Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d'Etudes des Tumeurs Uro-Génitales) study

PURPOSE: Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma. MATERIALS AND METHODS: A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point. RESULTS: There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses. CONCLUSIONS: To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.     

Acanthamoeba isolates belonging to T1, T2, T3, T4 and T7 genotypes from environmental freshwater samples in the Nile Delta region, Egypt

The free-living amoebae of the genus Acanthamoeba include non-pathogenic and pathogenic species and has been recently classified into 15 different genotypes, T1-T15. In this study, a survey was conducted in order to determine the presence and pathogenic potential of free-living amoebae of Acanthamoeba genus in freshwater sources associated with human activities in the Nile Delta region, Egypt. Identification of Acanthamoeba was based on the morphology of cyst and trophozoite forms and PCR amplification with a genus specific primer pair. The pathogenic potential of Acanthamoeba isolates was characterized using temperature and osmotolerance assays and PCR reactions with two primer pairs specific to Acanthamoeba pathogenesis. Isolates genotypes were also determined after ribosomal DNA sequencing. These data revealed that isolates belong to T1, T2, T3, T4 and T7 genotypes. As expected, T4 isolates exhibited the most pathogenic traits and were osmotolerant, temperature tolerant and expressed extracellular serine proteases. This is the first report presenting environmental distribution of Acanthamoeba genotypes in Egypt.     

Genetic immunization with LYVE-1 cDNA yields function-blocking antibodies against native protein

LYVE-1 is a surface bound hyaluronic acid (HA) receptor that is preferentially expressed by lymphatic endothelial cells (LEC). cDNA encoding full-length human LYVE-1 was coated onto gold particles that were then delivered via helium-assisted jet propulsion (gene gun) into the skin of Balb/C mice. LYVE-1 antisera, but not control pre-immune sera, recognized LYVE-1-transfected 293T cells by flow cytometry. While 40-70% of cultured human dermal microvascular endothelial cells (HMEC) were positive for LYVE-1 staining, human lung microvascular endothelial cells (LMEC) were negative. LYVE-1 antisera was used to effectively separate HMEC into LYVE-1 (hi) and LYVE-1(lo) populations that were enriched or depleted, respectively, for podoplanin, another LEC marker. By immunohistochemistry, LYVE-1 antisera detected CD31(lo) podoplanin(hi) lymphatic channels in normal and psoriatic human skin as well as in human tonsil. LYVE-1 antisera also blocked binding of FITC-labeled HA to HMEC (but not LMEC), demonstrating that these antibodies recognized regions of LYVE-1 required for HA binding. In summary, gene gun-assisted delivery of cDNA encoding LYVE-1 into skin resulted in reliable production of antisera that specifically and functionally recognized native LYVE-1 protein.     

The mathematical model of insulin desorption from the bioactive, fibrous artificial store

The aim of this study was to study insulin desorption from fibrous insulin artificial store in vitro as well as in vivo, with the intention to define a mathematical model that would describe this process. Release profile of cylindrical fibrous matrixes for various insulin concentrations, desorption temperatures, time periods, and pH were presented. Change of insulin concentration in the fibers and the effect of insulin release were discussed. This model was also used to predict the optimal conditions of the release process. Possibility of predicting the effect of the fibrous store design parameters (fibre radius, amount of bonded insulin, fiber type) on the resulting insulin release rate was the major advantage of this mathematical model. Also, taking all the relevant conditions regarding these experiments into consideration, by the application of mathematical model, the diffusion coefficient during insulin release was determined.     

