Randomized trial of 5-fluorouracil, leucovorin and cisplatin in advanced pancreatic cancer.

BACKGROUND/AIMS: Phase II trials of combined 5 fluorouracil, leucovorin and cisplatin have demonstrated an 18-28% response rate in advanced pancreatic carcinomas. We investigated the effect of this chemotherapy regime on patients' survival. METHODOLOGY: Patients included gave informed consent. They had an advanced and proven pancreatic adenocarcinoma. The trial was multicentric, prospective and randomized. It compared a 5-day course of leucovorin (200 mg/m2/day), 5-fluorouracil (375 mg/m2/day) and cisplatin (15 mg/m2/day) repeated every 21 days (23 patients) with a control group (22 patients). The main end points were survival time (Kaplan-Meier and log-rank methods) a[not readable: see text]side effects of chemotherapy. RESULTS: Association of leucovorin, 5-fluorouracil and cisplatin failed to demonstrate any advantage of this regimen compared with supported care alone. Median survival times were 8.6 months (SD +/- 1.8) and 7.0 months (SD +/- 0.6), respectively. The modulation of 5-fluorouracil by leucovorin and cisplatin was well tolerated with moderate toxic effects. CONCLUSIONS: This multicentric trial failed to demonstrate any advantage of the evaluated chemotherapy regime in the palliative treatment of cancer of the exocrine pancreas. Other trials including gemcitabine and/or radiotherapy are needed in advanced pancreatic adenocarcinoma.

Bile duct cysts in adults: a multi-institutional retrospective study. French Associations for Surgical Research.

OBJECTIVE: To review the features of adult patients undergoing surgery for bile duct cysts, focusing on the anatomy of the biliary tree as well as the long-term outcome. SUMMARY BACKGROUND DATA: Bile duct cysts (BDCs) are uncommon in Western countries, and the majority of reported cases originate from Asia. Japanese authors have emphasized the frequent association of extra- and intrahepatic bile duct dilatations, but grading of patients based on Todani's classification is often hindered by the absence of an accurate definition of types IC and IVA cysts. Moreover, despite the increasing use of extrahepatic cyst excision, little is known about the long-term outcome in patients with intrahepatic bile duct involvement. METHODS: Forty-two adult patients with BDC were treated between 1980 and 1992 in 17 institutions of the French Associations for Surgical Research. Clinical presentation, radiologic presurgical evaluation, and surgical procedures were analyzed. The long-term postsurgical outcome was derived from patient charts, attending physicians, or direct patient contact. RESULTS: Twelve patients (30%) had recurrent abdominal pain or jaundice from childhood. Seven (17%) had undergone prior cystenterostomy. Twenty-one (50%) had a Todani-type IVA cyst with extra- and intrahepatic bile duct involvement. Of these, nine had segmental, exclusively left-sided intrahepatic bile duct dilatation. Biliary carcinoma was encountered in five patients (12%). Extrahepatic cyst excision with a Roux-en-Y hepaticojejunostomy was performed in 34 patients with type I or IV cysts. The overall operative mortality rate was 2.4%. Long-term results were clearly correlated with cyst type: during a mean follow-up of 8.4 years, 11 of 12 patients (92%) treated by cyst excision for type I cyst remained free of symptoms, whereas 31% of patients who underwent surgery for type IV cyst had episodic or severe cholangitis with intrahepatic stones. CONCLUSIONS: In patients with BDC, particular attention must be given to the associated intrahepatic bile duct dilatations. We propose a modification of Todani's classification to distinguish cystic, segmental, and fusiform dilatations of the intrahepatic biliary tree in type IV cysts. In patients with segmental left intrahepatic cystic dilatations, combined left liver lobectomy and extrahepatic cyst excision is suggested to decrease late postsurgical biliary complications.

Assessment of biliary excretion of piperacillin-tazobactam in humans.

