Colorectal Cancer Carcinogenesis: a Multivariate Genetic Model in a Cohort of Romanian Population.

BACKGROUND: The molecular mechanism of carcinogenesis of sporadic colorectal cancer (CRC) involves genes with roles in folate metabolism, genes involved in metabolization of carcinogenic compounds from diet and tobacco smoke, and genes related to the DNA repair process. The aim of the study was to examine whether the MTHFRC677T, MTHFR- A1298C, TS-2rpt/3rpt, TS-1494del6bp, NAT2*5C-C481T, NAT2*5A-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, GSTM1-null, XRCC1-Arg399Gln, XRCC3-Thr241Met, XPD-Lys751Gln genetic variations are associated with CRC prognosis, in the presence of environmental and demographic factors. METHODS: We genotyped 150 patients diagnosed with sporadic CRC using PCR-RFLP and sequencing methods. The performance of the final model was quantified using Nagelkerke's coefficient, the Hosmer-Lemeshow test, C statistics, and Somers' (D) index, capable of describing the model's goodness-of-fit and discrimination. RESULTS: Multiple logistic regression analysis established a significant independent association of NAT2*18-A845C, MTHFR-C677T, XRCC3-Thr241Met, NAT2*7B-G857A, XPD-Lys751Gln, XRCC1-Arg399Gln and NAT2*6BG590A with an increased prevalence of sporadic CRC, regardless of the presence/absence of colonic tumors. After an adjustment for other polymorphisms and environmental risk factors, the risk to develop sporadic CRC was 2.25 (p = 0.011) and 2.31 (p = 0.01) in association with the NAT2*18-A845C and MTHFR-C677T genetic variants, respectively. The risk increased to 3.22 (p = 0.0005) and 3.69 (p = 0.0009) in association with the XRCC3Thr241Met and NAT2*7B-G857A polymorphisms. Also, patients carrying the XPD-Lys751Gln, XRCC1Arg399Gln, and NAT2*6B-G590A polymorphisms had a 4.16 (p < 0.0001), 5.16 (p < 0.0001), and 5.46-fold (p < 0.0001) increased risk for sporadic CRC, under the dominant genetic comparison model. In addition, we found an interaction between gender and alcohol, the effect of alcohol consumption on the risk of developing sporadic CRC being different in female and male patients. CONCLUSIONS: Our study confirmed the predictive role of some polymorphisms associated with DNA methylation and procarcinogen transformation into carcinogenic compounds in sporadic CRC risk and, also, the influence of environmental risk factors such as diet, smoking, and alcohol consumption on this association.

N-acetyl transferase 2/environmental factors and their association as a modulating risk factor for sporadic colon and rectal cancer.

OBJECTIVES: The aim of this study was to evaluate the association between environmental factors and colon or rectal cancer after adjusting for N-acetyl transferase 2 (NAT2) phenotypes. METHODS: Ninety-six patients with sporadic colon cancer, 54 with sporadic rectal cancer and 162 control subjects were genotyped for NAT2-T341C, G590A, G857A, A845C, and C481T using sequencing and PCR-RFLP analysis. RESULTS: The risk for colon cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, and NAT2*5A-C481T. The risk for rectal cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*7B-G857A, and NAT2*5A-C481T. High fried red meat intake associated with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele determines a risk of 2.39 (P=.002), 2.39 (P=.002), 2.37 (P=.002), 2.28 (P=.004), and 2.51 (P=.001), respectively, for colon cancer, whereas in the case of rectal cancer, the risk increased to 7.55 (P<.001), 7.7 (P<.001), 7.83 (P<.001), 7.51 (P<.001), and 8.62 (P<.001), respectively. Alcohol consumption associated with the NAT2 -T341C, G590A, G857A, A845C, and C481T rapid acetylator allele induces a risk of 10.63 (P<.001), 12.04 (P<.001), 9.76 (P<.001), 10.25 (P<.001), and 9.54 (P<.001), respectively, for colon cancer, whereas the risk for rectal cancer is 9.72 (P<.001), 11.24 (P<.001), 13.07 (P<.001), 10.04 (P<.001), and 9.43 (P<.001), respectively. Smokers with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele have a risk of 4.87, 4.25, 4.18, 3.81, and 3.82, respectively, to develop colon cancer. CONCLUSIONS: Fried red meat, alcohol, and smoking increase the risk of sporadic CRC, especially of colon cancer, in the case of rapid acetylators for the NAT2 variants.

