Invited commentary: Are specific inherited mutations important in clinical management of hereditary cancer syndromes?
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Hirschsprung Disease↗
Biomedical subjects
Jeffrey F Moley
Publications and source records attributed to Jeffrey F Moley.
Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors.
BACKGROUND: Most medullary thyroid carcinomas (MTCs) result from gain-of-function mutations in the RET proto-oncogene, which encodes a transmembrane tyrosine kinase receptor. Systemic therapies have not been effective in treating this disease. We evaluated the effects of 3 tyrosine kinase inhibitors (TKIs) on MTC cell growth and RET tyrosine kinase activity by using an in vitro model. METHODS: An MTC cell line (TT cells, RETc634 mutant) cultured in RPMI medium was exposed to varying concentrations of STI571, genistein, or allyl-geldanamycin with controls (no TKI) for 3 to 48 hours. Cellular protein was analyzed by immunoprecipitated Western blot analysis probing with a monoclonal antiphosphotyrosine antibody. Cell proliferation was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays. RESULTS: RET phosphorylation was inhibited at 24 hours of exposure to 5 to 20 micromol/L STI571 and 48 hours of exposure to genistein (200 micromol/L) and allyl-geldanamycin (6 micromol/L). RET protein was detected in equal concentrations in all experimental conditions. MTT and BrdU assays demonstrated a dose-dependent decrease in TT cell proliferation with exposure to the 3 TKIs. CONCLUSIONS: These TKIs selectively inhibit cell growth and RET tyrosine kinase activity of MTC cells in vitro in a dose manner. This study suggests the use of TKIs in human trials as a systemic therapy for MTC.
Benzamides↗
Gastrointestinal manifestations of multiple endocrine neoplasia type 2.
OBJECTIVE: To determine the clinical features, natural history, and role of surgery for gastrointestinal manifestations of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. SUMMARY BACKGROUND DATA: The MEN 2 syndromes are characterized by medullary thyroid carcinoma and other endocrinopathies. In addition, some patients with MEN 2A develop Hirschsprung's disease (HD), and all patients with MEN 2B have intestinal neuromas and megacolon that can cause significant gastrointestinal problems. METHODS: From 83 families with MEN 2A, eight patients with HD were identified (MEN 2A-HD). These and all patients with MEN 2B followed at the authors' institution (n = 53) were sent questionnaires to describe the onset and type of gastrointestinal symptoms and treatment they had before the diagnosis of MEN 2. Records of all patients responding were reviewed, including radiographic imaging, histology, surgical records, and genetic testing. RESULTS: Thirty-six of the 61 patients (59%) responded (MEN 2A = 8, MEN 2B = 28) to the questionnaires. All patients with MEN 2A-HD were operated on for HD 2 to 63 years before being diagnosed with MEN 2. All patients responding were underweight as infants and had symptoms of abdominal pain, distention, and constipation. Eighty-eight percent had hematochezia, 63% had emesis, and 33% had intermittent diarrhea before surgery. All patients with MEN 2A-HD had rectal biopsies with a diverting colostomy as the initial surgical procedure. This was followed by a colostomy takedown and pull-through procedure at a later interval. Ninety-three percent of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), and vomiting (14%). Seventy-one percent of patients with MEN-2B with gastrointestinal symptoms had radiographic imaging, 32% were admitted to the hospital, and 29% underwent surgery. CONCLUSIONS: Patients with MEN 2A-HD had a typical HD presentation and always required surgery. Patients with MEN 2B have significant gastrointestinal symptoms, but less than a third had surgical intervention. Understanding the clinical course and differences in these patients will improve clinical management.
Adolescent↗
Adrenalectomy for familial pheochromocytoma in the laparoscopic era.
OBJECTIVE: To report the results of treatment of patients with familial pheochromocytomas in the laparoscopic era. SUMMARY BACKGROUND DATA: The optimal surgical management of pheochromocytomas that arise in familial neoplasia syndromes may be complicated by bilateral involvement and associated endocrinopathies. METHODS: Twenty-one patients with familial pheochromocytomas (15 with multiple endocrine neoplasia [MEN] 2A, 4 with MEN 2B, 1 each with von Hippel-Lindau and neurofibromatosis type 1) underwent adrenalectomy between December 1993 and July 2001. Clinical, biochemical, and pathologic data were obtained by retrospective review of perioperative medical records, postoperative biochemical testing, and patient questionnaire. RESULTS: Mean age at diagnosis was 37 +/- 11 years. Twenty of the 21 patients had elevated urine catecholamines, and all had radiographic evidence of an adrenal tumor or tumors. Pheochromocytoma-related symptoms were present in 11 patients (52%). One patient with MEN 2B underwent open adrenalectomy due to previous adrenal surgery and megacolon. Laparoscopic adrenalectomy was attempted in the remaining 20 patients (9 right, 11 left, 2 bilateral). Two patients (9.1%) were converted to open adrenalectomy. Intraoperative hypertensive episodes occurred in 15 patients (71%) and were easily controlled medically. Mean operative time was 216 +/- 57 minutes, mean postoperative length of stay was 3.1 +/- 1.3 days, and mean tumor size was 3.1 +/- 1.0 cm. Minor complications occurred in three patients (14.3%) and major complications in two patients (9.5%). During a mean follow-up of 57 months, a contralateral pheochromocytoma developed in four patients with MEN 2 (33%); three of them underwent adrenalectomy. There have been no long-term complications related to hypertension or adrenalectomy. CONCLUSIONS: This study is the largest series of patients with familial pheochromocytoma undergoing adrenalectomy during the laparoscopic era. The results suggest that the laparoscopic approach is safe and effective for managing unilateral or bilateral adrenal medullary disease in this population.
Adrenal Gland Neoplasms↗
Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators.
The recent identification of several additional members of the family of sugar transport facilitators (gene symbol SLC2A, protein symbol GLUT) has created a heterogeneous and, in part, confusing nomenclature. Therefore, this letter provides a summary of the family members and suggests a systematic nomenclature for SLC2A and GLUT symbols.
Monosaccharide Transport Proteins↗