A. Bourgeon

Prognostic Value of Tumoral Thymidylate Synthase and p53 in Metastatic Colorectal Cancer Patients Receiving Fluorouracil-Based Chemotherapy: Phenotypic and Genotypic Analyses

PURPOSE The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid. PATIENTS AND METHODS Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively. RESULTS p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P =.047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P =.040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P =.035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P =.018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism. CONCLUSION Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity.

Characterization of centromere alterations in liposarcomas

Supernumerary ring and large marker chromosomes are a characteristic of atypical lipomas and well‐differentiated liposarcomas (ALP‐WDLPS) and are composed of amplified 12q14–15 sequences in association with variable segments from other chromosomes. Although stably transmitted, these chromosomes contain centromeric alterations, showing no detectable alpha‐satellite sequences. We performed C‐banding, fluorescence in situ hybridization, and immunostaining with anti‐centromere antibodies in 8 cases of liposarcomas with supernumerary rings and large markers, including 5 ALP‐WDLPS and 3 dedifferentiated‐LPS and high‐grade LPS. Our results with alpha‐satellite probes and anti‐CENPB antibodies confirm the lack of detectable alpha‐satellite sequences in the five ALP‐WDLPS supernumerary chromosomes, whereas centromeric activity was proved by the detection of kinetochores by using anti‐CENPC antibodies. In contrast, the high grade and dedifferentiated liposarcomas showed a different pattern. In 2 cases, amplified chromosome 12 sequences, including amplification of alpha‐satellite 12 sequences in 1 case, were present on chromosomes with typical centromeres. In another case, the rings were similar to WDLPS‐ALP rings, but a large marker contained a chromosome 5 centromere and amplified alpha‐satellite sequences from chromosome 8. ALP‐WDLPS is the first example of a tumor class for which the presence of stable analphoid chromosomes is a constant and specific abnormality. Formation of newly derived centromeres, so‐called neocentromeres, could be an original and effective way to maintain a selective advantage in neoplastic cells by conferring stability to the supernumerary chromosomes of ALP‐WDLPS. The activation of normally non‐centromeric sequences might be obtained by an epigenetic mechanism due to the peculiar chromatin conformation of these highly complex chromosomes.

Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: relationship with response to 5-fluorouracil and survival.

In vitro and clinical studies have suggested that high‐frequency microsatellite instability (MSI‐H) phenotype, p53 and K‐ras mutations might influence the response to chemotherapy in a variety of tumors, including primary colorectal cancers (CRC). Unresectable hepatic metastases from CRC are commonly treated with 5‐fluorouracil (5FU) and folinic acid. Since several new active drugs are now used for treating CRC, molecular determinants predictive to response to 5FU would thus be crucial for optimizing indications of chemotherapy to those patients. MSI‐H phenotype, p53 and K‐ras status were characterized in a prospective study of 56 patients with CRC metastatic to the liver and treated with 5FU‐based chemotherapy. The objective response rate after a 3‐month treatment was 32.1%. The prevalence of p53 mutations, K‐ras mutations and MSI‐H phenotype was 62.5%, 30.3% and 1.8%, respectively. No significant association was found between response to chemotherapy and p53 mutations (78% mutated tumors in responders vs. 55% in nonresponders; p = 0.10) and K‐ras mutations (39% mutated tumors in responders vs. 26% in nonresponders; p = 0.34). Survival was longer for patients with p53‐mutated metastases than for patients with unresected wild‐type p53 metastases (median survival 15 months vs. 17 months; p = 0.06). The determination of the MSI‐H phenotype, p53 and K‐ras status in hepatic metastases from CRC does not discriminate a group of patients that should preferentially benefit from 5FU‐based chemotherapy. The prognosis of patients with treated liver metastases is better when p53 is mutated.

Long-term outcome after laparoscopic fenestration of symptomatic simple cysts of the liver.

The reported prevalence of simple liver cysts (SLC) is 2–4 per cent1,2. Symptoms occur in 5–10 per cent of patients owing to a mass effect, rupture, bleeding or infection of the cyst1. Laparoscopic fenestration is the treatment of choice for symptomatic or complicated SLC1. This study assessed the long-term clinical and radiological outcome after laparoscopic treatment of 40 consecutive patients with symptomatic single or multiple SLC.

