Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer

Purpose  

Pemetrexed, an inhibitor of thymidylate synthase (TS) and additional folate-dependent enzymes, is clinically active in patients suffering from “non-squamous” non-small cell lung cancer (NSCLC). High expression of TS has been implied as biomarker predictive of resistance to pemetrexed. Against this background, we studied whether inhibition of mTOR could lower expression of TS and thus sensitize NSCLC cells to pemetrexed.     

Wire fractures in Solysafe septal occluders: a single center experience

Objectives : To determine the incidence of device fractures (DF) after implantation of a Solysafe® Septal Occluder (iSSO) and to assess the spectrum of associated problems. Background : In August 2010, after initial unpublished reports on DF, the manufacturer issued an “urgent field safety notice,” prompting all medical care providers to re‐examine all patients after iSSO. Methods : Prospective single center study. Extended follow‐up examination, including standardized fluoroscopy (sF), was performed in all patients after iSSO. Results : A total of 111 patients had undergone iSSO at our institution between June 2005 and July 2010. Median age and body weight were 50 years (9.3–79.6) and 75 kg (29–122), respectively. Indications for iSSO were (1) patent foramen ovale in patients with a history of cryptogenic stroke (n = 84; 76%) and (2) hemodynamically significant atrial septal defect of the secundum type (n = 27; 24%). A total of 113 devices were implanted. Complete follow‐up was available in 103 patients (92.8%). Median follow‐up was 1.9 years (0–5.2). There were no postimplantation neurological events or symptoms. The closure rate was 97.1%. DF was suspected on a chest X‐ray in one patient and documented in 10 patients by sF. The overall probability of freedom from DF was 82.3% after 5 years. One patient had embolization of a device fragment to the right pulmonary artery. So far, all patients with DF have been managed conservatively. Conclusions : The incidence of DF after iSSO is unacceptably high. sF is imperative for accurate diagnosis of DF. Further, follow‐up is needed to determine the risk of clinical complications and to optimize management. © 2012 Wiley Periodicals, Inc.     

Spinocerebellar ataxia type 3/Machado–Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions

Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta‐CAGexp from parent–offspring pairs, and delta‐CAGexp between siblings were obtained. One hundred and fifty‐nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta‐CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta‐CAGexp between 269 siblings correlated with their delta‐of‐age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.     

Men’s perspectives on women’s empowerment and intimate partner violence in rural Bangladesh

Intimate partner violence (IPV) may increase as women in patriarchal societies become empowered, implicitly or explicitly challenging prevailing gender norms. Prior evidence suggests an inverse U-shaped relationship between women’s empowerment and IPV, in which violence against women first increases and then decreases as more egalitarian gender norms gradually gain acceptance. By means of focus-group discussions and in-depth interviews with men in 10 Bangladeshi villages, this study explored men’s evolving views of women, gender norms and the legitimacy of men’s perpetration of IPV in the context of a gender transition. It examines men’s often-contradictory narratives about women’s empowerment and concomitant changes in norms of masculinity, and identifies aspects of women’s empowerment that are most likely to provoke a male backlash. Findings suggest that men’s growing acceptance of egalitarian gender norms and their self-reported decreased engagement in IPV are driven largely by pragmatic self-interest: their desire to improve their economic status and fear of negative consequences of IPV.     

Lebenslange Nachbehandlung und Sekund?rprophylaxe nach Herzinfarkt

Ein 60-jähriger Patient mit langjährigem Hypertonus, diätetisch schlecht eingestelltem Diabetes mellitus mit HbA_1c-Werten von 10%, Adipositas (Körpergröße 165 cm, Gewicht 85 kg) sowie Hyperlipoproteinämie kommt nach einem 2-wöchigen stationären Krankenhausaufenthalt wegen eines erlittenen Herzinfarkts in die ärztliche Praxis. Während des stationären Aufenthalts war im Rahmen des akuten Vorderwandinfarkts eine notfallmäßige Herzkatheteruntersuchung durchgeführt worden, die eine koronare Eingefäßerkrankung mit Verschluss der LAD erbracht hatte. Das Gefäß war mittels perkutaner transluminaler Koronarangioplastie (PTCA) rekanalisiert und mit einem Stent versorgt worden. Der Patient wurde aus dem Krankenhaus mit einer Medikation, bestehend aus Acetylsalicylsäure (ASS) 100 mg, Clopidogrel 75 mg, einem Angiotensinkonversionsenzym-(ACE-)Hemmer, einem -Blocker, einem Statin und einem Diuretikum, entlassen, nachdem er im Rahmen des Myokardinfarkts eine Linksherzinsuffizienz mit Lungenstauung sowie Beinödeme entwickelt hatte. Zurzeit ist der Patient klinisch beschwerdefrei und berichtet, dass er vor dem Akutereignis keine starke Angina pectoris verspürt habe. Beim Treppensteigen seien ihm aber schon eine gewisse Kurzatmigkeit und ein leichtes Druckgefühl in der Brust aufgefallen, denen er jedoch keine wesentliche Bedeutung beigemessen habe.Beruflich ist der Patient vornehmlich als freier Außendienstmitarbeiter mit dem Auto unterwegs oder am heimischen Schreibtisch tätig. Sportliche Aktivitäten werden verneint, dafür werden ca. zehn Zigaretten am Tag geraucht.     

