Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is one of the preferred initial treatment strategies for locally advanced rectal cancer. Responses are variable, and most patients still require surgery. The aim of this study was to identify molecular mechanisms determining poor response to CRT. METHODS: Global gene expression and pathway enrichment were assessed in pretreatment biopsies from patients with non-metastatic cT2-4 N0-2 rectal cancer within 7 cm of the anal verge. Downstream Akt activation was assessed in an independent set of pretreatment biopsies and in colorectal cancer cell lines using immunohistochemistry and western blot respectively. The radiosensitizing effects of the Akt inhibitor MK2206 were assessed using clonogenic assays and xenografts in immunodeficient mice. RESULTS: A total of 350 differentially expressed genes were identified, of which 123 were upregulated and 199 downregulated in tumours from poor responders. Mitochondrial oxidative phosphorylation (P < 0·001) and phosphatidylinositol signalling pathways (P < 0·050) were identified as significantly enriched pathways among the set of differentially expressed genes. Deregulation of both pathways is known to result in Akt activation, and high immunoexpression of phosphorylated Akt S473 was observed among patients with a poor histological response (tumour regression grade 0-2) to CRT (75 per cent versus 48 per cent in those with a good or complete response; P = 0·016). Akt activation was also confirmed in the radioresistant cell line SW480, and a 50 per cent improvement in sensitivity to CRT was observed in vitro and in vivo when SW480 cells were exposed to the Akt inhibitor MK2206 in combination with radiation and 5-fluorouracil. CONCLUSION: Akt activation is a key event in the response to CRT. Pharmacological inhibition of Akt activation may enhance the effects of CRT. Surgical relevance Organ preservation is an attractive alternative in rectal cancer management following neoadjuvant chemoradiotherapy (CRT) to avoid the morbidity of radical surgery. Molecular steps associated with tumour response to CRT may provide a useful tool for the identification of patients who are candidates for no immediate surgery. In this study, tumours resistant to CRT were more likely to have activation of specific genetic pathways that result in phosphorylated Akt (pAkt) activation. Pretreatment biopsy tissues with high immunoexpression of pAkt were more likely to exhibit a poor histological response to CRT. In addition, the introduction of a pAkt inhibitor to cancer cell lines in vitro and in vivo led to a significant improvement in sensitivity to CRT. Identification of pAkt-activated tumours may thus allow the identification of poor responders to CRT. In addition, the concomitant use of pAkt inhibitors to increase sensitivity to CRT in patients with rectal cancer may constitute an interesting strategy for increasing the chance of a complete response to treatment and organ preservation.

Magnetic resonance imaging following neoadjuvant chemoradiation and transanal endoscopic microsurgery for rectal cancer.

AIM: Full-thickness local excision after neoadjuvant chemoradiotherapy (CRT) for patients with rectal cancer and incomplete clinical response has been a treatment strategy for organ preservation. Follow-up of these patients is challenging since anatomic distortion and postoperative changes may be clinically indistinguishable from tumour recurrence. MRI may have a role in detecting recurrence. The aim of this study was to describe the MRI findings during follow-up in patients having local excision following CRT with and without local recurrence. METHOD: The data were collected retrospectively from a single centre. Fifty-three patients with rectal cancer who had full-thickness local excision after neoadjuvant CRT and near-complete response were eligible for the study. Patients with local recurrence were treated by radical salvage surgery. The main outcome was local MRI assessment findings during follow-up. RESULTS: Fifteen patients (five who developed local recurrence and 10 with no evidence of local recurrence) had MR images available for review and were included in the study. High signal intensity and thickening of the rectal wall were present in all patients with recurrent disease within the rectal wall. Overall, 80% of the patients with recurrence showed diffusion restriction. MRI mesorectal fascia status and circumferential resection margin showed agreement in all cases. A low signal intensity scar was seen in all patients without recurrent disease. CONCLUSION: MRI shows high signal intensity and thickening of the rectal wall in recurrent disease in comparison to a low signal intensity fibrotic scar in non-recurrent disease. These findings may be useful in surveillance of these patients.

Predicting complete response to neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.

