Influence of Molecular Status on Recurrence Site in Patients Treated for a Stage III Colon Cancer: a Post Hoc Analysis of the PETACC-8 Trial.

BACKGROUND: Recurrence patterns in stage III colon cancer (CC) patients according to molecular markers remain unclear. The objective of the study was to assess recurrence patterns according to microsatellite instability (MSI), RAS and BRAFV600E status in stage III CC patients. METHODS: All stage III CC patients from the PETACC-8 randomized trial tested for MSI, RAS and BRAFV600E status were included. The site and characteristics of recurrence were analyzed according to molecular status. Survival after recurrence (SAR) was analyzed. RESULTS: A total of 1650 patients were included. Recurrence occurred in 434 patients (26.3%). Microsatellite stable (MSS) patients had a significantly higher recurrence rate (27.2% vs. 18.7%, P = 0.02) with a trend to more pulmonary recurrence (28.8% vs. 12.9%, P = 0.06) when compared to MSI patients. MSI patients experienced more regional lymph nodes compared to MSS (12.9% vs. 4%, P = 0.046). In the MSS population, the recurrence rate was significantly higher in RAS (32.2%) or BRAF (32.3%) patients when compared to double wild-type patients (19.9%) (p < 0.001); no preferential site of recurrence was observed according to RAS and BRAFV600E mutations. Finally, decreased SAR was observed in the case of peritoneal recurrence or more than two recurrence sites. CONCLUSIONS: Microsatellite, RAS and BRAFV600E status influences recurrence rates in stage III CC patients. However, only microsatellite status seems to be associated with specific recurrence patterns. More than two recurrence sites and recurrence in the peritoneum were associated with poorer SAR.

Total mesorectal excision for cancer: histological and immunohistochemical evidence of nerve removal and risk-factor analysis.

AIM: Whether or not nerve-sparing rectal-cancer surgery can effectively prevent removal of the pelvic autonomic nerves has not been substantiated microscopically. We aimed to analyse the quality of nerve preservation in female patients by quantifying residual nerve fibres in total mesorectal excision specimens, to analyse pro-erectile function of the nerve fibres removed and to determine risk factors for pelvic denervation. METHOD: Serial transverse sections from female patients, 64 ± 18 years of age, were studied after the mesorectal fascia was inked and studied histologically [using anti-S100 and anti-neuronal nitric oxide synthase (nNOS) antibodies]. Nerve fibres located within 1 mm of the inked surface were counted and analysed according to type of surgery, tumour location, pT stage, circumferential resection margin and the necessity for a posterior colpectomy. RESULTS: Twelve specimens were analysed. Per specimen, the mean number of nerve-fibre sections outside the mesorectum was 5.3 ± 3.6 (range: 1-12). The mean number of fibres per specimen was 6.4 ± 4.1 in patients having a low-rectal tumour and 4.4 ± 2.9 in those with mid or higher rectal tumours (P = 0.42). The mean number of fibres was higher (9.2) for T4 tumours than for T2/T3 tumours (5.0 ± 3.5), but this difference was not statistically sigmificant (P = 0.25). Patients having abdominoperineal excision, a posterior colpectomy or a circumferential resection margin of less than 1 mm had significantly more nerve fibres in the specimen (10.6 ± 1.9 vs 4.4 ± 2.8; P = .041). Fibres localized at the anterolateral rectum corresponded to branches of the neurovascular bundle, expressing rich pro-erectile activity (positive anti-nNOS immunostaining). CONCLUSION: The neurovascular bundle is a key risk zone for pelvic denervation during total mesorectal excision. Abdominoperineal excision, posterior colpectomy and an invaded circumferential resection margin are associated with perineal denervation.

Optimal oncologic treatment of rectal cancer in patients over 75 years old: Results of a strategy based on oncogeriatric evaluation.

BACKGROUND: Few data are available on the management of elderly rectal cancer patients, and especially on the ability to provide optimal oncological treatment. The aim of this study was to determine the feasibility and results of multimodality treatment for rectal cancer in patients 75years and older after simplified comprehensive geriatric assessment (CGA) according to Balducci score. METHODS: We reviewed the charts of elderly patients who underwent surgery for localized middle or low rectal cancer. Patients were classified into three CGA groups depending on their functional reserve, comorbidities, geriatric syndromes, and life expectancy. RESULTS: Neoadjuvant therapy was discussed for 27 patients (47%), but only 56% of them were treated, including 8, 7, and 1 patient from CGA groups 1, 2, and 3, respectively. Fifty-three patients (93%) underwent sphincter-preserving surgical resection and four patients underwent abdominoperineal resection (7%). Postoperative complications were observed in 21 patients (37%). The postoperative complication rate was correlated non-significantly with age (<85years: 40.6%; ≥85years: 57.1%; P=0.3), and with the CGA (P=0.64). In total, 10 patients (18%) had definitive colostomy, including five anastomotic leakages (9%), and one incontinence (2%). The total rate of sphincter preservation was 82% (n=47). The risk of secondary definitive colonic stoma formation was not correlated with CGA (group 1: 14%; group 2/3: 16%; P=0.8). Estimated OS at five years was 52%. CONCLUSIONS: After routine geriatric assessment, elderly rectal cancer patients have good rates of sphincter conservation and acceptable morbidity/mortality.

