Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Lymph road mapping obtained via blue sentinel node detection to avoid middle colic artery resection for highly selected colon cancer cases: proof of a concept?

BACKGROUND: In theory, perioperative detection of lymph nodes with the injection of isosulfan blue dye should provide lymph road mapping (LRM) able to direct the resection. However, there is no supporting evidence for this theory in cases of colon cancer. We reanalysed all operative reports using the sentinel lymph node technique with blue dye injection. MATERIALS AND METHODS: The retrospective study included 140 patients who underwent the sentinel lymph node (SLN) procedure between February 2001 and November 2007, including 70 cases in which the in vivo technique was used. In 8 cases (11%), LRM was used by the surgeon to determine the extent of resection. RESULTS: In 5 cases, including limited or extended resection, the final pathological stage was II at the end of the follow-up period, and the patients had no recurrent disease. However, findings for 3 cases of stage III cancer were more relevant to the aims of this study. In these 3 patients, one with cancer (T3N1(3/22)) located at the hepatic flexure, and 2 with cancers (T3N2(7/41) and T2N2 (4/15)) at the splenic flexure, the middle colic artery was conserved as a result of LRM information. Of these 3 patients, 1 was alive without disease at 6-year follow-up and 2 at 5-year follow-up. CONCLUSION: LRM obtained via blue sentinel node detection makes it possible to avoid middle colic artery resection for selected colon cancer cases. LRM seems particularly suitable in cases of colonic flexure location or prior colon surgery.

[Complete (R0) resection is the only valid prognostic factor in abdominoperineal resection for recurrent cancer of the anal canal (a consecutive series of 95 patients)]. / Résection R0, seul facteur pronostique dans les amputations abdominopérinéales de rattrapage des cancers du canal anal (série consécutive de 95 patients).

INTRODUCTION: When radiation therapy fails to control cancer of the anal canal, the only therapeutic alternative is salvage abdomino-perineal resection (APR). Its role remains debatable since very few long-term survivals have been reported. No prognostic factors have yet been identified in the limited series of reported cases. PATIENTS: 95 APR's performed over a 20 year period are reviewed and analyzed. RESULTS: Median follow-up was 5.5 years. Only one prognostic factor was identified: an R0 resection (n=76) versus either R1 (n=9) or R2 (n=9) resection. Median survival for R0 APR was more than 10 years versus 1 year for R1 and R2 resections (p=0.001). There was no prognostic difference between salvage APR for disease progression (n=55) or for late recurrence (n=40). The sub-group of women<45 years of age (n=5) had a particularly poor prognosis with no survivors beyond 2 years. CONCLUSION: When anal cancer recurs after radiation therapy, a salvage APR is indicated. If an R0 resection can be achieved, median survival is greater than 10 years. However, the justification for APR when only an R1 or R2 resection can be achieved is much less clear; in such cases there was no survival beyond 3 years.

The differential response to chemotherapy of ovarian metastases from colorectal carcinoma.

PATIENTS AND METHODS: All patients with metastatic (ovarian and extraovarian) CRC who underwent resection of ovarian metastases in our institution from April 1988 to August 2006 were analyzed and the response to preoperative chemotherapy was evaluated according to the RECIST criteria, and analyzed with respect to the sites of metastases (ovarian and extraovarian). RESULTS: The studied population consisted of 23 women. At presentation, 20 patients had symptoms. Preoperative chemotherapy resulted in tumor control of measurable extraovarian metastases in 65% of cases. In contrast, no objective tumor response of ovarian metastases was observed, disease stabilization was obtained in only 3 patients (13%), and progression or occurrence of new ovarian metastases were observed in 20 patients (87%) (p=0.0005). With a median follow-up of 54 months [15-229], median overall survival was 30 months, and 3-year overall survival was 18%. CONCLUSION: Ovarian metastases are less responsive to chemotherapy compared to other sites. As these "metastatic sanctuaries" often cause symptoms, surgical resection should always be considered for ovarian metastases, even in the case of associated extraovarian metastases.

Acute pancreatitis following segmental pancreatic resection associated with portal vein thrombosis and aneurysm of the spleno-mesenteric venous confluence.

