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.     

Development of the area centralis and visual streak in the grey kangaroo Macropus fuliginosus

To further our understanding of area centralis and visual streak formation we have investigated the distribution and number of the total cell population in the retinal ganglion cell layer of the western grey kangaroo Macropus fuliginosus using adults and young from 7-200 days postnatal. This species was chosen since, as we describe, the adult possesses a particularly prominent area centralis and visual streak. By studying the total cell population we were able to compare cell distributions in immature retinae, in which cell types could not be distinguished, with topography in the adult. By 57 days postnatal a weak visual streak was apparent; a pronounced area centralis and visual streak were seen by 84 days although densities across the retina, particularly in the far periphery, were still considerably higher than in the adult. Dying cells were also observed up to 160 days, but not at 188 days or in the adult. The fall of approximately one third in the total cell number as the area centralis and visual streak developed is presumably related to cell death. Furthermore, at 57 days, dying cells were seen preferentially in retinal regions outside the immature visual streak and may therefore play a part in refining density gradients to their mature form. As the area centralis and visual streak developed, the relative lengths of the dorso-ventral and naso-temporal axes remained similar, suggesting that differential radial growth cannot underlie the changing live cell density gradients.     

Unrecognized staphylococcal pyarthrosis with rheumatoid arthritis

Four patients whose rheumatoid arthritis (RA) was complicated by staphylococcal arthritis were identified. All patients had active, long-standing disease with destructive changes. Affected joints included hip (two patients), knee (one patient), and shoulder (one patient). Pain and loss of motion in the affected joint were prominent, but toxic features of pyogenic infections--hectic fever, chills, sweats, local warmth, or erythema--were conspicuously absent. Two patients had moderate fever and three patients had mild leukocytosis. No patient was leukopenic. When present, fever was attributed to infected decubiti or urinary tract infection and treated with antibiotics. Therapy with corticosteroids and nonsteroidal antiinflammatory drugs (NSAIDs) probably masked symptoms and delayed the correct diagnosis. Purulent synovial effusions were discovered serendipitously--during arthrography (knee), attempted Girdlestone procedure (hip), and aspiration prior to steroid injection (shoulder). Sepsis was included in the preoperative diagnoses only once (hip). Prior instrumentation (aspiration or injection) of the affected joint was not a feature in any patients, although one patient had undergone insertion of a knee prosthesis one year prior to sepsis. Infectious organisms were Staphylococcus aureus in three patients and Staphylococcus epidermidis in one. Severe sequelae ensued in three of four patients: death from recurrent sepsis (one patient), loss of prosthesis leading to knee arthrodesis (one patient), and protracted sepsis with additional pyarthrosis (one patient). The only patient to regain preseptic joint function (shoulder) had not been on long-standing corticosteroids. Pyarthrosis must be considered in RA patients with unusually painful or stiff joints even in the absence of toxic symptoms.     

A Novel In Vitro Culture Model System to Study Merkel Cell Polyomavirus–Associated MCC Using Three-Dimensional Organotypic Raft Equivalents of Human Skin

Merkel cell polyomavirus (MCPyV) is a human polyomavirus causally linked to the development of Merkel cell carcinoma (MCC), an aggressive malignancy that largely arises within the dermis of the skin. In this study, we recapitulate the histopathology of human MCC tumors in vitro using an organotypic (raft) culture system that is traditionally used to recapitulate the dermal and epidermal equivalents of skin in three dimensions (3D). In the optimal culture condition, MCPyV+ MCC cells were embedded in collagen between the epidermal equivalent comprising human keratinocytes and a dermal equivalent containing fibroblasts, resulting in MCC-like lesions arising within the dermal equivalent. The presence and organization of MCC cells within these dermal lesions were characterized through biomarker analyses. Interestingly, co-culture of MCPyV+ MCC together with keratinocytes specifically within the epidermal equivalent of the raft did not reproduce human MCC morphology, nor were any keratinocytes necessary for MCC-like lesions to develop in the dermal equivalent. This 3D tissue culture system provides a novel in vitro platform for studying the role of MCPyV T antigens in MCC oncogenesis, identifying additional factors involved in this process, and for screening potential MCPyV+ MCC therapeutic strategies.     

