INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients.

OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.

The glycosphingolipid P1 is an ovarian cancer-associated carbohydrate antigen involved in migration.

BACKGROUND: The level of plasma-derived naturally circulating anti-glycan antibodies (AGA) to P1 trisaccharide has previously been shown to significantly discriminate between ovarian cancer patients and healthy women. Here we aim to identify the Ig class that causes this discrimination, to identify on cancer cells the corresponding P1 antigen recognised by circulating anti-P1 antibodies and to shed light into the possible function of this glycosphingolipid. METHODS: An independent Australian cohort was assessed for the presence of anti-P1 IgG and IgM class antibodies using suspension array. Monoclonal and human derived anti-glycan antibodies were verified using three independent glycan-based immunoassays and flow cytometry-based inhibition assay. The P1 antigen was detected by LC-MS/MS and flow cytometry. FACS-sorted cell lines were studied on the cellular migration by colorimetric assay and real-time measurement using xCELLigence system. RESULTS: Here we show in a second independent cohort (n=155) that the discrimination of cancer patients is mediated by the IgM class of anti-P1 antibodies (P=0.0002). The presence of corresponding antigen P1 and structurally related epitopes in fresh tissue specimens and cultured cancer cells is demonstrated. We further link the antibody and antigen (P1) by showing that human naturally circulating and affinity-purified anti-P1 IgM isolated from patients ascites can bind to naturally expressed P1 on the cell surface of ovarian cancer cells. Cell-sorted IGROV1 was used to obtain two study subpopulations (P1-high, 66.1%; and P1-low, 33.3%) and observed that cells expressing high P1-levels migrate significantly faster than those with low P1-levels. CONCLUSIONS: This is the first report showing that P1 antigen, known to be expressed on erythrocytes only, is also present on ovarian cancer cells. This suggests that P1 is a novel tumour-associated carbohydrate antigen recognised by the immune system in patients and may have a role in cell migration. The clinical value of our data may be both diagnostic and prognostic; patients with low anti-P1 IgM antibodies present with a more aggressive phenotype and earlier relapse.

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM×anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.

The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer.

OBJECTIVE: Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting ß-catenin dependent and independent Wnt signalling pathways. METHOD: Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines. RESULTS: Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of ß-catenin dependent Wnt signalling were inhibited, and ß-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation. CONCLUSION: This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).

Therapeutic drug monitoring of zuclopenthixol in a double-blind placebo-controlled discontinuation study in adults with intellectual disabilities and aggressive behaviour.

The trial was a double-blind, placebo-controlled comparison with a discontinuation design. 49 mentally retarded patients with aggressive behaviour were treated with zuclopenthixol at a dose of 2-20 mg/d. At each visit the clinical effect was evaluated. Correlations between dose, serum concentration, and efficacy measures were calculated. The mean dose was 10.0 mg/day (±5.17); the mean serum concentration 4.19 ng/mL (±3.16). Associations of dosage, serum concentration and clinical efficiency did not result in coherent patterns. Correlations with clinical efficiency measures appeared to be contradictory for dosage and serum concentrations, respectively. As no consistent associations between dosage, serum concentration, and clinical efficiency measures were found, different hypotheses explaining the results are discussed.

[Dual role of interleukin-6 for development of insulin resistance].

The review describes physiological and pathological role of interleukin-6 (IL-6) in control of tissues insulin sensitivity and its contrary shifts in different tissues. Analysis of actual data for IL-6 sources and its molecular mechanisms of action is given.

[Expression of the genes CelA and XylA isolated from a fragment of metagenomic DNA in Escherichia coli].

The glycosyl hydrolase genes cel5A and xyl3A previously isolated by ourselves within a fragment of DNA from the methagenomic library of cow rumen microflora DNA were sub-cloned and expressed in E. coli. The recombinant proteins Cel5A and Xyl3A were purified and characterized. Cellulase Cel5A belongs to the Family 5 glycosyl hydrolases and is a one-module 38.2 kDa enzyme that hydrolyses the 1,4-glycoside bonds of soluble cellulose substrates and amorphous cellulose, showing its maximal activity (31200 u/mg) on lichenan, a soluble substrate with mixed (beta-1,3-1,4) bonds. The end product of the amorphous cellulose hydrolysis is cellobiose. Cel5A is inactive toward the crystal forms of cellulose. Cel5A is an endoglucanase capable of exohydrolysis. The molecular mass of beta-xylosidase Xyl3A belonging to the Family 3 glycosyl hydrolases is 83.7 kDa. The enzyme is active only on xylooligosaccharides, with the maximal activity shown on xylobiose, the end product of the reaction being xylose. No activity on xylane was hitherto observed. Recombinant Cel5A and Xyl3A are stable over a wide range of pH and temperatures, their maximal activity being observed at pH 6.5 and at 55 degrees C.