Vascular abnormalities associated with acute pancreatitis are well-known and reported in the literature in up to 50% of the patients with acute necrotizing pancreatitis. Most reported vascular abnormalities are superior mesenteric and/or portal vein thromboses and arterial pseudo-aneurysms. Portal vein aneurysm and/or spleno-mesenteric venous aneurysm are rare entities. Furthermore, portal vein aneurysm can be complicated by portal vein thrombosis. We report a case of spleno-mesenteric vein aneurysm that unusually followed portal vein thrombosis and was secondary to postoperative pancreatitis following segmental pancreatic resection for a well-differentiated endocrine carcinoma. The patient was treated successfully with conservative treatment, although he developed a hepatic abscess two months after his treatment.

Functional results and quality of life for patients with very low rectal cancer undergoing coloanal anastomosis or perineal colostomy with colonic muscular graft.

BACKGROUND: The aim of this study was to compare functional results and quality of life (QoL) of two salvage techniques: coloanal anastomosis (CAA) or perineal reconstruction after abdominoperineal resection for very low rectal cancer. METHODS: Between 1991 and 2001, 50 patients were operated for a very low rectal adenocarcinoma and analyzed after a follow-up greater than one year and because there was no relapse or no treatment, they were included in the analysis. Thirty-eight patients had a CAA, including: straight anastomosis (n=23), J pouch (n=10), coloplasty (n=2) and intersphincteric resection (n=3). Twelve patients underwent a PC. RESULTS: Vaizey's incontinence score was equivalent for the two groups: CAA 12 (0-22) versus PC 11 (8-13). The only differences were more frequent fractioned stools for the CAA group and increased pad soiling for the PC group. Overall QoL scores (QLQ C-30) were equivalent for CAA and PC. CONCLUSIONS: For very low rectal tumors, the choice of surgical technique must be based on oncologic rather than future functional or QoL criteria, because both approaches seem to provide similar results.

Hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis of digestive and peritoneal origin: rationale.

Up to a few years ago peritoneal carcinomatosis was considered as an "incurable" disease. The aim of this paper is to review the surgical approach with curative intent to carcinomatosis: it consists of complete resection of macroscopic disease (R1), associated with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat residual microscopic disease, and to evaluate its indications. Overall 5-year survival of patients with peritoneal carcinomatosis treated by HIPEC is similar to that of patients with hepatic metastases treated with curative intent. Those patients should no longer be considered as patients with a terminal disease but as patients with a potentially treatable localized disease.

[Panniculectomy as first part of colorectal resection for cancer in a morbidly obese patient]. / La panniculectomie première comme voie d'abord dans la résection colorectale pour cancer chez le grand obèse.

We reported the case of a patient presenting a rectal cancer of the upper part with a BMI at 59 which was previously considered as a contraindication to surgery. To perform the operation we had to make as first step of the procedure a panniculectomy. The technique made possible the rectal resection under good conditions, without blood transfusion. The post-operative course was uneventful except a pulmonary embolism controlled with medical treatment. This procedure is feasible in colorectal surgery.

Treatment of synchronous peritoneal carcinomatosis and liver metastases from colorectal cancer.

AIM: To report our experience of peritoneal carcinomatosis (PC) discovered during abdominal exploration in patients with liver metastases (LM). METHODS: Liver resection plus cytoreductive surgery were combined in 24 patients with LM and moderate PC from colorectal origin treated with a curative intent between January 1993 and November 2003. RESULTS: The mean operative time was 357+/-112 min and median blood loss was 719 ml. One postoperative death occurred and postoperative morbidity was 58%. The mean hospital stay was 21.4+/-4.2 days. Three-year overall and disease-free survival rates were respectively 41.5% (confidence interval [CI]: 23-63) and 23.6% (CI: 11-45). Seven patients are disease-free with a mean follow-up of 27.8 months after their last surgery, 3 having a repeated hepatectomy. Three patients developed a peritoneal recurrence and 13 had recurrence in the liver. The only significant prognostic factor was a number of LMs of less than 3 (p < 0.01). CONCLUSION: A combined treatment of LM plus PC is feasible and is beneficial in selected patients presenting three or fewer metastases.