Preformed donor-reactive T cells that persist after ABO desensitization predict severe T cell-mediated rejection after living donor kidney transplantation – a retrospective study

Preformed donor-reactive T cells are relatively resistant to standard immunosuppression and account for an increased incidence of T cell-mediated rejection (TCMR) and inferior kidney allograft outcomes. We analyzed 150 living donor kidney transplant recipients (KTRs) of a first kidney allograft. Ninety-eight ABO-compatible (ABOc) and 52 ABO-incompatible (ABOi) KTRs were included. Samples were collected at 6 time points, before rituximab, before immunoadsorption and pretransplantation, at +1, +2, and +3 months posttransplantation, and donor-reactive T cells were measured by interferon-γ ELISPOT assay. Twenty of 98 ABOc (20%) and 12 of 52 ABOi KTRs (23%) showed positive pretransplant ELISPOT. Eight of 20 ABOc-KTRs (40%) with positive pretransplant ELISPOT showed TCMR, whereas 17 of 78 ABOc-KTRs (22%) with negative pretransplant ELISPOT did (P = 0.148). Seven of 12 ABOi KTRs (57%) with positive pretransplant ELISPOT showed TCMR, whereas only 3 of 40 ABOi KTRs (8%) with negative pretransplant ELISPOT did (P < 0.001). Interestingly, 6 of 7 ABOi KTRs with positive pretransplant ELISPOT that persists after ABO desensitization developed TCMR. Among 118 KTRs with negative pretransplant ELISPOT, 10 of 72 ABOc-KTRs (14%), but 0 of 46 ABOi KTRs, developed positive posttransplant ELISPOT (P = 0.006). Preformed donor-reactive T cells that persist despite ABO desensitization identify KTRs at highest risk of TCMR. Less de-novo donor-reactive T cells after ABO desensitization may account for less TCMR. Both, the use of rituximab and early initiation of calcineurin inhibitor-based maintenance immunosuppression may contribute to these findings.     

Adult inguinoscrotal sarcomas: outcome analysis of 21 cases,systematic review of the literature and meta-analysis

Purpose

Inguinoscrotal sarcomas are exceedingly rare tumors. The aim of this study was to enable clinicians an easy and rapid access to the available information on this tumor entity.

Methods

An updated series of 21 men treated for sarcoma of the inguinoscrotal region at our institution between 1992 and 2012 was analyzed, and a systematic review of the literature with meta-analysis of outcome data was performed. The review was focused on demographic data, survival rates, prognostic factors, sites of relapse and complete remissions or successful treatments for metastatic disease.

Results

With only 38 %, the proportion of high-grade tumors in our sample was lower than reported in the literature and the 10-year relapse-free, disease-specific and overall survival rates were favorable with 77, 93 and 81 %. Beside our series, twelve studies including 345 patients were identified in the literature. The weighed mean 10-year relapse-free, disease-specific and overall survival rates were 63, 64 and 50 %. Only in patients with rhabdomyosarcoma, durable control of metastatic disease has been reported in more than one case (n = 4). Successful treatment in these cases consisted of a combination of complete surgical resection of metastatic lesions, subsequent chemotherapy and (optional) radiotherapy.

Conclusions

Overall, about two-thirds of inguinoscrotal sarcomas may be cured. In series with a predominance of low-grade tumors, the long-term survival rates in completely excised inguinoscrotal sarcomas may be as favorable as in testicular germ cell tumors. Life-long surveillance is advisable to detect late recurrences.