Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma.

Interleukin (IL) 6 was measured in the serum of 138 patients with metastatic renal carcinoma before the initiation of IL-2 treatment. IL-6 was detectable in 66 patients with renal cancer (48%) and in only 8 of 70 normal adults (11%). Serum C reactive protein (CRP) and IL-6 levels are correlated, suggesting that IL-6 is involved in CRP increase in these patients. The interval between diagnosis of the primary tumor and metastasis was shorter in patients with a detectable serum IL-6 and/or serum CRP level greater than 50 mg/liter. Serum IL-6 and CRP levels were higher in subgroups of patients previously defined as having a poor life expectancy according to the Eastern Cooperative Oncology Group criteria. Pretreatment concentrations of IL-6 and CRP were higher in patients who experienced progressive disease after IL-2 treatment. Patients with detectable IL-6 had a shorter survival from the beginning of IL-2 treatment than patients without circulating IL-6 (median, 8 versus 16 months). Similarly, the median survival from the beginning of IL-2 therapy of patients with CRP levels greater than 50 mg/liter was 6 months, compared to 16 months in those with CRP levels below this threshold. None of the 21 patients with serum IL-6 concentrations greater than 300 pg/ml achieved response to any of the three IL-2 regimens. This subgroup has a median survival of 5 months after IL-2 treatment and consisted of 15% of the patients in our series. These results indicate that serum IL-6 and CRP levels are adverse prognosis factors in patients with metastatic renal cell carcinoma. Serum IL-6 level could help in the selection or stratification of the patients in future IL-2 trials.

Correlation between clinical response to interleukin 2 therapy and sustained production of tumor necrosis factor.

Twenty-five previously untreated patients with metastatic renal cell carcinoma were treated with 5-day cycles of continuous infusion of interleukin 2 (IL2) and lymphokine-activated killer cell reinfusion. Five achieved a partial response. Three patients were found to have detectable tumor necrosis factor (TNF) in serum before initiation of therapy. On the fifth day of therapy, 24 patients had circulating TNF with immunoradiometric assay whereas 13 had detectable biological activity. Two days after the end of IL2 therapy, TNF concentration (immunoradiometric assay) decreased in most cases but was still detectable in 17 patients. Thirteen patients had still circulating TNF bioactivity. Although there was no significant difference between TNF levels observed on the fifth day of therapy in the responder and nonresponder groups, 48 h after the end of IL2 infusion, both the TNF concentration and the biological activity were significantly higher in the group of responder patients. This result suggests that the clinical response to IL2 therapy in patients with metastatic renal cell carcinoma is correlated to a sustained production of TNF after the end of IL2 infusion.

Clinical application of retroviral gene transfer in oncology: results of a French study with tumor-infiltrating lymphocytes transduced with the gene of resistance to neomycin.

PURPOSE: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) has been reported to mediate tumor regression in some human cancers. To define better the biologic characteristics of TIL, especially survival and distribution in vivo, we performed a gene-marker study in patients with advanced malignancies. PATIENTS AND METHODS: We treated five patients with metastatic melanoma or renal cell carcinoma with adoptive immunotherapy. TIL were genetically modified, before their infusion, using a recombinant retroviral vector that contained the marker gene coding for resistance to neomycin (NeoR). RESULTS: All of the patients tolerated the treatment well and none of the theoretic safety hazards due to the retroviral gene transduction was observed. The presence of the NeoR gene in TIL was detected by Southern blot analysis, with an efficiency of transduction that ranged from 1% to 26%. With polymerase chain reaction (PCR) analysis, we demonstrated that gene-modified TIL can survive for several months after reinjection, since positive blood samples were observed up to day 260 following reinjection. Eight malignant biopsy specimens were obtained from three patients after cell infusion. TIL were detected in only four of these eight tumor deposits on days 7 and 260. CONCLUSION: These results confirm the feasibility and safety of using in vitro retroviral gene transduction in human lymphocytes to analyze their in vivo distribution for further therapeutic applications. However, a selective and prolonged retention of TIL at the tumor site was not found in this study.

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.

Interleukin-2 with and without LAK cells in metastatic renal cell carcinoma: the Lyon first-year experience in 20 patients.

