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Background Activating mutations of the tyrosine kinase receptor KIT have been described in both mastocytosis and gastrointestinal stromal tumors (GIST), but are usually found in separate domains and often respond differently to signal transduction inhibitors. We describe here a large family with both GIST, mastocytosis, and achalasia. Affected family members have a unique activating mutation in exon 9 of KIT which show promise to a novel signal transduction inhibitor. Methods Clinical data was collected from 15 family members, 7 of whom were variably affected with GIST, achalasia and mastocytosis. DNA was prepared from WBC of 12 subjects (6 affected and 6 unaffected) and exons 9, 11, 13 and 17 of KIT were amplified by PCR and directly sequenced. Results A unique activating single base pair mutation in the extracellular domain of KIT was found in all 6 affected subjects resulting in a K>I amino acid change at codon 509. Conclusions In the family reported here, a unique mutation in the extracellular domain leads to receptor activation resulting in GIST and mastocytosis as well as achalasia. Initial data suggests that this activation can be suppressed by signal transduction inhibitors and these patients may benefit from such therapy.

Cytogenetic analysis is of value in predicting clinical outcome of pediatric cases of acute lymphoblastic leukemia (ALL). Hyperdiploidy in these patients has significant impact on therapeutic outcome. Because of the technologic limitations of cytogenetic analysis in determining hyperdiploidy in some of these cases, we devised a method to analyze cytogenetically fixed material for cellular DNA content by standard flow cytometric methods. This technique greatly enhances out ability to interpret the observance of single cell anomalies and assess whether these cells are predictive of clonal stemlines or are a result of random events.

Objective To determine whether there has been a demonstrable increase in the prevalence of human papillomavirus (HPV)–infected palatine tonsils corresponding to the increase in incidence of HPV-positive oropharyngeal squamous cell carcinoma (SCC) over time. Design Review of archived, paraffin-embedded, noncancerous palatine tonsils. Setting A single institution in El Paso County, Colorado. Patients Age- and sex-matched patients 21 years and older from 2 different periods: January 1, 1979, to December 31, 1982, (group A) and January 1, 1997, to December 31, 2001 (group B). Main Outcome Measures Prevalence of oncogenic HPV-16 and HPV-18 in noncancerous palatine tonsils in relation to the incidence of HPV-positive oropharyngeal SCC. Results All specimens in both groups were negative for HPV-16 and HPV-18. Thus, the prevalence of HPV infection in the palatine tonsils of the general adult population was zero in both group A and group B. Conclusions This analysis shows a low prevalence of HPV infection in the palatine tonsils of the general adult population in a single county in Colorado known to have an increasing rate of HPV-positive oropharyngeal SCC. Analysis of oropharyngeal tissues from individuals at highest risk of developing HPV-positive oropharyngeal SCC (middle-aged men) is likely to provide a higher prevalence rate.

Fatal T-cell lymphomas developed in three patients with a chronic illness manifested by fever, pneumonia, dysgammaglobulinemia, hematologic abnormalities, and extraordinarily high titers of antibody to the Epstein-Barr virus (EBV) capsid antigen (greater than 10,000) and early antigen (greater than 640) but low titers to the EBV nuclear antigen (less than or equal to 40). To understand the pathogenesis of these tumors better, we determined the immunophenotype of the tumor cells and analyzed tumor-cell DNA for EBV genomes and for lymphoid-cell gene rearrangements. More than 80 percent of the cells in tumors had an activated helper T-cell phenotype (T4, T11, la positive). The EBV genome was found by in situ hybridization in tumor tissue from each patient. Southern blot assay of DNA digests from one patient showed the same pattern as that of the EBV-infected marmoset line, B95-8. DNA digests from two patients showed a monoclonal proliferation of T cells determined on the basis of uniform T-cell-receptor gene rearrangements and a single band for the joined termini of the EBV genome. We conclude that EBV may infect T cells and contribute to lymphomas in selected patients with severe EBV infections.