Laparoscopic Donor Nephrectomy of Dual Renal Artery Kidneys: Single Center Experience.

Background: Multiple renal artery (MRA) kidneys represent a special challenge for surgeons, during both donor nephrectomy and renal transplantation. AIMS: This study aims to evaluate both donors and recipients outcomes of laparoscopically procured dual renal artery (DRA) kidneys. Patients and Methods: We reviewed the medical records of all living kidney donors who underwent laparoscopic donor nephrectomy between April 2009 and December 2014, and their recipients. Operative details and immediate outcomes of both donors and recipients of DRA kidneys were compared to those of donors and recipients of single renal artery (SRA) kidneys. Results: From a total of 250 laparoscopic donor nephrectomies, 43 (17.2%) were on kidneys having DRAs. The mean operative time was statistically higher in the group with DRA (168.1 mins vs 135.3 mins, p=0.001), however, mean warm and cold ischemia times were the same. There were no complications reported among donors in neither groups, nor conversion to open nephrectomy. Lengths of hospital stay of the donors were similar in both groups. There was no statistically significant difference in immediate allograft function among the two groups. Conclusions: Laparoscopic procurement of kidneys with dual renal arteries is safe, reliable, and has no significant impact on the neither donor's outcome, nor allograft function.

GSTM1-null genotype as a risk factor for sporadic colorectal cancer in a Romanian population. Association with the NAT2-rapid-acetylator phenotype and exposure to environmental factors.

We evaluated the association between the presence of the GSTM1-null genotype and the combined presence of the GSTM1-null genotype/NAT2 rapid acetylator phenotype and the risk of developing sporadic colorectal cancer (CRC), as well as their interaction with environmental risk factors. One hundred and fifty patients with sporadic CRC and 162 controls were genotyped using PCR-RFLP analysis. For testing and quantification of the simple effect (main effect) and of the gene-gene and gene-environment interaction (modification effect), univariate and multivariate logistic regression was used. In the multiplicative model, from the genetic factors, GSTM1-null and NAT2*6B had a statistically significant influence on the risk for CRC, while from the environmental factors, smoking and diet had similar effects. The combination of GSTM1-null/NAT2 rapid acetylator phenotype/smoking behavior or GSTM1-null/NAT2 rapid acetylator phenotype/diet rich in fried red meat was not found to influence the sporadic CRC risk in Romanians, but the GSTM1-null genotype, NAT2 rapid acetylator phenotype influenced the sporadic CRC risk differently depending on the gender of the patient.

Hepaticojejunostomy for the management of sump syndrome arising from choledochoduodenostomy in a patient who underwent bariatric Roux-en-Y gastric bypass: A case report.

INTRODUCTION: Rapid weight loss following bariatric surgery is associated with high incidence of gallstones and complications that may need bilioenteric diversion. This presents a specific challenge in the management of this group of patients. CASE PRESENTATION: A 37 years old female underwent a Roux-en-Y gastric bypass (RYGB) in 2008 for morbid obesity. In 2009 she presented with obstructive jaundice and was diagnosed with choledocholithiasis successfully managed by open cholecystectomy and choledochoduodenostomy. In the following years, she developed recurrent attacks of fever, chills, jaundice, and right upper quadrant pain and her weight loss was not satisfactory. Imaging of the liver showed multiple cholangitic abscesses. Reflux at the choledochoduodenostomy site was suggestive of sump syndrome as a cause of her recurrent cholangitis and a definitive surgical treatment was indicated. Intraoperative findings confirmed sump at the choledochoduodenostomy site and also revealed the presence of a large superficial accessory duct arising from segment four of the liver with separate drainage into the duodenum distal to the choledochoduodenostomy site. A formal hepaticojejunostomy was done after ductoplasty. The Roux limb was created by transecting the jejunum 40cm distal to the foot anastomosis of the RYGB. The gastric limb was lengthened as part of this procedure which afforded the patient the additional benefit of weight loss. CONCLUSION: Choledochoduodenostomy should be avoided in patients with RYGB due to the risk of sump syndrome which requires conversion to a formal hepaticojejunostomy.

Inguinal prosthetic hernioplasty by anterior prosthetic enforcement of the fascia transversalis--a novel surgical technique.

A new technique of prosthetic inguinal hernioplasty is presented. The originality of the technique is the position of the mesh: between the transversus muscle and fascia transversalis. The surgical technique is presented in details. The procedures of choice for inguinal hernia repair, from the literature of the past years, are discussed.