Distribution of HPV16 and 18 intratypic variants in normal cytology, intraepithelial lesions, and cervical cancer in a Mexican population

OBJECTIVE: Several intratype variants of HPV16 and 18 have been identified. These variants are associated with populations from different geographic regions, and show a differential distribution among the severity of the cervical lesion, most likely due to different pathogenic potential. The objective of this study was to investigate the variant distribution of HPV16 and 18 in a Mexican population and its association with the severity of the cervical lesion and the histological lineage of cervical cancer. METHODS: HPV types 16 and 18 detection was performed in 412 samples of preinvasive and invasive specimens from patients attending a Primary Health-Care Center, an Early Cervical Lesion Clinic, or a Cancer Center. Distribution of HPV variants was correlated with the cytological findings and tumor cell types using contingency tables. Statistical difference was tested with the Fisher's Exact Test or its Fisher-Freeman-Halton extension for RXC tables. Alpha value was set at the P < 0.05. RESULTS: Among the 277 women included in this study without cancer, 63.5% (176 cases) had a normal cytology; from the remaining 101 women, 53.5% were LSIL (54 cases), and 46.5% HSIL (47 cases). From a total of 135 invasive carcinomas, 78.5% were squamous (106 cases); 6.6% adenocarcinoma (9 cases); 9.6% adenosquamous (ADSC) (13 cases); and 5.1% were undifferentiated carcinoma (7 cases). HPV16 E and AA-a were evenly distributed among preinvasive and invasive lesions. However, the isolate AA-c was exclusively found in cervical cancer. HPV18 Var-1(E) was almost exclusively found in invasive lesions, while the HPV18 Var-2(Af) predominated in normal or preinvasive lesions. In invasive cancer, this variant was found only in squamous tumors. CONCLUSIONS: The differential distribution of HPV16 and 18 variants in cervical lesions we found further supports experimental data on the different pathogenic potential of HPV16 and 18 variants for cervical cancer development.     

Multidetector CT for congenital heart patients: what a paediatric radiologist should know

Multidetector CT (MDCT) is increasingly used for imaging congenital heart disease (CHD) patients in addition to echocardiography, due to its ability to provide high quality three-dimensional images, giving a comprehensive evaluation of complex heart malformations. Using 4-slice or 16-slice CT, diagnostic information in CHD patients is limited to extra-cardiac anatomy, mainly the pulmonary arteries, aorta and venous connections. Due to high heart rates in babies however, coronary evaluation and intra-cardiac analysis were not reliable with the first generations of MDCT. Larger detector size with 64-slice CT and faster acquisition time, up to 75 ms for one slice, has progressively improved coronary and intra-cardiac visualization. Because radiation dose is the main concern, especially in children, every attempt to minimize dose whilst preserving image quality is important: the ALARA concept should always be applied in this population. The 80 kVp setting is now well accepted as a standard for more and more radiological teams involved in CT of children. Different acquisition strategies are now possible for childhood coronary imaging, using retrospective or even prospective gating. Using the latest technology, sub-mSv acquisitions are now attainable for scanning a whole thorax, providing a complete analysis of any 3-D cardiac malformation, including coronary artery course visualisation. This review will describe how technological developments have improved image quality with continuous reduction of radiation dose.     

Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study

Aims/hypothesis

Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes.

Methods

We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l.

Results

During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio.

Conclusions/interpretation

DHEA serum levels might be an independent marker of type 2 diabetes.

     

Significantly elevated foetal haemoglobin levels in individuals with glucose 6-phosphate dehydrogenase disease and/or sickle cell trait: a cross-sectional study in Cape Coast,Ghana

Background

Previously published data have demonstrated that sickle red blood cells produce twice as much reactive oxygen species (ROS) suggesting that co-inheritance of sickle cell disease (SCD) and glucose 6-phosphate dehydrogenase (G6PD) enzymopathy could lead to more severe anaemia during sickling crises. Elevated foetal haemoglobin (Hb F) levels have been shown to have positive modulatory effects on sickling crises and disease outcomes. This study sought to assess how inheritance of G6PD enzymopathy affects the level of Hb F and haemoglobin concentration in adults in steady state.

Methods

This cross-sectional study selected 100 out-patients (41 males and 59 females) visiting the University of Cape Coast hospital, between January, 2016 and May, 2016. Cellulose acetate electrophoresis (pH 8.2–8.6), methaemoglobin reductase test, modified Betke alkaline denaturation methods were used to investigate haemoglobin variants, qualitative G6PD status, and %Hb F levels in venous blood samples drawn from these participants. Data was analysed with GraphPad Prism 6 and SPSS and significance set at p < 0.05.