A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with pretreated gastroenteropancreatic well-differentiated endocrine carcinomas.

UNLABELLED: Only a few drugs are active in the treatment of well-differentiated endocrine carcinomas (WDEC). We evaluated the combination of the so-called 'de Gramont schedule' and irinotecan in these tumors in a phase II study. METHODS: 20 patients were enrolled in the study. The combination regimen included irinotecan, 180 mg/m(2) on day 1, followed by 200 mg/m(2) folinic acid in a 2-hour infusion, an intravenous 10-min bolus of 400 mg/m(2) 5-fluorouracil (5FU) and finally 600 mg/m(2) 5FU in a 22-hour infusion. Folinic acid and 5FU were repeated on day 2. Clinical, biological and morphological parameters were assessed by CT every 8 weeks. The site of the primary tumor was the pancreas in 10 cases, the lung in 3 cases and other sites in 7 cases. Sixteen patients had previously received chemotherapy, and 6 of them had had two lines of treatment. Six patients had previously been treated with chemoembolization. RESULTS: The median number of cycles administered was 8. Grade 3-4 neutropenia was observed in 8 patients, and 1 patient experienced febrile neutropenia. There was no toxicity-related death. No complete symptomatic response was observed in 7 evaluable patients; 4 patients had an objective biological response. One patient achieved a morphological objective response, stabilization was observed in 15, but progression occurred in 3 patients. Median survival was 15 months. CONCLUSION: The above-mentioned combination of LV5FU2 + irinotecan does not yield major activity in heavily pretreated unresectable metastatic gastroenteropancreatic WDEC, and significant toxicity was observed.

EGFR in colorectal cancer: more than a simple receptor.

BACKGROUND: Advances in the understanding of tumor biology have led to the development of targeted therapies allowing progress in colorectal cancer treatment. One of the most promising targets is the epidermal growth factor receptor (EGFR). METHOD: The presence and distribution of high- and low-affinity EGFR was investigated retrospectively in a group of 82 colorectal cancer samples (43 normal colon-colon cancer paired samples) using a specific ligand binding assay (Scatchard Analysis). FINDINGS: A large majority of tumor samples exhibited one class of high-affinity binding sites (78%). Eighteen cases (22%) exhibited both high- and low-affinity binding sites. A wide interpatient variability was observed for the site number, with physiologically-relevant high-affinity sites ranging from 7 to 310 fmol/mg protein in tumors and from 6 to 313 fmol/mg protein in normal mucosa. A significant positive correlation was demonstrated between tumor and normal mucosa for the high-affinity Kd values and for the number of high-affinity sites, suggesting a common regulation for both tumor and normal tissue. INTERPRETATION: These observations (i) could explain recently-reported clinically-active EGFR targeting in colorectal tumors apparently negative for EGFR, and (ii) may offer a plausible explanation for the link observed between toxicity in normal tissue (cutaneous rash) and clinical outcome of patients treated with anti-EGFR drugs. Present data extends our understanding of EGFR identity in colorectal cancer which could be useful in reconsidering the predictive tools for the identification of tumors putatively responsive to EGFR targeted therapy.

Incidence of unsuspected and treatable metastatic disease associated with operable colorectal liver metastases discovered only at laparotomy (and not treated when performing percutaneous radiofrequency ablation).

