Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer.

In this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 x 10(6) IU/m2/day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 micrograms/m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 micrograms/m2 was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic-like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.

Alteration of the inner surface of venous catheters by antineoplastic drugs.

Septic complications and thrombosis are frequent causes of long-term venous catheter implantation failure and tend to occur more frequently in oncology than in patients using catheters for hyperalimentation only. The purpose of this in vitro study was to study extensively the inner surface behaviour and the possible changes in their mechanical properties of various silicone and polyurethane catheters after exposure to a flow of the most common antineoplastic drugs. Silicone catheters appeared to be the best choice for cytostatic drug infusions because of their chemical stability, but the addition of an opacifier imposes a protective inner and outer layer to improve their surface properties for biocompatibility.

Intravenous interleukin-2 just after high dose BCNU and autologous bone marrow transplantation. Report of a multicentric French pilot study.

This multicentric pilot study was conducted in order to evaluate the feasibility of early interleukin-2 (IL2) after high dose chemotherapy requiring autologous bone marrow transplantation (ABMT). BCNU at 800 mg/m2 was followed, 3 days later, by the reinjection of the bone marrow cells. At day 4, IL2 at 18 x 10(6) i.u./m2/day was given as a continuous infusion during a minimum of 6 days (first phase of study) or for 6 more days after 1 day break (second phase of the study). Twenty patients were included. Toxicity was not negligible, with one toxic death, but IL2 therapy does not damage the haematological recovery of most patients. However, a 6-day IL2 treatment period only appears tolerable. In 18 evaluable patients, three responses were observed: one complete response (CR) of short duration in a non-Hodgkin's lymphoma, one CR (24 months +) and one partial response (PR) (6 months) in two patients with metastatic gastric adenocarcinoma. This study confirms that IL2, restricted to a 6-day treatment period, is feasible immediately after high-dose chemotherapy requiring ABMT without haematological problem in most patients. The response rate was unexpected for a pilot study and this combined therapy obviously requires further study.

A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain.

This study compared the efficacy and the adverse effects of controlled-release morphine (CRM) suspension (SAR 213) and CRM tablets (Moscontin) in the treatment of cancer pain. This multicenter, randomized, double-blind, double-dummy, crossover study was carried out on 52 patients. Each patient received both study treatments given at an equivalent dosage of morphine during each of two 7-day periods. The primary outcome variable was the severity of pain assessed three times daily by means of a visual analogue scale. Secondary criteria of efficacy were the severity of pain assessed by verbal rating scale, the need for "rescue" doses of immediate-release morphine, treatment preference, and indices of quality of life (activity, mood, sleep). There were no statistically significant differences in the parameters assessed when comparing the two groups. This study shows that, when prescribed at the same doses, CRM suspension and CRM tablets have similar efficacy and adverse effects, as well as the same duration of action. The results of this first clinical study carried out on CRM suspension are especially relevant for patients with cancer pain who have difficulty swallowing.

Energy expenditure during allogeneic and autologous bone marrow transplantation.

Resting energy expenditure (REE) was measured by indirect calorimetry during allogeneic and autologous bone marrow transplantation in order to evaluate the evolution in allogeneic and autologous recipient patients. REE values obtained with indirect calorimetry and compared with values using the Harris-Benedict formula were different. Evolution of REE during aplasia were significantly different in autologous and allogeneic recipients with an increase 11.5 ' 10.8 cent for autologous and a decrease of - 7.3 ' 8.9 cent in allogeneic bone marrow transplantation (BMT) patients. There were no differences in nutritional status and REE before BMT, at discharge and 1 month after discharge between the two groups but all patients had inflicted damage on their nutritional status at discharge from hospital after BMT. However, these patients differed because of the decrease in oral nutritional intake and an increase in the length of aplasia and hospital stay in allogeneic patients. Currently, there is no proof that recommendations for nutritional interventions or results of nutritional investigations in allogeneic BMT can be extrapolated in autologous patients. Harris-Benedict formula does not estimate the energy expenditure of patients submitted to massive chemotherapy and BMT with enough precision because of the great differences in individuals.

