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.     

Characteristics of the delayed rectifier K current compared in myocytes isolated from the atrioventricular node and ventricle of the rabbit heart

The delayed rectifier potassium current (I _K) is known to be important in action potential repolarisation and may contribute to the diastolic pacemaker depolarisation in pacemaker cells from the heart. In this study, using whole-cell patch clamp, we investigated the characteristics of I _K in morphologically normal cells from the atrioventricular node (AVN) and ventricle of the rabbit heart. Cells were held at −40 mV and 5 μM external nifedipine was used to block L-type calcium current (I _Ca,L). Significant I _K was observed with pulses to potentials more positive than −30 mV. The steady-state activation curve in both cell types showed maximal activation at between + 10 and + 20 mV. Half-maximal activation of I _K occurred at −4.9 and −4.1 mV with slope factors of 8.3 and 12.4 mV in ventricular and AVN cells, respectively. Using pulses of increasing duration, significant I _K tails after repolarisation from + 40 mV were observed with pulses of 20 ms and increased with pulses up to 100–120 ms in both cell types. Pulses of longer duration did not activate further I _K and this suggested that only the rapid component of I _K, called I _Kr, was present in either cell type. Moreover, I _K tails after pulses to all potentials were blocked completely by E-4031, a selective blocker of I _Kr. The reversal potential of I _K varied with the concentration of external K. Superfusion of AVN cells with medium containing 4, 15 and 40 mM [K⁺]_o resulted in reversal potentials of −81, −56 and −32 mV, respectively, which are close to values predicted if the I _K channel were highly selective for K. The time constants for deactivation of I _K in ventricle and AVN on return to −40 mV after a 500-ms activating pulse to + 60 mV were 480 ms and 230 ms, respectively. The faster deactivation of I _K in AVN cells was a distinguishing feature and suggests that there may be differences in the I _Kr channel protein between ventricular and AVN cells. Received: 24 July 1995 /Received after revision: 20 October 1995 /Accepted: 23 October 1995     

The hyperpolarisation-activated current,I f,is not required for pacemaking in single cells from the rabbit atrioventricular node

Using electrophysiological and radiotracer studies in parallel, we have investigated the characteristics of the endogenous Na⁺-dependent amino acid transporter (system B^0,+) in Xenopus oocytes with regard to ion dependence, voltage dependence and transport stoichiometry. In voltage-clamped oocytes (–60 mV) superfusion with saturating concentrations of amino acids (1 mM) in 100 mM NaCl resulted in reversible, inward currents (mean±SEM): alanine, 1.83±0.09 nA (n=21); arginine, 2.54±0.18 nA (n=17); glutamine, 1.73±0.10 nA (n=19). Only arginine evoked a current in choline medium (0.50±0.13 nA, n=10), whereas Cl^– replacement had no effect on evoked currents. The glutamine-evoked current was saturable (I _max=1.73 nA, glutamine K _m=0.12 mM) and linearly dependent upon voltage between –90 and –30 mV. Using direct and indirect (activation) methods, we found that transport can proceed with Na⁺/amino acid coupling stoichiometry of either 11 or 21, but coupling was the same for each amino acid tested (alanine, arginine and glutamine) within a batch of oocytes (i.e. from a single toad). Despite the net single positive charge on arginine, the magnitude of the net transmembrane charge movement during Na⁺-coupled arginine transport was identical to that for the zwitterionic neutral amino acids glutamine and alanine; this may be explained by a concomitant stimulation of K⁺ efflux during arginine transport with a putative coupling of 1 K⁺1 arginine.     

The tissue microarray data exchange specification: A community-based,open source tool for sharing tissue microarray data

Background  

Tissue Microarrays (TMAs) allow researchers to examine hundreds of small tissue samples on a single glass slide. The information held in a single TMA slide may easily involve Gigabytes of data. To benefit from TMA technology, the scientific community needs an open source TMA data exchange specification that will convey all of the data in a TMA experiment in a format that is understandable to both humans and computers. A data exchange specification for TMAs allows researchers to submit their data to journals and to public data repositories and to share or merge data from different laboratories. In May 2001, the Association of Pathology Informatics (API) hosted the first in a series of four workshops, co-sponsored by the National Cancer Institute, to develop an open, community-supported TMA data exchange specification.     

