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Temozolomide (TEM) is an active treatment in metastatic neuroendocrine tumors (NETs). Patients affected by glioblastoma multiforme or advanced melanoma treated with TEM who have deficiency of OWe conducted a systematic review of the literature and meta-analysis, based on PRISMA methodology, searching in the main databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library and clinical trial.gov) and the proceedings of the main international congresses, until April 26, 2021.Twelve out of 616 articles were selected for our analysis, regarding a total of 858 NET patients treated with TEM-based chemotherapy. The status of MGMT had been tested in 513 (60%) patients, using various methods. The pooled overall response rate (ORR) was higher in MGMT-deficient compared with MGMT-proficient NETs, with a risk difference of 0.31 (95% confidence interval, CI: 0.13-0.50; p 0.001; IOur meta-analysis suggested that MGMT status may be predictive of TEM efficacy. However, due to the high heterogeneity of the evaluated studies the risk of biases should be considered. On this hypothesis future homogeneous prospective studies are warranted.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

// Teresa Peart 1, 2 , Yudith Ramos Valdes 1 , Rohann J. M. Correa 1, 3 , Elena Fazio 1, 2 , Monique Bertrand 1, 4, 5 , Jacob McGee 1, 4 , Michel Prefontaine 1, 4 , Akira Sugimoto 1, 4, 5 , Gabriel E. DiMattia 1, 3, 4, 5 , Trevor G. Shepherd 1, 2, 4, 5 1 Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada 2 Departments of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada 3 Departments of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada 4 Departments of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada 5 Departments of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada Correspondence to: Trevor G. Shepherd, e-mail: tshephe6@uwo.ca Keywords: ovarian cancer, spheroid, LKB1, AMPK, tumour cell dormancy Received: May 14, 2015 Accepted: May 23, 2015 Published: June 05, 2015 ABSTRACT Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5′-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

Recent genomics analysis of the high-grade serous subtype of epithelial ovarian cancer (EOC) show aberrations in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that result in upregulated signaling activity. Thus, the PI3K/AKT pathway represents a potential therapeutic target for aggressive high-grade EOC. We previously demonstrated that treatment of malignant ascites-derived primary human EOC cells and ovarian cancer cell lines with the allosteric AKT inhibitor Akti-1/2 induces a dormancy-like cytostatic response but does not reduce cell viability. In this report, we show that allosteric AKT inhibition in these cells induces cytoprotective autophagy. Inhibition of autophagy using chloroquine (CQ) alone or in combination with Akti-1/2 leads to a significant decrease in viable cell number. In fact, Akti-1/2 sensitizes EOC cells to CQ-induced cell death by exhibiting markedly reduced EC50 values in combination-treated cells compared with CQ alone. In addition, we evaluated the effects of the novel specific and potent autophagy inhibitor-1 (Spautin-1) and demonstrate that Spautin-1 inhibits autophagy in a Beclin-1-independent manner in primary EOC cells and cell lines. Multicellular EOC spheroids are highly sensitive to Akti-1/2 and CQ/Spautin-1 cotreatments, but resistant to each agent alone. Indeed, combination index analysis revealed strong synergy between Akti-1/2 and Spautin-1 when both agents were used to affect cell viability; Akti-1/2 and CQ cotreatment also displayed synergy in most samples. Taken together, we propose that combination AKT inhibition and autophagy blockade would prove efficacious to reduce residual EOC cells for supplying ovarian cancer recurrence. © The Author 2014. Published by Oxford University Press. All rights reserved.

People with severe mental illness (SMI) have a reduced life expectancy. A major cause of mortality is cardiovascular disease.The aims of this study were to document the prevalence of cardiovascular risk factors in people with SMI engaged in community psychiatric rehabilitation and compare prevalence rates to the general, and Aboriginal and Torres Strait Islander (ATSI) populations of Australia.A cross-sectional audit was conducted on patients receiving care from Melbourne's Inner-West Area Mental Health Service. Profiles were collected on: smoking status, body mass index, waist circumference, blood pressure, diabetic status and fasting lipid profiles. These were compared with the general and ATSI Australian populations.Complete data were available for 60 patients. Most were involuntary patients with a diagnosis of schizophrenia or schizoaffective disorder. Patients were more likely to smoke, be obese, have dyslipidaemia and the metabolic syndrome compared with the general and ATSI populations of Australia. Patients were more likely to have diabetes than the general population but had similar rates to the ATSI population. Patients had similar rates of hypertension to the general population but were less likely to be hypertensive compared with the ATSI population.Australians living with SMI have very high rates of cardiovascular risk factors, far in excess of the general Australian population and comparable with the ATSI population.