[Inflammation as a factor of the pathogenesis of insulin resistance and type 2 diabetes].

Insulin resistance (IR) is a leading factor of type 2 diabetes (T2D), the central and governing component of the metabolic syndrome (MS), that also appears as obesity, glucose intolerance, dyslipidemia, and essential hypertension. Recent experimental studies have indicated that proinflammatory cytokines, adipocytokines, and transcription factors are implicated in the pathogenesis of IR, as evidenced by a number of clinical observations in patients with MS and T2D, in whom IR correlates with the status of chronic mild inflammation. Based on the results of these studies, a search for methods for exposure of IR has been initiated, by controlling inflammation. The first results encourage and suggest that anti-inflammatory agents improve tissue susceptibility to insulin and they are promising for the treatment of MS and T2D.

[Therapeutic education in the field of infection diseases: the example of HIV infection]. / Education thérapeutique en maladie infectieuse: l'exemple de l'infection à VIH.

The advent of antiretroviral therapies represent a major therapeutic progress which dramatically modifies HIV seropositive people's life during the past fifteen years. After the violence of a formerly rapidly fatal disease comes nowadays the heaviness of a chronic disease. If some problems are new for the patients, it also represents new challenges for the caregivers. Due to the lack of access to medications in certain context or because of nonadherence to treatment, the full potential of these therapies is difficult to reach. We present here the experience of a therapeutic patient educational program for HIV seropositive persons. This program aimed not only to develop patient's skills to elicit them to find a balance between their life and their disease, but also to improve the skills of the caregivers to face the problem of chronicity.

[Adiponectin: pathophysiological aspects].

The review presents the currently available data on the role of adipokines, adinonectin in particular, in the regulation of metabolic processes. The pathological role of adinonectin receptors in insulin resistance, diabetes mellitus, metabolic syndrome, atherosclerosis, and other cardiovascular diseases is discussed in detail.

Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients.

BACKGROUND: A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s. In the mid-1980s, however, retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era. During the last 10 years, deliberate transfusion pretreatment of transplant patients has been discontinued. METHODS: Within a collaborative project of 14 transplant centers, prospective recipients of cadaver kidney grafts were randomized to receive either three pretransplant transfusions or transplants without transfusions. RESULTS; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions (at 1 year: 90+/-2% vs. 82+/-3%, P=0.020; at 5 years: 79+/-3% vs. 70+/-4%, P=0.025). Cox regression analysis showed that this effect was independent of age, gender, underlying disease, prophylaxis with antilymphocyte antibodies, and preformed lymphocytotoxins. CONCLUSIONS; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens.

Comparison of serological and DNA PCR-SSP typing results for HLA-A and HLA-B in 421 Black individuals: a Collaborative Transplant Study report.

In a recent study, we observed a discrepancy rate of 8.5% between the results of molecular and serological HLA class I typing in Caucasian kidney donors and recipients. In the present study we addressed the question how often black individuals are mistyped using the serological technique. 421 Blacks whose HLA typing results were reported to the Collaborative Transplant Study (CTS) were typed retrospectively for HLA-A and -B using a PCR-SSP method. 78 of the 421 individuals (18.5%) showed a discrepancy for HLA-A and 107 individuals (25.4%) for HLA-B. 36.3% of all individuals tested showed either an HLA-A or an HLA-B discrepancy. 13.1% of the discrepancies at the HLA-A locus were due to antigen misassignments and 4.8% were due to missed antigens. HLA-B discrepancies were caused in 15.7% by antigen misassignments and in 10.5% by missed antigens. These results demonstrate an impressive advantage of the PCR-SSP method for HLA-A and HLA-B locus typing over serological typing in black individuals. The high typing discrepancy rate observed in Blacks provides a strong argument for replacing serological typing by the DNA method. It is likely that this will improve the HLA matching correlation in clinical transplantation in Blacks.

Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU.

