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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.

Objectives/Hypothesis: To document the increasing incidence of oropharyngeal (OP) cancer and to provide evidence that this increase is caused by oncogenic human papilloma virus (HPV). Study Design: Epidemiologic review and retrospective case series analysis. Methods: We collected data from Colorado and the United States comparing the average annual age-adjusted incidence rates of OP and non-OP head and neck cancer between the periods 1980 to 1990 and 1991 to 2001. We obtained data on 72 patients with OP cancer from a single county in Colorado, from 1980 through 2004. HPV status was determined by DNA-polymerase chain reaction. We assessed disease-specific survival. Results: The average annual age-adjusted incidence of OP cancer in males in Colorado increased from 2.54 per 100,000 to 3.47 (P < .05) or 36.6%, whereas the U.S. rate increased from 4.34 to 4.81 (P < .05) or 10.8%. The rates in females and the rates of non-OP head and neck cancer decreased. Of the 72 cases, 50 (69%) were positive for HPV subtype 16. The ratio of HPV-positive to HPV-negative cases prior to 1995 was 0.72 (8:11) but was 3.81 (42:11) afterward. Survival was positively affected by HPV status (hazard ratio of 0.15, confidence intervals 0.07–0.36, P < .001). Disease-specific survival was 83% in the HPV-positive patients and 15% in the HPV-negative group. Conclusions: OP cancer incidence is increasing in Colorado males and to a lesser extent in U.S. males. The HPV-positive OP cancer cases were more frequent in the later years of the study. Disease-specific survival was much better in the HPV-positive patients, confirming that HPV testing defines a unique subset of patients. These findings suggest that HPV oncogenesis accounts for the increase in average annual age-adjusted incidence of OP cancer.

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.

Evaluation of proteinuria in a 66-year-old white female detected the presence of two distinct anomalous proteins: a gamma heavy chain devoid of light chains and an intact IgM-lambda paraprotein. The gamma heavy chain protein was incomplete, antigenically corresponding to the Fc portion of the molecule. Subsequent diagnostic studies of the patient revealed the simultaneous presence of an adenocarcinoma of the colon and an extranodal well-differentiated lymphocytic lymphoma involving the lungs, pulmonary hilum, and upper gastrointestinal tract. Levels of the two paraproteins were unaltered by surgical excision of the colonic carcinoma but were reduced by chemotherapy directed at the lymphoma.

Thymectomized AKR mice, which have a low incidence of leukemia, show a high incidence when treated with rabbit antiserum against leukemic cells. The leukemia-promoting effect of normal rabbit serum and antiserum against non-leukemic cells is less than that of anti-leukemic cell serum. No clear leukemia-producing effect of antiserum was observed in mice over 500 days old. Antisera given to non-thymectomized mice, which have a high incidence of leukemia over a characteristic age-range, did not affect age of leukemia development. Anti-serum against leukemic cells reacted with purified Gross leukemia virus. It is suggested that leukemic transformation represents a response to immunological attack on the virus or against viral-associated cellular antigens, and that an additional age-dependent factor is required for leukemogenesis.

Attenuated total reflectance infrared spectra of films of vitamin D-egg lecithin mixtures show low frequency shifts for the vitamin -OH stretching and the [PO 2 − stretching absorption of the phospholipid. These shifts maximize at a 2 sterol:1 phospholipid ratio and appear to represent formation of a hydrogen-bonded complex of lecithin with vitamin D. Films of vitamin D trap nonpolar solvents, e.g. , carbon tetrachloride, but this phenomenon is not seen in phospholipid-vitamin D mixtures. The results are interpreted in terms of a possible interaction of vitamin D with phospholipids in cell membranes and the potential effects of such an interaction on calcium binding by membrane systems.

A case report of paraplegia secondary to a malignant B-cell lymphoma primary in the cauda equina is presented. Initial diagnosis was suggested on cytocentrifuge preparations of cerebrospinal fluid with subsequent tissue confirmation following bilateral laminectomy (T12-L3). Histologically, the tumor was a diffuse "histiocytic" lymphoma by Rappaport's or large noncleaved FCC lymphoma by Lukes and Collins classification. Immunologic studies typed the tumor as a B-cell neoplasm with lambda light chains. Following an extensive evaluation of the patient, the lymphoma was found to be limited to the lower spinal cord. Although radiotherapy was initiated there was no improvement of her neurological symptoms, and CSF cytology remains positive for rare malignant cells 2 months after diagnosis. A complete reevaluation at 3 months after laminectomy was negative for lymphoma involvement of other sites.

The purity of AKR murine leukemia virus obtained by isopycnic centrifugation was compared with the purity obtained by combining velocity sedimentation and isopycnic centrifugation methods. Evaluation of AKR and Rauscher viral purity by electron microscopy and by analysis of [ 3 H]uridine-labeled viral RNA demonstrated that the velocity centrifugation step is essential for the removal of contaminants banding in the viral density region (1.19 – 1.15 g/ml). For studies requiring relatively pure oncornavirus preparations, a combination of both velocity sedimentation and isopycnic centrifugation steps are suggested. Viral recovery of about 50% was obtained by the method described.

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.