BACKGROUND: When patients with resectable colorectal liver metastases (LM) are treated with percutaneous radiofrequency (RF), some unsuspected intrahepatic and extrahepatic metastases, detectable only at laparotomy, might be ignored and left untreated. This would result in a reduced cure rate. Our purpose was to discover the incidence of unsuspected and surgically treatable intrahepatic and extrahepatic metastases discovered at laparotomy. METHODS: The data of 506 patients who underwent a laparotomy and then a hepatectomy for colorectal LM were prospectively collected and retrospectively analyzed. All patients had undergone at least two types of preoperative liver imaging (but no fluorodeoxyglucose-positron emission tomography). RESULTS: Unsuspected metastases were discovered at laparotomy in 209 patients (41.3%). There were extrahepatic metastases in 82 patients (16.2%), additional LM in 152 patients (30%), and both in 25 patients (4.9%). Liver palpation and intraoperative ultrasound allowed for detecting additional LM in 125 (24.7%) and 48 (9.4%) patients, respectively. All of them were resected. When only the 124 patients who presented with 1 to 3 LM measuring <3 cm in diameter (candidates for percutaneous RF) were considered, the results were similar. Moreover, the incidence of unsuspected metastases was similar when the periods of surgery (before and after January 1996) were considered. CONCLUSIONS: Laparotomy permits discovery of and treatment with a curative intent of unsuspected intrahepatic or extrahepatic metastases in at least one third of patients with classically resectable colorectal LM. This does not support the use of percutaneous RF ablation instead of hepatic resection for this population, because it will result in an important survival decrease.

Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression.

BACKGROUND: Late radiation enteritis in humans is associated with accumulation of extracellular matrix and increased connective tissue growth factor (CTGF) expression that may involve intestinal muscular layers. AIMS: We investigated the molecular pathways involved in maintenance of radiation induced fibrosis by gene profiling and postulated that alteration of the Rho pathway could be associated with radiation induced fibrogenic signals and CTGF sustained expression. PATIENTS AND METHODS: Ileal biopsies from individuals with and without radiation enteritis were analysed by cDNA array, and primary cultures of intestinal smooth muscle cells were established. Then, the effect of pharmacological inhibition of p160 Rho kinase, using Y-27632, was studied by real time reverse transcription-polymerase chain reaction, western blot, and electrophoretic mobility shift assay. RESULTS: Molecular profile analysis of late radiation enteritis showed alterations in expression of genes coding for the Rho proteins. To investigate further the involvement of the Rho pathway in intestinal radiation induced fibrosis, primary intestinal smooth muscle cells were isolated from radiation enteritis. They retained their fibrogenic differentiation in vitro, exhibited a typical cytoskeletal network, a high constitutive CTGF level, increased collagen secretory capacity, and altered expression of genes coding for the Rho family. Rho kinase blockade induced a simultaneous decrease in the number of actin stress fibres, alpha smooth muscle actin, and heat shock protein 27 levels. It also decreased CTGF levels, probably through nuclear factor kappaB inhibition, and caused decreased expression of the type I collagen gene. CONCLUSION: This study is the first showing involvement of the Rho/Rho kinase pathway in radiation fibrosis and intestinal smooth muscle cell fibrogenic differentiation. It suggests that specific inhibition of Rho kinase may be a promising approach for the development of antifibrotic therapies.

[Surgical treatment of peritoneal carcinomatosis]. / Traitement chirurgical des carcinoses péritonéales: 2--la chimiohyperthermie.

Surgical treatment of peritoneal carcinomatosis with curative intent involves the resection of all macroscopic malignant tissue and the treatment of microscopic residual tissue with local chemotherapy. Intraperitoneal chemotherapy is efficient only when associated with hyperthermia. This article details the technical aspect of intraperitoneal chemohyperthermia. These techniques involve specific and important features. At these conditions, peritoneal carcinomatosis can be cured in two-thirds of cases.

Surgical management of primary anorectal melanoma.

BACKGROUND: This aim of this study was to analyse outcome after surgery for primary anorectal melanoma and to determine factors predictive of survival. METHODS: Records of 40 patients treated between 1977 and 2002 were reviewed. RESULTS: Twelve men and 28 women of mean age 58.1 (range 37-83) years were included in the analysis. Overall and disease-free survival rates were 17 and 14 per cent at 5 years. Median overall survival was 17 months and disease-free survival was 10 months. The 5-year survival rate was 24 per cent for patients with stage I tumours, and zero for those with stage II or stage III disease. There was no significant difference in overall survival after wide local excision (49 and 16 per cent at 2 and 5 years respectively) and abdominoperineal resection (33 per cent at both time points). In patients with stage I and stage II disease, there was a significant association between poor survival and duration of symptoms (more than 3 months), inguinal lymph node involvement, tumour stage and presence of amelanotic melanoma. CONCLUSION: Anorectal melanoma is a rare disease with a poor prognosis. Wide local excision is recommended as primary therapy if negative resection margins can be achieved.