Background Stanniocalcin 2 (STC2) is a secreted protein activated by (PKR)-like Endoplasmic Reticulum Kinase (PERK) signalling under conditions of ER stress in vitro. Over-expression of STC2 in mice leads to a growth-restricted phenotype; however, the physiological function for STC2 has remained elusive. Given the relationship of STC2 to PERK signalling, the objective of this study was to examine the role of STC2 in PERK signalling in vivo. Results Since PERK signalling has both physiological and pathological roles in the pancreas, STC2 expression was assessed in mouse pancreata before and after induction of injury using a cerulein-induced pancreatitis (CIP) model. Increased Stc2 expression was identified within four hours of initiating pancreatic injury and correlated to increased activation of PERK signalling. To determine the effect of STC2 over-expression on PERK, mice systemically expressing human STC2 (STC2 Tg ) were examined. STC2 Tg pancreatic tissue exhibited normal pancreatic morphology, but altered activation of PERK signalling, including increases in Activating Transcription Factor (ATF) 4 accumulation and autophagy. Upon induction of pancreatic injury, STC2 Tg mice exhibited limited increases in circulating amylase levels and increased maintenance of cellular junctions. Conclusions This study links STC2 to the pathological activation of PERK in vivo, and suggests involvement of STC2 in responding to pancreatic acinar cell injury.

AA. have tested a new drug (Ceftriaxone) on 40 children affected by upper and lower respiratory tract infectious diseases. As shown by results, this new drug has been remarkably effective and easy to use since it may be administered once in a day; moreover, the tested drug has not caused any kind of tissue or parenchymal involvement.

A series of hydrochloride derivatives 2a – 9a and quaternary ammonium derivatives 3b – 9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M 1 –M 5 receptors expressed in CHO cells. Compound 8b , a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M 4 activity as competitive antagonist. Moreover 8b , acting as an allosteric modulator, was able to retard the dissociation rate of [ 3 H]- N -methylscopolamine from CHO-M 4 cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.

Background: Knowledge of clinical course in advanced jejunoileal neuroendocrine tumors (NETs) is poor. Aim: To investigate progression-free survival (PFS), overall survival (OS), and possible predictors for disease progression (DP) in advanced jejunoileal NETs. Patients and Methods: We carried out a multicenter, retrospective analysis of incoming patients with sporadic advanced jejunoileal NETs. PFS and OS were assessed by Kaplan-Meier analysis. Risk factors for progression were analyzed by the Cox proportional hazards method. Results: Of the 114 patients enrolled, 46.5% had functioning tumors, 93.9% had stage IV disease, and 57.3 and 42.7% were G1 and G2 tumors, respectively. During a median follow-up of 48 months (interquartile range 29–84 months), DP occurred in 61.4% of patients, after 19 months (interquartile range 10–41 months) from diagnosis. Median PFS was 36 months. The 2-year and 5-year PFS were 59 and 33%, respectively, while 5-year OS was 77.5%. Ki67 was the sole strong independent risk factor for unfavorable outcome according to multivariate analysis, being significantly associated with both PFS and OS. Conclusions: DP occurred in the majority of patients with advanced jejunoileal NETs, with median PFS being 36 months. Ki67 was a significant predictor of DP and should be considered in determining appropriate treatments and planning follow-up for these patients.

Cloricromen is a new drug that inhibits platelet aggregation in man and in experimental thrombosis. Twenty patients with a history of atherothrombotic stroke received cloricromen (100 mg, twice daily) for 30 days in order to evaluate its effects on plasma fibrinogen, antithrombin III, and other variables of the haemostatic system. A statistically significant decrease in the prothrombin time ( P < 0.01) was found only after 30 days of therapy. This decrease was transient and disappeared 15 days after the end of treatment. No statistically significant changes in plasma fibrinogen levels, antithrombin III, partial thromboplastin time, or platelet count were observed compared with baseline values. No side-effects were reported. This study did not reveal an effect of cloricromen on coagulative variables in patients with cerebrovascular occlusive disease.

We describe two young women affected with syncopal episodes and occipital headache exacerbated by cough, sneezing, rising, or effort. MRI revealed in both patients type I Arnold-Chiari malformation. A craniospinal pressure dissociation with brainstem compression may be involved in the pathogenesis of headache and syncope.