Piperacillin-tazobactam concentrations in serum and bile were measured intraoperatively in 10 patients undergoing cholecystectomy (group 1) and 5 cholecystectomized patients provided with external bile duct drainage (group 2). Each patient received a single intravenous dose of piperacillin at 4 g plus tazobactam at 0.5 g over 30 min. Drug concentrations in both serum and bile were measured by high-performance liquid chromatography. In group 1 patients, serum and bile specimens and gallbladder wall fragments were collected at mean times of 70 and 83 min postinfusion, respectively. The mean concentrations of piperacillin and tazobactam were, respectively, 69.1 +/- 41.5 (standard deviation) and 9.9 +/- 5.1 microg/ml in serum, 630.4 microg/ml (range, 24.8 to 1,194 microg/ml) and 11.8 microg/ml (range, 3.6 to 22 microg/ml) in choledochal bile, 342.3 microg/ml (range, 1.1 to 1,149 microg/ml) and 7.7 microg/ml, (range, 0.2 to 23.1 microg/ml) in gallbladder bile, and 49.3 microg/g (range, 9.7 to 223 microg/g) and 2.9 microg/g (range, 0.1 to 5.9 microg/g) in the gallbladder wall. In group 2 patients, the amounts of drugs recovered in bile drainage obtained over 12 h were 28.4 +/- 18.0 and 1.0 +/- 0.5 mg for piperacillin and tazobactam, respectively. Peak piperacillin and tazobactam concentrations in bile reached 358 +/- 242 and 10.8 +/- 4.2 microg/ml, respectively. Comparison of drug levels in serum and bile suggests an underlying active secretion process for piperacillin elimination into the bile, unlike that of tazobactam. From a therapeutic viewpoint, given the concentrations of tazobactam recorded in bile fluid and tissue, the addition of this beta-lactamase inhibitor to piperacillin therapy might be of interest in the management of biliary tract infections, mostly in patients at risk of mixed aerobic-anaerobic infections due to beta-lactamase-producing organisms.

[Cystic dystrophy on an aberrant duodenal pancreas. Apropos of a case]. / Dystrophie kystique sur pancréas aberrant duodénal. A propos d'une observation.

Cystic dystrophy of the aberrant pancreas is a rare poorly understood condition which is difficult to diagnose and treat. The primary clinical signs are epigastralgia associated with poor general health and complications due to stenosis of the duodenum. Endoscopy gives the most information on tissue lesions and cystic formations in the duodenal mucosa. Although the condition is benign, and due to the lack of sufficient history in endoscopically treated cases, cystic dystrophy of the aberrant duodenal pancreas appears to require duodenopancreatectomy.

[Predictive factors of recurrence in surgically treated rectal villous tumors. Therapeutic approach based on 184 cases]. / Les facteurs prédictifs de récidive des tumeurs villeuses rectales opérées. Attitude thérapeutique à propos de 184 cas.

The aim of this retrospective study on 184 operated cases was to propose a therapeutic management scheme for villous tumours of the rectum. Among the 184 operated patients, 167 (90,7%), mean age 65 years, were seen after a follow-up of 2 to 20 years. The tumour was most often localized in the rectal ampoula (141 cases) and was benign in 65 p. 100. Endoanal surgery was performed in 76 patients among whom recurrence was observed in 29.7%. Posterior exeresis (Kraske method) was performed in 52 cases with a recurrence rate of 31.9%). Finally, abdominoperineal amputation was performed 20 times, essentially for advanced stage tumours. Based on the statistical analysis of the recurrence factors for these different techniques, we have concluded that endoanal surgery predominates for benign tumours smaller than 5 cm situated at least 8 cm from the anus. Above the size of 5 cm, due to the major risk of tumourectomy, we believe rectal exeresis is the most rational treatment.

Role of intrahepatic protein binding in the hepatobiliary extraction profile of cefixime in humans.