[Surgical treatment of peritoneal carcinomatosis]. / Traitement chirurgical des carcinoses péritonéales: 1 la péritonectomie.

Surgical treatment of peritoneal carcinomatosis with curative intent involves the resection of all macroscopic malignant tissue and the treatment of microscopic residual tissue with local chemotherapy. Surgical procedures for peritoneal carcinomatosis involve specific features and should be performed at the condition that all supramillimetric deposit could be removed with an acceptable postoperative quality of life. This article details the technical aspect of peritonectomy.

Efficacy of intraperitoneal chemohyperthermia with oxaliplatin in colorectal peritoneal carcinomatosis. Preliminary results in 24 patients.

BACKGROUND: The complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease, leads to cure in some patients. We report preliminary results on survival in a phase II study using oxaliplatin (LOHP). PATIENTS AND METHODS: Twenty-four patients with macroscopic colorectal PC underwent complete resection of the PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m(2) in 2 l/m(2), during 30 min at 43 degrees C, at a flow rate of 2 l/min. During the hour preceding IPCH, they received an intravenous administration of 5-fluorouracil (400 mg/m(2)) and leucovorin (20 mg/m(2)). RESULTS: Mean peritoneal tumoral extension (Sugarbaker's Index) was 16.9 +/- 9.5, median operative duration was 490 min and median blood loss was 965 ml. There were two postoperative deaths (8%) by intracerebral hemorrhage, and morbidity rate was 41.6%. Minimal follow-up was 18 months and median follow-up was 27.4 months (range 18.3-49.6). At 1, 2 and 3 years, overall survival rates were 83%, 74% and 65%, and disease-free survival rates were 70%, 50% and 50%, respectively. Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. A peritoneal index >24 influenced survival, with a 17% recurrence rate at 2 years versus 63% when it was <24 (P = 0.005). CONCLUSION: This new modality of treatment, when feasible, gives encouraging preliminary results, with a promising 3-year survival rate of 65%.

The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option?

Due to their rarity, only few trials have studied the role of the doxorubicin-streptozotocin (DS) combination in advanced well-differentiated pancreatic endocrine carcinomas (AWDPEC). However, the published results are inconsistent. We reviewed all AWDPEC (5-year period, 45 patients) treated in our institution with the DS combination for: objective response rate (ORR), progression-free survival, overall survival (OS) and toxicity. An ORR of 36% (95% Confidence Interval (CI) 22-49) was obtained, with 16 partial responses (PR). The mean duration of PR was of 19.7 months. Two and 3-year OS rates were 50.2 and 24.4%, respectively. Toxicities were mainly digestive (grade > or =3 vomiting, 13%) and haematological (grade > or =3 neutropenia, 24%). Previous systemic chemotherapy and malignant hepatomegaly were associated with a poorer ORR (P=0.033, P=0.016) and OS (P=0.008, P=0.045). Multivariate analysis demonstrated previous chemotherapy as the only independent predictive-factor for survival (P=0.013). In conclusion, our data confirm the sensitivity of AWDPEC to the DS combination, with an ORR of 36% and a remarkable median response duration of 19.7 months, and suggests that it could be considered as a valid option in first-line therapy.

Necrotizing pancreatitis after radiofrequency destruction of pancreatic tumours.

BACKGROUND: Intraoperative radiofrequency (RF) can be used to treat multiple small pancreatic tumours. PATIENTS AND METHODS: Two patients with multiple pancreatic metastases from renal cancer were treated with RF destruction of the pancreatic tumours. The first was treated with a monopolar device and the second with a bipolar device. A high temperature (>90 degrees C) was used, and one patient underwent cooling of the intrapancreatic common bile duct. RESULTS: The destruction of tumours was effective. However, the two patients presented post-operatively a severe necrotizing pancreatitis, with life-threatening hemorrhagic complications. CONCLUSION: RF destruction of pancreatic tumours is dangerous with current devices.