Thirty-one patients with metastatic renal cell carcinoma were seen at the Centre Léon Bérard from October 1987 to October 1988. According to our protocol, 11 were excluded leaving 20 in the study. The median age was 55 years (range 36 to 79 years). The median number of metastases was 9 (range 2 to 29) and the median number of metastatic sites was 3 (range 1 to 4). Seventeen patients received a continuous infusion of recombinant interleukin-2 (rIL-2) of 3 x 10(6) U/m2/day, on days 1 to 5, with lymphapheresis on days 7 to 10 and IL-2 + LAK on days 11 to 15. Three patients received IL-2 alone. The clinical toxicity of IL-2 was as expected (100% fever, 88% erythema, 88% vomiting, 87% weight gain, 76% oliguria, 76% diarrhoea, 70% pruritus, 70% weakness, 41% severe hypotension, 41% acute renal failure, 33% disorientation, 23% respiratory distress, 12% ventilation and 5% coma) with no toxic deaths. Other toxicity was mild (median platelet nadir was 93,000 and median nadir of Hb 8.1 g/dl) except for the creatinine level which was found to be between 200 and 400 mumol/l in 45% of the courses and over 400 mumol/l in 24% of the courses. Eight capillary leak syndromes were observed. Among the three patients receiving IL-2 alone, one PD, one SD and one early toxicity were recorded. Among 15 evaluable patients receiving IL-2 + LAK, three had PR (20%) and two mixed response (PR and progression before 2 months); two had stable disease and eight had progression. No clinical or biological factor was able to predict response. However, the five objective responses were observed among the eight patients with a capillary leak syndrome. Lymphocyte peaks or platelet nadir were not related to response in this group of patients. The median number of harvested mononuclear cells was 9.8 x 10(10) and the median number of mononucleated cells reinjected was 5.9 x 10(10).

Evaluation of the informed consent procedure in cancer patients candidate to immunotherapy.

By addressing questionnaires to 24 cancer patients candidate to immunotherapy, we evaluated both the effects and the effectiveness of the medical information provided to the patient on their knowledge of the disease and the treatment. Most patients had correctly understood the information but 69% stated that they had been unable to ask all the questions they wished, and 62% required additional information. Most patients admitted to being emotionally distressed throughout the interview. These results are not significantly different from those obtained in patients candidate to new chemotherapy agents, but show that important improvements in the informed consent procedure are required.

Recombinant interleukin-2 in metastatic renal cell carcinoma--a European multicentre phase II study.

This multinational, multicentre study represents the introduction of recombinant interleukin-2 (rIL-2) in Europe. From December 1987 to June 1989, 57 eligible patients with metastatic renal cell cancer were treated with rIL-2 administered as continuous intravenous infusion. 8 out of 51 evaluable patients responded (16%), 2 complete remission (CR) and 6 partial remission (PR). 10 patients had no change (20%). The response duration for CR was 209 and 394+ days. The median response duration for PR was 371 (range 140-506+) days. Dose-limiting grade 3-4 toxicities were hypotension in 52% of the patients, arrhythmia (4%), dyspnoea (8%), creatinine rise (4%), peripheral neurotoxicity (10%) and central neurotoxicity (10%). Toxicities most often recovered solely on interrupted therapy. 2 patients died due to catheter-related septicaemia and one patient died of rIL-2 induced renal failure. The study confirmed the antitumour efficacy of rIL-2 in renal cell cancer. Toxicities were numerous, but manageable by close observation in a normal oncology ward without routine use of an intensive care unit.

Myocardiotoxicity of 5 fluorouracil.

We report a case of specific myocardiotoxicity due to 5 F.U. not previously described in man. A 41-year-old man was admitted to the ICU for heart and renal failure, appearing 24 h after 5 days treatment with 5 F.U. and cis-platinum. Dopamine was necessary to maintain blood pressure. Two-D echocardiography and a right heart catheterisation confirmed the alteration of myocardial contractility. After 2 weeks a complete cardiac recovery occurred.

Bacteremia following cardiac arrest and cardiopulmonary resuscitation.

After out of hospital CPR thirty three resuscitated patients were studied for bacteremic complications. Thirteen patients (39%) had two or more positive blood cultures during the twelve hours following CPR. Source of superinfection was a central venous catheter in one case (staphylococcus). The twelve other bacteremic patients had fetid diarrhea a few hours after admission. The same organism were found in blood and faeces (streptococcus D, Escherichia coli, Pseudomonas aeruginosa, acinetobacter, enterobacter). Mesenteric ischemia caused by a low cardiac output may explain the diarrhea and the intestinal origin of the septicemia. All patients (12 cases) with diarrhoea and bacteremia died. Patients who recovered without neurologic sequelae (4 cases) had never been septic and never had diarrhea.