The hepatobiliary extraction profile of cefixime, a dianionic cephalosporin antibiotic, was studied in 10 patients, each of whom was provided with T-tube drainage of his or her common bile duct after cholecystectomy. After a single 200 mg oral dose, cefixime biliary clearance proved to be nonlinear, mostly in its initial phase, which is consistent with a concentrative uptake and intracellular protein binding for the drug. The latter process appears to be saturable and to operate at a rate that correlates with the total amount of cefixime recovered in the 24-hour bile drainage. Such findings seem to confirm the significant role played in vivo by hepatic ligandin in the hepatobiliary extraction of organic anions. The data also show that a single 200 mg oral dose of cefixime yields drug levels in bile substantially higher than the minimal inhibitory concentrations for the most frequent Enterobacteriaceae in biliary tract infections. Accordingly, this cephalosporin could be an interesting alternative in both prophylaxis and treatment of biliary tract infections.

Pancreatic localization of a Castleman's tumour.

Castleman's tumour is a rare anatomo-clinical entity. Most cases of Castleman's tumour occur in the mediastinum. The histopathology demonstrates benign angiofollicular lymph node hyperplasia. The pancreatic localization is uncommon and has only been reported once. We describe a new case with literature review.

[Surgical widening of strictures in the small intestine in Crohn disease]. / Les plasties d'élargissement dans la maladie de Crohn du grêle.

Twenty-two stricture plasties were performed in five patients with multiple stenosis of the small intestine due to Crohn's disease. Immediate post-operative results were satisfactory but progressive degradation followed. These findings are similar to those reported in the literature on this technique which does not give better results than other methods since none have an effect on the clinical course of the disease. The only advantage is to decrease the amount of intestinal mutilation.

[Colorectal cancer in patients over the age of 80 years]. / Le cancer colo-rectal chez les sujets de plus de 80 ans.

Between January 1, 1973 and December 31, 1986, 1.734 patients underwent colorectal resections for carcinoma. The patients were divided into two groups: group I included 163 patients > 80 years on first presentation; group II comprised 1.571 patients < 80 years. The total perioperative mortality rates of the elderly and younger group were 15.3 percent and 5 percent respectively (p < 0.001). The surgical mortality rates in group I were 7.4 percent after elective operations versus 4.5 percent in group II and were not statistically different. Emergency surgery was associated with a significantly higher incidence of perioperative deaths at any age (p < 0.001). In the elderly group, most deaths (88%) resulted from complications of coexisting medical disorders or thrombo-embolic complications. The 5 year survival for the young and elderly groups were 46.2 percent and 35 percent respectively (p < 0.05). However, excluding patients dying from nonmalignant disease, the 5 year survival rate did not differ significantly between the two groups of patients (49.5 percent versus 42.2 percent).

[Proctocolectomy with ileo-anal anastomosis performed with mechanical suture without mucosectomy and without protective ileostomy]. / Coloproctectomie avec anastomose iléo-anale effectuée par suture mécanique sans mucosectomie et sans iléostomie de protection.

Abdominal proctocolectomy with formation of an ileal reservoir anastomosed onto the anal canal using a stapler device is described. This technique avoids also stripping the mucosa from the anal canal which is time consuming and often difficult and incomplete. The avoidance of a temporary ileostomy did not lead to an increase in post operative complications. Seventeen patients have undergone this procedure for ulcerative colitis and the advantages and disadvantages of it are discussed.

Regulatory role of enteric kappa opioid receptors in human colonic motility.

The effects of different kappa opioid agonists and antagonists on spontaneous mechanical activities and responses to electrical transmural nerve stimulation of both longitudinal and circular muscle strips from the human sigmoid colon were studied. A superfusion apparatus was used to record isometric contractions. Exogenously added kappa agonists did not modify spontaneous contractile activities on either type of strip. Nerve stimulation induced a triphasic response composed of a first contraction (C1) followed by a relaxation (C2) and an off-contraction (C3); this response was mediated by cholinergic excitatory nerves and non-adrenergic, non-cholinergic excitatory and inhibitory nerves. Dynorphin 1-13 and the synthetic kappa agonist trans-3,4-dichloro-N-methyl-N-(2- [1pyrolidinyl]-cyclohexyl) dramatically decreased the amplitude of the excitatory components C1 and C3. The effects of both kappa agonists were blocked in presence of the kappa antagonist Nor-Binaltorphimine. The delta antagonist ICI 174864 did not prevent the inhibition of the contractions C1 and C3 induced by dynorphin. Therefore, these data suggest that kappa receptors are involved in the neuroregulation of smooth muscle of human colon and mediate inhibition of cholinergic and non-cholinergic excitatory transmission within myenteric plexus.

