Diagnosis of gastrointestinal stromal tumors: A consensus approach

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease

There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. It was therefore of interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal fluid and peripheral blood of women undergoing laparoscopic procedures. The presence and concentrations of IL-8 in relation to endometriosis, infertility and abdominal pain were evaluated. Samples of peritoneal fluid (n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive patients undergoing laparoscopic surgery for various gynaecological indications (abdominal pain, infertility, sterilization). IL-8 was present in the peritoneal fluid of most women (87%). The concentration of IL-8 in the peritoneal fluid was higher in women with endometriosis compared to women without (P = 0.02). This difference was more pronounced in early (stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal fluid were also higher in women with early endometriosis compared to women with later stages of the disease (P = 0.003). Peripheral blood concentrations did not correlate with peritoneal fluid concentrations of IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an important factor that may contribute to the pathogenesis of endometriosis possibly by promoting neovascularization. This information can be a guide in the development of new therapeutic approaches for the treatment of endometriosis.      

The Turner syndrome research registry: Creating equipoise between investigators and participants

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient‐powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33‐item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side‐by‐side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.     

Trichosporon beigelii, an emerging pathogen resistant to amphotericin B.

Trichosporon beigelii caused fatal disseminated infections that were resistant to amphotericin B in two granulocytopenic patients. In vitro susceptibility studies demonstrated that both index strains of T. beigelii were inhibited but not killed by amphotericin B at achievable concentrations in serum. The minimum lethal concentration for both isolates was greater than or equal to 18 micrograms/ml. Five of seven other isolates were found to have a similar pattern of amphotericin B resistance. The fact that the minimum lethal concentration of T. beigelii was many times greater than its MIC was consistent with a resistance pattern of tolerance. We concluded that T. beigelii may be resistant in vitro to amphotericin B and that this in vitro resistance was correlated with refractory, disseminated trichosporonosis in granulocytopenic patients. T. beigelii should be included in the expanding list of amphotericin B-resistant fungi.     

Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.     

Mapping cis-regulatory domains in the human genome using multi-species conservation of synteny

Our inability to associate distant regulatory elements with the genes they regulate has largely precluded their examination for sequence alterations contributing to human disease. One major obstacle is the large genomic space surrounding targeted genes in which such elements could potentially reside. In order to delineate gene regulatory boundaries, we used whole-genome human-mouse-chicken (HMC) and human-mouse-frog (HMF) multiple alignments to compile conserved blocks of synteny (CBSs), under the hypothesis that these blocks have been kept intact throughout evolution at least in part by the requirement of regulatory elements to stay linked to the genes they regulate. A total of 2116 and 1942 CBSs >200 kb were assembled for HMC and HMF, respectively, encompassing 1.53 and 0.86 Gb of human sequence. To support the existence of complex long-range regulatory domains within these CBSs, we analyzed the prevalence and distribution of chromosomal aberrations leading to position effects (disruption of a gene's regulatory environment), observing a clear bias not only for mapping onto CBS but also for longer CBS size. Our results provide an extensive data set characterizing the regulatory domains of genes and the conserved regulatory elements within them.     

Studies on the adsorbability of graft-versus-host-reactive lymphocytes

A certain proportion of normal lymphoid cells from organs of different anatomical origin can react against allogeneic histocompatibility antigens, e.g. they can mediate a graft-versus-host (GVH) reaction. The present study was undertaken in order to obtain information about the antigen-specific receptors on GVH-reactive lymphocytes. We used fibroblast monolayers as cellular immunoadsorbents.

The results showed that with the methods employed we could not adsorb specifically GVH-reactive lymphocytes in a reproducible way, irrespective of whether these cells were from normal lymphoid organs like spleen, lymph nodes, thymus and bone marrow, from artificial sources like thymus and spleen of anti-thymocyte antiserum treated mice or from spleens of semi-allogeneic, irradiated, thymocyte-reconstituted mice. The most pronounced effect of adsorption on fibroblast monolayers on normal lymphocytes was a non-specific enhancement of their GVH potential.

These findings are discussed on the basis of recent results showing both syner-gistic and antagonistic effects of T-lymphocyte subpopulations.

     

The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching

To determine the effects of creatine supplementation during short-term resistance training overreaching on performance, body composition, and resting hormone concentrations, 17 men were randomly assigned to supplement with 0.3 g/kg per day of creatine monohydrate (CrM: n=9) or placebo (P: n=8) while performing resistance exercise (5 days/week for 4 weeks) followed by a 2-week taper phase. Maximal squat and bench press and explosive power in the bench press were reduced during the initial weeks of training in P but not CrM. Explosive power in the bench press, body mass, and lean body mass (LBM) in the legs were augmented to a greater extent in CrM (P0.05) by the end of the 6-week period. A tendency for greater 1-RM squat improvement (P=0.09) was also observed in CrM. Total testosterone (TT) and the free androgen index (TT/SHBG) decreased in CrM and P, reaching a nadir at week 3, whereas sex hormone binding globulin (SHBG) responded in an opposite direction. Cortisol significantly increased after week 1 in CrM (+29%), and returned to baseline at week 2. Insulin was significantly depressed at week 1 (–24%) and drifted back toward baseline during weeks 2–4. Growth hormone and IGF-I levels were not affected. Therefore, some measures of muscular performance and body composition are enhanced to a greater extent following the rebound phase of short-term resistance training overreaching with creatine supplementation and these changes are not related to changes in circulating hormone concentrations obtained in the resting, postabsorptive state. In addition, creatine supplementation appears to be effective for maintaining muscular performance during the initial phase of high-volume resistance training overreaching that otherwise results in small performance decrements.