BACKGROUND: Molecular imaging using positron emission tomography/computerized tomography (PET/CT) may add relevant incremental diagnostic information to standard structural cross-sectional imaging. Such information may allow identification of patients with rectal cancer that are more likely to develop complete tumor regression after neoadjuvant chemoradiation therapy (CRT). The objective of this report was to identify PET/CT features that are associated with a complete response after CRT. METHODS: 99 cT2-4N0-2M0 distal rectal cancer patients (≤7 cm from anal verge) were included in this prospective single center trial (NCT 00254683). Patients underwent baseline PET/CT followed by 54 Gy and 5-fluorouracil-based neoadjuvant CRT. After completion of therapy, patients underwent 6- and 12-week PET/CT. Clinical assessment of tumor response was performed at 12 weeks and was blinded to radiological information. Patients were treated according to clinical assessment. RESULTS: There were seven patients with a complete pathological response (pCR) and 16 with a complete clinical response (cCR) (23 complete responders). Comparison of pCR exclusively and non-pCR revealed that only baseline primary tumor standard uptake value (SUV) was a significant predictor of response. Comparison of complete responders (pCR or cCR) and non-complete responders showed that depth of rectal wall uptake at baseline PET/CT (p = 0.002) and variation between baseline and 12-week maximum standard uptake value (SUVmax) of primary tumor (p = 0.001) were independent predictors for complete response at multivariate analysis. A decrease >67 % between baseline and 6-week or 76 % between baseline and 12-week SUVmax were associated with complete response (pCR or cCR; p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Positron emission tomography/computerized tomography at baseline, 6 and 12 weeks, may provide information regarding patients with a higher likelihood of developing complete tumor regression following neoadjuvant CRT.

Clinical relevance of positron emission tomography/computed tomography-positive inguinal nodes in rectal cancer after neoadjuvant chemoradiation.

AIM: Inguinal nodes may be a possible route for lymphatic spread in patients with distal rectal cancer. The outcome was examined for patients with distal rectal cancer undergoing neoadjuvant chemoradiation (CRT) and having 2-fluorine-18-fluoro-2-deoxy-d-glucose (FDG)-avid inguinal nodes using positron emission tomography/computed tomography (PET/CT) imaging. METHOD: Ninety-nine consecutive patients with cT2-4N0-2M0 distal rectal adenocarcinoma were enrolled in a clinical trial (NCT00254683) and underwent baseline PET/CT followed by 54 Gy and 5-fluorouracil-based CRT. After CRT, patients underwent 6- and 12-week PET/CT. Patients with positive inguinal node uptake were compared with patients with negative uptake. The inguinal region was not included in the field of radiation therapy. RESULTS: Seventeen (17%) patients had baseline positive inguinal node FDG uptake. They were more likely to have the tumour closer to the anal verge (2.0 vs 4.2 cm; P = 0.001). Of these, eight (47%) demonstrated a positive inguinal uptake at PET/CT after 12 weeks from CRT. Patients with inguinal node FDG uptake after CRT (positive PET at baseline and 12 weeks) had a significantly worse 3-year overall and disease-free survival (P = 0.02 and P = 0.03). After a median follow-up period of 22 months, none of these patients had developed inguinal recurrence. CONCLUSION: Uptake of inguinal nodes at PET/CT may be present in up to 17% of patients with distal rectal cancer, particularly with ultra-low tumours. Nearly half of these nodes no longer show uptake after CRT despite the groin area not being included in the radiation field. Persistence of inguinal node uptake 12 weeks after CRT completion may be a marker for worse oncological outcome.

Role of biopsies in patients with residual rectal cancer following neoadjuvant chemoradiation after downsizing: can they rule out persisting cancer?

