Biomedical subjects
Publications and source records attributed to J J DeCosse.
Familial polyposis is a systemic defect of growth regulation. Extracolonic expressions are common and serious, about equal in risk to carcinoma of the large intestine. Periodic surveillance of the upper gastrointestinal tract is particularly important. More intensive surveillance of the large intestine may lead to better results in patients with polyposis who have carcinoma of the large intestine develop.
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This two phase study was designed to observe the toxicity and effectiveness of retinoids on oral leukoplakia. The study design included patients who had visible and measurable oral leukoplakia without history of synchronous oral cancer or oral cancer within the previous 2 years. Documentation of the lesion by direct measurement and photography, as well as a biopsy at the beginning and at the end of the study (for verification of the histologic appearance of the lesion), were performed in each patient. Sixteen patients with oral leukoplakia were treated with 13-cis-retinoic acid formulated in a troche in the strength of 1 mg. Three patients received 3 mg/day, 8 patients received 5 mg/day, and 5 patients received 10 mg/day. The initial visible responding event appeared to be a thinning of the leukoplakia with reduction in the whitish surface leaving a reddish, velvety epithelium. If resolution occurred, the velvety area became pink, assuming the color and texture of the normal adjacent mucosa. Toxicity of the drug appeared to be acceptable among the evaluable patients. Of the 11 patients, 3 demonstrated complete response and 6 demonstrated partial response after 6 months of treatment with the drug under study. Recurrences developed in two of the three patients with complete response, and neither of the two showed complete histologic and cytologic regression. One of the patients with partial response went on to complete response after cessation of treatment. Under the condition of our study, a treatment effect was observed with small amounts of topical 13-cis-retinoic acid and that the level of toxicity was acceptable.
Pyloroplasty increased the invasiveness of duodenal tumors in Wistar rats receiving N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 weeks (83 mg/l in drinking water) (Arch. Surg., 117, 768-771). To assess morphologic and kinetic alterations, analyses of tritiated thymidine (3HTdR) pulse-labeled fundic, antral and duodenal mucosa were carried out. The normal appearance of MNNG-treated antral and duodenal mucosa was characterized by the appearance of elongated hyperactive columns exhibiting elevated levels of DNA synthesis. Pyloroplasty in carcinogen-treated rats induced both a 3-fold enhancement in the number of these elongated columns and an elevation in the number of proliferating cells within them (P less than 0.001). In the MNNG and pyloroplasty treated duodenal mucosa 26% of columns contained over 130 cells/column rather than an average of 100 cells in normal appearing MNNG-treated mucosa. DNA synthesis was increased by 23% within these hyperactive glands (11.3 proliferative cells/column vs. 9.4/column in normal appearing mucosa). Pyloroplasty creates both an increase of gastric bile reflux and an increase of the gastric evacuation rate, conditions which influence cell proliferation. Such alterations in antro-pyloro-duodenal physiology contribute to the increased cellular activity observed, promote malignant transformation and foster the expression of invasiveness.
Postoperative complications after surgery of the colon and rectum are related most often to sepsis, anastomotic disruption, hemorrhage, urinary tract injury, bowel stoma, and sexual dysfunction. Improved safety in colorectal surgery requires comprehensive preparation of the patient with attention to associated diseases, clear surgical judgement, excellence in technical skill, and aggressive postoperative management of any complications that may develop.
The effect of ascorbic acid supplementation on CF1 mice fed ascorbic acid for approximately six months at dose levels of 1%, 5%, and 10% of diet was investigated by analysis of tissue ascorbic acid concentration in the liver, kidney, stomach, small intestine, and large bowel. The effect on epithelial cell proliferation was also examined in the small and large bowel but only at the 5% level. In the control animals, ascorbic acid concentration was lowest in the liver (0.406 +/- 0.07 mg/g) and highest in the small bowel (0.754 +/- 0.16 mg/g). Dietary intake of 5% and 10% ascorbic acid significantly elevated levels in the liver (0.741 +/- 0.13; p less than 0.05), and all doses of ascorbic acid significantly raised tissue concentrations in the kidney and colon. No difference was observed in the percentage of DNA-synthesizing cells in the jejunum of controls or animals fed 5% ascorbic acid at 1 or 24 hours after 3HTdR injection. However, at 1 hour a significantly decreased level of proliferation was observed in the distal colon of ascorbic-acid-treated mice compared with controls (labeling index [L.I.] = 7.3 +/- 0.28 vs. 10.1 +/- 1.15; p less than 0.05), and an even greater suppression of DNA synthesis was achieved by 24 hours (L.I. = 11.4 +/- 1.06 vs. 18.6 +/- 1.61; p less than 0.01). None of the doses of ascorbic acid employed was toxic to the experimental mice.
