français : validité de l’adaptation française du questionnaire Agresseur/Victime révisé d’Olweus (1996)

Bullying is a widespread problem in schools. There would be a benefit in the availability of a valid instrument for its measurement in France. The Olweus Bully/Victim Questionnaire revised (BVQr) (Olweus, 1996) [21] is one of the most widely used bullying self-report in the world, but no data are available on its validity for its use with French adolescents.     

Calcium currents are altered in the vascular muscle cell membrane of spontaneously hypertensive rats

Calcium currents were recorded during whole-cell voltage clamp in cultured azygos venous muscle cells from 1-3-day-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Different holding potentials were used to separate total cell current into its transient (T) and sustained or long-lasting (L) components. In recordings from 30 WKY and 30 SHR vascular cells, total cell calcium current was the same between cells from normotensive (167 +/- 20 pA) and hypertensive (139 +/- 15 pA) rats. However, the relative proportion of T and L calcium currents was different between WKY and SHR cells. In WKY cells, the peak amplitude of the L current was less than that of the T current (42 +/- 30% of total current), whereas in SHR cells, the L current was greater (62 +/- 3% of total current). Calcium currents in vascular muscle cells from SHR were activated and inactivated at more positive potentials than in cells from WKY. This study directly compares transmembrane calcium current in isolated cells from WKY and SHR blood vessels and shows that the proportions of T and L calcium channels activated by depolarization are altered in this genetic model of hypertension.     

Health Benefits of Fiber Fermentation

Although fiber is well recognized for its effect on laxation, increasing evidence supports the role of fiber in the prevention and treatment of chronic disease. The aim of this review is to provide an overview of the health benefits of fiber and its fermentation, and describe how the products of fermentation may influence disease risk and treatment. Higher fiber intakes are associated with decreased risk of cardiovascular disease, type 2 diabetes, and some forms of cancer. Fiber may also have a role in lowering blood pressure and in preventing obesity by limiting weight gain. Fiber is effective in managing blood glucose in type 2 diabetes, useful for weight loss, and may provide therapeutic adjunctive roles in kidney and liver disease. In addition, higher fiber diets are not contraindicated in inflammatory bowel disease or irritable bowel syndrome and may provide some benefit. Common to the associations with disease reduction is fermentation of fiber and its potential to modulate microbiota and its activities and inflammation, specifically the production of anti-inflammatory short chain fatty acids, primarily from saccharolytic fermentation, versus the deleterious products of proteolytic activity. Because fiber intake is inversely associated with all-cause mortality, mechanisms by which fiber may reduce chronic disease risk and provide therapeutic benefit to those with chronic disease need further elucidation and large, randomized controlled trials are needed to confirm causality.Teaching Points? Strong evidence supports the association between higher fiber diets and reduced risk of cardiovascular disease, type 2 diabetes, and some forms of cancer.? Higher fiber intakes are associated with lower body weight and body mass index, and some types of fiber may facilitate weight loss.? Fiber is recommended as an adjunctive medical nutritional therapy for type 2 diabetes, chronic kidney disease, and certain liver diseases.? Fermentation and the resulting shifts in microbiota composition and its activity may be a common means by which fiber impacts disease risk and management.