AIM: The study aimed to determine the value of postchemoradiation biopsies, performed after significant tumour downsizing following neoadjuvant therapy, in predicting complete tumour regression in patients with distal rectal cancer. METHOD: A retrospective comparative study was performed in patients with rectal cancer who achieved an incomplete clinical response after neoadjuvant chemoradiotherapy. Patients with significant tumour downsizing (> 30% of the initial tumour size) were compared with controls (< 30% reduction of the initial tumour size). During flexible proctoscopy carried out postchemoradiation, biopsies were performed using 3-mm biopsy forceps. The biopsy results were compared with the histopathological findings of the resected specimen. UICC (Union for International Cancer Control) ypTNM classification, tumour differentiation and regression grade were evaluated. The main outcome measures were sensitivity and specificity, negative and positive predictive values, and accuracy of a simple forceps biopsy for predicting pathological response after neoadjuvant chemoradiotherapy. RESULTS: Of the 172 patients, 112 were considered to have had an incomplete clinical response and were included in the study. Thirty-nine patients achieved significant tumour downsizing and underwent postchemoradiation biopsies. Overall, 53 biopsies were carried out. Of the 39 patients who achieved significant tumour downsizing, the biopsy result was positive in 25 and negative in 14. Only three of the patients with a negative biopsy result were found to have had a complete pathological response (giving a negative predictive value of 21%). Considering all biopsies performed, only three of 28 negative biopsies were true negatives, giving a negative predictive value of 11%. CONCLUSION: In patients with distal rectal cancer undergoing neoadjuvant chemoradiation, post-treatment biopsies are of limited clinical value in ruling out persisting cancer. A negative biopsy result after a near-complete clinical response should not be considered sufficient for avoiding a radical resection.

Factors affecting management decisions in rectal cancer in clinical practice: results from a national survey.

BACKGROUND: Management of rectal cancer has become increasingly complex and a multidisciplinary approach is considered of key importance for improving outcomes. A national survey among specialists involved in this multidisciplinary setting was performed. METHODS: A web-based survey containing 11 questions regarding rectal cancer management was sent to surgeons and medical oncologists registered by their corresponding societies as members. Statistical analysis was performed using the chi-square and Fisher's exact tests for all categorical variables according to response to individual questions. Multivariate analysis was performed using Cox's logistic regression. RESULTS: Overall, 418 email recipients responded the survey. Local staging was performed without either magnetic resonance imaging or endorectal ultrasound by 64% of responders. Seventy-two percent considered that final management decision should be made after neoadjuvant chemoradiation therapy. Additionally, 46% considered that an alternative procedure (local excision or observation) was appropriate in a patient with a complete clinical response. Colorectal surgeons were more frequently in favor of longer intervals after completion of chemoradiation therapy (P = 0.001) and of alternative management procedures after a complete clinical response (P = 0.02). After multivariate analysis, the choice of a watch and wait approach after a complete clinical response following neoadjuvant chemoradiation therapy was significantly more frequent among surgeons (OR 3.5, 95% CI 1.8-7.1). CONCLUSIONS: Surgeons seem to be more in favor of tailoring management of rectal cancer according to tumor response after neoadjuvant chemoradiation therapy, with longer intervals after chemoradiation therapy, decisions about treatment strategy being made after chemoradiation therapy instead of before, and the use of alternative surgical procedures after a complete clinical response following neoadjuvant therapy.

Bioinformatics construction of the human cell surfaceome.

Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.

Hepatic adenoma. Timing for surgery.

BACKGROUND/AIMS: Hepatic adenoma (HA) is a rare benign tumor of the liver. Tumor resection has been recommended for symptomatic or enlarging HA because of the risk of intraperitoneal, intrahepatic hemorrhage or even the development of hepatocellular carcinoma. From 1989 to 2003 we reviewed the medical records and radiology files of 28 patients with a proved diagnosis of hepatic adenoma. This article summarizes a single-center experience with surgical treatment of hepatic adenoma. METHODOLOGY: 24 patients were female and 4 were male. Twenty-two patients had a history of oral contraceptive use. Abdominal pain was presented in 19 patients and 3 of them had had an acute episode. The mean age was 36.3 years. Preoperative assessment included liver test, ultrasonography and computed tomography in all patients plus technetium (99mTc)-sulfur colloid and 99mTc-labeled DISIDA (dimethyliminoacetic acid) liver scintigraphy (n=19) and magnetic resonance imaging (n=22). RESULTS: Operative procedures included enucleation in 3 patients, two of them associated with hepatic segmentectomy; resection of one or two segments in 14 patients; left and right hemihepatectomy respectively in 7 and 3 patients; right extended hepatectomy in one patient and nonanatomic resection in one patient. There was no postoperative death and the complications were: bile leakage (re-operation) one patient, intraperitoneal abscess (re-operation) one patient, pleural effusion two patients, venous thrombosis one patient and wound infection one patient. CONCLUSIONS: We recommend that since the diagnosis has been well-established both enucleation or anatomically based resections of hepatic adenoma should be performed in all cases mainly in female patients taking oral contraceptives with tumors greater than 3cm for the risk of hepatic hemorrhage or even when malignancy cannot be excluded.

