Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic melanoma.

PURPOSE: To evaluate the activity and the toxicity of the combination of cisplatin (CDDP)/recombinant interleukin-2 (rIL-2) and interferon alfa-2a (IFN alpha) in disseminated malignant melanoma (DMM). PATIENTS AND METHODS: Between December 1990 and March 1992, 39 patients with biopsy-proven metastatic malignant melanoma (MM), bidimensionally measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 2 entered this protocol. Seventy-nine percent had received previous chemotherapy including platinum complex (15%) and alpha interferon (44%). They received CDDP (100 mg/m2 on day 0) followed by IL-2 18.10(6) IU/m2/d continuous intravenous (IV) infusion from day 3 to day 6 and from day 17 to day 21. The cycle was repeated on day 28. Subcutaneous IFN alpha 9.10(6) IU three times weekly was administered throughout the treatment period. From day 66 or 94, patients were administered a maintenance cycle with CDDP 100 mg/m2, subcutaneous IL-2 5.10(6) IU/m2/d from day 15 to day 19 and from day 22 to day 26 and IFN alpha 9.10(6) IU three times weekly repeated every 5 weeks (maximum four cycles). RESULTS: Among 39 assessable patients, five patients achieved complete responses (CRs). Sixteen patients had partial responses (PRs). The overall objective response rate was 53.8%. The number of metastatic sites was the only response-predictive factor. Toxicity was manageable in a routine patient setting and there was no life-threatening toxicity. CONCLUSION: These results seem to indicate a possible synergy between CDDP/rIL-2 and IFN alpha in MM.

Chemoimmunotherapy of metastatic malignant melanoma. The Salpétrière Hospital (SOMPS) experience.

Optimistic results were obtained in the treatment of 39 patients with surgically incurable metastatic malignant melanoma using a regimen including 2 to 3 monthly induction cycles of cis-diamminedichloroplatinum (CDDP), recombinant interleukin-2 (rIL-2) and interferon alpha-2a (IFN alpha-2a). 33 of 39 patients were pretreated with chemotherapy (dacarbazine and/or fotemustine:31, CDDP:6) and 17 of 39 with IFN alpha-2a. Overall response rate was 54% with 13% achieving a complete response for up to 59+ weeks. Moderate to severe side-effects were reversible on rIL-2 cessation and toxicity was manageable in a routine inpatient setting. These results are especially encouraging as they were seen in previously treated patients, classically low responders, including 3 who were resistant to cisplatin or other platinum complexes. The question remains if this regimen bypasses traditional mechanisms of drug resistance.

Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

New method of cardiac output measurement using ultrasound velocity dilution in rats.

The aim of this study was to validate a new technique for the measurement of cardiac output (CO) based on ultrasound and dilution (COUD) in anesthetized rats. A transit time ultrasound (TTU) probe was placed around the rat carotid artery, and ultrasound velocity dilution curves were generated on intravenous injections of saline. CO by COUD were calculated from the dilution curves for normal and portal hypertensive rats in which CO was known to be increased. COUD was compared with the radiolabeled microsphere method and with direct aortic TTU flowmetry for baseline CO and drug-induced CO variations. CO in direct aortic TTU flowmetry was the ascending aorta blood flow measured directly by TTU probe (normal use of TTU flowmetry). The reproducibility of COUD within the same animal was also determined under baseline conditions. COUD detected the known CO increase in portal hypertensive rats compared with normal rats. CO values by COUD were correlated with those provided by microsphere technique or direct aortic TTU flowmetry (adjusted r = 0.76, P < 10(-4) and r = 0.79, P < 0.05, respectively). Baseline CO values and terlipressin-induced CO variations were detected by COUD and the other techniques. Intra- and interobserver agreements for COUD were excellent (intraclass r = 0.99 and 0.98, respectively). COUD was reproducible at least 10 times in 20 min. COUD is an accurate and reproducible method providing low-cost, repetitive CO measurements without open-chest surgery. It can be used in rats as an alternative to the microsphere method and to direct aortic flowmetry.

Hepatic hyper-vitaminosis A: importance of retinyl ester level determination.

We report the case of a 32-year-old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol-binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri-sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper-vitaminosis A may be normal and lead to under-estimation of liver vitamin A overload.

A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma.

Tamoxifen (TAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDP-IL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41% response rate (95% CI, 21-61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.

[Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha]. / Pulsions suicidaires chez des malades atteints d'hépatite chronique C au cours ou au décours du traitement par l'interféron alpha.

