Molecular biology: the message, its language, and the surgeon.
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Biomedical subjects
Publications and source records attributed to E Passaro.
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Gastrinomas are pancreatic endocrine neoplasms that arise either sporadically or are inherited as part of the multiple endocrine neoplasia type I syndrome (MENI). Loss of heterozygosity (LOH) in the region flanking the MENI gene at chromosome 11q13 has been documented in a few sporadic and familial pancreatic endocrine tumors, but not previously in sporadic gastrinomas. It has therefore been suggested that gastrinomas develop by a mechanism different from other tumors associated with the MENI syndrome. We report LOH on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors have LOH for markers flanking the MENI region. Molecular evaluation of segments of chromosomes 3, 13, and 17 known to contain cloned or putative tumor suppressor genes fail to show LOH except at one locus in one tumor. These data suggest that a tumor suppressor DNA segment exists at 11q13 that may be involved in the development of sporadic gastrinomas.
Mucosal hemodynamics (by reflectance spectrophotometry) and mucosal damage (by histologic examination) following acute colonic ischemia were evaluated in different anatomic locations in the colon of anesthetized rats. The reflectance spectrophotometer provides an index of mucosal hemoglobin concentration (IHB) and an index of oxygen saturation of hemoglobin (ISO2). The patterns of ischemia without congestion (decreases IHB, decreases ISO2) during superior mesenteric artery occlusion, and ischemia with congestion (increases IHB, decreases ISO2) during portal vein occlusion, previously demonstrated in the stomach and duodenum, are also applicable to the colon. The significant linear correlations between changes (as percent of baseline) in IHB, ISO2, and hydrogen gas clearance suggest that changes in these indices are adequate indicators of changes in colonic mucosal perfusion. Superior mesenteric artery ligation produced significant reductions in both indices, and an increase in damage in the mucosa of the cecum, transverse colon, splenic flexure, and left colon, but not the rectum. Inferior mesenteric artery ligation produced only slight reduction in these indices and minimal damage only in the mucosa of the splenic flexure. These results support the hypothesis that the superior mesenteric artery is more important than the inferior mesenteric artery in maintaining colonic perfusion and colonic mucosal integrity in the rat.
An overview of molecular biology is presented for the practicing surgeon. Definitions of the constructs and activity of DNA, RNA, and protein synthesis are defined. These principles are illustrated in their use in recombinant DNA technologies. A glossary is provided for the terms utilized.
DNA is the fundamental guide for the cell's processes. The alterations in DNA that can lead to abnormal or absent proteins and the role of chromosomal alterations in changing the function of the DNA are reviewed. The role of viruses in derailing a cell's normal functions, the major mechanisms of oncogene action, and tumor suppressor genes are also discussed.
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Ischemia and reperfusion of the small intestine and colon in rats were produced by reversible occlusion (for 30 min and 1 or 3 h) of the superior mesenteric artery and the aorta above the inferior mesenteric artery. Despite a greater reduction of mucosal perfusion in the colon than in the small intestine with 30 min of ischemia, the depth of mucosal damage was significantly smaller in the former than in the latter. Thirty minutes of ischemia followed by 1 h of reperfusion induced an increase in polymorphonuclear leukocyte infiltration in both locations. Exacerbation of mucosal injury occurred only in the small intestine, suggesting that reperfusion injury is independent of polymorphonuclear leukocyte infiltration. Reperfusion after 1 or 3 h of ischemia did not exacerbate mucosal damage in either location. Allopurinol significantly diminished the exacerbation of injury after reperfusion in the small intestine. The protective effect of allopurinol, however, was neither associated with an improvement in perfusion nor a reduction in polymorphonuclear leukocyte infiltration. These data indicate that there is a window (30 min) of reperfusion injury in the small intestine, but there is no evidence of reperfusion injury in the colon.
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The salient contributions of the Zollinger-Ellison syndrome have made it unique. No pancreatic endocrine tumor described before (insulinoma) or subsequently (glucagonoma, somatostatinoma, vipoma, pancreatic-polypeptidoma) has been the topic of such a variety of studies, or has been such an inspiration and rich source of new ideas for investigation and ultimate improvement in patient care.