Evaluation of molecular markers in hepatic metastasis of colorectal adenocarcinoma.

BACKGROUND/AIMS: There were 49 patients studied, coming from The Liver Unit at the "Hospital das Clinicas da Faculdade de Medicina da USP (N=41) and from "Prof. Dr. Angelita Habr-Gama and Joaquim Gama-Rodrigues Surgery Institute", SP (N=8); all of which had hepatic metastasis of colorectal adenocarcinoma, with no evidence of concurrent metastasis in any other organs and were submitted to surgical treatment, during the period of 1992 to 2002, with the aim of analyzing the immunoexpression of the p53, ki-67, p16 and molecular markers in order to relate the disease-free period with the prognosis. METHODOLOGY: The patient's clinical data were analyzed retrospectively for verification of information such as age, gender, size of the hepatic metastasis and/or the largest lesion, number of satellite nodules resected and compromised, margin of resection free from neoplasia. RESULTS: The immunoexpression of the p53 was associated with the shortest period of life free from disease (p = 0.04). The proliferation marker ki-67 was not associated with the reduction of the disease-free interval and survival; the immunoexpression of the proliferation marker p16 was not associated with the reduction of disease-free period and survival, however, it was associated with hepatic metastasis synchronism. In patients who received postoperative systemic chemotherapy with 5-FU and leucovorin, the immunoexpression on the hepatic metastasis was not associated with a longer disease-free interval. CONCLUSIONS: Molcular markers may be useful to evaluate hepatic metastasis of colorectal Adenocarcinoma.

Larger amounts of nitrite and nitrate-reducing bacteria in megaesophagus of Chagas' disease than in controls.

In the megaesophagus of Chagas' disease, chronic esophagitis is caused by stasis of swallowed food and saliva. In this environment, the overgrowth of aerobic and anaerobic bacteria, including nitrate-reducing bacteria, is observed. The reduction of nitrate into nitrite by the action of these bacteria has been associated with the formation of volatile nitrosamines in different situations of gastric bacterial overgrowth. We have hypothesized that this phenomenon could occur in the esophageal lumen of patients with megaesophagus. To evaluate the concentration of nitrite, the presence of volatile nitrosamines and the concentration of nitrate-reducing bacteria in the esophageal lumen of patients with non-advanced megaesophagus of Chagas' disease and in a group of patients without esophageal disease. Fifteen patients with non-advanced megaesophagus [megaesophagus group (MG)] and 15 patients without any esophageal disease [control group (CG)] were studied. Saliva samples were taken for nitrate and nitrite quantitative determination and esophageal stasis liquid samples were taken for nitrate and nitrite quantitative determination, volatile nitrosamines qualitative determination and reductive bacteria quantitative determination. MG and CG were equivalent in nitrate and nitrite saliva concentration and in nitrate esophageal concentration. Significant difference was found in nitrite (p = 0.003) and reductive bacteria concentration (p < 0.0001), both higher in MG. Volatile nitrosamines were identified in three MG patients and in none of the CG patients, but this was not significant (p = 0.113). There is a higher concentration of reductive bacteria in MG, responsible for the rise in nitrite concentration at the esophageal lumen and, eventually, for the formation of volatile nitrosamines.

An evaluation of gastric scintigraphy pre- and postpyloroduodenal peptic stenosis dilation.