[Comparative study of accidents and complications of laparoscopic cholecystectomy in cirrhotic and non cirrhotic patients]. / Etude comparative des accidents et des complications de la cholécystectomie laparoscopique chez les cirrhotiques et les non cirrhotiques.

Among a total of 9000 laparoscopic cholecystectomies, 60 (0.66%) were performed in cirrhotics patients. We have analyzed the presence of intra- and postoperative complications and have made a statistical comparison between cirrhotics and the group of 8940 non-cirrhotics. Cirrhosis was associated with a higher rate of conversions, of intra- and postoperative complications and mortality. The particularities of the intervention in cirrhotic patients are evaluated. Data analysis shows that cirrhotic patients have special problems regarding operation indication, surgical technique and pre- and postoperative treatment.

Ruptured hydatid cyst of the liver with biliary obstruction: presentation of a case and review of the literature.

The case of a 66 year old woman admitted with a picture of jaundice acute cholangitis is reported. Ultrasonography showed a dilatation of intrahepatic bile ducts, gallbladder hydrops with several stones, enlarged common bile duct (CBD) with hyperechoic material inside and a cystic tumor with hydatid features. With a strong suspicion of a hydatid cyst ruptured in the biliary tree with biliary obstruction, endoscopic cholangiopancreatography was performed. The diagnosis was confirmed by endoscopic retrograde cholangiopancreatography and the hydatid membranes were extracted from the CBD with subsequent clinical improvement. The second step of treatment comprised the surgical cure of the cyst and cholecystectomy. The data from the literature are finally presented with a special emphasis on the ultrasound diagnosis and the endoscopic treatment.

In situ thermal ablation of focal liver neoplasms, with a special emphasis on the intraoperative ultrasound-guided radio frequency ablation method.

In the last two decades an important number of image-guided procedures have been developed in order to treat focal liver tumors through ablation in a similar way with the surgical procedure, which is still considered as the curative method for patients with resectable hepatic tumours. Unfortunately this criteria does not apply to all patients and in those cases (nonsurgical patients), the techniques are becoming frequently used as standard independent or adjuvant therapies. Tumour ablation using thermal procedures is now considered as one of the most promising among these alternative ablation therapies. It is the goal of these techniques together with the continuous improvement in technology and increasing clinical experience, to become the treatment of choice for limited liver tumours, challenging surgical resection

Radiofrequency by open surgical approach in the treatment of hepatic tumours: early experience with 14 cases.

The aim of the study was the evaluation of radiofrequency in the treatment of hepatic tumours during laparotomy performed for hepatic tumours. The initial experience with 14 patients operated for hepatic tumours (5 primary and 9 metastatic) is presented. The paper also presents the technique concerning the intensity and duration of the power applied, the association with the surgical resection, the immediate postoperative evolution and the dynamics of the hepatic enzymes as well as the postoperative results of ultrasound and CT examinations performed within the first 6 weeks. The indications of RF during laparotomy and the place of RF ablation in the treatment of liver tumours in comparison with other ablation techniques are discussed

Gallbladder carcinoma. A clinical study of a series of 38 cases.

We analyse a series of 38 cases of gallbladder carcinoma. All cases presented gallbladder stones and IVB was the most frequent TNM stage--29 cases (76.31%). Preoperative diagnosis was made in 9 cases (23.69%), all of them by ultrasound examination. Resective procedures was possible in 8 cases (21%), whereas radical cholecystectomy was possible only in 3 cases (7.9%). The histological findings were: adenocarcinoma in 28 cases (73.67%), papillary adenocarcinoma in 3 cases (7.89%) and undifferentiated carcinoma in 7 cases (18.4%). We conclude that the late presentation due to the absence of specific symptoms and the poor diagnosis performance were responsible for the failure of detection in early stages and therefore for the poor prognosis of gallbladder carcinoma.

Selective ex-vivo photothermal ablation of human pancreatic cancer with albumin functionalized multiwalled carbon nanotubes.

