Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model.

The bacterial cytosine deaminase (CD) gene converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil. We have previously shown, in a rat liver metastasis model from colon carcinoma, that intratumoral injection of a CD-expressing plasmid into the animals followed by 5-FC treatment results in the regression of the treated tumor as well as distant uninjected tumors. The aim of this study was to further analyze the mechanisms associated with tumor regression induced upon application of suicide CD/5-FC strategy. Tumor regression was associated with an increased apoptosis, the recruitment of natural killer cells, CD4- and CD8 T lymphocytes within the tumors and an increased expression of several cytokines/chemokines mRNAs. These data indicate that the CD/5-FC suicide strategy is associated with the triggering of cellular and molecular events leading to an efficient antitumor immune response involving both innate and acquired immunity.

[Common bile duct stones: the surgical treatment is always valid]. / La calcolosi del coledoco. Il trattamento chirurgico resta sempre valido.

AIM: The treatment of common bile duct stones has changed with the new therapeutic techniques, that have replaced the conventional therapy, represented by surgery. Anyway, they could cause some problems, that must be regarded. Therefore, we wish to confirm the importance of the conventional surgery in the management of patients with common bile duct stones. METHODS: A total of 147 patients were operated for common bile duct stones (73 in emergency and 74 in election). The intraoperative cholangiography was carried out in 141 patients and a choledocoscopy in 130 patients. A drain of Kehr was positioned in 120 patients, a bilio-digestive anastomosis in 26 cases and in 1 case there was a direct suture of the common bile duct without drain. All patients were treated with a short-term antibioticotherapy, protracted to 5 days in the emergency cases. In the patients with the drain of Kehr there was a control cholangiography after 7 days from operation and it was removed after 25 days. The analysis of the results was done dividing the patients according to the age: <75 years old and >75 years old. RESULTS: Nobody died during the operation. Complications were 17.4% in the patients >75 years old and 2,6% in the patients <75 years old. There were 2 death, in the postoperative period, for the group >75 years old. Cases operated in emergency were 68.1% of "old" patients and 37.2% of "young" patients. The postoperative period was 14.9+/-9.2 days for the "old" group and 10.9+/-5.2 days for the "young" group. CONCLUSIONS: The treatment of common bile duct stones is still a surgical treatment, particularly for "old" patients.

Subcutaneous or intrahepatic injection of suicide gene modified tumour cells induces a systemic antitumour response in a metastatic model of colon carcinoma in rats.

BACKGROUND: Suicide gene therapy consists of the transfer into tumour cells of a "suicide" gene that can convert a non-toxic compound into a lethal drug. Expression of the cytosine deaminase gene leads to the conversion of the non-toxic compound 5-fluorocytosine to 5-fluorouracil. We have recently shown that "suicide cell based vaccination" consisting of intrahepatic injection of cytosine deaminase expressing colon cancer cells followed by 5-fluorocytosine treatment induces regression of a distant wild-type liver tumour in rats. AIMS: This study was conducted to test if (i) a distant bystander effect on a liver tumour can be induced after subcutaneous suicide cell based vaccination and (ii) suicide cell based vaccination is efficient in limiting tumour dissemination to extrahepatic compartments. METHODS: An aggressive variant of rat colon carcinoma cells was selected after successive passages in vitro. Rats carrying an experimental liver "metastasis" generated by injection of these cells were vaccinated by subcapsular or subcutaneous injection of cytosine deaminase expressing cells followed by 5-fluorocytosine treatment. RESULTS: Subcutaneous and subcapsular vaccination induced 70% regression in the median volume of the pre-established liver tumour (p=0.001) and abolished tumour dissemination compared with control animals. CONCLUSIONS: This study has compared for the first time the efficiency of subcutaneous and intrahepatic suicide cell based vaccination in a metastatic colorectal carcinoma model in rats. The results indicate that both modes of vaccination are equally efficient in inducing a systemic antitumour response, suggesting that this strategy is a powerful approach against the development and dissemination of metastatic colon carcinoma.