BACKGROUND: The usual treatment of pyloroduodenal peptic stenosis has been mainly surgical, through pyloroplasty or gastric resection, with or without vagotomy. Since the first description of treatment for this peptic complication by endoscopic balloon dilation perfomed by Benjamin in 1982 [2], this procedure has become a therapeutic option in association with the medical treatment of peptic disease. The aim of this study is to evaluate the results involving clinical, endoscopic, and gastric emptying scintigraphy parameters. METHODS: Between August 1998 and February 2000, 20 patients with pyloroduodenal stenosis refractory to conservative treatment were treated at the Gastrointestinal Endoscopy Unit of the University of São Paulo Medical School. All patients who presented clinical manifestations of pyloroduodenal stenosis underwent upper gastrointestinal endoscopy to confirm peptic stenosis. Biopsy of the narrowing for the confirmation of a benign disease and gastric biopsy for Helicobacter pylori detection were performed. The treatment consisted of dilation of the stenosis with type TTS (Through The Scope) hydrostatic balloon under endoscopic control, treatment of Helicobacter pylori infection, and gastric acid suppression with oral administration of proton pump inhibitor. All patients, except one who was excluded from this study, were submitted to a clinical endoscopic assessment and gastric emptying evaluation by ingestion of (99m)Tc before and after the treatment. Endoscopic evaluation considered the diameter of the stenotic area before and after treatment. A scintigraphic study compared the time of gastric emptying before and after balloon dilation. RESULTS: Nineteen patients completed treatment by hydrostatic balloon dilation. Clinical symptoms such as bloating (p < 0.0001), epigastric pain (p = 0.0159), gastric stasis (p < 0.0001), and weight gain (p = 0.036) showed significant improvement. The diameter of the stenotic area increased significantly (p < 0.01) after the dilation treatment as well as a better gastric emptying of (99m)Tc (p < 0.0001). CONCLUSION: The dilation of the peptic pyloroduodenal stenosis using a hydrostatic balloon is a safe and effective procedure. The evaluation with gastric scintigraphy by ingestion of (99m)Tc is an effective method of assessment for the improvement of gastric function, because its results corresponded to the clinical improvement after endoscopic treatment.

Lower esophageal sphincter analysis using computerized manometry in patients with chagasic megaesophagus.

Due to the introduction of computer technology into manometry laboratories, three-dimensional manometric images of the lower esophageal sphincter can be constructed based on radially oriented pressures, a method termed 'computerized axial manometry.' Calculation of the sphincter pressure vector volume using this method is superior to standard manometric techniques in assessing lower esophageal sphincter function in patients with gastroesophageal reflux disease and idiopathic achalasia. Despite similarities between idiopathic achalasia and chagasic esophagopathy found using clinical, radiological, and manometric studies, controversy around lower esophageal sphincter pressure persists. The goal of this study was to analyze esophageal motor disorders in Chagas' megaesophagus using computerized axial manometry. Twenty patients with chagasic megaesophagus (5 men, 15 women, and average age 50.1 years, range 17-64) were prospectively studied. For three-dimensional imaging construction of the lower esophageal sphincter, a low-complacency perfusion system and an eight-channel manometry probe with four radial channels placed in the same level were used. For probe traction, the continuous pull-through technique was used. Results showed that the lower esophageal sphincter of patients with chagasic megaesophagus have significantly elevated pressure, length, asymmetry, and vector volumes compared to those of normal volunteers (P < 0.05). Aperistalsis of the esophageal body waves was observed in all patients and contraction amplitude was lower than that in normal patients. We conclude that patients with chagasic megaesophagus have hypertonic lower esophageal sphincter and aperistalsis of the esophageal body.

Congenital achalasia: facts and fantasies.

Achalasia, a poorly relaxing lower esophageal sphincter, produces a functional obstruction and the expected symptoms of dysphagia, regurgitation and eventually weight loss. The cause of achalasia remains largely unknown in Western countries, Chagas' disease being the most frequent etiology in Brazil. We report on two sets of monozygotic male twins with typical manifestations of achalasia. The majority of authors attribute a limited contribution unless achalasia is related to a multisystem disorder, like the triple-A or Allgrove's syndrome, an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. The four cases reported demonstrated the genetic influence of achalasia in patients without multisystem disorders. We believe that idiopathic achalasia is a syndrome with similar clinical, pathological, radiological and manometric evolution, but with a great variety of etiological agents, one of them being the congenital form.

Lipid peroxidation in bariatric candidates with nonalcoholic fatty liver disease (NAFLD) -- preliminary findings.

