Dysgerminoma in three patients with Swyer syndrome

<p>Abstract</p> <p>Background</p> <p>Dysgerminoma is the most common malignant germ cell tumor of the ovary. This malignancy can be associated with pure gonadal dysgenesis or Swyer syndrome, mixed gonadal dysgenesis and partial gonadal dysgenesis.</p> <p>Case presentation</p> <p>Dysgerminoma developed in 3 phenotypic female patients with 46 XY pure gonadal dysgenesis. All patients presented first with abdominopelvic mass. Laparatomy was done. 46 XY karyotype was made by lymphocyte culture. Then these patients underwent gonadectomy that histopathology results were streak ovaries without evidence for malignancy. Two patients received postoperative adjuvant therapy.</p> <p>Conclusion</p> <p>In Patients with Swyer syndrome the risk of dysgerminoma is high and gonadectomy is recommended. Also 5% of dysgerminomas are discovered in phenotypic female and 46 XY karyotype, thus in adolescent with dysgerminoimas and amenorrhea, karyotype should be done.</p

Internet addiction: a 21st century epidemic?

Internet addiction, while not yet officially codified within a psychopathological framework, is growing both in prevalence and within the public consciousness as a potentially problematic condition with many parallels to existing recognized disorders. The rapid and unfettered increase in the number of people accessing a relatively unrestricted internet substantially increases the possibility that those suffering with an underlying psychological comorbidity may be at serious risk of developing an addiction to the internet, lending further credence to this hitherto understudied condition. In this commentary, I outline my recommendations for improved diagnosis, study and prevention of internet addiction

Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85

The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is not appropriate for withholding surgery in high-risk patients with aortic stenosis: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is a widely used risk assessment tool in patients with severe aortic stenosis to determine operability and to select patients for alternative therapies such as transcatheter aortic valve implantation. The objective of this study was to determine the accuracy of the EuroSCORE in predicting mortality following aortic valve replacement (AVR).</p> <p>Methods</p> <p>The logistic EuroSCORE was determined for all consecutive patients that underwent conventional AVR between 1995 and 2005 at our institution. Provincial Vital Statistics were used to determine all-cause mortality. The accuracy of the prognostic risk prediction provided by logistic EuroSCORE was assessed by comparing observed and expected operative mortality.</p> <p>Results</p> <p>During the study period, a total of 1,421 patients underwent AVR including 237 patients (16.7%) that had a logistic EuroSCORE > 20. Among these patients, the mean predicted operative mortality was 38.7% (SD = 18.1). The actual mortality of these patients was significantly lower than that predicted by EuroSCORE (11.4% vs. 38.7%, observed/expected ratio 0.29, 95% CI 0.15–0.52, P < 0.05). The EuroSCORE overestimated mortality within all strata of predicted risk. Although medium-term mortality is significantly higher among patients with EuroSCORE > 20 (log rank P = 0.0001), approximately 60% are alive at five years.</p> <p>Conclusion</p> <p>Actual operative mortality in patients undergoing AVR is significantly lower than that predicted by the logistic EuroSCORE. Additionally, medium-term survival following AVR is acceptable in high-risk patients with EuroSCORE > 20. More accurate risk prediction models are needed for risk-stratifying patients with severe aortic stenosis.</p

Characterization of ERK Docking Domain Inhibitors that Induce Apoptosis by Targeting Rsk-1 and Caspase-9

<p>Abstract</p> <p>Background</p> <p>The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play an important role in cancer cell proliferation and survival. ERK1/2 proteins also are important for normal cell functions. Thus, anti-cancer therapies that block all ERK1/2 signaling may result in undesirable toxicity to normal cells. As an alternative, we have used computational and biological approaches to identify low-molecular weight compounds that have the potential to interact with unique ERK1/2 docking sites and selectively inhibit interactions with substrates involved in promoting cell proliferation.</p> <p>Methods</p> <p>Colony formation and water soluble tetrazolium salt (WST) assays were used to determine the effects of test compounds on cell proliferation. Changes in phosphorylation and protein expression in response to test compound treatment were examined by immunoblotting and <it>in vitro </it>kinase assays. Apoptosis was determined with immunoblotting and caspase activity assays.</p> <p>Results</p> <p><it>In silico </it>modeling was used to identify compounds that were structurally similar to a previously identified parent compound, called <b>76</b>. From this screen, several compounds, termed <b>76.2</b>, <b>76.3</b>, and <b>76.4 </b>sharing a common thiazolidinedione core with an aminoethyl side group, inhibited proliferation and induced apoptosis of HeLa cells. However, the active compounds were less effective in inhibiting proliferation or inducing apoptosis in non-transformed epithelial cells. Induction of HeLa cell apoptosis appeared to be through intrinsic mechanisms involving caspase-9 activation and decreased phosphorylation of the pro-apoptotic Bad protein. Cell-based and <it>in vitro </it>kinase assays indicated that compounds <b>76.3 </b>and <b>76.4 </b>directly inhibited ERK-mediated phosphorylation of caspase-9 and the p90Rsk-1 kinase, which phosphorylates and inhibits Bad, more effectively than the parent compound <b>76</b>. Further examination of the test compound's mechanism of action showed little effects on related MAP kinases or other cell survival proteins.</p> <p>Conclusion</p> <p>These findings support the identification of a class of ERK-targeted molecules that can induce apoptosis in transformed cells by inhibiting ERK-mediated phosphorylation and inactivation of pro-apoptotic proteins.</p

