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.     

Transfer of the active form of transforming growth factor-beta 1 gene to newborn rat lung induces changes consistent with bronchopulmonary dysplasia

Bronchopulmonary dysplasia is a chronic lung disease of premature human infancy that shows pathological features comprising varying sized areas of interstitial fibrosis in association with distorted large alveolar spaces. We have previously shown that transfer of active transforming growth factor (TGF)-beta 1 (AdTGF beta 1(223/225)) genes by adenovirus vector to embryonic lungs results in inhibition of branching morphogenesis and primitive peripheral lung development, whereas transfer to adult lungs results in progressive interstitial fibrosis. Herein we show that transfer of TGF-beta1 to newborn rat pups results in patchy areas of interstitial fibrosis developing throughout a period of 28 days after transfer. These areas of fibrosis appear alongside areas of enlarged alveolar spaces similar to the prealveoli seen at birth, suggesting that postnatal lung development and alveolarization has been inhibited. In rats treated with AdTGF beta 1(223/225), enlarged alveolar spaces were evident by day 21, and by 28 days, the mean alveolar cord length was nearly twice that in control vector or untreated rats. Hydroxyproline measurements confirmed the presence of fibrosis. These data suggest that overexpression of TGF-beta 1 during the critical period of postnatal rat lung alveolarization gives rise to pathological, biochemical, and morphological changes consistent with those seen in human bronchopulmonary dysplasia, thus inferring a pathogenic role for TGF-beta in this disorder.     

The role of fluid hydrostatic pressure in bone-implant interface load transfer

Permeability of the soft tissue-bone system surrounding artificial joints fixed in cancellous bone was measured in four adult dogs after implants had been in place 2 months. Fluid was forced through a cavity formed by removal of the implant, the cavity was capped with a stopper to allow for pressure generation. Surface permeability of the 2-month-old implant cavity was 45 times less than the permeability of freshly drilled holes in cancellous bone. A mathematical model of a rigid implant resting on a biphasic solid-fluid layer showed the fluid carried 90% of the load when the implant cavity permeability was assumed, but only 27% when the freshly drilled permeability was used. The results suggest caution in interpreting finite-element models with bonded interfaces and suggest a possible role of the fluid in biological response at the interface.     

Evaluation of Twenty-Three Blood Culture Media

Several investigators have evaluated clinically a variety of commercially available blood culture media. No agreement has been reached as to which of these media is optimal for detection of bacteremia. The purpose of this study was to determine the rate of recovery of microorganisms from various blood culture media. A total of 23 blood culture media were inoculated with 7 to 15 microorganisms per bottle in the presence or absence of an erythrocyte-serum mixture. The results demonstrated that blood culture media differed in their ability to support the growth of microorganisms. At 4 days after inoculation, only 10 of the 23 blood culture media supported the growth of 91% (10 of the 11) or more of the test microorganisms. The recovery rate of microorganisms depended not only upon the type of medium but also upon the manufacturer of the type of blood culture medium. The addition of an erythrocyte-serum mixture to the blood culture media did not influence the difference in the recovery rate of microorganisms among media and the same type of medium prepared by different manufacturers. The majority (15 of the 23) of the blood culture media supplemented with the erythrocyte-serum mixture failed to support the growth of 91% or more of the test microorganisms at 4 days after inoculation. These results have demonstrated that blood culture media need to be improved. Better quality control measures should also be implemented to evaluate commercial blood culture media.     

Further evidence for the vitality of chondrocytes in the mandibular condyle as revealed by 35S-sulfate autoradiography

Histochemical and autoradiographic studies using ³⁵S-sulfate indicate that the majority of the cartilage cells in the developing mandibular condyle of the young mouse are active, vital cells. Concomitant with the increase of hypoxic conditions within the deeper layers of the cartilage, an increase in sulfated glycosaminoglucuronoglycans synthesis takes place. Hypertrophic chon-drocytes in the premineralized and mineralized zones reveal marked ³⁵S-sulfate uptake in comparison with the less differentiated cells in the chondroblastic and perichondrial zones. These observations of radiosulfate activity support the concept that calcification processes in the condylar cartilage are not necessarily accompanied by degeneration and death of the hypertrophic chondrocytes. The radiosulfate activity of the surviving chondrocytes in the vicinity of the ossification front indicates possible modulation into osteoprogenitor cells.     

Genetic damage detected in CD-1 mouse pups exposed perinatally to 3'-azido-3'-deoxythymidine or dideoxyinosine via maternal dosing, nursing, and direct gavage: II. Effects of the individual agents compared to combination treatment

We previously reported extraordinary increases in micronucleated erythrocytes in CD-1 mouse pups exposed to 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI; 50/250, 75/375, 150/750 mg/kg/day AZT/ddI) by gavage throughout gestation and lactation, followed by direct pup dosing beginning postnatal day (PND) 4 (Bishop et al. [2004]: Environ Mol Mutagen 43: 3-9). That study was conducted to explore the potential for genetic damage in newborns exposed perinatally to antiretrovirals in order to reduce maternal-infant transmission of HIV-1. Because dramatic increases in frequencies of micronucleated erythrocytes were seen in exposed pups, additional studies were conducted to clarify the relative contribution of each drug to the observed damage. Pregnant CD-1 mice were administered AZT (50, 75, 150 mg/kg/day) or ddI (250, 375, 750 mg/kg/day) by gavage twice daily in equal fractions beginning prior to mating and continuing throughout gestation and lactation. Direct pup dosing (same regimens) began on PND 4. Peripheral blood erythrocytes of male pups were screened for micronuclei on PNDs 1, 4, 8, and 21. Significant increases in micronucleated erythrocytes were observed in pups and dams exposed to AZT at all doses and sampling times. The highest micronucleus levels were observed in pups on PND 8 after the initiation of direct dosing. In contrast, effects seen in pups and dams treated with ddI were minimal. These results demonstrate that AZT, a component of many anti-HIV combination therapies, induces chromosomal damage in perinatally exposed neonatal mice. Comparison of micronucleated cell frequencies induced by AZT alone or in combination with ddI suggests that ddI potentiates AZT-induced chromosomal damage following direct exposure.     

Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.