[The surgical treatment of liver metastasis of carcinoid tumors]. / Le traitement chirurgical des métastases hépatiques des tumeurs carcinoïdes.

Liver metastasis of carcinoid tumors from the digestive tract are rare entities, with characteristic symptoms and slow evolution. Symptomatic metastases may justify surgical resection. Herein, we report a series of nine patients, who underwent 14 hepatic resections (6 major and 8 minor), which was radically operated in 71%. The postoperative mortality was zero and the morbidity was 7%. Mean follow-up was 82 month (median 75 months) and global survival rate was 89%. Two patients are in complete remission. Our experience suggest that surgical hepatic resection, when feasible, is efficient and associated with prolonged survival despite a high recurrence rate.

[Vaccination by suicide gene therapy against a model of hepatic metastasis from colon cancer in the rat]. / Vaccination par thérapie génique suicide contre un modèle de métastases hépatiques de cancer colique chez le rat.

UNLABELLED: Suicide gene therapy consists of transferring into tumor cells a viral or bacterial gene encoding for an enzyme which converts a non-toxic product into a lethal drug. STUDY AIM: To analyze the therapeutic potential of vaccination with tumor cells expressing the bacterial cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) treatment in a rat liver metastasis model. MATERIAL AND METHOD: We used a rat colon carcinoma cell line which, after subcapsular or intraportal injection in syngenic animals, generates single or multiple experimental liver metastases, respectively. We have shown that introduction of a vector expressing the CD gene in this colon carcinoma cell line results in 5-FC sensitivity (PRObCD). RESULTS: Intrahepatic subcapsular injection of PRObCD tumor cells, followed by 5-FC treatment, induces total regression of a wild-type tumor pre-established in the contralateral liver lobe in 45% of animals with a 96% decrease in mean volume (p < 0.0001), demonstrating the existence of a distant bystander effect. This vaccination significantly increased the survival of rats with single (log-rank p < 0.0001) or multiple (log-rank p = 0.01) liver metastasis CONCLUSIONS: These results suggest that suicide gene-modified tumor cells can act as potent therapeutic vaccines against liver metastasis from colon carcinoma.

Regression of experimental liver tumor after distant intra-hepatic injection of cytosine deaminase-expressing tumor cells and 5-fluorocytosine treatment.

Cytosine deaminase (CD) gene of E. coli converts the non-toxic compound 5-fluorocytosine (5-FC) into 5-fluorouracil. We have introduced a vector expressing the CD gene in a rat colon carcinoma cell line. Expression of the CD gene confers 5-FC sensitivity to these cells in vitro and in vivo. In a bifocal model consisting in a simultaneous engrafment of a CD+ tumor on one lobe of the liver and a wild-type parental tumor on the opposite lobe, treatment with 5-FC results in regression of both type of tumors, indicating the existence of a distant bystander effect.

Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors: evidence of distant bystander effect.

BACKGROUND: The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide gene when introduced into cancer cells, killing the cells when they are exposed to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma. METHODS: We introduced a plasmid vector containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma cell line. Intrahepatic injection of the modified cells in syngeneic animals generates a single experimental liver "suicide tumor." We then analyzed the effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase-expressing cells in vivo as well as protection against wild-type cancer cells. RESULTS: Treatment with 5-fluorocytosine induced regression of cytosine deaminase-expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the end of 30 days and a statistically significant difference in tumor volumes between treated and control animals (two-sided P<.0001). Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals. Moreover, in animals with established wild-type liver tumors, injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a statistically significant increase in survival time (two-sided P<.0001). In vivo immunodepletion and immunohistologic analysis of experimental tumors indicate that natural killer cells are the major immune component involved in this antitumor effect. CONCLUSIONS AND IMPLICATIONS: Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.

[Giant diverticula of the colon. Apropos of 2 cases]. / Les diverticules géants du côlon. A propos de deux cas.