Influence of acute renal failure on FPIA rapid serum assay of midazolam and its main metabolite.

We recently developed a simple and fast assay technique, providing the possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its main and pharmacologically active metabolite, in the serum of sedated ICU patients; this activity referred to as M-like. We identified certain patients in whom M-like activity appeared abnormally high in comparison with HPLC assays. Their common denominators were: long-term sedation with M, and seriously impaired renal function. Further, the conjugates of OM (OMG) accumulated in patients with acute renal failure could contribute to the sedation. We compared the metabolic and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either presenting with normal renal functions (group 1) or with a picture of acute renal failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis was performed before and after hydrolysis of OMG. Before hydrolysis there was a dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results were not different within group 1, while in group 2 the FPIA response exceeded that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in group 2, in each group (vs HPLC) and from one group to another, the FPIA signal (the M-like activity) showed a significant increase. It would be important to take OMG into account as a coprotagonist in sedation whenever circumstances predispose to its accumulation.

[Pharmacokinetics of high-dose melphalan (200 mg/m2) in a case of total renal insufficiency]. / Pharmacocinétique du melphalan administré à haute dose (200 mg/m2) dans un cas d'insuffisance rénale totale.

The pharmacokinetics of the alkylating agent melphalan was determined in a dialysed patient, 30 years old, who underwent unilateral orchidectomy for a malignant testicular tumor. Melphalan was included in a polychemotherapy treatment with eight 1-h infusions of 230 mg of etoposide (VP 16), then one 5-min infusion of 370 mg of melphalan (200 mg/m2) followed by autologous bone marrow grafting (ABMG). In this patient, melphalan pharmacokinetics was different from that of patients without important renal dysfunction for the area under the concentration curve (1,324 mg.l-1.min). However, with a melphalan elimination half-life of 80 min, ABMG could be performed, as usually, 24 h after melphalan administration. Plasma alpha-fetoprotein (AFP) concentrations showed that chemotherapy was efficient. Furthermore, we observed a modification of etoposide kinetics due to melphalan.

[Treatment with cytokines of metastatic kidney cancer: the Lyon experience]. / Traitement par les cytokines du cancer du rein métastatique: l'expérience lyonnaise.

Between October 1987 and June 1992, 244 patients with metastatic renal carcinoma were referred to our Institute. One hundred and sixty-nine were included in immunotherapy protocols. The 40 most recent patients were included in the ongoing multicentric randomised Crecy study. The previous patients were treated with IL2 as a continuous infusion or high doses intravenous IL2 combined with alpha interferon (IFN) or a combination of IL2 and IFN as subcutaneous low doses. Some patients received as rescue treatment a combination of IL2 with Tumor Necrosis Factor (TNF). First line immunotherapy with cytokines gave 14-25% response rates in these patients with 5-10% of complete persistent remissions. The most intensive regimen was responsible for the most severe toxicity as well as the highest response rate. TNF does not appear to be of great concern since its systemic administration induced important limiting toxicities. This work emphasizes the need for prospective studies in order to evaluate the optimal mode and schedule of treatment as well as to investigate the impact of immunotherapy on survival.

[Analysis of changes in serum levels of TNF, IL-1 and IL-6 during administration of IL-2. Correlation with clinical response to treatment]. / Analyse des modifications des concentrations sériques de TNF, d'IL-1 et d'IL-6 au cours de l'administration d'IL-2. Corrélation avec la réponse au traitement.

We have investigated the serum concentrations of TNF, IL-1 and IL-6 in 49 patients with metastatic renal carcinoma receiving interleukin 2 (IL-2) or a combination of IL-2 and interferon alpha (IFN). Our results demonstrate that IL-2 and/or IFN induce an increase of serum concentrations of IL-1 and TNF in 95% and 75% of the patients respectively. Serum IL-6 levels increase in 44% of the patients. Serum concentrations of IL-1 and TNF remain elevated 48 hours after the end of IL-2 infusion. IL-1 and TNF levels are higher in patients receiving a combination of IL-2 and IFN. TNF and IL-1 levels in serum are significantly higher in responders to IL-2 treatment 48 hours after the end of IL-2 infusion. These two biological criteria enable a subgroup of patients with a very low response rate to IL-2 to be defined. The persistent increase of these cytokines in serum indicates a persistent activation of the immune system lasting after the end of IL-2 treatment which could be involved in the antitumor response.