BACKGROUND: Pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains incompletely known, and oxidative stress is one of the mechanisms incriminated. The aim of this study was to evaluate the role of liver oxidative stress in NAFLD affecting morbidly obese patients. METHODS: 39 consecutive patients with BMI >40 kg/m2 submitted to Roux-en-Y gastric bypass were enrolled, and wedge liver biopsy was obtained during operation. Oxidative stress was measured by concentration of hydroperoxides (CEOOH) in liver tissue. RESULTS: Female gender was dominant (89.7%) and median age was 43.6 +/- 11.1 years. Histology showed fatty liver in 92.3%, including 43.6% with nonalcoholic steatohepatitis (NASH), 48.7% with isolated steatosis and just 7.7% with normal liver. Liver cirrhosis was present in 11.7% of those with nonalcoholic steatohepatitis. Concentration of CEOOH was increased in the liver of patients with NASH when compared to isolated steatosis and normal liver (0.26+/- 0.17, 0.20+/- 0.01 and 0.14+/- 0.00 nmol/mg protein, respectively) (P < 0.01). Liver biochemical variables were normal in 92.3% of all cases, and no difference between NASH and isolated steatosis could be demonstrated. CONCLUSIONS: 1) Nonalcoholic steatosis, steatohepatitis and cirrhosis were identified in substantial numbers of morbidly obese patients; 2) Concentration of hydroperoxides was increased in steatohepatitis, consistent with a pathogenetic role for oxidative stress in this condition.

Is it feasible to reach the bypassed stomach after Roux-en-Y gastric bypass for morbid obesity? The use of the double-balloon enteroscope.

BACKGROUND AND STUDY AIMS: Endoscopic evaluation of the excluded stomach after Roux-en-Y gastric bypass surgery for morbid obesity is a challenge, and the pathological changes that take place in the bypassed stomach are unclear. A new double-balloon method of evaluating the bypassed stomach after Roux-en-Y gastric bypass surgery for morbid obesity is described here. PATIENTS AND METHODS: This new enteroscope uses two balloons, one attached to the tip of the endoscope and the other to the distal end of the soft overtube. The procedures were carried out in six patients using the retrograde route, through the end-to-side jejunal anastomosis via the duodenobiliopancreatic limb up to the bypassed stomach. RESULTS: The bypassed stomach was reached in five of six patients (83.3 %). An endoscopic appearance of atrophic gastritis was found in three patients, mild in two cases and severe in one case with intestinal metaplasia. Erosive and hemorrhagic gastritis was found in two patients. CONCLUSIONS: Endoscopic evaluation of the bypassed stomach via the retrograde route after Roux-en-Y gastric bypass for morbid obesity is feasible using the double-balloon enteroscope.

The main hepatic anatomic variations for the purpose of split-liver transplantation.

BACKGROUND/AIMS: Variant hepatic anatomy must be recognized and appropriately managed during split-liver transplantation to ensure complete vascular and biliary supply to both grafts. The aim of this study was to demonstrate the importance of an assessment of the hepatic anatomical structures for the purpose of split-liver transplantation. MATERIAL AND METHODS: Human cadaveric livers (n = 60) were obtained during routine autopsies. The cadavers and the livers had to comply with the following requirements: (1) minimum age 18 years, (2) no liver pathology expected from medical history, and (3) no liver pathology noted at autopsy. Resections were carried out en bloc with liver, celiac trunk, left gastric artery, lesser omentum, superior mesenteric artery, and head of the pancreas. The main anatomical structures of the liver as hepatic artery, portal vein, biliary tree, and hepatic veins were dissected and correlated hepatic segments for the application of liver splitting. RESULTS: The right the median, and the left hepatic veins were unique, with in 59 (98.3%), 53 (88.3%) and 46 (76.3%) cases, respectively. The portal vein trunk divided into right and left branches in 59 (98.3%) cases. A median branch appeared in 9 (15.2%) cases and no bifurcation of the portal vein occurred in 1 (1.6%) case. The right and left hepatic ducts were multiple in 47 (78.3%) and 57 (95%) cases, respectively, however, the median, hepatic duct was unique in 16 (26.6%) cases. Examining the intrahepatic distribution of the right hepatic duct, we found 4 branches in 28 (59%) cases (segments V, VI, VII, and VIII) 2 branches in 11 (23%) cases, (segments V and VI) and 2 branches in 8 (17%) cases (segments VII and VIII). Fifty-seven cadavers had multiple left hepatic ducts. The intrahepatic dissection showed that the distribution of the major branches were toward hepatic segments II and III. Three separate branches of the left hepatic duct were found in 11 (19%) cases (segments II, III, and IV). Two intrahepatic ducts coming from hepatic segments V and VI drained separately into the left intrahepatic biliary tree in 1 (2%) case. The arterial supply of the liver was by right and left hepatic artery with only 9 (15%) cases there being median hepatic artery. The right hepatic artery, coming from the superior mesenteric artery, was present in 15 (25%) cases and a left hepatic artery originating from the left gastric artery in only 2 (3.3%) cases. The left hepatic artery had 2 exceptional origins, in 1 (1.6%) case coming directly from the abdominal aorta and in the other from the superior mesenteric artery. The right and left hepatic artery was accessory, in 11 (18.3%) and 2 (3.3%) cases, respectively. The right hepatic artery was dominant in 4 (6.6%) cases. The median hepatic artery was directed to segment IV in 6 (10%) cases and to segment II and III in 3 (4.9%) cases. CONCLUSION: The study showed that the technique of controlled liver splitting for transplantation in 2 recipients is an acceptable method to increase the number of liver allografts. The anatomical and technical details of the splitting procedure are critical for the success of this technique. Good graft function and avoidance of complications depend on each graft having an intact arterial and portal blood supply as well as biliary and venous drainage from all retained liver segments. The absence of a bifurcation of the portal vein is a rare anomaly and would certainly contraindicate a partition.