A Modified RMCE-Compatible Rosa26 Locus for the Expression of Transgenes from Exogenous Promoters

Generation of gain-of-function transgenic mice by targeting the Rosa26 locus has been established as an alternative to classical transgenic mice produced by pronuclear microinjection. However, targeting transgenes to the endogenous Rosa26 promoter results in moderate ubiquitous expression and is not suitable for high expression levels. Therefore, we now generated a modified Rosa26 (modRosa26) locus that combines efficient targeted transgenesis using recombinase-mediated cassette exchange (RMCE) by Flipase (Flp-RMCE) or Cre recombinase (Cre-RMCE) with transgene expression from exogenous promoters. We silenced the endogenous Rosa26 promoter and characterized several ubiquitous (pCAG, EF1α and CMV) and tissue-specific (VeCad, αSMA) promoters in the modRosa26 locus in vivo. We demonstrate that the ubiquitous pCAG promoter in the modRosa26 locus now offers high transgene expression. While tissue-specific promoters were all active in their cognate tissues they additionally led to rare ectopic expression. To achieve high expression levels in a tissue-specific manner, we therefore combined Flp-RMCE for rapid ES cell targeting, the pCAG promoter for high transgene levels and Cre/LoxP conditional transgene activation using well-characterized Cre lines. Using this approach we generated a Cre/LoxP-inducible reporter mouse line with high EGFP expression levels that enables cell tracing in live cells. A second reporter line expressing luciferase permits efficient monitoring of Cre activity in live animals. Thus, targeting the modRosa26 locus by RMCE minimizes the effort required to target ES cells and generates a tool for the use exogenous promoters in combination with single-copy transgenes for predictable expression in mice

Right Hepatectomy in Patients over 70 Years of Age: An Analysis of Liver Function and Outcome.

BACKGROUND: As a consequence of the increase in life expectancy, hepatobiliary surgeons have to deal with an emerging aged population. We aimed to analyze the liver function and outcome after right hepatectomy (RH) in patients over 70 years of age. METHODS: From January 2006 to December 2009, we prospectively collected data of 207 consecutive elective hepatectomies. In patients who had RH, cardiac risk was assessed by a dedicated preoperative workup. Liver failure (LF) was defined by the "fifty-fifty" criteria at postoperative day 5 (POD) and morbidity by the Clavien-Dindo classification. Liver function tests (LFTs) and short-term outcome were retrospectively analyzed in patients over (elderly group, EG) and younger (young group, YG) than 70 years of age. RESULTS: Eighty-seven consecutive RH were performed during the study period. Indication for surgery included 90 % malignancy in 47 % of patients requiring preoperative chemotherapy. ASA grade &gt; 2 (44 vs. 16 %, p = 0.027), ischemic heart disease (17 vs. 5 %, p = 0.076), and preoperative cardiac failure (26 vs. 2 %, p &lt; 0.001) were more frequent in the EG (n = 23) than in the YG (n = 64). Both groups were similar regarding rates of normal liver parenchyma, chemotherapy and intraoperative parameters. The overall morbidity rates were comparable, but the serious complication (grades III-V) rate was relatively higher in the EG (39 vs. 25 %, p = 0.199), particularly in patients with diabetes mellitus (100 vs. 29 %, p = 0.04) and those who had additional nonhepatic surgery (67 vs. 35 %, p = 0.110) and transfusions (44 vs. 30 %, p = 0.523). The 90-day mortality rate was similar (9 % in the EG vs. 3 % in the YG, p = 0.28) and was related to heart failure in the EG. LFTs showed a similar trend from POD 1 to 8, and patients ≥70 years of age had no liver failure. CONCLUSIONS: Age ≥70 years alone is not a contraindication to RH. However, major morbidity is particularly higher in the elderly with diabetes. This high-risk group should be closely monitored in the postoperative course. Liver function is not altered in the elderly patient after RH