[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.

[Local low-dose thrombolytic treatment with sequential urokinase-plasminogen in deep central venous thrombosis]. / Traitement thrombolytique local à faibles doses par des séquences urokinase-plasminogène des thromboses veineuses profondes centrales.

Four patients with recent central deep vein thrombosis (pelvis-superior mediastinum) were treated by local low dose infusions of urokinase (500 to 1000 IU/kg/h for 6 to 9 hours) followed by plasminogen (20 to 30 microkatals/h for 2 to 3 hours) associated with simultaneous anticoagulation with heparin. The treatment was continued for 83 to 160 hours until control phlebography showed dissolution of the thrombus. There were no haemorrhagic complications despite the presence of a number of risk factors which contraindicated treatment by a systemic route. Fibrinogen and FDP levels did not alter significantly. This therapeutic approach is worth considering and should be integrated among the therapeutic options available for cases of central deep vein thrombosis.

[A case of hepatic and splenic peliosis occurring in the puerperium after normal pregnancy]. / Une observation de péliose hépatique et splénique survenue dans le post-partum au terme d'une grossesse normale.

The authors report a case of Peliosis of the liver and of the spleen that occurred at term after a normal pregnancy that lasted 38 weeks. The delivery was complicated by amniotic infection with hemorrhagic shock and uterine inertia that gave rise to the need for a sub-total hysterectomy in order to stop the bleeding. The progress of the case was made worse by the development of the disseminated intra-vascular coagulation syndrome with septicaemia and pulmonary oedema. When the operation was carried out to stop the bleeding it was noted that the liver was enlarged, hard, smooth and dark in colour and the histological specimen showed a major degree of Peliosis hepatis. The same lesions were found in the region of the spleen and a lymph node. The patient died 14 days after delivery of acute renal failure together with cerebral oedema and septic shock. The authors consider that the aetiology of the Peliosis could be due to hormone changes of pregnancy associated with septicaemia. The anatomical evolution of Peliosis hepatis to widespread necrosis of the parenchyma makes it possible to understand that the condition of diffuse intra-vascular coagulation will not improve in the presence of hepato-cellular insufficiency.

[Changes in renal function induced by anesthesia]. / Modifications de la fonction rénale induites par l'anesthésie.

The rate of urine formation and its composition are influenced by the different drugs used during surgery. Anaesthetics act on renal function, not only directly, but also by producing changes in cardiovascular function and in neuroendocrine activity. Many factors may be incriminated: lowered blood pressure and cardiac output, increased sympathetic outflow (renal nerve stimulation and increased plasma catecholamines), increased release of renin, angiotensin and vasopressin. The effects of anaesthetics on the kidney go beyond a simple change in basal haemodynamics and include, for some drugs, an alteration in the ability for the kidney to autoregulate its blood flow and glomerular filtration rate. Studies on toad bladders showed a decrease in transport of water, sodium and organic anions. But, in fact, renal effects of anaesthetics in man and animals depend on the species, the anaesthetic and the method used to study the effect. Most barbiturates and inhalational anaesthetics tend to decrease renal blood flow (RBF) and glomerular filtration rate (GFR). These trends are gradually reversed during recovery. The effects of ketamine and diazepam are not clearly defined. Morphine and fentanyl decrease urine flow and GFR, whilst RBF increases or decreases, depending on whether a direct or indirect measurement technique was used. Muscle relaxants have little effect on renal function. Spinal and epidural anaesthesia only slightly decrease GFR and RBF in proportion to the decrease in mean arterial pressure. Obviously, the preexisting intravascular volume and the quantity of intravenous fluids given strongly influence the renal response to spinal and epidural anaesthesia. Some studies have shown that urine flow rate, creatinine clearance, urinary sodium excretion and RBF are reduced during mechanical ventilation with positive end-expiratory pressure. Surgery itself influences renal function by inducing alterations in prerenal haemodynamics. Operative stress leads to an increase in circulating catecholamines and angiotensin. Significant fluid shifts, excessive blood loss and redistribution of a third space may lead to a prerenal oliguric state, increasing secretion of vasopressin. Acute renal failure (ARF) is a frequently lethal complication of critical surgical illness, due to a variety of factors which interfere with glomerular filtration and tubular reabsorption, such as renal hypoperfusion or nephrotoxic insults. In fact, the initiating aggression ultimately culminates in the development of one or more of the maintenance factors (decreased tubular function, tubular obstruction, decreased GFR and RBF) that reduce urine flow and osmolar excretion. Good management during the perioperative period tends to minimize the risk of developing ARF.

