Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families.

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.     

Liver and lung resection for colorectal metastasis

Aim: To examine the survival benefit of liver and lung resection for colorectal metastasis and the potential prognostic factors that affect patient survival. Methods: All patients who had resection of lung or liver metastasis for colorectal metastasis in Queen Elizabeth Hospital, Hong Kong from 1995 to 2004 were retrospectively reviewed. The overall and disease‐free survival was analysed, in particularly between liver and lung metastasis. All factors that may have affected the survival were entered into Cox's proportional hazards regression model to identify significant variables associated with survival. Results: At 5 years, the overall survival of patients who had resection of lung and liver metastasis was 44% and 38%, respectively; the disease‐free survival was 26% and 24%, respectively. Overall and disease‐free survival of patients with resection of lung metastasis was comparable to those with resection of liver metastasis. The differentiations of primary tumour and time to metastasis were shown to be significant prognostic factors influencing overall survival. Those patients with systemic chemotherapy after resection of colorectal metastasis demonstrated a significantly higher probability of overall survival. Conclusion: Resection of lung and liver metastases from colorectal origin was safe and both procedures improved survival. The use of chemotherapy after resection of metastasis significantly improved the overall survival.     

Radiation therapy induced modulation of wound healing at experimental vein graft anastomoses.

OBJECTIVES: The aim of this study was to investigate if radiation therapy (RT) favorably modulates wound healing at vein graft anastomoses. MATERIALS AND METHODS: Jugular vein grafts were sewn into carotid arteries in 32 rats which were randomly divided into two groups: RT (gamma source, 14 Gray, n=16) and control (C, sham irradiation, n=16). Grafts and adjacent arteries were analyzed at 2 (n=8) and 8 weeks (n=8) by histology, immunohistochemistry, and morphometry. RESULTS: Although, RT did not reduce the overall occurrence of intimal hyperplasia, the distribution differed. RT led to a reduction of intimal hyperplasia in arterial segments (median: C: 41.873 microm2; RT: 6.452 microm2, p < 0.0007). In contrast, RT augmented intimal hyperplasia in vein grafts (median: C: 30.287 microm2; RT: 90.455 microm2, p < 0.014). Vein graft diameters after RT were enlarged (median: C: 2.098 microm; RT: 3.381, p < 0.031). Over 80% of the cells were of mesenchymal origin in both groups. CONCLUSIONS: RT reduced intimal hyperplasia in arterial segments. However, RT led to graft dilatation and increased intimal hyperplasia in vein grafts. RT did not favorably modulate the vascular wound healing response in this model.     

IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.