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Chemopreventive agents are natural or synthetic agents administered to prevent, inhibit or reverse one or more of the stages of carcinogenesis. Natural agents include vitamins, coumarin, indoles, flavones, plant sterols and selenium salts. Synthetic agents include retinoids, phenolic antioxidants, protease inhibitors and prostaglandin synthesis inhibitors. All have demonstrated inhibition of tumor models in vitro or in vivo. These agents may work in different ways; by stimulating the immune response, by inducing gene suppression, by detoxifying carcinogens, by blocking oxidative damage to DNA or by other mechanisms. Human trials are being carefully initiated. Retinoids have demonstrated effectiveness in controlling some proliferative skin tumors. In the gastrointestinal tract, ascorbic acid has demonstrated a modest suppressive effect on adenomas of the rectum in patients with polyposis. There is initial evidence that 13-cis-retinoic acid is effective in modifying leukoplakia of the oral cavity.
The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid. Over a two year period we tested this hypothesis in a randomized, double-blind study of 49 patients with polyposis coli. Of 36 patients who were evaluable at completion, 19 had received ascorbic acid, 3 g/day, and 17 had received a placebo. We found a reduction in polyp area in the ascorbic acid-treated group at nine months of follow-up (P less than 0.03) and trends toward reduction in both number and area of rectal polyps during the middle of the trial. A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect. Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover. Although these results have no current therapeutic value, our findings support continued studies of chemoprevention in this and other high risk settings.
Nineteen male Wistar rats received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in drinking water (83 mg/L) to initiate glandular adenocarcinoma of the stomach; eight control rats received tap water. After 12 weeks a pyloroplasty was performed on nine rats receiving MNNG and three control rats. Ten MNNG-treated rats and five control rats had no operation. All were observed for 38 weeks before being killed. No difference in the incidence of antral adenocarcinomas was found between the MNNG-treated groups; however, those without operation showed in situ changes in the duodenum and those treated with pyloroplasty showed five invasive adenocarcinomas. In this model pyloroplasty alone did not increase the risk of gastric cancer but increased the risk of duodenal tumors. Pyloroplasty apparently accelerated the gastric evacuation rate, resulting in greater insult to the duodenal mucosa. Such a condition may require a higher proliferative rate in the duodenum and may increase subsequent formation of malignant tumors.
The records of 50 patients with localized primary gastric lymphoma were reviewed and clinical and prognostic factors characterized. Pathologic material was reclassified according to Rappaport's, Lukes-Collins, and Lennert's Kiel classifications. Factors with the greatest prognostic significance included initial stage as determined by surgery and pathology, absolute tumor size, degree of penetration through the stomach wall, and histologic grade of the lymphoma. After surgical resection for cure, the overall 5-year disease-free survival was 47%. For stage I disease, this was 78% vs 29% for stage II (P = 0.006). Patients with lymphomas less than 5 cm in diameter had 58% 5-year disease-free survival vs 32% for those with tumors greater than 10 cm (P = 0.06). Full-thickness penetration decreased 5-year survival from 75% to 38% (P = 0.06). Patients with histologically low-grade lymphomas had a better prognosis than those with high-grade lymphomas. The most significant correlation of histology to survival was seen with the Kiel classification with a 5-year survival of 39% for centroblastic polymorphous lymphoma vs 66% for LP immunocytoma. When lymphoma recurred it developed outside the abdomen in a majority of patients. The addition of abdominal radiation therapy to surgical resection made no significant impact on survival for either stage I or II disease.
The technique of modified radical mastectomy (total mastectomy and axillary dissection) as carried out by members of the Breast Service at Memorial Sloan-Kettering Cancer Center is presented. As described by Patey, the pectoralis minor muscle is removed to facilitate dissection of the upper levels of the axilla. Care is taken to preserve the principal neurovascular bundle to the pectoralis major muscle. Indications for and complications of the procedure are indicated, with particular emphasis given to selection of patients for modified radical mastectomy or radical mastectomy.
The idea that the longitudinal muscle of the muscularis externa of the colon is confined to the colonic teniae in the monkey and human is a common conceptual error. Forty-six colon specimens taken from human and nonhuman primates were reviewed histologically and the distribution and structure of the longitudinal muscle were evaluated. We found that the longitudinal muscle forms a complete coat around the colon although it is considerably thicker in the region of the teniae coli. In addition to its anatomic importance, this observation has implications for the physiology of colon muscle and for certain current hypotheses concerning the etiology of diverticulitis.
A predictable and progressive experimental intestinal obstruction, simulating a malignancy but without neoplastic change has been produced by application of a silicone rubber ring around the bowel of 20 rats, seven dogs, and five monkeys. Serosal reaction produced fibrous tissue that resulted in an "apple core" obstruction. An easily assembled extraluminal balloon device of silicone rubber can be used to produce acute and progressive experimental obstruction, especially of the large bowel.
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