[Morphine therapy: evaluation of patient information]. / Thérapeutique morphinique: évaluation de l'information des patients.

Pain is frequent in the course of cancer and can have negative consequences on patients quality of life. The great majority of patients can be helped by simple treatments. The prescription of morphine (M) must be preceded by some explanations. In order to verify the reality of these explanations, a study was done in a 230 comprehensive beds Cancer Centre, with 129 patients, randomized between all the patients hospitalized. In an open questionnaire, different aspects were studied. One hundred answers were studied: 63 patients did not have M at any time: group M-; 37 patients had M (19) or have had M (18): group M+; 97% of the patients in group M+ thought that M decreased pain, for 85% patients in group M-. Morphine treatment was effective in 92% of patients M+, and not very effective in 5%; 67% of patients M- thought that M is efficient but 17% did not know; 76% of patients M+ did not worry about M; 13% worried et 11% did not know. For patients M- only 48% did not worry; 41% worried and 11% did not know. The side effect known by the patients, and spontaneously quoted were constipation (12 patients in M+ group). For 14 patients there was no problem and 2 did not know. In M- group 49 patients did not know. Only 8% of M+ group were afraid by addiction, but 44% in group M-; 97% patients M+ said that they could stop without problem against only 38% of the patients in M- group. For 16% of M+ group, the use of M had a bad signification about their disease, but 52% of M- group thought that if morphine was used in their cases, the meaning would be very bad. The differences between the two groups allow to think that the prescription of M in this study is explained, and that the patients receiving M are rather well informed. Patients with cancer but without M do not have good information and their knowledge is similar than general population. The use of recommended therapy and explanations allowed patients with M therapy to be comfortable with this prescription.

[Adverse effects of interleukin 2]. / Effets secondaires de l'interleukine 2.

Interleukin 2, has frequent and important side effects. Toxic effects observed are systemic (fever, chills, malaise), hemodynamic (capillary leak syndrome, hypotension), cardiac (arrhythmia, infarction), renal (renal dysfunction), infectious (septicemia), cutaneous, hematologic, gastrointestinal, endocrinologic and metabolic. Side effects are dose-dependent, generally reversible, with a mortality from 1 to 3%. Regimens of administration and other cytokine combinations affect interleukin 2 toxicity. If the treatment of these side effects is well known, selection of patients and specialized care unit remain always necessary.

[Staphylococcus nasal carriage and infection of central venous ports in oncology]. / Portage nasal staphylococcique et infection des systèmes d'accès veineux central en cancérologie.

OBJECTIVE: To assess the risk of infection of either subcutaneously implanted central venous access devices or percutaneous central venous catheters inserted via a subcutaneous tunnel in cancer patients with a positive staphylococcal nasal carriage. STUDY DESIGN: Prospective study. PATIENTS: The study included 266 patients undergoing cancer chemotherapy. METHOD: A nasal swab was taken prior to insertion of the venous access device and the patients were followed over 30 days for the occurrence of a staphylococcal infection (hemoculture and device or site of insertion). RESULTS: A nasal staphylococcal nasal carriage was found in 227 patients. Out of the 15 developing a device infection, a staphylococcal nasal colonization was existing in nine patients. Bacteriological screening a sensitivity of 60% and a specificity of 13%. CONCLUSION: Bacteriological screening at the time of device insertion of a central venous access device is of no value for the detection of patients at risk of staphylococcal infection of the device.

[Polyurethane catheters and antineoplastic chemotherapy. An experimental study]. / Cathéters en polyuréthane et chimiothérapie antinéoplasique. Etudeexpérimentale.

An in vitro study of the effect of cytotoxic drugs on polyurethane catheters was carried out. The drugs used--vincristine, doxorubicin, cisplatin and carmustine--damage the surface of silicone elastomer catheters. The irregularities produced seem to be preferential sites for thrombus formation and adhesion of bacterial microcolonies. Electron microscopy examination of the catheters dipped in the drug solutions for different time intervals revealed the appearance of different patterns of damage. The irregularities produced seemed to be less pronounced than for silicone catheters. Polyurethane was highly sensitive to doxorubicin. These changes could well have clinical repercussions. The compatibility of catheters and drugs should be routinely tested before being put on the market.

