Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates

Effects of sarcopenia and malnutrition on morbidity and mortality in gynecologic cancer surgery: results of a prospective study

Background: Malnutrition and sarcopenia often occur simultaneously in cancer patients and are thought to have harmful effects on both surgical and oncological outcomes. Therefore, we want to evaluate the effects of sarcopenia and malnutrition on severe postoperative complications and overall survival in gynecologic cancer patients. Methods: We assessed nutritional parameters and run a bioelectrical impedance analysis in 226 women. Extracellular mass to body cell mass index, phase angle alpha, muscle mass, and fat mass were evaluated. To determine if patients suffer from sarcopenia, we ran the Timed 'Up and Go' test, performed hand grip strength, and calculated a skeletal muscle index. Postoperative complications were categorized using Clavien-Dindo Classification. Utilizing ROC analysis and logistic regression, we determined predictive clinical factors for severe postoperative complications. Kaplan-Meier method and log-rank test were used for overall survival analysis. Results: Of the 226 female patients, 120 (53%) had a BMI ≥ 25 kg/m2 , 56 (26%) had a phase angle 1 (OR 4.56, 95% CI: 1.46-14.28, P = 0.009), BMI ≥ 25 kg/m2 (OR 8.22, 95% CI: 3.01-22.48, P 1 (HR 2.51, 95% CI: 1.25-5.03, P = 0.01), hypoalbuminemia (HR 2.15, 95% CI: 1.28-3.59, P = 0.004), phase angle < 4.5° (HR 1.76, 95% CI 1.07-2.90, P = 0.03), tumour stage ≥ III A (HR 2.61, 95% CI: 1.53-4.45, P < 0.001), and severe postoperative complications (HR 2.82, 95% CI: 1.80-4.41, P < 0.001) were predictors of overall mortality. Conclusions: We observed that preoperatively assessed ECOG status > 1, BMI > 25 kg, as well as phase angle alpha 1, hypoalbuminemia, phase angle < 4.5° as well as FIGO stage ≥ III A and severe postoperative complications within 30 days correlate significantly with poor overall survival

Pre-Operative Malnutrition in Patients with Ovarian Cancer: What Are the Clinical Implications? Results of a Prospective Study.

BackgroundMalnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian cancer (EOC) and impact on survival.MethodsIn our prospective observational monocentric study, we included the patients with primary and recurrent EOC, tubal or peritoneal cancer conducted. We assessed serum laboratory parameters, body mass index, nutritional risk index, nutritional risk screening score (NRS-2002), and bio-electrical impedance analysis.ResultsWe recruited a total of 152 patients. Patients > 65 years-old, with ascites of >500 mL, or with platinum-resistant EOC showed statistically significant increased risk of malnutrition when evaluated using NRS-2002 (p-values= 0.014, 0.001, and 0.007, respectively). NRS-2002 p = 0.009). The patients with NRS-2002 ≥ 3 had a median overall survival (OS) of seven months (95% CI = 0-24 months), as compared to the patients with NRS-2002 p = 0.001). A phase angle (PhAα) ≤ 4.5 was the strongest predictor of OS.ConclusionsIn our study, we found malnutrition to be an independent predictor of incomplete cytoreduction and independent prognostic factor for poor OS. Preoperative nutritional assessment is an effective tool in the identification of high-risk EOC groups characterized by poor clinical outcome

The need for more workshops in laparoscopic surgery and surgical anatomy for European gynaecological oncology trainees: a survey by the European Network of Young Gynaecological Oncologists.

OBJECTIVE: The objective of this study was to highlight the relative preference of European gynecologic oncology trainees for workshops that could support and supplement their training needs. METHODS: A Web-based survey was sent to 900 trainees on the European Network of Young Gynaecological Oncologists database in November 2011. Respondents were asked to rate a 13-item questionnaire (using a 1- to 5-point Likert scale) on workshop topics they felt would most benefit their training requirements. Free text space for additional topics was also provided. Descriptive analysis was used to describe the mean scores reported for different items. A complete linkage hierarchical cluster analysis with Dendron plot was used to assess any clustering of data, and Cronbach α was used to assess the internal reliability of the questionnaire. RESULTS: One hundred ninety trainees from 37 countries responded to the survey, giving a 21% response rate. The 3 most important topics reported were laparoscopic surgery; surgical anatomy, and imaging techniques in gynecologic oncology. The Dendron plot indicated 4 different clusters of workshops (research related skills, supportive ancillary skills, related nonsurgical subspecialties, and core surgical skills) reflecting different competencies trainees need to meet. There was no significant association between individual country of training and workshop preference. The mean duration of the workshop preferred by 71% of respondents was 2 days. Cronbach α of the 13-item questionnaire was 0.78, which suggests good internal consistency/reliability. CONCLUSIONS: This report for the first time highlights the relative importance and significance European trainees attach to some of their training needs in gynecologic oncology. Laparoscopic surgery, surgical anatomy, and imaging appear to be the 3 areas of greatest need. The European Society of Gynaecological Oncology, other national specialist societies, and institutions should direct additional training efforts at these areas