UNLABELLED: We report 5 cases of psychiatric side effects in patients treated with alpha interferon for chronic viral C hepatitis. The first case includes depression with suicidal impulses without a suicide attempt; there was a positive rechallenge of interferon. In the second and third cases, depression occurred during interferon therapy, but has not disappeared after interferon withdrawal. In the 4th and 5th cases, depression occurred after interferon withdrawal. Overall, suicide was attempted in 4 cases after interferon withdrawal and was responsible for 2 deaths. The prevalence of suicide attempts during the 6 to 12 months of interferon therapy was 0% compared to 1.3% during the 6 months after interferon therapy (P < 0.05) in 306 patients with chronic hepatitis C treated by interferon in our local area network during the same period. IN CONCLUSION: a) depression does not always disappear after interferon is discontinued; b) regular psychiatric follow-up is justified during treatment with interferon; c) psychiatric supervision should be continued, even more frequently after interferon withdrawal; d) the increased risk of psychiatric side-effect due to interferon as well as their severity suggest interferon should be administered with caution; e) the role of interferon can only be evaluated in controlled studies including the incidence and predictive value of emotional disorders.

[Value of tissue harmonic imaging in biliary lithiasis]. / Apport de l'imagerie harmonique dans la pathologie lithiasique du système biliaire.

AIM OF THE STUDY: To define the role of harmonic imaging in the study of biliary lithiasis. SUBJECTS AND METHODS: We included 50 consecutive patients with suspected biliary lithiasis. Three independent observers compared results of harmonic imaging and conventional ultrasonography. RESULTS: This study showed a better interobserver agreement with harmonic imaging for acoustic shadow (kappa=0.87 vs 0.68) and intra-hepatic biliary stones (kappa=0.79 vs 0.49). More stones and more lithiasic gallbladders were seen with harmonic imaging (27 vs 24) and visualization of gallbladder sludge and the acoustic shadow from stones (P=0.01) was better. Ultrasound examination appears to be easier and faster and the diagnosis is more certain with harmonic imaging than with conventional ultrasonography (P=0.005). CONCLUSION: Harmonic imaging provides more information on biliary lithiasis and a more certain diagnosis.

[Occurrence of non-Hodgkin's lymphoma in chronic viral hepatitis C]. / Survenue d'un lymphome non hodgkinien au cours d'une hépatite chronique virale C.

INTRODUCTION: We report the occurrence of non-Hodgkin's lymphoma during the course of chronic hepatitis C treated with alpha-interferon. EXEGESIS: Specific viruses such as Epstein-Barr virus and human T-cell leukemia viruses I and II may be at the origin of various lymphomas in human. The presence of B cell lymphoma in the course of chronic hepatitis C has already been described and could be related to the lymphoid tropism of hepatitis C virus. CONCLUSION: This new report of an association between chronic hepatitis C and B cell lymphoma should lead physicians to search for signs of lymphoma in patients with chronic hepatitis C.

[Percutaneous cholecystostomy in non-surgical patients]. / Cholécystostomie percutanée chez le patient inopérable.

PURPOSE: To assess the efficacy and complications of percutaneous cholecystostomy (PC) in the treatment of acute cholecystitis in non-surgical patients. MATERIALS AND METHODS: Retrospective study of 25 cases (16 males and 9 females) of PC. The average age was 82 years (range: 59-95). Eight had acute acalculous cholecystitis (AAC) and 17 had acute calculous cholecystitis (ACC). US-guided percutaneous cholecystostomy was performed in most cases; CT-guidance was required in 5 cases. RESULTS: One technical failure and one complication (abdominal wall hematoma) occurred. PC was successful for sepsis control in 21 patients (5 AAC and 16 ACC): delayed cholecystectomy was performed in one patient, and one patient had recurrent acute cholecystitis at one month that responded to medical management. For the 4 remaining patients: 1 corresponded to the technical failure, and failure of sepsis control was observed in the 3 others patients (2 AAC, 1 ACC). PC was the definitive treatment or resulted in sepsis control in 84% of cases. PC was the definitive treatment, without recurrence, in 76% of cases. CONCLUSION: US or CT guided percutaneous cholecystostomy is an effective treatment, with a low rate of complication, in elderly or critically ill patients. PC can be used as a definitive treatment or as a temporizing measure in critically ill patients allowing for delayed definitive surgical/endoscopic management.

[Evaluation of a new MRI cholangiography sequence with a half-Fourier acquisition technic]. / Evaluation d'une nouvelle séquence de cholangiographie IRM avec acquisition en demi-plan de Fourier.