Modeling the pregnant woman in driving position

Despite motor vehicle crashes being the leading cause of traumatic fetal morbidity, only a few researches have tried to study the automobile crashes on pregnant women. The possible negative effect of the restraint systems and the injuries mechanisms involved in car crashes with pregnant women are therefore still poorly understood. In this context, the aim of this study is to develop a numerical model of the whole human body with a gravid uterus, in order to investigate car crash scenarios and to evaluate alternative security systems to improve protection of both the woman and the fetus. A 3D reconstruction based on a set of MRI images led us to a good spatial representation of the pregnant woman in driving position. The anatomical precision will make progress possible in the field of traumatology of the pregnant woman.

Ursodeoxycholic acid modulates cyclosporin A oral absorption in liver transplant recipients

Abstract— The aim was to study the ursodeoxycholic acid (UDC) effect on the cyclosporin A (CsA) pharmacokinetics after oral administration of the microemulsion formulation Neoral® (CsA‐ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA‐ME‐induced toxicity. At entry into the study, 12 patients who underwent orthotopic liver transplantation received CsA‐ME, for at least 6 months. They then received a cotreatment CsA‐ME plus UDC (13.8 mg.kg−1.day−1) for three months. Blood concentrations of CsA were measured using a monoclonal antibody specific for the parent compound. The kinetic data were analysed by a mathematical model incorporating a time dependent rate coefficient for CsA intestinal absorption, before and after UDC treatment. Changes in serum markers of hepatic and renal injury were assessed. Individual serum bile acids were determined by chromatography. Serum levels of UDC increased from 3 to about 45 % of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absorption. In the nine non‐cholestatic patients, UDC reduced the absorption rate and the bioavailability of CsA without modifying the elimination rate constant of CsA and the CsA pre‐drug levels. In contrast, in the three cholestatic patients, the bioavailability tended to be higher and the absorption rate faster when CsA was combined with UDC. UDC significantly decreased elevated γ‐glutamyl transferase and creatinine serum levels and induced some clinical improvements such as disappearance of headaches in four patients. In conclusion, a 3‐month UDC treatment modifies CsA intestinal absorption without affecting CsA elimination rate constant. On the other hand, UDC supplementation appears to improve CsA tolerability.

Division of the right posterior attachments of the head of the pancreas with a linear stapler during pancreaticoduodenectomy: vascular and oncological considerations based on an anatomical cadaver-based study

BackgroundSection of the right posterior attachment (RPA) of the pancreatic head from the adventicia of the superior mesenteric artery (SMA) is the last step of pancreaticoduodenectomy. This procedure might be technically demanding, time consuming and potentially dangerous. A method using a stapler has been proposed to simplify this step of the pancreaticoduodenectomy.MethodsTo evaluate the potential consequences of RPA section using this new method, we used an experimental model of pancreaticoduodenectomy in 20 cadavers. After RPA stapling, the residual areolar tissue located between the staple line and SMA was removed (by sub adventicial dissection) and weighed. This allowed an evaluation of: (1) the theoretical risk of SMA injury and (2) the potential carcinological consequences of using stapling division, in comparison with the lymphadenectomy obtained with the conventional sub-adventicial dissection.ResultsA right hepatic artery was accidentaly injured in 10% of cases because of the lack of arterial dissection and arterial anatomy recognition. Forty-three percent of the RPA containing nerves and lymphatics remains in place. Using the stapling technique for RPA division theoretically increases the risk of micro or macroscopically positive margin after surgical resection.ConclusionThe result of this human cadaver-based dissection suggests that the use of the mechanical stapling device for final division of the RPA might increase the risk of SMA injury. The risk of vascular injury has been reported in surgical literature and is confirmed by this study. Such results (10% of accidentaly injury) may not be representative in leaving human patients, thanks to the use of a detectable palpable pulse of the SMA. The latter is important in avoiding vascular injury during RPA division. This study also shows that this new technique may increase the risk of incomplete tumor resection.

Treatment of hepatic metastases of colorectal cancer by electrochemotherapy: An experimental study in the rat ☆

