Molecular Basis of Inherited Colorectal Carcinomas in the Macedonian Population: An Update.

Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.

Functional outcome and quality of life after restorative proctocolectomy and ileal pouch-anal anastomosis.

Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with medically refractory ulcerative colitis, ulcerative colitis with dysplasia or cancer, or familial adenomatous polyposis (FAP). The aim of this study is to report our 6-year experience of restorative proctocolectomy and IPAA at a tertiary referral centre. Chart review was performed for 7 patients undergoing IPAA from 2006 to 2010. Preoperative histopathological diagnoses were ulcerative colitis (n=5), FAP (n=1) and other (n=1). We collected data regarding patient demographics, type and du-ration of the disease, previous operations and indications for surgery. We analysed the operative protocols and postoperative pathological diagnoses. Early (within 30 days after surgery) and late complications were noted. Follow-up was conducted upon annual function and a quality of life questionnaire, physical examination and endoscopic evaluation of the pouch. Postoperative histopathological diagnoses were: ulcerative colitis (n=3), indeterminate colitis (n=2), FAP (n=1) and colonic necrosis and gangrene (n=1). The average age of the operated patients was 48, with a female predomination of 71%. The mean duration of the follow-up was 4 years. We report 2 cases of steroid use prior to operation as well as 2 cases of extraintestinal manifestations. We report no septic complications and 3 cases of pouchitis. Functional results and quality of life were good to excellent in all 7 cases of IPAA. Restorative proctocolectomy with IPAA is a safe procedure with a low morbidity rate. Functional results are generally good and patient satisfaction is high.

Preservation of the vegetative pelvic nerves and local reccurence in the operative treatment of rectal cancer.

Life quality of the patients operated from rectal cancer is a serious problem. Despite the curing as a primary objective in the treatment of the rectal cancer, special attention is paid to the life quality upon the performed operation on the subjected patients. The analyzed series consists of 29 patients with rectal cancer, operated on at the Digestive Surgery Clinic within the framework of the Clinical Centre in Skopje, in the period between 2001-2006. Our series involves patients from the T2 and T3 stage of the illness, where it possible to preserve the vegetative pelvic nerves, that are characterized by a relatively long-lasting symptomatology and relatively high percentage of lymphatic metastases. The standardization of the operative intervention resulted in an increase in the number of patients with continuous operations and preservation of the neuro-vegetative plexus without influencing the radicalism of the intervention. The application of the Stapler and Double Stapler technique brought about an increase in the number of continuous operations characterized by a termino-terminal colorectal anastomosis. On the other hand the preventive creation of LOOP ileostomies in the case of the ultra low resections resulted in a decrease in the level of dehiscence of this type as one of the most common and most difficult complications. The preservation of the pelvic neuro-vegetative plexus prolongs the operation time by 30 to 60 minutes, depending on the case and the patient. We assume that the procedure does not have a particular influence on the frequency of the complications, and at the same time it positively affects the revival of the urinal and sexual function. Taking into consideration the fact that the lymphatic dissection increases the possibility of removal of the malignant tissue and enables an adequate "staging" and on the other hand the preservation of the pelvic plexus improves the quality of life, both in terms of the sexual function and the function of the urinary bladder, it is recommended that this way of treatment becomes an integral part in the surgical treatment of the rectal cancer.