Giant diverticulum of the colon is a rare complication of the colonic diverticulosis. It generally involves the sigmoid colon. In the chronic form, without symptoms or with only a few non-specific symptoms, an abdominal mass is frequently palpable. A plain abdominal radiogram, showing a gas-filled cyst, can suggest the diagnosis. If needed, an abdominal CT scan is appropriate and seems to be more accurate than a barium enema. The treatment of choice is a segmental resection of the colon involving the giant diverticulum, followed by a direct anastomosis. Despite the old age of these patients, both postoperative morbidity and mortality are low and justify such a radical approach. The acute clinical presentation (about 20%) is generally due to a peritonitis by perforation of the giant diverticulum and requires an emergency colectomy.

[Presacral myelolipoma]. / Myélolipome présacré.

Presacral myelolipoma is a rare benign tumour of unknown aetiology, composed of mature adipose tissue with intermixed normal haematopoietic cells. Computed tomography is of help in the diagnosis but biopsy is mandatory in order to avoid unnecessary surgery. A case is reported.

[Congenital hepatic fibrosis. Five cases with late occurrence in adults]. / Fibrose hépatique congénitale. Cinq cas à révélation tardive chez l'adulte.

Congenital hepatic fibrosis (CHF), is an autosomal recessive disease, presenting principally in childhood with portal hypertension and/or cholangitis, and often associated with renal malformations. The forms presenting later in adults are rare, and illustrated herein by 4 cases with dominant cholangitis, and one latent form. Biological tests and radiological imaging are often normal. The histopathologic diagnosis, sometimes difficult on liver needle biopsy is based on fibrous enlargement of portal areas, with numerous and tortuous bile ducts, lined by regular, cuboidal epithelium. Interportal fibrosis can mimic cirrhosis. In CHF, cholangitis are favoured by intrahepatic biliary dilatation, sometimes related to Caroli's disease, associated in 25% of cases. Suppurative complications, sometimes fatal explain the severity of cholangitis forms of CHF, contraindicating inopportune cholangiography and biliary surgery.

DNA ploidy by image cytometry in urothelial carcinomas. Comparison of touch imprints and paraffin-embedded biopsies from 31 patients.

OBJECTIVE: To compare DNA content measured by image cytometry from touch imprints and formalinfixed, paraffin-embedded samples in bladder carcinomas. STUDY DESIGN: Thirty-one biopsies of urothelial carcinomas were selected for a prospective study. Imprints of fresh specimens were performed. Cell suspensions were obtained from dewaxed samples by the procedure of Hedley. Sections 7 microns thick were used for carcinoma in situ and small biopsies. The DNA ploidy index was measured on Feulgen-stained slides using an image cytometer. RESULTS: From imprint analysis, seven grade 1 carcinomas (n = 9) were found to be diploid (78%). Nine grade 2 carcinomas (n = 12) exhibited aneuploidy (75%), as did all grade 3 and in situ carcinomas (n = 10). Multiploidy was demonstrated from imprints in four cases instead of the two detected from dewaxed tissue. In 27 cases (87%), G0/G1 peaks obtained from paraffin blocks showed a shift to the left. In five cases (16%), variations in the DNA index were responsible for discrepancies in the DNA ploidy evaluation between fresh imprints and dewaxed samples of the same tumors. CONCLUSION: Image cytometry on Feulgen-stained imprints of bladder biopsies is a simple and reliable procedure for assessing DNA ploidy in urothelial carcinomas, providing great sensitivity for detecting small aneuploid peaks and multiploid tumors. DNA image analysis of touch preparations is especially useful for carcinoma in situ and small biopsies unsuitable for Hedley's technique.

Bacterial translocation during portal clamping for liver resection. A clinical study.

