High-grade ovarian serous carcinoma patients exhibit profound alterations in lipid metabolism.

Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.

Accumulated Metabolites of Hydroxybutyric Acid Serve as Diagnostic and Prognostic Biomarkers of Ovarian High-Grade Serous Carcinomas.

Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities.

Salvage surgery due to bowel obstruction in advanced or relapsed ovarian cancer resulting in short bowel syndrome and long-life total parenteral nutrition: surgical and clinical outcome.

OBJECTIVE: Salvage surgery for patients with highly advanced or relapsed epithelial ovarian cancer (EOC) complicated by bowel obstruction and resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate surgical and clinical outcome in these highly palliative situations. METHODS: We evaluated all patients with EOC who underwent salvage extraperitoneal en bloc intestinal resection with terminal ileostomy or jejunostomy resulting in SBS and total parenteral nutrition owing to bowel obstruction between May 2003 and January 2012 in our institution. RESULTS: Thirty-seven patients were identified (median age, 58 years; range, 22-71 years), 3 (8.1%) with primary and 34 (91.6%) with relapsed EOC. Five patients (13.5%) were platinum sensitive. Median residual intestinal length was 70 cm (range, 10-180 cm); 21 patients (56.8%) had a residual intestinal length less than 1 m. Operative 30-day mortality and major morbidity rates were 10% and 51%, respectively. Median overall survival was 5.6 months (range, 0.1-49 months). One-year and 2-year overall survival rates were 18.3% (95% confidence interval, 5.1%-31.5%) and 8.1% (95% confidence interval, 0%-18.0)%, respectively. Within a median follow-up period of 5 months (range, 0.2-49 months), 4 patients (10.8%) are still alive. No significant differences in survival were seen between patients with or without major complications, tumor residuals, or residual intestinal length of less than 1 m versus greater than 1 m. CONCLUSIONS: Salvage palliative surgery in EOC due to bowel obstruction resulting in SBS and in need of long-life total parenteral nutrition is associated with high morbidity rates and low overall survival. These surgeries should ideally be performed only in a multidisciplinary setting with adequate infrastructure and possibility of home care support. Conservative management should be the route of action in the absence of acute abdomen or intestinal perforation.

First patient treated with a re-challenge of catumaxomab in recurrent malignant ascites: a case report.

In the past, treatment for malignant ascites focussed on symptomatic relief or treatment of the underlying disease. A promising option evolved with catumaxomab (Removab(®)) in 2009. Since catumaxomab is a bispecific, trifunctional antibody with mouse-rat origin, so far repeated treatment cycles were not an option due to the occurrence of human anti-drug antibodies (HADA). Nevertheless, the good results obtained so far raised the question whether a repeated treatment cycle with catumaxomab could be feasible and effective. We report on a 74-year-old female patient with breast cancer and peritoneal carcinomatosis. To our knowledge, this is the first patient world-wide to be treated with a repeated cycle of catumaxomab. HAMA (human anti-mouse antibodies) values were identified in blood and ascites samples. Ascites samples were also stained to identify and quantify cells, positive for EpCAM (epithelial cell adhesion molecule) and CD45. The patient tolerated the second cycle without unexpected side effects and remained puncture-free for another 45 days. Analysis of blood and ascites revealed a quick increase in HAMA values in the blood samples after 1 week, but considerably lower HAMA values and delayed increase in the ascites samples. Also a distinct and continuous decrease of EpCAM-positive cells was observed in the ascites samples under treatment. A strong increase in CD45-positive cells was detected after the beginning of the second cycle, with a consecutive decline toward the end. This first experience suggests that a repeated cycle of catumaxomab might be feasible and effective. As a consequence, a phase II trial (SECIMAS) was initiated.

Impact of obesity on operative morbidity and clinical outcome in primary epithelial ovarian cancer after optimal primary tumor debulking.

BACKGROUND: Obesity is a common and increasing condition in Western countries and seems to be associated with increased carcinogenesis and tumor invasiveness. We evaluated operative and clinical outcome in patients operated to treat primary epithelial ovarian cancer (EOC) according to their body mass index (BMI). METHODS: All consecutive EOC patients who underwent cytoreductive surgery in our institution between September 2000 and April 2010 were systematically evaluated according to their BMI (kg/m(2)). Survival was calculated by Kaplan-Meier curves. Logistic regression and Cox regression analysis were performed to identify the impact of obesity on surgical outcome and survival. RESULTS: Three hundred six patients were evaluated. A total of 40.2% were classified as overweight; 87 (28.4%) had a BMI of 25-30 kg/m(2) and 36 (11.8%) had a BMI of ≥30 kg/m(2). No statistically significant differences regarding tumor-related characteristics and comorbidities existed between normal-weight and overweight patients. Median operation time was significantly longer (P = 0.024) in overweight versus normal-weight patients (280 min; range 40-529 vs. 257 min; range 32-592, respectively). Complete tumor resection rates were equivalent between the two patient groups (68.6% vs. 72.5%; P = 0.543) with similar median overall and progression-free survival in both groups (43 vs. 42 months and 21 vs. 17.8 months, respectively). Operative morbidity was also not significantly different between the two groups. By comparable morbidity, operative procedures were similar between normal-weight and overweight patients, apart from higher intestinal and diaphragmatic resection rates in the overweight patients (61% vs. 43.7%; P = 0.004 and 24.4% vs. 14.2%; P = 0.034). In multivariate analysis, BMI of ≥25 kg/m(2) did not reveal any prognostic significance in respect of survival, operative morbidity, and complete tumor resection. CONCLUSIONS: BMI does not appear to influence tumor stage, histology, differentiation grade, or tumor marker levels in patients with primary EOC. Also, BMI is not an independent predictive and prognostic marker of survival, operative outcome, or morbidity at the time of primary tumor debulking.

Human vestibular cortex as identified with caloric stimulation in functional magnetic resonance imaging.

Anatomic and electrophysiological studies in monkeys have yielded a detailed map of cortex areas receiving vestibular afferents. In contrast, comparatively little is known about the cortical representation of the human vestibular system. In this study we applied caloric stimulation and fMRI to further characterize human cortical vestibular areas and to test for hemispheric dominance of vestibular information processing. For caloric vestibular stimulation we used cold nitrogen to avoid susceptibility artifacts induced by water calorics. Right and left side vestibular stimulation was repetitively performed inducing a nystagmus for at least 90 s after the end of the stimulation in all subjects. Only the first 60 s of this nystagmus period was included for statistical analysis and compared with the baseline condition. Activation maps revealed a cortical network with right hemispheric dominance, which in all subjects comprised the temporoparietal junction extending into the posterior insula and, furthermore, the anterior insula, pre- and postcentral gyrus, areas in the parietal lobe, the ventrolateral portion of the occipital lobe, and the inferior frontal gyrus extending into the inferior part of the precentral sulcus. In conclusion, caloric stimulation in fMRI reveals a widespread cortical network involved in vestibular signal processing corresponding to the findings from animal experiments and previous functional imaging studies in humans. Furthermore, this study demonstrates a strong right hemispheric dominance of vestibular cortex areas regardless of the stimulated side, consistent with the current view of a rightward asymmetrical cortical network for spatial orientation.