[Bacterial meningitis and intrathecal treatment of chronic pain]. / Méningite bactérienne et traitement intrathécal de la douleur chronique.

A case is reported of bacterial meningitis related to an intradural implant used in the treatment of pain into which morphine was administered daily. The infection began on the third day after implantation of the system. Because of its efficiency in controlling pain, it was not removed; the infection was successfully treated with local and general antibiotic treatments only. The system was used 121 days.

[Electromagnetic location of central venous catheters]. / Repérage électromagnétique des cathéters veineux centraux.

A new technique, the Cath Finder (Pharmacia Deltec) system, for locating central venous catheters is described. It was initially designed to facilitate the insertion of the PAS Port (Pharmacia Deltec), a long central venous catheter with an implantable chamber. It is based on a low intensity high frequency electromagnetic field generated by a locator wand. A preconnected sensor guide wire is introduced into the catheter so as to make the catheter tip detectable by the electromagnetic field. The wand is placed over an appropriate landmark on the anterior chest wall (third right rib, parasternally). When the centre of the field has been passed over by the sensor tip in the catheter-sensor assembly, a light signal is set off. This technique is simple and easily mastered. It is far less cumbersome than the usual techniques, like fluoroscopy and chest X-rays. The Cath Finder provides reliable continuous information on the position of the catheter tip during its insertion. It seems to provide an acceptable alternative to peroperative fluoroscopy. The accuracy of this system was assessed in ten patients. All had malignancies and required long term central venous access. In 6 cases, catheterisation and locating of the catheter were uneventful. In 2 cases, the catheter entered a wrong vein. The diagnosis having been made with the Cath Finder system, the false route was amended and the catheter placed accurately. In one case, the sensor in the catheter broke.(ABSTRACT TRUNCATED AT 250 WORDS)

[Isolated increase in the bleeding time: the hemorrhagic risk and therapeutic problems]. / Allongement isolé du temps de saignement: risque hémorragique et problème thérapeutique.

An isolated increase of the bleeding time is rare. In the young, there may exist a history of bleeding disorders such as epistaxis. In middle age, the increased risk of bleeding during surgery is low but real, and depending on the type of surgery. There are many drugs responsible for increased bleeding time; these must be avoided: the principle that one haemostatic defect is often well tolerated whereas two are not is very real. So the management of such patients during surgery must be meticulous and the use of some drugs must be avoided. Careful surgical management with regard to haemostasis undoubtedly allows many patients with this sort of defect to undergo surgery without excessive bleeding. Some treatments are possible (e.g. steroids, DDAVP), but their routine use is not warranted.

[Peripheral venous catheter embolism]. / Embolie de cathéter veineux périphérique.

The accidental embolization of peripheral venous catheter fragments seems to be a rare event. Removal of the catheter embolus is usually recommended, because of the high morbidity and mortality rates from sepsis, perforation, thrombosis and arrhythmias. We report a case, in which the diagnosis was made 17 years after the embolization by the means of a systematic chest X-ray. The use of spiral CT scan with computerized post-processing 3D reconstruction confirmed the diagnosis. Because of good tolerance during this very long term, a not-to-treat decision was taken.

[Factor VII deficiency and surgery]. / Déficit en facteur VII et chirurgie.

Factor VII deficiency is a rare disorder (1/500,000), with manifestations similar to those experienced by patients with haemophilia. Excessive bleeding during surgical procedure is prevented by factor VII administration. We report two cases of patients presenting a factor VII deficiency who were treated for oncological surgery. In the first patient with a severe congenital factor VII deficiency (8%), a continuous infusion of factor VII prevented the development of perioperative bleeding. In the second case, with a probably acquired factor VII deficiency (33%) related to a leiomyosarcoma, bleeding was prevented by a single preoperative factor VII injection.

[Surface changes of intravenous catheters after antineoplastic chemotherapy]. / Modifications de surface des cathéters veineux après chimiothérapie antinéoplasique.

