Gary P. Lawton

Preservation of Muscle Fascia to Decrease Lymphedema after Complete Axillary and Ilioinguinofemoral Lymphadenectomy for Melanoma

BACKGROUND In patients with melanoma, there is considerable concern about the clearance of clinically negative nodes, partly because of the unacceptable morbidity reported after regional lymphadenectomy. The advent of sentinel lymph node biopsies has allowed us to select those patients with positive sentinel lymph nodes for completion node dissections. The purpose of this article is to demonstrate that when complete lymph node dissection is indicated, it can be performed with a low risk of lymphedema using the fascia-preserving technique. STUDY DESIGN The records of 209 consecutive patients with melanoma who underwent fascia-preserving axillary (n = 116) or ilioinguinofemoral (n = 93) lymphadenectomy by a single surgeon between January 1984 and April 1998 were reviewed. In each operation, care was taken not to disrupt the muscle fascia at the site of lymphadenectomy. RESULTS In the fascia-preserving axillary group, there were 59 men and 47 women with mean age of 53 years (range 21 to 79 years). There were three recurrences (3%) outside the borders of dissection. Transient upper extremity edema (8%) resolved over a median of 5 months, and permanent upper extremity edema occurred in 5% of patients. In the ilioinguinofemoral group, there were 19 men and 37 women with a mean age of 52 years (range 21 to 88 years). There was one recurrence (2%) outside the borders of dissection. Transient lower extremity edema (48%) resolved over a median of 12 months, and permanent lower extremity edema occurred in 14% of patients. CONCLUSIONS Preservation of the muscle fascia during lymph node dissection results in a lower incidence of permanent edema, with no increased risk of recurrence.

Evidence for a regulatory role for histamine in gastric enterochromaffin-like cell proliferation induced by hypergastrinemia.

BACKGROUND/AIMS Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-like (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective H1-histamine antagonist, terfenadine, on gastric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation. METHODS The rodent mastomys received the H2-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels and tissue histamine content were assayed by radioimmunoassays, and tissue chromogranin levels determined (Western blot analysis). In vivo cell proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day, 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cells quantitated. To evaluate the direct action on ECL cells we then studied the effect of terfenadine on histamine secretion and DNA synthesis (BrdU uptake) in an isolated preparation (approximately 90% pure) of ECL cells. RESULTS Loxtidine increased serum gastrin levels, mucosal thickness, tissue chromogranin levels, tissue histamine content, BrdU incorporation, ECL cell number, and proliferating ECL cells (all parameters p < 0.05). Terfenadine alone, irrespective of dosage, had no significant effect. The high dose in combination with loxtidine significantly inhibited the increase in tissue chromogranin levels, tissue histamine content, ECL cell number and proliferating ECL cells (p < 0.05), but did not alter other parameters, compared to loxtidine alone. The low does did not alter the loxtidine-induced changes. In pure isolated ECL cells, terfenadine did not alter histamine secretion either alone or in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC50 10(-10) M). CONCLUSIONS Terfenadine specifically inhibited the effect of loxtidine-induced ECL cell proliferation in vivo and significantly inhibited ECL cell DNA synthesis in vitro. We postulate that histamine, through an H1 receptor, positively modulates gastric ECL cell proliferation.

Enterochromaffin‐like Cell Pathobiology of Mastomys

Until recently, gastric neoplasia was regarded as predominantly adenocarcinoma in origin. Stromal tumors of unknown malignant potential were considered of interest, but rare. More recently, attention has been focused upon the development of neuroendocrine neoplasia of the gastric fundus.’ These lesions are predominantly of enterochromaffin cell, or enterochromaffin-like cell origin. Of particular interest are reports that enterochromaffin-like (ECLHerived tumor cells may be present in 40% of gastric carcinomas of the diffuse type.2 In general, it appears that there is a significant relationship between either low acid states or hypergastrinemia, and the genesis of fundic ECLomas.% The characterization of the cells involved in the neoplasm and the pathophysiology of the lesion itself are not yet clearly delineated. In order to investigate the biology of the enterochromaffin-like cell type, and the genesis of its neoplasia, we have studied the rodent species mastomys. This animal derives from the sub-Saharan desert areas and was initially used in the epidemiologic study of plague vectors. During these studies, it became apparent that a large percentage of the animals died from gastric neoplasia, which was later characterized as gastric carcinoid.’~~ More detailed studies revealed the tumor to be of ECL cell rig in.^ The lesion produces histamine and can be generated in association with hypergastrinemia related to a sustained low acid state. In previous studies, we have demonstrated that any pharmacotherapeutic agent capable of producing prolonged and sustained acid inhibition generates a sequence of hyperplasia, dysplasia, and neoplasia of the fundic ECL cells of mastornys.’&l2 In untreated animals of our breeding strain, 15-30% spontaneously develop gastric carcinoids within two years. Under circumstances of sustained acid inhibitory therapy, up to 80% of animals will develop gastric carcinoids within four months.’OIn order to investigate the regulatory mechanisms responsible for the development of this neoplastic phenomenon, we evaluated a number of agents with respect to their ability to induce ECL cell neoplasia. We used the irreversible histamine-H, receptor antagonist (H,RA), loxtidine, to generate a sustained low acid state. Because it was apparent that there was a predominant female incidence in the development of the neoplasia, we further