Effect of Down syndrome on the dimensions of dental crowns and tissues

Abnormal growth in Down syndrome (DS) is reflected by variable reduction in size and simplification in form of many physical traits. This study aimed to compare the thickness of enamel and dentine in deciduous and permanent mandibular incisor teeth between DS and non‐DS individuals and to clarify how these tissues contribute to altered tooth size in DS. Sample groups comprised 61 mandibular incisors (29 permanent and 32 deciduous) from DS individuals and 55 mandibular incisors (29 permanent and 26 deciduous) from non‐DS individuals. Maximum mesiodistal and labiolingual crown dimensions were measured initially, then the crowns were sectioned midsagittally and photographed using a stereomicroscope. Linear measurements of enamel and dentine thickness were obtained on the labial and lingual surfaces of the crowns, together with enamel and dentine–pulp areas and lengths of the dentino‐enamel junction. Reduced permanent crown size in DS was associated with a reduction in both enamel and dentine thickness. After adjustments were made for tooth size, DS permanent incisors had significantly thinner enamel than non‐DS permanent teeth. The DS permanent teeth also exhibited significant differences in shape and greater variability in dimensions than the non‐DS permanent teeth. Crown dimensions of deciduous incisors were similar in size or larger in DS compared with non‐DS deciduous teeth. Enamel and dentine thicknesses of the deciduous teeth were similar in DS and non‐DS individuals. The findings indicate that growth retardation in DS reduces both enamel and dentine deposition in the permanent incisors but not in the earlier‐forming deciduous predecessors. The results are also consistent with the concept of amplified developmental instability for dental traits in DS. Am. J. Hum. Biol. 13:690–698, 2001. © 2001 Wiley‐Liss, Inc.     

Prevalence and burden of bipolar disorders in European countries.

A literature search, supplemented by an expert survey and selected reanalyses of existing data from epidemiological studies was performed to determine the prevalence and associated burden of bipolar I and II disorder in EU countries. Only studies using established diagnostic instruments based on DSM-III-R or DSM-IV, or ICD-10 criteria were considered. Fourteen studies from a total of 10 countries were identified. The majority of studies reported 12-month estimates of approximately 1% (range 0.5-1.1%), with little evidence of a gender difference. The cumulative lifetime incidence (two prospective-longitudinal studies) is slightly higher (1.5-2%); and when the wider range of bipolar spectrum disorders is considered estimates increased to approximately 6%. Few studies have reported separate estimates for bipolar I and II disorders. Age of first onset of bipolar disorder is most frequently reported in late adolescence and early adulthood. A high degree of concurrent and sequential comorbidity with other mental disorders and physical illnesses is common. Most studies suggest equally high or even higher levels of impairments and disabilities of bipolar disorders as compared to major depression and schizophrenia. Few data are available on treatment and health care utilization.     

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.     

Re-emergence of Posttraumatic Stress Disorder Nightmares With Nursing Home Admission: Treatment With Prazosin

Seniors with a history of emotional trauma decades earlier can experience a recurrence of posttraumatic stress disorder symptoms when transitioning to a nursing home. We present the case of an 86-year-old male Holocaust survivor admitted to a nursing home for physical therapy and rehabilitation 6 weeks after the death of his wife; the patient was expressing a persistent death wish. Despite the multiple risk factors for depression, his distress was specifically related to the reemergence of nightly posttraumatic nightmares. Over the course of 1 week of treatment with 1 mg prazosin at bedtime, his nightmares and his death wish completely resolved. He achieved his rehabilitation goals and was discharged to a community setting. This report highlights the importance of considering posttraumatic stress disorder in nursing home residents with a history of emotional trauma, and understanding how to address these symptoms pharmacologically and nonpharmacologically.