BACKGROUND Electrochemotherapy, which consist of local or systemic administration of a cytotoxic agent followed by application of electric pulses to a tumor, has proved effective for various types of tumors in animals and for cutaneous and head and neck cancers in human beings. This is the first study to investigate the efficacy of electrochemotherapy for treatment of hepatic metastases of colorectal cancer in the rat. METHODS After induction of a solitary hepatic metastasis in 36 male BDIX rats, the animals were randomized to one of four groups: B-E-(no treatment), B+E-(intratumoral bleomycin), B-E+ (application of electric pulses to the tumor), and B+E+ (electrochemotherapy: intratumoral bleomycin followed by application of electric pulses). RESULTS Groups B-E and B-E+ had no tumor response. Group B+E had one partial response. Group B+E+ had seven partial responses and two complete responses. The difference in terms of response between group B+E+ and the other three groups was statistically significant (P < .05). Comparison of the mean posttherapy tumor volumes (B-E-, 50.6 mm3; B+E-, 58.7 mm3; B-E+, 46 mm3; and B+E+, 5.65 mm3) revealed a significantly smaller residual tumor in group B+E+ than in the other three groups (P < .05). CONCLUSIONS Electrochemotherapy is an effective means to reduce the volume of hepatic metastases of colorectal cancer in the rat. Additional research is required to determine the optimum treatment duration, dose effects, volume of tumor that can be treated by electrochemotherapy, and impact on survival. Such experimental studies are indispensable prerequisites for clinical trials.

Rupture spontanée de rate sur pancréatite chronique calcifiante: À propos de 3 observations

Resume La rupture spontanee de rate (RSR) est une complication rare de la pancreatite chronique calcifiante (PCC). L’anemie et l’etat de choc hemorragique ne font pas toujours partie du tableau clinique initial et peuvent retarder le diagnostic. Malgre un traitement conservateur efficace, le traitement doit etre chirurgical car la rupture de rate est liee aux effets locaux de la pancreatite chronique calcifiante. Nous rapportons trois observations de cette complication peu frequente. La rupture spontanee de rate inaugurale a permis de faire le diagnostic de pancreatite chronique calcifiante chez deux malades. Le traitement a consiste en une splenectomie en urgence. Le diagnostic de pancreatite chronique calcifiante etait connu chez le troisieme malade mais l’absence de saignement actif a justifie un traitement conservateur qui s’est solde par un echec. Nous discutons l’interet d’une pancreatectomie caudale dans le meme temps que la splenectomie afin de reduire les taux de complications post-operatoires et de reinterventions. Nous discutons aussi de la place de la radiologie interventionnelle et de la laparoscopie.Spontaneous rupture of the spleen is a rare complication of chronic calcifying pancreatitis. Anemia and hemorrhagic shock may not occur, making diagnosis more difficult. Favourable response to conservative treatment does not prevent the need for splenectomy, as calcifiying chronic pancreatitis may progress locally. We report three cases of spontaneous rupture of the spleen. In two cases, splenic rupture revealed calcifying chronic pancreatitis and both patients underwent urgent splenectomy. In the third case, the patient was known to have calcifying chronic pancreatitis, and splenectomy was performed because of unsuccessful conservative treatment. We discuss the role of distal pancreatectomy during splenectomy to reduce the rate of postoperative complications and additional surgery. We also discuss the role of arterial embolisation and laparoscopy in the management of this rare condition.

Adénocarcinome sur endobrachyœsophage. Étude de 28 cas réséqués

STUDY AIM: The aim of this retrospective study was to report a series of 28 patients with adenocarcinoma (ADK) arising in Barretts esophagus (BE), treated by esophagectomy. PATIENTS AND METHODS: From 1992 to 1998, 28 patients were operated on for ADK in BE. There were 27 men and one woman (mean age: 65 years) classified as ASA I (n = 2), ASA II (n = 15) and ASA III (n = 11). Eighteen patients had a long story of gastro-esophageal reflux disease which required surgical repair in five of them. Dysphagia was the main symptom (n = 19). Surgical procedures included 15 Ivor Lewis operations, nine esophagectomies without thoracotomy and four esophagogastrectomies by the left thoracic approach. RESULTS: Pathological examination of the specimens showed an EBO with adenocarcinoma (n = 27) and a high grade dysplasia (n = 1). Among five patients with a previously known BE, three under endoscopic surveillance had high grade dysplasia (n = 1) and limited T1 tumor (n = 2), while the other two patients without surveillance developed an invasive tumor (T3N1). There were three postoperative deaths (mortality rate: 10%), all arising from pulmonary failure. Median survival was 16.6 months. All patients resumed a normal diet. The actuarial survival rates were 63%, 42% and 15.2% respectively at 1, 2 and 4 years. A multivariate analysis could identify 3 prognostic factors: ASA score previously known BE under surveillance, length of BE. CONCLUSION: Adenocarcinoma arising in BE is very often diagnosed too late. Patients with high risk BE require an endoscopic survey. High grade dysplasia detected in two successive examinations by two different pathologists may require prophylactic esophagectomy, but local endoscopic management presently under evaluation could be efficient in the future.