[Role of non-steroidal anti-inflammatory agents in the perioperative period. Usefulness and limitations]. / Place des anti-inflammatoires non stéroïdiens en période périopératoire. Intérêt et limites.

Nonsteroidal antiinflammatory drugs (NSAIDs), including various chemical families of drugs, inhibit prostaglandin synthesis and act on the central nervous system. Prostaglandins are involved in regulation of regional circulations, cell turn-over in the gastrointestinal tract, and in primary haemostasis. The patterns of action of NSAIDs result in analgesic properties, but also in adverse effects. NSAIDs are increasingly used perioperatively, alone or associated with opioids or local anaesthetics, because of their analgesic and opioid sparing properties. Some of their adverse effects, especially ischaemic acute renal failure and gastrointestinal complications, can be life-threatening, and increased haemorrhagic risk is an issue for spinal or epidural anaesthesia in patients taking aspirin. Safe use of NSAIDs is possible in consideration of contraindications (elderly patient, hypovolaemia, cirrhosis, congestive heart failure, renal failure, active gastrointestinal ulcer, bleeding diathesis, pregnancy), and requires close monitoring of renal function if they must be used in patients at risk for renal failure. NSAIDs are not ulcerogenic in the short-term in healthy subjects. They must be used with caution in patients with a preexisting haemostatic defect or undergoing haemorrhagic surgical procedures.

[Side effects of therapeutic plasma exchange. A controlled prospective study]. / Effets indésirables des échanges plasmatiques thérapeutiques. Etude prospective contrôlée.

Solutions of human albumin are generally used as plasma substitutes during therapeutic plasma exchanges. The safety of 2 solutions of human albumin was evaluated in a multicentre, randomized, double-blind trial. Between June, 1984 and February, 1986, 80 patients who were undergoing plasma exchanges for the first time entered the study and were randomly assigned into 2 groups according to whether they received plasma albumin (PM) or placental albumin (PC). Each patient had 6 plasma exchanges over a 2-week period. Failure was defined as the occurrence of an untoward effect during an exchange. No significant difference in the number of failures was found between the 2 albumins (PM 23/40, PC 15/40; P = 0.07). However, when the type of adverse reaction was taken into account there was a significant difference between the two treatment groups regarding the number of febrile episodes (PM 8, PC 2; P = 0.043) and shivering fits (PM 9, PC 2; P = 0.023). Thus, the nature of the albumin has no significant influence on the overall safety of plasma exchanges, but it seems that different methods of preparation may affect the type of untoward effect observed.

[The circulation of anesthetic agents at Edouard-Herriot Hospital]. / Le circuit du médicament en anesthésie à l'hôpital Edouard-Herriot.

In order to improve quality, practice evaluation is a major tool for hospital management. For many years anaesthesia has been monitored by some form of quality assurance programme. However, despite the improvement in anaesthetic techniques, major problems persist, particularly with the use of anaesthetic agents. Drug administration is the first cause for malpractice and death in anaesthesia. The aim of this study was to analyse drug circuits in anaesthesia, with special reference to French regulations. In 13 theatres, doctors and nurse anaesthetists were interviewed by a pharmacist with a focus on following items: prescription, preparation, administration, management, storage, conservation, information, and regulations. Results demonstrated that practice organisation and information transfers were mainly by oral route. The low proportion of written information, especially for preoperative prescription, did not comply with regulations. Nurse anaesthetists were the main actors in drug handling. Common practice patterns throughout the hospital were non existing. In each theatre, a storage of usual drugs for four weeks was found, whereas in pharmacies drugs were stocked for a 2-week period only. Standardised and written procedures, as well as pharmaceutical practice guidelines, are essential for decreasing the risk and improving quality. Such a procedure requires the full participation of anaesthetists and nurses.