Diet and colorectal cancer: current evidence for etiology and prevention.

The etiology of colorectal cancer (CRC) involves the interaction of cell molecular changes and environmental factors, with a great emphasis on diet components. But the paths connecting lifestyle characteristicas and the colorectal carcinogenesis remain unclear. Several risk factors are commonly found in western diets, such as high concentrations of fat and animal protein, as well as low amounts of fiber, fruits and vegetables. A large number of experimental studies have found a counteractive effect of fiber on neoplasia induction, especially in relation to fermentable fiber (wheat bran and cellulose). Epidemiological correlation studies have also indicated that a greater ingestion of vegetables, fruit, cereal and seeds is associated to a lower risk for colorectal neoplasia. Moreover, beneficial properties of fiber (especially from vegetable sources) were documented in more than half of case-control studies. Nevertheless, recent epidemiological data from longitudinal and randomized trials tended not to support this influence. Future research should evaluate what sources of fiber provide effective anti-neoplasic protection, carrying out interventional studies with specific fibers for longer periods. Red meat, processed meats, and perhaps refines carbohydrates are also implicated in CRC risk. Recommendantions to decrease red meat intake are well accepted, although the total amount and composition of specific fatty acids may have distinct roles in this setting. Current evidence favors the substitution of long and medium-chain fatty acids and arachidonic acid for short-chain fatty acids and eicosapentaenoic acid. Excess boy weight and excess energy intake inducing hyperinsulinemia have been also associated to CRC, as well as personal habits such as physical inactivy, high alcohol consumption, smoking and low consumption of folate and methionine. Thus, current recommendations for decreasing the risk of CRC include dietary measures such as increased plant food intake; the consumption of whole grains, vegetables and fruits; and reduced red meat intake.

Diet and colorectal cancer: current evidence for etiology and prevention / Dieta y cáncer colorrectal: evidencia actual sobre la etiología y la prevención

The etiology of colorectal cancer (CRC) involves the interaction of cell molecular changes and environmental factors, with a great emphasis on diet components. But the paths connecting lifestyle characteristic as and the colorectal carcinogenesis remain unclear. Several risk factors are commonly found in western diets, such as high concentrations of fat and animal protein, as well as low amounts of fiber, fruits and vegetables. A large number of experimental studies have found a counteractive effect of fiber on neoplasia induction, especially in relation to fermentable fiber (wheat bran and cellulose). Epidemiological correlation studies have also indicated that a greater ingestion of vegetables, fruit, cereal and seeds is associated to a lower risk for colorectal neoplasia. Moreover, beneficial properties of fiber (especially from vegetable sources) were documented in more than half of case-control studies. Nevertheless, recent epidemiological data from longitudinal and randomized trials tended not to support this influence. Future research should evaluate what sources of fiber provide effective anti-neoplasic protection, carrying out interventional studies with specific fibers for longer periods. Red meat, processed meats, and perhaps refines carbohydrates are also implicated in CRC risk. Recommendantions to decrease red meat intake are well accepted, although the total amount and composition of specific fatty acids may have distinct roles in this setting. Current evidence favors the substitution of long and medium-chain fatty acids and arachidonic acid for short-chain fatty acids and eicosapentaenoic acid. Excess boy weight and excess energy intakeinducing hyperinsulinemia have been also associated to CRC, as well as personal habits such as physical inactivy, high alcohol consumption, smoking and low consumption of folate and methionine. Thus, current recommendations for decreasing the risk of CRC include dietary measures such as increased plant food intake; the consumption of whole grains, vegetables and fruits; and reduced red meat intake