Results

Forty one percent of the participants demonstrated qualitative G6PD enzymopathy whereas only 10% demonstrated Hb AS type (Sickle cell trait, SCT). 5% of the participants co-inherited SCT and G6PD enzymopathy. %Hb F levels in G6PD deficient males was significantly higher than in G6PD deficient females [(p = 0.0003, 2.696% (males) vs 1.975% (females)], although the %Hb F levels was comparable in non-G6PD deficient individuals. %Hb F levels were significantly elevated in males with SCT only (p < 0.05), or G6PD enzymopathy only (p < 0.0001), or SCT + G6PD enzymopathy (p < 0.0001) compared to males with none of these pathologies even though their respective haemoglobin levels were comparable. Male participants with G6PD enzymopathy + SCT co-inheritance had significantly elevated %Hb F when compared to their counterparts with only G6PD enzymopathy (p < 0.001). Male gender [(p = 0.001, OR: 6.912 (2.277–20.984)] partial defective G6PD enzyme [(p = 0.00, OR: 7.567E8 (8.443E7–6.782E9)] SCT [(p = 0.026, OR: 4.625 (1.196–17.881)] were factors associated with raised %Hb F levels ≥2.5.

Conclusion

The inheritance of G6PD defect and/or SCT significantly elevate %Hb F levels in the steady state even though haemoglobin levels are not affected.

     

Comparison of sexual and drug use behaviors between female sex workers in Tijuana and Ciudad Juarez, Mexico

Female sex workers (FSWs) have been documented to have high rates of sexually transmitted diseases and HIV in many parts of the world. However, little work has been done to characterize the prevalence of these infections along the U.S.-Mexican border, where sexual tourism and culturally sanctioned sex work among nationals is widespread. The objective of this study was to compare differences in background characteristics, HIV risk behaviors, drug use, and sexually transmitted infection/HIV prevalence between FSWs who participated in a behavioral risk intervention in two U.S.-Mexican border cities. Baseline data were collected from March 2004 through September 2005. Data from 295 FSWs were compared between Tijuana and Ciudad (Cd.) Juarez. Among 155 FSWs in Tijuana and 140 in Cd. Juarez, HIV seroprevalence was 4.8% and 4.9%, respectively. FSWs in Cd. Juarez were more likely to test positive for active syphilis (31.3%) compared with Tijuana (11.8%) but did not differ in terms of the prevalence of gonorrhea and chlamydia. FSWs in both sites reported high levels of unprotected sex and use of drugs; however, FSWs in Cd. Juarez were more likely than those in Tijuana to ever have injected drugs (75% vs. 25%, p <.001). Heroin and cocaine use and injection drug use were significantly more common in Cd. Juarez, whereas methamphetamine use was more common in Tijuana. Injection of vitamins was common in both cities. Logistic regression analyses suggested that being younger, working in Cd. Juarez, and using heroin or cocaine were independently associated with active syphilis infection. In Tijuana, methamphetamine use was strongly associated with active syphilis infection. These preliminary results suggest that risk profiles for HIV/sexually transmitted infection among FSWs in these two Mexico-U.S. border cities differ, suggesting a need to tailor interventions to the specific needs in each city.     

VEGF inhibitors in cancer therapy

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is thought to play a critical role in tumor growth and metastasis. Consequently, anti-VEGF therapies are being actively investigated as potential anti-cancer treatments, either as alternatives or adjuncts to conventional chemo or radiation therapy. Among the techniques used to block the VEGF pathway are: 1) neutralizing monoclonal antibodies against VEGF or its receptor, 2) small molecule tyrosine kinase inhibitors of VEGF receptors, 3) soluble VEGF receptors which act as decoy receptors for VEGF, and 4) ribozymes which specifically target VEGF mRNA. Recent evidence from phase III clinical trials led to the approval of bevacizumab, an anti-VEGF monoclonal antibody, by the FDA as first line therapy in metastatic colorectal carcinoma in combination with other chemotherapeutic agents. However, may challenges still remain, and the role of anti-VEGF therapy in the treatment of other solid tumors remains to be elucidated. The aim of this article is to review the progress of clinical investigations involving VEGF inhibitors in the treatment of different types of solid tumors.