[Surgery of stomach carcinoma--established and controversial procedures. Retrospective 1-year analysis with discussion of current aspects]. / Magencarcinomchirurgie--Bewährtes und Kontroverses. Retrospektive 10-Jahres-Analyse mit Diskussion aktueller Aspekte.

BACKGROUND: Current problems in gastric cancer surgery concern the extent of gastric resection, the need for abdominal evisceration, the degree of lymphadenectomy, and optimal preoperative tumor staging procedure. PATIENTS AND METHODS: In a restrospective analysis, data on epidemiology, extent of surgery, histopathology, postoperative complications, mortality, and survival in 284 gastric cancer patients were evaluated. RESULTS: Our results are in favor of subtotal gastrectomy performed for all T stages located in the distal or middle third, provided that a tumor-free margin of 5 cm in intestinal type and 10 cm in diffuse Lauren's type tumor can be achieved. Additional organ resections are indicated only if direct tumor invasion has occurred, and should not be part of an extended lymphadenectomy procedure. The degree of lymph node removal should be guided by the primary tumor site. Multimodal therapeutic approaches and high postoperative mortality after exploratory laparotomy justify the use of diagnostic laparoscopy in T3/4 tumors and if diagnostic scans suggest possible tumor spread. CONCLUSION: Even though surgery for gastric cancer is well standardized, a tailored surgical approach to different extent of gastric cancer appears warranted.

[Diagnostic and therapeutic strategies in local recurrence of stomach carcinoma]. / Diagnostische und therapeutische Strategien beim Lokalrezidiv des Magenkarzinoms.

Despite clear margins at the time of resection, 7 to 20% of the patients experience local recurrence of the primary stomach tumor. Intraluminal recurrence is rare but curable in 50% of the cases without distant metastases. Extraluminal recurrent gastric cancer comprises the typical pattern of recurrence and cannot be removed in most of the patients. Predisposing factors that favor the development of recurrent tumors are: higher tumor stages, extended lymph node involvement, tumor grades 3 and 4, diffuse type according to Lauren's classification, and intraoperative perforation of the primary gastric carcinoma.

Treatment of surgically induced acute liver failure by transplantation of conditionally immortalized hepatocytes.

The shortage of human livers available for hepatocyte isolation limits its clinical application. The availability of cloned, conditionally immortalized hepatocytes that could be grown in culture but would lose their transformed phenotype and provide metabolic support upon transplantation would greatly facilitate the treatment of acute liver failure. Toward this goal, we transduced isolated Lewis rat hepatocytes using a replication-defective recombinant retrovirus capable of transferring a gene encoding a thermolabile mutant simian virus 40 T antigen (SV40ts). The cloned, immortalized hepatocytes proliferate at 33 degrees C. At the nonpermissive temperatures (37-39 degrees C), they stop growing and exhibit characteristics of differentiated hepatocytes. These cells did not produce tumors when transplanted in mice with severe combined immunodeficiency disease or in syngeneic rats. To induce acute liver failure, Lewis rats were subjected to 90% hepatectomy (Hpx) and given 5% oral dextrose. All rats that did not undergo hepatocyte transplantation died within 96 hr. Fifty percent of rats that received intrasplenic injection of 10 x 10(6) primary Lewis rat hepatocytes (G2, n=6) or 10 x 10(6) SV40ts-conditionally immortalized (SV40ts-ci) hepatocytes (G3, n=8) 1 day before 90% hepatectomy survived, whereas 80% of rats that received an intraperitoneal injection of 200 x 10(6) primary Lewis rat hepatocytes (G4, n=10) or 200 x 10(6) SV40ts-ci hepatocytes (G5, n=10) on the day of hepatectomy survived. Survival after intraperitoneal injection of a cellular homogenate of 200 x 10(6) primary Lewis rat (G7, n=9) or SV40ts-ci hepatocytes (G8, n=10) on the day of Hpx was 33% and 40%, respectively, whereas survival after intraperitoneal injection of 200 x 10(6) Lewis rat bone marrow cells (G6, n=7) was 29%. Thus, transplanted, conditionally immortalized hepatocytes can be as effective as primary hepatocytes in supporting life during acute liver insufficiency. This work represents the first step in developing an hepatocyte cell line that would partially alleviate the organ-donor shortage and could be of potential clinical value.

Use of gene therapy to suppress the antigen-specific immune responses in mice to an HLA antigen.

Hematopoietic chimerism has been used in the laboratory to induce life-long immunologic tolerance to donor antigens. The present study demonstrates that mice transplanted with autologous bone marrow cells retrovirally transduced to express HLA-A2.1 develop a significantly depressed immune response to this antigen while retaining normal reactivity to HLA-B7. Retrovirus-mediated transduction was performed using whole bone marrow-producer cell coculture. This approach did not result in significant gene transfer into hematopoietic progenitor cells. Despite this, the antibody response to HLA-A2.1 in mice reconstituted with genetically modified BMC was completely suppressed three months following bone marrow transplantation. Cell-mediated immunity to HLA-A2.1 was partially suppressed in three-fourths of animals tested three months later, although one animal had a CTL profile similar to that an of HLA-A2.1 transgenic mouse. Complete suppression of the antibody-mediated immune response occurred when only one-third of mice had evidence of the introduced genes in their spleen and one-tenth had the introduced sequences in their circulating WBCs by PCR. In conclusion, engineering of BMC to express donor MHC genes may be an alternative to xenogeneic BMT to induce chimerism and tolerance. More efficient transduction of bone marrow progenitor cells may result in more persistent gene expression and long-lasting transplantation tolerance in recipients of genetically modified bone marrow. Successful application of this technology may also be useful in altering immune responses to other external and self antigens.

Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy.

Transplantation of hepatocytes has been shown to provide metabolic support during liver failure in experimental models. The potential clinical application of hepatocyte transplantation, however, is limited by the need for readily available, well-characterized cells, and a worldwide shortage of donor organs. A clonal hepatocyte cell line that could be grown economically in vitro and would exhibit a differentiated, nontransformed phenotype following transplantation would be an attractive solution to this problem. To test this alternative, primary Lewis rat hepatocytes were conditionally immortalized by retroviral transduction with a thermolabile mutant Simian virus 40 (SV40) large T antigen. The cloned immortalized cells proliferate in culture at 33 degrees C and stop growing at 37 degrees C to 39 degrees C. Transplanted into normal livers, these hepatocytes integrate normally into liver cords. When transplanted into the spleens of portacaval-shunted rats, they protect recipients from hyperammonemia-induced hepatic encephalopathy. The cells engrafted in the spleen exhibit normal morphology, secrete bile, and express albumin messenger RNA. The protection from hyperammonemia is reversed by splenectomy. These studies show that hepatocytes can be conditionally immortalized, expanded in culture, and are capable of providing metabolic support in chronic liver insufficiency. Safeguards that could make these cells clinically useful can be accomplished using currently available technology.