In vivo hepatocyte retrovirus-mediated gene transfer through the rat biliary tract.

Delivering retroviruses targeted to hepatocytes in vivo involves the injection of retroviruses directly into the blood stream of the portal vein. The aim of this work was to delineate the conditions for delivering retroviruses in vivo by perfusing in situ the bile duct of the regenerating rat liver, and to study the hepatocyte transgene expression. At 24 hr after partial hepatectomy, during the S phase of the cell cycle, regenerating livers were perfused for 2.8+/-0.5 hr through the bile duct with 36.2+/-6.8 ml (0.3+/-01 ml/min) of fresh culture supernatant containing amphotropic recombinant retroviruses encoding the beta-galactosidase gene. The virus total titer was 1.5 x 10(8) ffu (group I) or 6.5 x 10(8) ffu (groups II and III). The hepatic artery blood flow was either maintained (groups I and II) or interrupted (group III) during bile duct perfusion. Liver biopsies taken 7 days later showed that 31.4+/-24.2% (group I), 58.7+/-23.6% (group II), and 45.1+/-21.4% (group III) of hepatocytes expressed beta-galactosidase activity, predominantly in the periportal and mediolobular zones. This study demonstrates that hepatocytes of regenerating rat livers that have entered the S phase of the cell cycle as a result of partial hepatectomy can be transduced in vivo by retroviral vectors delivered in situ by bile duct perfusion. Furthermore, the number of transduced hepatocytes closely correlated with the viral total titer and was diminished by hepatic artery blood flow occlusion during perfusion.

The European Organization for Research and Treatment of Cancer Gastrointestinal Group Trials: surgery and liver surgery in Europe.

The aim of the Gastrointestinal Tract Cancer Cooperative Group is to develop protocols concerning the different aspects of gastro-intestinal tract malignancies, diagnosis, biology and treatment. All projects involving surgery are discussed first in the Surgery Committee. A multidisciplinary approach has always been one of the major principles of the group. This article provides an overview of the recent and present activities of the GI group of the EORTC in relation to surgery.

Prolonged survival after resection of pancreatoblastoma and synchronous liver metastases in an adult.

Pancreatoblastoma is an uncommon pediatric neoplasm with distinct acinar and squamoid cell differentiation. Pancreatoblastoma is exceedingly rare in adults with only ten reported cases. Pancreatoblastoma in adults has a poor prognosis and no survival without recurrence exceeding 30 months has been reported. We report the first adult case of pancreatoblastoma revealed by gastric bleeding due to segmental hypertension. On computed tomography scan, the tumor appeared lobulated and extended from the splenic hilum to the portal vein. Two hypervascular centimetric hepatic metastases were observed in segments III and VII. The patient was operated and a distal pancreatectomy with splenectomy associated with two hepatic wedge resections was performed. The diagnosis of pancreatoblastoma was made on immunohistochemical examination. The patient received 6 cycles of adjuvant therapy. After three years of follow-up, the patient was well with no sign of recurrence on computed tomography scan. This case suggests that in the presence of pancreatic tumor of unknown origin, aggressive management including complete surgical resection and adjuvant chemotherapy should be attempted even in the presence of synchronous liver metastases.

Resection of liver metastases from colorectal cancer--how can we improve results?

Resection of liver metastases due to large bowel cancer has become an important part of treatment. In recent years, there have been advances in technique and the selection of patients has been extended. Surgery is the only modality which currently offers the possibility of long-term survival. Resection combined with chemotherapy may offer improved survival, but more data are needed. Chemotherapy may cause regression of metastases to permit resection where initially they were considered unresectable. The data available from such studies are presented.

Surgical management of hepatic metastases from colorectal malignancies.

Liver metastasis represents the major cause of death of patients who have been treated for colorectal adenocarcinoma. Spontaneous survival rarely exceeds two years. Surgery can offer long-term survival and resection should be considered when liver metastases can be totally resected with clear margins and when there is no non-resectable extra-hepatic disease. The choice between anatomical or wedge resection depends on the number and the location of the metastases but does not influence survival. Clamping methods limit blood loss. Operative mortality is generally less than 5%. The five-year survival rate after surgical resection varies from 20% to 45% according to several prognostic factors. The longer survival is observed in patients with fewer than four lesions, with lesions smaller than 4 cm, without extra-hepatic disease, with lesions that appeared more than two years after the resection of a stage I or II colorectal cancer and whose CEA level is normal. After resection, follow-up can detect hepatic recurrence that can be treated with repeat hepatectomy. The efficacy of systemic chemotherapy using new agents can increase the number of patients amenable to surgery. Regional therapies with cryotherapy or radiofrequency ablation can help to treat unresectable or non-totally resectable lesions and may improve survival. The effects on survival of adjuvant treatments, including pre- or postoperative systemic or postoperative intra-arterial chemotherapy, are currently under evaluation.