La etiología del cáncer colorrectal (CCR) implica la interacción entre los cambios celulares moleculares y los factores ambientales, con un gran énfasis sobre los componentes de la dieta. Pero los caminos que conectan las características del estilo de vida con la carcinogénesis siguen siendo inciertos. En las dietas occidentales se encuentran, habitualmente, diversos factores de riesgo como las concentraciones elevadas de grasa y proteínas de origen animal, así como cantidades bajas de fibra, frutas y vegetales. Un gran número de estudios experimentales han encontrado que la fibra contrarresta la inducción de neoplasia, especialmente en relación con la fibra fermentable(salvado de trigo y celulosa). Los estudios de correlación epidemiológica también han indicado que una mayor ingestión de vegetales, frutas, cereales y semillas se asocia con un riego menor de neoplasia colorrectal. Además, en más de la mitad de los estudios de casos-control, se documentaron las propiedades beneficiosas de la fibra (especialmente de origen vegetal). Sin embargo, los datos epidemiológicos recientes de estudios longitudinales y de distribución aleatoria no tendían a apoyar esta influencia. La investigación futura debería evaluar qué fuentes de fibra proporcionan una protección antineoplásica realizando estudios de intervención con fibras concretas, durante periodos más prolongados. Las carnes rojas y las procesadas, y quizás los hidratos de carbono refinados, también están implicadas en el riesgo de CCR. Están bien aceptadas las recomendaciones para disminuir la ingestión de carne roja, aunque la cantidad total y la composición de ácidos grasos concretos pueden tener efectos distintos en este contexto. La evidencia actual se decanta por la sustitución de los ácidos grasos de cadena larga y media y del ácido araquidónico por los ácidos grasos de cadena corta y por el ácido eicosano pentanoico. El exceso de peso corporal y el exceso de aporte de energía que induce una hiperinsulinemia también se han relacionado con el CCR, así como los hábitos personales como la inactividad física, el consumo elevado de alcohol, el tabaquismo y el consumo bajo de folatos y metionina. Por lo tanto, las recomendaciones actuales para disminuir el riesgo de CCR incluyen medidas dietéticas como aumentar los alimentos de origen vegetal, el consumo de granos completos, vegetales y frutas y reducir el consumo de carnes rojas

Gastrectomy with extended lymphadenectomy for primary treatment of gastric cancer.

BACKGROUND: The appropriate extent of lymph node clearance during gastrectomy for cancer remains controversial. METHODS: Medline, Embase, the Cochrane register and other databases were searched for studies reporting node dissection technique, 5 year survival and mortality after gastrectomy. Comparisons with systematic bias in treatment allocation and patients who received perioperative chemotherapy were excluded. Meta-analysis was performed separately for randomized and non-randomized comparisons. RESULTS: Two randomized and two non-randomized comparisons of limited (D1) versus extended (D2) node dissection and 11 reports of one dissection type were analysed. For D2 the randomised trials showed no overall survival benefit (Risk ratio (RR) = 0.95, 95 per cent c.i. 0.83-1.09) and an increased postoperative mortality (RR = 2.23, c.i. 1.45-3.45), apparently related to pancreatico-splenectomy and surgical inexperience. A trend towards survival benefit for D2 was observed for T3+ tumours (RR = 0.68, c.i. 0.42-1.10). Non-randomized comparisons found no survival benefit for D2 (RR = 0.92, c.i. 0.83-1.02), but decreased postoperative mortality (RR = 0.65, c.i. 0.45-0.93). Nine observational studies of D2 reported better results than two studies of D1 surgery, but in very different settings. CONCLUSIONS: Evidence for D2 dissection is inconclusive. No overall survival advantage has emerged, but some patients with intermediate stage disease may benefit. Excess operative mortality appears to be associated with pancreatico-splenectomy, low case volume and lack of specialist training.