PURPOSE: The aim of this study was to evaluate a new MR cholangiography sequence in which thick slices are obtained with half Fourier acquisition (SSFSE) in biliary obstructive diseases. PATIENTS AND METHODS: Fifty patients with suspected bile duct obstruction were prospectively investigated with MR cholangiography using SSFSE sequence with thick slices. The gold standard was ERCP (n = 40), percutaneous cholangiography (n = 1) or surgical findings (n = 9). According to this gold standard, 17 patients had bile duct lithiasis and 21 had neoplastic obstruction. RESULTS: The sensitivity and specificity of MR cholangiography were 100% and 94% for the diagnosis of lithiasis obstruction and 95% and 97% for neoplastic obstruction. Agreement between the MR cholangiogram and the gold standard was good whatever the site of obstruction (range of kappa values: 0.79-1). CONCLUSION: MR cholangiography with SSFSE sequence is a useful, precise and easy to use technique. Acquisition time for thick slices is short (< 2 sec) limiting cardiorespiratory artefacts and eliminating the need for post-treatment.

[Recurrent stomal hemorrhage treated by transjugular intrahepatic portosystemic anastomosis and embolization of stomal varices]. / Hémorragies stomiales récidivantes traitées par anastomose portosystémique intrahépatique transjugulaire et embolisation des varices stomiales.

Bleeding stomal varices is a rare complication of portal hypertension. We report the case of a cirrhotic patient, with a history of colonic adenocarcinoma, who had recurrent bleeding stomal varices. Treatment with transjugular intrahepatic portosystemic shunt and stomal varice embolization was performed because failure of medical treatment of portal hypertension and sclerotherapy. Twenty six months later only one stomal hemorrhage was noted. This suggests that transjugular intrahepatic portosystemic shunt and stomal varice embolization is effective in case of recurrent bleeding of stomal varices.

[Prevention of esophageal varix rupture]. / Prévention de la rupture des varices oesophagiennes.

PRIMARY PREVENTION: Preventive measures against esophageal varicose vein bleeding are needed for grade 2 risk resulting from the presence of large varix. Medical or endoscopic methods can be used. USEFUL DRUGS: With beta-blockers the incidence of a first bleeding episode is significantly reduced and mortality is almost significantly reduced. Three controlled trials have demonstrated that a nitrate derivative beta-blocker combination improves the efficacy of beta-blockers in terms of reduced bleeding. Nitrates can be prescribed alone in case of a contraindication for beta-blockers but the efficacy is poorly demonstrated. SCLEROTHERAPY: Both incidence of first bleeding episode and mortality are significantly reduced after sclerotherapy. Variable results have however been reported and sclerotherapy is probably only effective in high-risk patients; the consensus conference has not recommended its use. On the contrary, endoscopic ligature is probably useful since 5 preliminary studies have demonstrated a significant effect on first bleeding and mortality. Its relative contribution compared with propranolol remains to be demonstrated. RECOMMENDATIONS: The first intention therapy should rely on beta-blockers or nitrates in case of a contraindication or adverse effect. Endoscopic ligature can be discussed in high-risk patients. The beta-blocker-nitrate combination and the beta-blocker-endoscopic treatment combination cannot be recommended at the present time. SECONDARY PREVENTION: Meta-analyses have shown that beta-blockers or sclerotherapy significantly reduce the incidence of recurrent bleeding and mortality. Sclerotherapy significantly reduces the risk of recurrent bleeding compared with beta-blockers although there is no difference in mortality and the incidence of complications is significantly greater with sclerotherapy. Associating the two methods can significantly reduce recurrent bleeding but has no effect on mortality. Elastic ligature is significantly more effective in terms of recurrent bleeding and mortality or complication rate. Transjugular intrahepatic portosystemic shunt (TIPS) significantly reduces the incidence of recurrent bleeding but has no effect on mortality and the risk of hepatic encephalopathy is increased. PRACTICAL ATTITUDE: Elastic ligature can be proposed as a first intention treatment. Sclerotherapy is useful to eradicate varix after size reduction by ligature and to prevent recurrence. In case of failure, a TIPS or surgical shunt can be discussed. Liver transplantation would be indicated in high-risk patients keeping in mind that digestive tract bleeding is a supplementary argument favoring transplantation. RECOMMENDATIONS: The international consensus group (CFEHTP) recommends elastic ligature or beta-blockers, endoscopic treatment being preferred. TIPS or surgical shunt may be discussed in case of failure.

[Mucinous ductal ectasia. Apropos of 2 cases]. / Ectasie canalaire mucineuse. A propos de 2 cas.

Mucinous ectasia of the pancreas ducts is a recently described cystic lesion which usually occurs in acute pancreatitis. Endoscopic retrograde pancreatography provides diagnosis. Mucinous ductal ectasia is considered to be a precancerous lesion. Surgical exeresis is recommended. Our two cases emphasize the difficulties encountered for differential diagnosis with other cystic lesions of the pancreas.