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Infantile hypertrophic pyloric stenosis (IHPS) is a common childhood pathology affecting approximately 1-5 children pro 1000 newborns, with a genetic background as suggested by the familial occurrence. RET is a candidate gene for IHPS due to its role in the development of the intrinsic innervation and ganglia of the smooth musculature and the association of RET variants with another motility disorder (Hirschsprung's disease). Accordingly, we investigated RET-IHPS associations through sequencing of the complete RET coding region in 32 IHPS patients. Genotype frequencies were compared between patients and 48 controls using the Cochran-Armitage trend test or Fischer's test for exact p-values. We found 19 RET variants in IHPS, including polymorphisms in the promoter region (c.-200 G>A and c.-196 C>A). There was no statistically significant difference between the frequencies of the variants in both groups. There was no deviation from the Hardy-Weinberg equilibrium, yet a significant correlation (linkage disequilibrium) for variants in the promoter region, in exons 11, 13, 14 and 19 and in the 3' UTR. We conclude that RET variants are present in IHPS patients yet show no significant statistical association with the IHPS phenotype, suggesting at best an adjuvant role for RET in IHPS., (© Georg Thieme Verlag KG Stuttgart · New York.)

Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families.

Introduction: Expression of hemagglutinin antigen of influenza virus (HA) by the murine colon carcinoma cell line (CT-26) produces systemic immunization against tumor challenges in the cecum, liver and lungs but not in the brain of BALB/c-mice. Immunization with IL-4 expressing CT-26 cells inhibits lung metastases formation. The purpose of our study was to examine the effects of HA or IL-4 expression on brain metastases formation., Methods: Using selective internal carotid artery injections, brain metastases formation of HA or IL-4 expressing CT-26 cells with and without subcutaneous pre-immunization was evaluated in Balb/c mice., Results: Systemic pre-immunization with HA or IL-4 expressing tumor cells cannot protect against brain metastases, while the local, intracerebral expression of HA or IL-4 inhibits the growth of hematogenous brain metastases., Conclusion: Pre-immunization with HA or IL-4 expressing tumor cells did produce systemic immunity against liver and lung metastases but not against brain metastases. Local, intracerebral expression of HA or IL-4 prevents from cerebral metastases formation in an animal model.

Hereditary colorectal cancer syndromes account for about 7% of all colorectal carcinomas. The most frequent form is Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Identification, cloning and sequence analysis of the predisposing genes enables identification of mutation carriers and non-mutation carriers, respectively. These genetic informations can be used in an individually tailored clinical surveillance program and may ultimately result in standard preventive surgical treatment. In classical FAP the surgical standard is performing a restorative proctocolectomy. It is still unclear now, if this procedure should be modified in attenuated forms (colectomy with ileorectostomy). Due to a high rate of synchronous and metachronous carcinomas a subtotal colectomy in the case of first colon cancer seems to be indicated in HNPCC patients. A proctocolectomy or a restorative proctocolectomy should be weighed in case of carcinomas in the lower rectum. These procedures should be performed under the precondition of identification of the pathogenic germline mutation in the patient, only. In addition, a synchronous prophylactic hysterectomy with oophorectomy should be recommended postmenopausal gene carriers. Intensive counseling of the patient should proceed these preventive procedures involving surgeons, gastroenterologists, geneticists, molecular biologists, gynecologists, physicians and psychologists. It is recommended to have patients treated exclusively in specialized centers. Currently, six interdisciplinary centers for cancer surveillance and early diagnosis in hereditary colorectal cancer are being sponsored in Germany by the Deutsche Krebshilfe since 1999. In the future clinical studies have to be conducted to evaluate the efficacy of extended colorectal resections versus efficacy of surveillance and conventional resections according to general oncological principles.

Cancer development and progression has been associated with numerous genetic events in tumor cells. Germline mutations of caretaker and gatekeeper genes are responsible for hereditary cancer syndromes. Exogenous factors in conjunction with functional germline variants of a variety of genes may contribute to tumor initiation in sporadic malignant disease. Furthermore, pathways to neoplasia require somatic events in the developing tumor. Acquired or inherited genetic instability permits stepwise tumor progression. The most fearsome aspect of tumor progression is dissemination of tumor cells to draining lymph nodes of the primary or to distant organs, which limits effectiveness of surgical therapy. Cellular heterogeneity of malignant neoplasms has important implications for chemotherapy and radiotherapy. An increasing understanding of the molecular biology of tumors is the prerequisite for improved prediction, prevention and therapy of malignant disease.

New techniques in molecular biology and increasing insights in the genetic basis of tumorigenesis led to the development of therapeutic agents composed of genetic information. The majority of gene therapy trials is targeted towards cancer therapy. The most frequently used strategy is immunotherapy which comprises transfer of genes encoding cytokines, costimulatory molecules or tumorspecific antigens to enable cells of the immune system to identify and destroy tumor cells. The second important strategy makes use of suicide genes to selectively kill tumor cells. Compensation of genetic defects by the downregulation of activated oncogenes or the restoration of tumor suppressor gene functions is the third concept to revert the malignant phenotype of cancer cells.

Colorectal cancer is one of the most frequent cancers in the Western hemisphere. It seems to be well established that colorectal tumors develop as a result of an accumulation of inherited and/or acquired somatic mutational events in tumor suppressor genes and oncogenes. An increasing understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Therefore, strategies have been developed for predictive molecular diagnosis and preventive surgical treatment of colorectal cancer syndromes. In the future surgical research will participate in research and development in the field of molecular diagnosis of colorectal cancer and will then evaluate the clinical management concepts as a result.

Surgical research needs structural and organizational conditions. These have to ensure, that the young surgeon finds the opportunity for scientific activities and development in a highly professional environment.

Breast cancer is the most common malignancy among women. Genetic predisposition is considered to account for 5-10% of all cases while the majority of these cancers are sporadic and caused by complex interactions of exogenous and endogenous factors. The inherited predisposition can be due to germline mutations in one of several cancer susceptibility genes. For high risk families the two most important genes are BRCA1 on chromosome 17q, which confers a high risk of both, breast and ovarian cancer and BRCA2 on chromosome 13 associated with high penetrance of breast cancer but lower risk of ovarian cancer. A high risk of breast cancer is conferred by mutations in the p53 tumor suppressor gene as part of the rare Li-Fraumeni-syndrome, and possibly also by the estrogen receptor gene. Other cancer genes associated with a less increased risk of breast cancer are the autosomal recessive ataxia telangiectasia (AT) gene and the HRAS1 gene. Germline mutations in BRCA1 and BRCA2 account for the majority of families with multiple cases of breast and/or ovarian cancer and also at least 10% of cases below the age of 40 years. Genetic testing for BRCA1 mutations is not generally recommended except for women with a strong family history. The aim for the management of familial breast cancer should be the establishment of interdisciplinary teams to cover genetic counseling, molecular analysis, onco-surgical therapy, psychosocial support and clinical follow-up.

Using the method proposed by Traverso and Longmire, a partial duodenopancreatectomy was performed on 18 patients without concomitant gastric resection sparing the bulbus duodeni. It had been reported that the postoperative increase in ulcer formation on the anastomosis could be avoided by a duodenal inhibition of gastric secretion. Since, however, ulcers were found in 7 patients on an average of 13 months following surgery, it must be presumed that the duodenal acid inhibition is not sufficient. For this reason Whipple's operation is again being performed in combination with the subtotal gastric resection.