Coexisting carcinoid tumors in familial adenomatous polyposis-associated upper intestinal adenomas.

Upper gastrointestinal polyps and extraintestinal tumors are well recognized in association with familial adenomatous polyposis (FAP). Although carcinoid tumors have been reported in association with sporadic colonic neoplasms and ulcerative colitis, to date, carcinoids have not been reported in association with FAP. We report a patient with FAP who has recurrent carcinoid tumors located at the bases of duodenal adenomas. The genetic basis of carcinoid neoplasms is still uncertain. This report may represent the clinical effect of the APC gene mutation on the enterochromaffin cell line manifesting as recurrent carcinoid tumors in physical association with intestinal adenomas. Future genetic analysis and epidemiological studies may be of value in determining whether a true association exists.

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

Duplication 14(q31----qter).

A 29 year old black female with delayed development and multiple congenital anomalies showing a duplication of 14(q31----qter) is presented. Although clinical features associated with partial duplication of the distal long arm of chromosome 14 are variable, there are some features which are distinctive of this chromosomal abnormality. The clinical findings of 14 cases with duplication distal 14q are compared in an effort to define a recognisable syndrome.

Surgical management of primary motor disorders of the esophagus.

Primary motor disorders of the esophagus can be managed surgically with excellent results. Between the years 1972 and 1983, 40 patients were managed by us. The patients ranged in age from 14 to 79 years (mean 36.3 years). Thirty-six patients were managed primarily by the authors and 4 patients secondarily. The distribution of the hypodynamic states were achalasia in 29 patients, vigorous achalasia in 5 patients, and diffuse spasm in 1 patient, whereas the hyperdynamic states were squeeze syndrome in 2 patients, super-squeeze syndrome in 1 patient, and hypertensive lower esophageal sphincter in 2 patients. Of the 36 patients in hypodynamic states, 27 had a modified Heller myotomy and reconstruction of the gastroesophageal junction with a Belsey fundoplication and 9 had only a modified Heller myotomy. There was only one patient with reflux esophagitis. It occurred after myotomy and Belsey fundoplication for a hypertensive lower esophageal sphincter and hiatus hernia. Four patients were managed secondarily for complicated recurrent problems, one with a Belsey fundoplication and three with a jejunal interposition graft. We recommend myotomy, with or without a Belsey fundoplication, for management of primary motor disorders and avoidance of total Nissen fundoplication and a lengthening Collis gastroplasty.