Rheumatoid vasculitis: Experience with 13 patients and review of the literature

Rheumatoid vasculitis is an uncommon but potentially catastrophic complication of RA. There are few current extensive experiences and no consensus regarding the clinical, laboratory, histologic features, and management or prognosis of rheumatoid vasculitis. We therefore reviewed selected observations in 13 patients followed over the past decade and compared them with patients reported and with results of a survey of North American Rheumatologists. Our patients were seven men and six women (age, 33 to 70 years) who had had active RA for 4 to 36 years. They exhibited sensory neuropathy, mononeuritis multiplex, Felty syndrome, cutaneous lesions, leg ulcers, gangrene, anemia, leukocytosis, eosinophilia, high titers of RF, hypocomplementemia, and CICs or cryoglobulinemia approximately as frequently as other reported patients with rheumatoid vasculitis, but they displayed constitutional symptoms, subcutaneous nodules, ischemic changes, and proteinuria rather less consistently than in other series. These observations were not necessarily as expected by survey respondents. We, as in other series and suggested by survey respondents, tended to select penicillamine or cytotoxic drugs (or plasmapheresis) for patients with mononeuritis, gangrene, or leg ulcers, and nonsteroidal antiinflammatory drugs, antimalarials, gold, or penicillamine for sensory neuropathy or digital lesions. Four patients died, two deteriorated, and seven were stable or improved, a finding that was also similar to the experiences of others. Rheumatoid vasculitis is an uncommon, potentially catastrophic syndrome with varying clinico-pathologic features that have different prognostic implications and should be managed individually.     

A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1.

BACKGROUND: Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of extracellular matrix, and in the progression of some epithelial cancers. Here, we establish the clinical significance of matriptase and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), during the progression of human prostate cancer (CaP). METHODS: The expression patterns of matriptase and HAI-1 were determined in primary cultures of normal human prostate epithelial (NHPE) cells, human CaP cells LNCaP, DU-145, CWR22Rnu1, and PC-3, and in tissue samples of 172 patients with normal prostate, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and adenocarcinoma of different tumor grades. RESULTS: The protein and mRNA levels of matriptase were significantly higher in all carcinoma cells as compared with NHPE cells. Conversely, all CaP cells exhibited a reduced expression of HAI-1 as compared with NHPE cells. A progressive increase in the protein levels of matriptase was observed with increasing tumor grade in CaP specimens as compared with normal and BPH tissue specimens. Tissue samples of normal prostate exhibited a high constitutive protein level of HAI-1 compared with BPH and low-grade cancer with a progressive loss with increasing tumor grade. CONCLUSION: The increased expression of matriptase and loss of HAI-1 may be an important event during the progression of CaP in humans. We suggest that the ratio of these two gene products may serve as a promising biomarker for CaP progression and a potential marker for establishing the efficacy of therapeutic and chemopreventive interventions.     

An unexpected amide bond cleavage: poly (ethylene glycol) transport forms of vancomycin. 2

PEG-amide vancomycin derivatives (V(3) position) have been synthesized and found to behave as prodrugs in vivo, demonstrating anti-microbial activity in mice when challenged with Staphylococcus aureus. The corresponding PEG-carbamate derivatives do not manifest this in vivo activity, although both classes of compounds have similar in vitro rat plasma stability. Thus, it appears that extra vascular cleavage of the amide bond can occur if the condition of extended circulation of the conjugate is met, resulting in the release of vancomycin.     

Relationship between hypochondriacal concerns and personality dimensions and traits in a military population

Our aim was to examine the relationship between personality dimensions and hypochondriacal concerns and somatic symptoms in a military population. The Schedule of Nonadaptive and Adaptive Personality along with measures of hypochondriacal concerns and somatic symptoms were administered to 602 military veterans who had been on active duty during the 1991 Gulf War. Factor analyses identified six separable dimensions-two of hypochondriacal concerns, two of somatic symptoms, and two of possible mechanisms of symptom generation-for study. Multiple regression models determined the proportion of variation in these measures of somatic distress explained by personality scales. Personality measures explained between 26% and 38% of the variance in hypochondriacal concerns and somatic symptoms, and Negative Temperament accounted for most of this. Moderately strong positive correlations were observed between trait scales Mistrust, Low Self-Esteem, and Eccentric Perceptions and the various measures of somatic distress. Thus, when Negative Temperament was taken into account, few significant correlations between personality measures and hypochondriacal concerns or somatic symptoms remained. Negative temperament or neuroticism is strongly associated with hypochondriacal concerns. Important features of hypochondriasis and somatic distress appear to lie within the domain of personality. It remains for future research to show whether negative temperament is a vulnerability factor for hypochondriasis or hypochondriasis is itself a personality disorder.