A preclinical model of hepatocyte gene transfer: the in vivo, in situ perfused rat liver.

Delivering retroviruses targeted to hepatocytes in vivo involves the injection of retroviruses directly into the portal vein. The aim of this work was to establish a clinically relevant system for retrovirus-mediated gene transfer in a new model of in vivo, in situ perfused rat liver and to study the transgene expression. At 24 h after partial hepatectomy, the liver was completely excluded from the splanchnic circulation using an extracorporeal shunt. Two independent normothermal, oxygenated perfusion systems were used. First, liver perfusion was carried out with a recirculating system (1 h). Culture supernatant containing retroviruses (1.5 x 10(8) ffu/ml, beta-galactosidase gene) was used as perfusate. Then the liver perfusion was maintained for more 30 min in a single liver passage system using culture medium without retroviruses as perfusate. High hepatocyte transduction rates (up to 34.4%) were obtained. PCR analysis showed no provirus in extrahepatic organs. Viral titrations performed simultaneously (inflow and outflow liver lines) showed that after 1 h of perfusion (up to 30 successive liver passages) retroviruses were still detected in the liver outflow perfusate (up to 2.0 x 10(7) ffu/ml). Washing the liver for 30 min dramatically decreased the leakage of retroviruses in the outflow. In order to be of clinical use, the injection of retroviruses targeted to hepatocytes in vivo should be done while the liver is completely excluded from the splanchnic circulation to avoid any extrahepatic retrovirus diffusion.

Continuous versus intermittent portal triad clamping for liver resection: a controlled study.

OBJECTIVE: The authors compared the intra- and postoperative course of patients undergoing liver resections under continuous pedicular clamping (CPC) or intermittent pedicular clamping (IPC). SUMMARY BACKGROUND DATA: Reduced blood loss during liver resection is achieved by pedicular clamping. There is controversy about the benefits of IPC over CPC in humans in terms of hepatocellular injury and blood loss control in normal and abnormal liver parenchyma. METHODS: Eighty-six patients undergoing liver resections were included in a prospective randomized study comparing the intra- and postoperative course under CPC (n = 42) or IPC (n = 44) with periods of 15 minutes of clamping and 5 minutes of unclamping. The data were further analyzed according to the presence (steatosis >20% and chronic liver disease) or absence of abnormal liver parenchyma. RESULTS: The two groups of patients were similar in terms of age, sex, nature of the liver tumors, results of preoperative assessment, proportion of patients undergoing major or minor hepatectomy, and nature of nontumorous liver parenchyma. Intraoperative blood loss during liver transsection was significantly higher in the IPC group. In the CPC group, postoperative liver enzymes and serum bilirubin levels were significantly higher in the subgroup of patients with abnormal liver parenchyma. Major postoperative deterioration of liver function occurred in four patients with abnormal liver parenchyma, with two postoperative deaths. All of them were in the CPC group. CONCLUSIONS: This clinical controlled study clearly demonstrated the better parenchymal tolerance to IPC over CPC, especially in patients with abnormal liver parenchyma.

Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in colorectal primary tumours and metastases.

We investigated the possible role of chromosome 10q losses in colorectal cancer metastasis by carrying out an allelic imbalance study on a series of microsatellite instability-negative (MSI-) primary tumours (n=32) and metastases (n=36) from 49 patients. Our results demonstrate that 10q allelic losses are associated with a significant proportion (25%) of MSI- colorectal tumours, but are not involved in the metastatic process. PTEN and BMPR1A, two genes located in the common deleted region, were screened for mutations in samples with loss of heterozygosity. The absence or low frequency of mutations indicates that the inactivation of these genes by deletion of one allele and mutation of the other one plays only a minor role in MSI- tumours.

A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).

Progressive myoclonus epilepsy of the Lafora type or Lafora disease (EPM2; McKusick no. 254780) is an autosomal recessive disorder characterized by epilepsy, myoclonus, progressive neurological deterioration and glycogen-like intracellular inclusion bodies (Lafora bodies). A gene for EPM2 previously has been mapped to chromosome 6q23-q25 using linkage analysis and homozygosity mapping. Here we report the positional cloning of the 6q EPM2 gene. A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase). The gene, denoted EPM2, presents alternative splicing in the 5' and 3' end regions. Mutational analysis revealed that EPM2 patients are homozygous for loss-of-function mutations in EPM2. These findings suggest that Lafora disease results from the mutational inactivation of a PTPase activity that may be important in the control of glycogen metabolism.