[Local recurrence after surgery for cancer of the rectum]. / Récidives loco-régionales après cancer du rectum opéré.

Local tumor recurrence rates after curative rectal cancer surgery are reportedly high and herald a poor diagnosis. Extramural recurrence is most common and is due to the failure to remove all of the tumor during the initial operation. In the rarer anastomotic recurrence, the implantation of exfoliated malignant cells is possible, but histochemical changes in the mucosa surrounding a tumor may be considered as an alternative cause of local recurrence. Local recurrence rates did not improve when the distal margins were extended over 2 cm, but microscopic lateral tumor extension appears to be the major determinant of recurrence. Early diagnosis is based on frequent CEA assays, history, physical examination, endoscopy, endoluminal ultrasound and pelvic CT scan. Aggressive treatment involving a combination of field irradiation, surgical debulking and intra-operative radiation can result in local control and long-term survival in 10 to 25% of patients.

[Pancreatojejunostomy or pancreatogastrostomy after cephalic pancreatoduodenectomy]. / Pancréato-jéjunostomie ou pancréato-gastrostomie après duodéno-pancréatectomie céphalique?

The propensity for leakage at the site of pancreatojejunostomy continues to be a major reason for morbidity and death after pancreaticoduodenectomy. Pancreatogastrostomy has been introduced as a possible alternative to pancreatojejunostomy and although this procedure was developed experimentally more than 50 years ago its use has not gained widespread clinical use. The purpose of this study was to evaluate the role of pancreatogastrostomy. Pancreatogastrostomy was performed in 15 patients with pancreatic resection for carcinoma and compared with 57 pancreatojejunostomy. Our experience confirms that pancreatogastrostomy is a safe and easy method and suggest that it may be used more frequently.

Colorectal cancer in patients over 80 years of age.

Between January 1, 1973, and December 31, 1986, 1,734 patients underwent colorectal resections for carcinoma. Patients were divided into two groups: Group I included 163 patients aged greater than or equal to 80 years on first presentation; Group II comprised 1,571 patients aged less than 80 years. The total perioperative mortality rates for the elderly and young group were 15.3 percent and 5 percent, respectively (P less than 0.001). The surgical mortality rates after elective operations in Groups I and II were 7.4 and 4.5 percent, respectively, and were not statistically different. Emergency surgery was associated with a significantly higher incidence of perioperative deaths at any age (P less than 0.001). In the elderly group, most deaths (88 percent) resulted from complications of coexisting medical disorders or thromboembolic complications. The 5-year survival for the young and elderly group were 46.2 percent and 35 percent, respectively (P less than 0.05). However, excluding patients dying from nonmalignant disease, the 5-year survival rate did not differ significantly between the two groups of patients (49.5 percent vs. 41.2 percent).

Morphine stimulates HIV replication in primary cultures of human Kupffer cells.