Thirty-three patients with liver metastases of colorectal cancer were treated by intra-arterial 5-FU chemotherapy. The median survival time of all patients was 14 months. A partial remission could be observed in nine patients, and a further 15 patients had stable disease. Patients were treated on an outpatient basis and the toxicity of treatment was mild. We observed no case of sclerosing cholangitis or chemical hepatitis. Intra-arterial 5-FU chemotherapy provided treatment results similar to those reported for FUdR but with less hepatobiliary toxicity.

Maximal lactate steady state during the second decade of age.

Maximal lactate steady state (MLSS) presumably corresponds to the highest constant workload that can be performed by oxidative metabolism. The anaerobic and, to a minor extent, the oxidative metabolism have been reported to be affected by age. The second decade of life is the key period in the change in energy metabolism between children and adults. The aim of this study was to evaluate the effects of age on MLSS in 34 male subjects (age: 15.4 +/- 2.8 yr, range: 11-20 yr; height: 171.8 +/- 14.9 cm, range: 134-191 cm; body mass: 59.6 +/- 15.5 kg, range: 27-90 kg) performing an incremental load test to determine maximal workload and several constant load tests for MLSS measurement on a cycle ergometer. MLSS (4.2 +/- 0.7 mmol.l-1, range: 2.8 to 5.5 mmol.l-1) and MLSS intensity related to maximal workload (66.5 +/- 7.7%, range: 50-84%) were independent of age. MLSS heart rate (180.1 +/- 10.1 min-1, range: 156-208 min-1) decreased (P < 0.01) with increasing age, whereas absolute (157.2 +/- 54.8 W, range: 65-240 W) and relative MLSS workload (2.6 +/- 0.5 W.kg-1, range: 1.5 to 4.1 W.kg-1) and absolute (236.9 +/- 79.0 W, range: 100-350 W) and relative maximal workload (3.9 +/- 0.6 W.kg-1, range: 2.7 to 5.5 W.kg-1) increased (P < 0.001) with age. The age independence of MLSS supports the theory that neuromuscular factors may contribute to the frequently observed changes in response to given exercise with physical maturity more than changes in oxidative metabolism and/or glycolysis.

Setting up a decision support system with decision tables.

The aim of our study was to develop a decision support system using a conventional method which can be used as a shell for different applications. So it was necessary to find a method which allows separation of decision principles and decision algorithms. In addition, documentation of the patient records should be simplified. This could be attained by using the decision table technique and the programming language MUMPS. The general system developed was applied to the therapy decision for patients with liver metastases. The application system was clinically evaluated in a randomized group of patients. In 84% of the study group the therapy proposal of the system concurred with the therapy actually applied. Representation of knowledge in the form of tables is easily understandable by physicians. Since decision tables can be seen as a medium of communication between physician and system manager, knowledge acquisition is simplified.

Steroid derivatives. LXXIX. Microbial 15 beta-hydroxylation of 17 alpha-acetoxy-16-methylene derivatives of the pregnane series by the action of Cunninghamella blakesleeana.

Hydroxylation of 17 alpha-acetoxy-6-chloro-16-methylene-4,6-pregnadiene-3,20-dione (Chlorosuperlutin, I) by Cunninghamella blakesleeana yielded a 15 beta-hydroxyderivative II. Analogous transformation of 17 alpha-acetoxy-16-methylene-4,6-pregnadiene-3,20-dione (Superlutin, IV) included a hydroxylation in position 15 beta and probably also in 11 beta with a concomitant reduction of the 6,7-double bond.

[Liver resection in patients with metastases of colorectal cancers. Results and prognostic factors]. / Leberresektion bei Patienten mit Metastasen colorectaler Carcinome. Ergebnisse und prognostische Faktoren.

From October 1981 until July 1987 82 patients underwent hepatic resection for liver metastases of colorectal primary tumors. Operative mortality was 4.8%. This included, the median survival time was 25 months in a group of patients followed-up for at least one year postoperatively. Factors showing statistically significant influence on survival are: node-negative primary tumor, less than four metastases resected, only one liver lobe involved and decrease of CEA below 5 micrograms/ml if preoperatively elevated. Factors showing only a tendency to result in improved survival rates are the grading of the primary tumor and the percentage of liver involvement by tumor. The survival time after liver resection is similar in patients with synchronous and metachronous metastases. Thus, the time interval between the removal of the primary tumor and the detection of liver metastases seems to be gained lifetime.