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Chromogranin A (Cg A) is a protein that is coreleased with peptide hormones from gut endocrine cells and tumors. Plasma levels of Cg A, pepsinogen group I, and gastrin were measured in 31 patients with gastrinoma. Mean Cg A level in 10 patients with gastrinoma who were not operated on was 169 +/- 32 ng/mL, while in 9 control patients it was 28 +/- 5 ng/mL. In 18 patients with gastrinoma with residual tumor after total gastrectomy, the mean Cg A level was 45 +/- 6 ng/mL, and in 10 patients with normal gastrin levels after total gastrectomy and tumor excision, the mean Cg A level was 40 +/- 4 ng/mL. In 7 patients in whom pregastrectomy and postgastrectomy Cg A levels were measured, the mean reduction was 94 +/- 27 ng/mL, or 66%. There was no correlation between Cg A levels and amount of tumor, presence of metastases, or multiple endocrine neoplasia type I syndrome. There was a significant correlation between Cg A and pepsinogen I levels but no correlation between Cg A and gastrin levels. The results suggest that the elevated plasma Cg A levels in patients with gastrinoma are determined primarily by the trophic effects of gastrin on gastric enterochromaffinlike cells rather than by corelease from the gastrin-producing tumor itself.
Heterotopic tissue in lymph nodes is both unknown to clinicians and a potential source of confusion with metastatic disease. We reviewed the English literature and found 289 cases of heterotopic tissue in lymph nodes. The majority (84%) of these patients were operated on for malignant neoplasms. The most frequent sites of occurrence was the pelvis (67%), followed by the axilla (14%), neck (14%), groin (3%), abdomen (2%), and mediastinum (less than 1%). The tissue seen is site-specific and frequently resembles a neighboring organ. Three cases have been reported in which heterotopic tissue was mistaken for metastatic disease. These cases illustrate the importance of being familiar with heterotopic tissue in lymph nodes and identifying it when it does occur, to avoid inappropriate therapy.
Our experience with 47 sporadic gastrinomas suggests that no less than 85% of these tumors are located to the right of the superior mesenteric artery. This finding is unexpected because approximately 75% of insulinomas and glucagonomas are located to the left of the superior mesenteric artery. All of our extrapancreatic gastrinomas have been located to the right. These observations prompted us to determine if other extrapancreatic gastrinomas were also predominantly located to the right side. We searched the world's literature and found 10 cases of ovarian gastrinomas and one case of a renal gastrinoma. Nine of these remote extrapancreatic gastrinomas were located on the right side. This distribution of remote extrapancreatic gastrinomas is similar to our experience with peripancreatic gastrinomas. This unexpected right-sided preponderance of both remote and peripancreatic gastrinomas suggests a common origin for both.
Pancreatic endocrine tumors are grouped together by their common histologic, cytochemical, and ultrastructural features. Although useful conceptually, this paradigm has been unable to predict the anatomic location of different tumor types. Successful surgical excision of these tumors would be facilitated by an improved understanding of their anatomic distribution. Based on the available data, a bimodal distribution of pancreatic endocrine tumors was identified. Cluster 1 (gastrinomas, pancreatic polypeptide (PP)-secreting tumors, somatostatinomas) had 75% of tumors to the right of the superior mesenteric artery, whereas cluster 2 (insulinoma, glucagonoma) had 75% of tumors to the left of the superior mesenteric artery (p less than 0.05). This distribution is similar to that distribution predicted based on the volume density of the corresponding islet cells for insulinoma, glucagonoma, and PP-secreting tumors, but not for somatostatinoma. These findings suggest that pancreatic endocrine tumors are derived from similar cytologic precursors as pancreatic islet cells, and their distribution may be a consequence of embryologic development from either the ventral (cluster 1) or dorsal (cluster 2) pancreatic buds.
With the availability of DNA recombinant technology and DNA and RNA sequencing techniques, diseases can now be studied and treated at a molecular level, while unlimited quantities of a pure protein product can be produced through gene cloning. Before the end of this century, gene therapy will be used to repair genetic defects. This article explains these advances in genetic technology and suggests their relevance in clinical problems and practice.
The role of surgery in the treatment of gastrinoma is unclear. The purpose of this study was to determine prospectively the surgical cure rate using a controlled clinical trial. Eleven patients who fit the entry criteria underwent abdominal exploration and attempted tumor resection for cure. A historical control group was used for comparison. Cure was defined as: (1) normal serum gastrin level, (2) no response to intravenous secretin, (3) no symptoms when antisecretory medications are stopped, and (4) no tumor recurrence on follow-up examination. Tumors found in both groups tended to be small (1.5 cm vs. 2.2 cm), multiple (71% vs. 40%), and in lymph nodes (70% vs. 70%). All tumors identified were located anatomically within the gastrinoma triangle. Tumors were found in 10 of 11 patients (91%) in the study group, and significantly more patients had their tumors excised for cure as compared to controls (82% vs. 27%, p less than 0.05). The current prospective cure rate for gastrinoma is higher than previously appreciated and tumors within lymph nodes do not preclude curative resection.