Intravenous drug abusers represent a high risk group for HIV infection in Europe and North America. Although the use of blood-contaminated needles undoubtedly constitutes the main factor of transmission of the virus, an effect of the drug itself either on the immune system or on virus replication, thus favouring the initiation of the infection, may not be excluded. We have formerly established that primary cultures of human Kupffer cells (KC) are permissive for HIV1. In this paper, we describe the effect of morphine hydrochloride on the multiplication of different isolates of HIV1 in cultured human KC. KC were obtained by dissociation of human liver fragments with collagenase and purified by centrifugal elutriation. Five-day-old KC were infected with HIV1; at different intervals, the production of virus was quantitated by the reverse transcriptase activity associated with the particles present in the culture medium. In primary cultures of KC preincubated for 48 h and maintained in the presence of morphine, the production of viral particles was increased. This enhancing effect was found with 3 different HIV1 isolates. Treatment of KC with morphine prior to infection was not required for the stimulation to take place, which indicated that the enhancing effect was not related to a more efficient adsorption of the virus to the KC plasma membrane. Stimulation of HIV1 production was observed for all the concentrations of morphine used (0.05 to 0.5 mg/ml). These results, if confirmed in vivo, may shed new light on the risk factors related to the intravenous administration of heroin.

[Role of pancreaticojejunostomy in the treatment of chronic pancreatitis. A study of 105 operated patients]. / Place de la pancréatico-jéjunostomie dans le traitement des pancréatites chroniques. Etude de 105 opérés.

105 patients with intractable pain due to chronic pancreatitis were selected for treatment by lateral pancreatico-jejunostomy (according to the procedure of Partington Rochelle) after pre operative endoscopy had revealed a dilatation of the main pancreatic duct (mean : 6 mm). Pancreatico-jejunostomy was the unique procedure in 59 patients; it was associated with a biliary or duodenal diversion in 46 others patients. 2 patients died post-operatively and 12 required a second operation some years subsequent to the pancreatic drainage, for biliary stenosis due to the progress of the sclerosis. 8 of the 22 late death were in direct relation with the persistence of alcohol intake and 4 others died from an extra pancreatic cancer. Peptic ulcer complicating pancreatico-jejunostomy appeared in three patients and two of them died from hemorrhage. Mean observation time was 65 years. Long term results were excellent or improved in 93.4% what pain relief concern, but the progression of exocrine or endocrine pancreatic insufficiency indicates that decompression of the dilated pancreatic duct does not prevent continuing destruction of pancreatic glandular tissue. In spite of these good results, the rational for duct drainage as a mean to decrease the intraductal pressure secondary to stricture is unclear. Neither the patency of the anastomosis, nor the presence or not of pancreatic lithiasis or the size of the dilated pancreatic duct seem to be crucial for pain relief after pancreatico-jejunostomy. Notwithstanding of the dubiousness of the mechanism of action of the drainage procedure, pancreato-jejunostomy remains the most effective procedure for relief of pain in chronic pancreatitis with dilated duct.

[Colonic cancers. A retrospective study of 1122 surgically-treated patients]. / Les cancers du côlon. Etude rétrospective portant sur 1122 malades opérés.

A retrospective study of 1122 cancers of the colon operated by the same surgical team from 1973 to 1989 makes a number of statements possible: In spite of the improved diagnostic means, 66 (5.8%) only of the cancers were of Dukes' type A. 116 patients had complications, ie. perforation in 9 cases and obstruction in 107, among which 59 were operated within 24 hours. The rate of resection is very high: 93.8%. In 8.1% of all cases the excision was extended because of invasion of neighboring tissues. Curative resection was performed in 844 patients, while surgery was palliative in 278, including 205 excisions. The total operative mortality was 5.8%, sinking to 3.9% for curative surgery. It is as high as 22% in emergent surgery. Since 1981, it has been lower than 1% and only caused by general factors. The survival rate of 557 patients after more than 5 years is 46.6%. This rate was studied according to various parameters (sex, location, features of excision, Dukes' stage, involvement of lymph nodes). Lymph node involvement and Dukes' stage are the only factors having a significant influence on survival. In 90.0% of cases, the long-term death of patients followed up for more than 5 years is caused by hepatic metastases (66.6%), local recurrence (13.3%) or both (20%). The occurrence of local recurrence or hepatic metastases can sometimes be treated by second surgery, which has been performed in 20 patients: 11 hepatic resections with a 26.8% survival at 5 years, and 9 excisions for local recurrence with 12.4% survival at 5 years.