The process of laser-mediated ablation of cancer cells marked with biofunctionalized carbon nanotubes is frequently called "nanophotothermolysis". We herein present a method of selective nanophotothermolisys of pancreatic cancer (PC) using multiwalled carbon nanotubes (MWCNTs) functionalized with human serum albumin (HSA). With the purpose of testing the therapeutic value of these nanobioconjugates, we have developed an ex-vivo experimental platform. Surgically resected specimens from patients with PC were preserved in a cold medium and kept alive via intra-arterial perfusion. Additionally, the HSA-MWCNTs have been intra-arterially administered in the greater pancreatic artery under ultrasound guidance. Confocal and transmission electron microscopy combined with immunohistochemical staining have confirmed the selective accumulation of HSA-MWCNTs inside the human PC tissue. The external laser irradiation of the specimen has significantly produced extensive necrosis of the malign tissue after the intra-arterial administration of HSA-MWCNTs, without any harmful effects on the surrounding healthy parenchyma. We have obtained a selective photothermal ablation of the malign tissue based on the selective internalization of MWCNTs with HSA cargo inside the pancreatic adenocarcinoma after the ex-vivo intra-arterial perfusion.

NAT2 polymorphisms and sporadic colorectal cancer survival.

BACKGROUND AND AIM: NAT2 gene polymorphisms can influence colorectal cancer (CRC) risk. We aimed to determine the extent to which NAT2 gene polymorphisms influence the survival of patients with sporadic colorectal cancer. METHODS: Seventy patients with sporadic colorectal cancer that underwent surgery at the 3rd Surgical Department of Cluj-Napoca between October 2003-May 2005 were randomly selected. Correlations between NAT2*5C(T341C), NAT2*5A(C481T), NAT2*6B(G590A), NAT2*7B(G857A) polymorphisms and survival of patients with different Dukes-MAC stages of CRC were analyzed. We compared patients with a slow acetylator genotype with those having an intermediate or rapid acetylator genotype. RESULTS: The slow acetylator 341CC genotype is a negative prognostic factor, 20% vs. 30.8%, as compared to rapid acetylator 341TT/TC genotypes (p=0.02) in the patients diagnosed with stage C CRC. For the same stage patients, the slow acetylator 481CC was a positive prognostic factor, 33% vs. 25% (p=0.03). The slow acetylator 590AA was a negative prognostic factor for the survival of patients with stages B and C, 0% vs. 31% (p=0.02). The slow acetylator 857AA genotype was a negative prognostic factor for the patients in stage B, survival rate 0.69% vs. 50%, and positive for patients with stage C, survival rate 50% vs. 21% (p=0.0101). The rapid acetylator 341TT/TC represented a good prognostic factor, while the slow 341CC a negative one for stage D patients (p= 0.04, survival of 18.9%) HR=0.30 with 95%, CI[0.025- 0.9810]. CONCLUSION: The NAT2 gene may be considered as a prognostic factor for the survival of patients with CRC.

C677T and A1298C mutations in the MTHFR gene and survival in colorectal cancer.

BACKGROUND AND AIMS: Our preliminary results laboratory have shown some association between C677T and A1298C MTHFR mutations and factors influencing survival in colorectal cancer. We studied the survival of patients with colorectal cancer depending on the initial Dukes-MAC stage of the disease at the time of diagnosis and the MTHFR mutation present. METHODS: We randomly selected 69 patients with sporadic colorectal cancer who underwent surgery at the Surgical Clinic III Cluj between October 2003 and May 2005. The study ended on 15 March 2008. Survival data was verified in 48 cases. Survival analyses were performed using Kaplan-Mayer survival curves and median survival time was calculated. The comparison of two or more categories was performed using the Logrank test, considering the threshold value p less or equal to 0.05. RESULTS: In both stage B and C patients with the CT/TT mutation have a poorer survival rate than those with the wild CC genotype (p less than 0.05). The presence of the C677T mutation (CT or TT genotype) in patients diagnosed in stage D did not result as a significant survival risk factor (HR=0.537, 95% CI 0.128-2.184) p>0.05. Patients diagnosed with stage C colorectal cancer, who have the 1298C allele, have significantly better survival than those without this allele, 60% vs. 15.4%, (p=0.0016). CONCLUSIONS: In our study in both stage B and C, patients with the CT/TT mutation have poorer survival than the wild CC genotype. In stage B patients, the A1298C mutation is a negative prognostic factor. The presence of the A1298C mutation in a hetero- or homozygous form plays a protective role in stage C.

Host-related predictive factors for anastomotic leakage following large bowel resections for colorectal cancer.