OBJECTIVE: To determine the incidence and the clinical importance of gut-bacterial translocation after portal triad clamping for liver resection. DESIGN: Cohort study. SETTING: Multispecialty referral center. PATIENTS: Five cirrhotic and 10 noncirrhotic patients requiring liver resection. INTERVENTIONS: Elective liver resection under normothermic ischemic conditions (mean +/- SD duration, 40.2 +/- 13.1 minutes). Simultaneous sampling for qualitative culture of the systemic and portal blood, the upper gastrointestinal tract fluid, and a mesenteric lymph node (MLN) before and after liver resection. MAIN OUTCOME MEASURES: Positive culture rate, type of organism isolated, and septic complications rate. RESULTS: Before resection, blood cultures and MLNs were sterile in all but 1 patient; this culture-positive patient had had a recent colon resection for occlusive carcinoma and was excluded from further analysis. After resection, systemic and portal blood cultures were sterile in all cases. Conversely, the MNLs were culture positive in 6 (43%) of 14 patients. Coagulase-negative staphylococci were the most common isolates. A weak correlation was observed between the organisms isolated from the MLNs and those simultaneously present in the upper gastrointestinal tract fluid. There was no relationship between bacterial translocation and the outcome as patients with culture-positive MLNs showed no evidence of intraperitoneal septic complications and the only patient with a septic complication (a subphrenic abscess) had negative cultures after resection. CONCLUSION: A significant bacterial translocation in the MLNs occurs after portal triad clamping and liver resection, although not clinically relevant.

Resection of the suprarenal inferior vena cava. The role of prosthetic replacement.

OBJECTIVE: To review the role of prosthetic replacement after resection of the suprarenal portion of the inferior vena cava (IVC). DESIGN: Retrospective review of a series of six patients with malignant infiltration of the suprarenal IVC undergoing operation in the last 11 years. SETTING: Multispecialty referral center. PATIENTS: One primary leiomyosarcoma and five involvements of the IVC by liver carcinoma (n = 2), adrenal carcinoma (n = 2), and recurrent renal carcinoma (n = 1). INTERVENTIONS: En bloc resection of the tumor with the IVC under total vascular exclusion of the liver in four cases, combined major liver resection in four cases, venous resection including the renal confluence in four cases, prosthetic venous replacement in four cases, and no venous replacement in two cases. MAIN OUTCOME MEASURES: Mortality, venous patency, clinical assessment, and malignant recurrence. RESULTS: One postoperative death (renal failure) following extended resection with right nephrectomy and ligature of the left renal vein. Graft patency was controlled in survivors, with good functional result. Among two patients without venous replacement, one with complete caval obstruction and marked collateral circulation has had a good result, and one with partial caval obstruction experienced transient symptoms of venous insufficiency. Malignant recurrence led to death in four patients (4, 6, 37, and 42 months after surgery). CONCLUSIONS: Suprarenal IVC reconstruction is justified in selected cases, with good functional results. When the renal confluence is resected along with the IVC, renal vein reconstruction may be needed to avoid acute renal failure. The oncologic results of such extensive resections are poor. Adjuvant therapy should be evaluated.

Transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome after failure of surgical shunting.

A case of acute Budd-Chiari syndrome in a 26-year-old woman is reported. After a mesocaval shunt, the patient remained asymptomatic for 21 months, but ascites and hepatomegaly reappeared due to inferior vena cava stenosis subsequently treated by balloon dilation. Recurrence of stenosis indicated the need for a cavoatrial shunt with an expanded polytetrafluoroethylene prosthesis, which was followed by a complete recovery during the next 29 months. Radiological follow-up with magnetic resonance imaging demonstrated progressive hepatomegaly, thrombosis of the cavoatrial shunt, and stenosis of the mesocaval shunt. A transjugular intrahepatic portosystemic shunt was carried out, despite the absence of any patent residual hepatic vein at the usual level, by perforating the inferior vena cava and liver up to the right portal vein. An expandable 12-mm stent was successful in decreasing liver congestion. Dilation of the transjugular intrahepatic portosystemic shunt was done 15 months later, and the patient remains asymptomatic after a follow-up of 18 months.