During long-term venous catheter implantation, septic and thrombotic complications are quite frequent. In the case reported, the failure of systemic and local antibiotic therapy during repeated septicaemia due to Bacillus cereus at the time of intensive chemotherapy led to a scanning electron microscopy study of the used silicone catheter. There were marked changes of the inner surface with a lot of cellular remains, in contrast with the usual non thrombogenic property of the silicone. An in vitro study was carried out with antitumour agents. Duration of exposure and drug concentration were identical to those used in in vivo perfusions. There were marked changes of the inner surface, which could lead to important modifications of the properties of the silicone. The damage depended on the drug. Silicone was slightly sensitive to vicristin and carmustin, but highly sensitive to cisplatin and doxorubicin. The compatibility of catheter material with the drugs used, especially for oncologic chemotherapy, must be tested systematically.

[Hemodilution and peroperative autotransfusion during harvest for bone marrow graft]. / Hémodilution et autotransfusion peropératoire dans les prélèvements pour greffe de moelle osseuse.

In order to avoid the infectious and immunological complications of homologous blood given to autologous bone marrow graft recipients, intraoperative haemodilution together with delayed salvage of the red blood cells contaminating the marrow graft were used prospectively over a period of 6 months. This was carried out in 74 patients, i.e. 2 allogenic and 72 autologous donors (mean age 27.2 +/- 19.7 years). A mean of 13.66 +/- 7.10 ml.kg-1 bone marrow were harvested. Fluid replacement was carried out, volume for volume, with a modified fluid gelatin (Plasmion) (n = 73; 14.6 +/- 6.6 ml.kg-1), glucose 5% (n = 54; 9.64 +/- 4.88 ml.kg-1) and Ringer solution (n = 33; 8.1 +/- 3.3 ml.kg-1). No haemodynamic problems occurred. Autologous blood transfusion was possible in 54 patients; mean volume of bone marrow harvested was 631 +/- 298 ml, and a mean of 293 +/- 154 ml of blood was retransfused to the patients (mean haematocrit of the blood units: 0.536 +/- 0.048). Nine of these patients were also given homologous blood. In the other 20, the volume of bone harvested marrow was significantly lower than in the autologous transfusion group (430 +/- 202 ml; p less than 0.05), and red blood cell salvage was not possible; only 3 patients received homologous blood. Finally only 16.2% of the patients in this series were given homologous blood. It is concluded that intentional isovolaemic haemodilution together with autotransfusion of salvaged blood can reduce the need for homologous blood during bone marrow harvesting.

[Perforation of the esophagus during attempted endotracheal intubation]. / Perforation de l'oesophage par fausse route lors de l'intubation trachéale.

A case is reported of oesophageal perforation which occurred during an attempt to carry out endotracheal intubation. A 54-year-old female patient was scheduled for mastectomy. She had no clinical features likely to predict a difficult endotracheal intubation. After induction with thiopentone, phenoperidine and suxamethonium, three attempts were made to carry out tracheal intubation with a Mallinckrodt Lo-pro tube, internal diameter 7.5 mm. During the third attempt, the oesophagus was accidentally intubated. The diagnosis was made before any insufflation was carried out. Another anaesthetist took over, and intubated the patient. At that time, there was left-sided cervical emphysema which quickly spread. An oesophageal perforation was suspected, and the patient was given 500 mg of metronidazole and 1 g of cefotetan. Postoperatively, the antibiotics were continued, and the patient had nothing by mouth. Oesophagography showed a posterior fistula in the upper third. Conservative treatment was continued until the seventh day, when another oesophagography was carried out. This showed that the perforation had completely healed. This rather rare complication of endotracheal intubation may have a poor prognosis if it results in mediastinitis. The diagnosis and prognosis of this complication and its treatment, whether conservative or surgical, are discussed.

[Preoperative chemotherapy of ovarian cancer in anesthesia and resuscitation]. / Chimiothérapie préopératoire du cancer ovarien en anesthésie et réanimation.

Anti-mitotic chemotherapy has become more efficient but also more toxic. This toxicity complicates later operations. Sixty cases of ovarian cancer one analysed and the various complications related to chemotherapy described.