Male contraception: a realistic option?

This review illustrates the principle of hormonal male contraception and gives an overview of current trials aiming at the development of a marketable hormonal contraceptive for men. The principle of male hormonal contraception is based on strong suppression of gonadotropins in order to arrest spermatogenesis at the spermatogonial stem cell level, thus leading to azoospermia or severe oligozoospermia. Until now, it has not been possible to interrupt spermatogenesis effectively without simultaneously inhibiting the production of androgens by Leydig cells, resulting in a deficiency of extra-testicular androgens. Therefore, testosterone needs to be replaced. By administering exogenous testosterone alone azoospermia can be reached in East Asians, whereas azoospermia is only achieved in two-thirds of Caucasian volunteers so that in these men an additional agent is required. Currently injectable testosterone combined with gestagens or administered as implants are being tested for possible licensing. Although scrotal and non-scrotal testosterone patches, orally administered testosterone undecanoate and testosterone gels are generally well tolerated and provide stable testosterone levels in the normal range, their use showed generally disappointing efficacy due to insufficient gonadotropin suppression. Further large multi-centre studies are required to establish the contraceptive efficacy of the most promising steroid combinations.     

Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival.

PURPOSE: Bone marrow neoangiogenesis plays an important pathogenetic and possible prognostic role in acute myeloid leukemia (AML). Members of the vascular endothelial growth factor (VEGF) and angiopoietin family represent the most specific inducers of angiogenesis secreted by AML blasts. We therefore correlated expression of angiogenic factors with clinical variables. PATIENTS AND METHODS: We investigated the expression of VEGF-A, VEGF-C, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), and the receptor Tie2 by quantitative polymerase chain reaction in a cohort of 90 patients younger than 61 years with de novo AML entered into the German AML Süddeutsche H?moblastose Gruppe Hannover 95 trial. Uni- and multivariate analyses were performed using clinical and gene expression variables. RESULTS: Univariate analysis of overall survival indicated the following variables as prognostic factors: good response on a day-15 bone marrow examination after initiation of induction chemotherapy, karyotype, and high Ang2 expression. In multivariate analysis, only bad response and log Ang2 expression remained of statistical significance, with a hazard ratio of 3.51 (95% CI, 1.91 to 6.47) and 0.75 (95% CI, 0.61 to 0.91), respectively. Subgroup analysis suggested that the prognostic impact of Ang2 expression was especially evident in cohorts with low VEGF-C and Ang1 mRNA levels. CONCLUSION: These results show that expression of Ang2 represents an independent prognostic factor in AML. Additional research into interactions of angiogenic cytokines in the pathogenesis of bone marrow angiogenesis in AML is warranted.     

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.

PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.     

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.     

Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non‐SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3‐7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ²(1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.     

Evidence-based practice: Quality indicator analysis of antecedent exercise in autism spectrum disorders

The purpose of the research was to conduct a quality indicator analysis of studies exploring the effects of antecedent exercise on self-stimulatory behaviors of individuals with autism spectrum disorders (ASD). Educational Resources Information Center (ERIC), Google Scholar, SPORTDiscus, PsychINFO, and PubMed/MedLine databases from 1980 to October 2010 and reference lists of included articles were searched. Twelve research studies employing group experimental (Gersten et al., 2005) or single-subject designs (Horner et al., 2005) met inclusion criteria. Each study was assessed for the presence and clarity of quality indicators. Group experimental and single-subject designs met 48% and 82% of quality indicators, respectively. This suggests that the effects of antecedent exercise on self-stimulatory behaviors of individuals with ASD is incomplete and claims of exercise being an evidence-based practice are premature. Several indicators were difficult to interpret or lacking clear definitions. Recommendations for clarifying and applying the quality indicators are offered.     

Feeding of a well‐cooked beef diet containing a high heterocyclic amine content enhances colon and stomach carcinogenesis in 1,2‐dimethylhydrazine‐treated rats

Epidemiologic studies have linked the consumption of red meat and the consumption of highly browned meats containing high levels of heterocyclic aromatic amines (HCAs) to increased risk of colorectal cancer or polyps. The present study determined the effects of long‐term feeding of beef‐containing diets with low and high levels of HCAs (in the context of a low or high beef tallow diet) on a standard 1,2‐dimethylhydrazine (DMH)‐induced colon tumorigenesis protocol. Very lean beef was cooked by a variety of methods at different temperatures, and the levels of the major HCAs (2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline, 2‐amino‐3,4,8‐trimethylimidazo[4,5‐f]quinoxaline, and 2‐amino‐l‐methyl‐6‐phenylimidazo[4,5‐f]pyridine) were measured by high‐performance liquid chromatogra‐phy. Diets incorporating beef containing low or high levels of HCAs were fed for 12 weeks, during which DMH was administered to induce colon tumors, followed by various dietary regimens as promotional stimuli. Feeding of a beef diet high in HCAs resulted in more DMH‐induced colon adenocarcinomas, but only in the context of a low‐fat diet. The high‐HCA diets increased stomach tumors in all DMH‐treated rats. An apparent interaction of high HCA with a high fat level reduced the colon tumor incidence and tumor numbers in those diets containing both factors. These results support the epidemiologic data linking well‐cooked meat to increased risk for colon and stomach cancer, but the role of dietary fat level remains puzzling.