AIM: To identify the risk, the host-related prognostic factors and their predictive value for anastomotic leakage after colorectal resections following cancer. METHOD: 993 patients who underwent large bowel resection and primary anastomosis above 12 centimeters from the anal verge, without a temporary or permanent stoma at the Surgical Hospital No.3 (Cluj-Napoca, Romania) were retrospectively reviewed. RESULTS: 32 (3.22 percent) anastomotic leaks were confirmed. Univariate analysis showed that the preoperative variables significantly associated with anastomotic leakage included: weight loss, smoking, cardiovascular disease, lung disease, hypoproteinemia, diabetes, anemia, leukocytosis, presence of two or more underlying diseases. Alcohol use, cerebrovascular disease, bowel preparation, type of anastomosis, tumor location, stage and histology were not significant variables. Hypoproteinemia (total serum protein level < or = 6 g/dl) and anemia (serum hemoglobin level < or = 11 g/dl) remained significant in the logistic regression model. The prognostic role of serum hemoglobin and proteins for the anastomotic leak was assessed using ROC curve analysis. For the cut-off value of serum protein level = 5.5 g/dl, a sensitivity of 61.6 percent and a specificity of 84.2 percent were calculated. The area under the curve was 0.703 (p= 0.0024). The area under the curve for serum hemoglobin was 0.616 (p=0.028). A sensitivity of 64.0 percent and a specificity of 64.7 per cent were obtained for a cut-off value of 9.4 g/dl. CONCLUSION. A serum protein level lower than 5.5 g/dl and serum hemoglobin lower than 9.4 g/dl could be considered as host-related predictive markers for anastomotic leak in large bowel resections for cancer.

MTHFR polymorphisms as prognostic factors in sporadic colorectal cancer.

AIM: Theoretically, individuals having at least one mutant allele present a modified activity of the MTHFR enzyme and low methylation, DNA synthesis-repair respectively, which could imply a higher risk of colorectal cancer. The purpose of this study was to investigate the relations of these mutations with the clinico-pathological aspects of colorectal cancer. MATERIAL AND METHOD: The study included 69 patients with sporadic colorectal cancer. The relative risk in homozygous patients with a normal allele and for mutations C667T and A1298C, in heterozygous patients with one normal and one mutant allele, and for homozygous patients for the mutant allele was calculated. RESULTS: C667T and A1298C mutations represent a risk factor for colorectal cancer with an OR (odds ratio) = 2.13 (CI (0.51-8.91)) and 3 (CI(0.3-29.58), respectively, in homozygous patients. These mutations are associated with a more frequent location of lesions at the colon level, OR=2.3 and 2.15 respectively. The incidence of the A1298C mutation was more frequent in stage N0 than N+ (p<0.05), pT2 vs. pT3 (p<0.05), as well as in Dukes stages B and D vs. A or C (p<0.05). CONCLUSIONS: The results obtained support the hypothesis of an increased colorectal cancer prevalence in patients with one of the MTHFR gene mutations. These patients develop colon cancer more frequently, they present lymph node invasion more rarely, and develop more often distant metastases.

NAT2 gene polymorphism and sporadic colorectal cancer. Prevalence, tumor stage and prognosis. A preliminary study in 70 patients.

AIM: Theoretically, individuals with a NAT2 rapid acetylator genotype are exposed to a higher risk of developing colorectal cancer. We attempted to study this relationship. MATERIAL AND METHODS: We evaluated a group of 70 patients with sporadic colorectal cancer and 40 controls. We calculated the relative risk for patients homozygous for the normal allele NAT2*5C, NAT2*5A, NAT2*6B, NAT2*7B, for heterozygous patients and for patients homozygous for the mutant allele. RESULTS: We found an increased risk for patients with a rapid acetylator genotype to develop colorectal cancer. Rapid acetylators, homozygous negative or heterozygous for the NAT2*5C, NAT2*5A and NAT2*6B mutations have an increased risk of colorectal cancer compared to homozygous positive patients.The analysis of the NAT2*5C genotype shows that the majority of the cases are at stage pT3 for rapid acetylators, 41 cases (74.54%), compared to slow acetylators, where the majority of cases are at stage pT4, 10 cases (66.66%) (p<0.05). The genotype with a rapid acetylator phenotype of the NAT2*5C, NAT2*5A and NAT2*7B variants was most frequently associated with Dukes stage B. The NAT2*5C, NAT2*5A and NAT2*7B gene variants with a slow acetylator pheno-type were most frequently associated with Dukes stage C. CONCLUSIONS: Rapid acetylators, homozygous negative or heterozygous for the NAT2*5C, NAT2*5A and NAT2*6B mutations have a higher risk of colorectal cancer compared to positive homozygotes. Rapid acetylators have earlier stages of colorectal cancer and a better prognosis than slow acetylators, who are diagnosed in more advanced stages.