[Rehabilitation after total knee arthroplasty of hip and knee]. / Revalidation après les arthroplasties de hanche et de genou.

Numbers of total hip and knee arthroplasties are increasing on a regular basis. Clinical pathways tend to shorten the duration of hospitalization in acute care after surgery. Therefore, the preoperative preparation of the patient and his abilities for postoperative rehabilitation should be carefully addressed. Before the surgical intervention, it is recommended that the patient receives an educational program and a physical preparation. After the surgical intervention, the patient can benefit from a home-based rehabilitation program supervised by a physiotherapist, if there were no preoperative reasons for prolonging the hospital stay and if the surgery took place without complications. Some patients may benefit from postsurgical rehabilitation in a specialized locomotor rehabilitation long-stay care unit. The indications for inpatient multidisciplinary rehabilitation are : two simultaneous arthroplasties, revision of a previous hip or knee arthroplasty, postsurgical complications, advanced age, comorbidities influencing the rehabilitation process, social difficulties, necessity for adaptation of the environment, insufficient or unadapted out-patient (para)medical care. The goals of the rehabilitation treatment depend on the patient's characteristics and environment, on the properties of the prosthesis and on the postsurgical complications. The functional prognosis of a total joint arthroplasty of the knee or hip is excellent, provided that there are no post-surgical complications and that the patient benefits from adequate rehabilitation therapy. The present paper describes the different phases of rehabilitation treatment and the general and specific complications of total hip and knee arthroplasties that may influence the rehabilitation outcome.

Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes.

BACKGROUND: A prospective phase II study was conducted to evaluate the efficacy and toxicity of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer. PATIENTS AND METHODS: Patients had a maximum of three prior chemotherapy lines with no more than two prior platinum-containing regimens and a progression-free interval after the last dose of platinum <12 months. A total dose of 4 mg/m(2)/cycle (0.8 mg/m(2)/day from day 1 to day 5) was administered, repeated every 28 days. RESULTS: From June 2005 to December 2005, 69 assessable patients were enrolled. The best overall response to study treatment by combined CA-125 and RECIST criteria was partial response in 17 patients (24.6%) and disease stabilization in 22 patients (31.9%). The median time to progression and overall survival were 3.8 and 16.2 months, respectively. A total of 312 cycles were administered. Neutropenia grade 4 and thrombocytopenia grade 4 occurred in 17.4% and 7.2% of patients, respectively. Diarrhea grade 4 was never observed. Asthenia and fatigue were reported by 36.2% and 18.8% of patients, but were all grade 2 or less. CONCLUSION: Gimatecan is a new active agent in previously treated ovarian cancer with myelosuppression as main toxicity.

Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate.

The toxic effects and tissue uptake of both cisplatin and oxaliplatin--[(1R, 2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O']platinum--were previously shown to vary similarly according to dosing time in mice. A 4-hour infusion of cisplatin resulted in fewer side effects and allowed administration of higher doses at 16 hours than at 4 hours in patients with cancer. We hypothesized that the continuous venous infusion of oxaliplatin for 5 days would be less toxic and would deliver a higher dose to the patient if the drug were infused at a circadian rhythm-modulated rate (peak at 16 hr; schedule B) rather than at a constant rate (schedule A). We tested this hypothesis in a randomized phase I trial. We escalated the dose of oxaliplatin to the patient by 25 mg/m2 per course. Courses were repeated every 3 weeks. An external, multichannel, programmable-in-time pump was used for the infusions. Toxicity was assessable for 94 courses in 23 patients (12 patients with breast carcinoma, nine with hepatocellular carcinoma, and two with cholangiocarcinoma). The incidence of neutropenia of World Health Organization grades II-IV and the incidence of distal paresthesias were 10 or more times higher (P less than .05) with schedule A than with schedule B. In addition, vomiting was 55% higher (P = .15) with schedule A than with schedule B. Furthermore, with schedule B, the mean dose of oxaliplatin (P less than .001) and its maximum tolerated dose (P = .06) could be increased by 15% over those doses with schedule A. An objective response was achieved in two of the 12 patients with previously treated breast cancer. We recommend that the dose of oxaliplatin for phase II trials be 175 mg/m2, delivered according to the circadian rhythm-modulated rate.

Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons.

The use of oxaliplatin, a relatively new chemotherapeutic agent, is somewhat limited since it produces a specific peripheral neuropathy regarding other neurotoxic anticancer platinum analogues. In order to investigate the mechanism of such a peripheral neuropathy, the effects of 1-100 micromol/l oxaliplatin were assessed on the nodal ionic currents of single frog myelinated axons as a model of peripheral excitable membranes. Oxaliplatin decreased both Na(+) and K(+) currents in a dose-dependent manner and within 5-10 min, without producing any marked changes in the current kinetics. It was about three to eight times more effective in reducing the Na(+) than the K(+) current. In addition, it shifted the voltage-dependence of both Na(+) and K(+) conductances towards negative membrane potentials. A negative shift in the steady-state inactivation-voltage curve of the peak Na(+) current was also observed in the presence of oxaliplatin. These effects were not reversed by washing the myelinated axons with an oxaliplatin-free solution for at least 30 min. It is concluded that oxaliplatin modifies the voltage-dependent ionic channels mainly by altering the external surface membrane potential. The knowledge of such a mechanism may help to counteract the neurotoxic action of this anticancer agent.

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Clinical pharmacokinetics of oxaliplatin: a critical review.

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252-273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve(0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients. These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients.

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).

Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma.

From November 1986 to April 1989, 16 patients with advanced measurable pancreatic carcinoma were involved in a pilot phase I-II study. 5-Fluorouracil was given every 3 weeks by 5-day continuous chronomodulated venous infusion (CMVI) with peak 5-FU delivery at 4 a.m. Intrapatient dose escalation started at 1200 mg/m2/day up to 1600 mg/m2/day in the absence of grade III (WHO) toxicity. Mucositis and diarrhoea were dose limiting in the 131 cycles given. Three partial responses (21%) and 5 stable diseases were seen in the 14 patients with measurable disease. Dose intensity after three or after six courses (1800 mg/m2/week) was significantly correlated with time to progression (Pearson r = 0.64; P < 0.004). These results, although modest, support a multicentre phase II trial with 5-FU CMVI.

Oxaliplatin activity against metastatic colorectal cancer. A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate.

Oxaliplatin (L-OHP) is a non-nephrotoxic third generation platinum complex with proven antitumoral activity and minimal haematological toxicity. Circadian scheduling has allowed significant increases in L-OHP dosage and dose intensity and decreases in its toxicities. This phase II trial has tested the antitumour activity of a 5-day circadian schedule of continuous venous infusion of L-OHP against metastatic colorectal cancer. Initial dose was 150 mg/m2/course. An intrapatient dose escalation scheme by 25 mg/m2/course was planned up to 200 mg/m2/course, according to toxicity criteria. The delivery rate of L-OHP was sinusoidally modulated along the 24-h time scale, and was highest at 1600 h. A programmable-in-time ambulatory pump was used, so that all patients could receive their treatment at home. 29 of 30 patients registered were eligible. 25 had failed previous chemotherapy. Three objective responses were observed (response rate: 10%), in patients progressive while on chemotherapy with 5-fluorouracil and folinic acid. Toxicity was moderate. Dose-limiting toxicities were diarrhoea and peripheral sensitive neuropathy. The latter adverse effect appeared to be cumulative. L-OHP, as delivered under this circadian schedule, exhibits clinical antitumour activity against metastatic colorectal cancer. These results, which await further confirmation, support the place of L-OHP in combination regimens including 5-fluorouracil.

Factors predicting for efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU)+/-folinic acid (FA) in a compassionate-use cohort of 370 5-FU-resistant advanced colorectal cancer (CRC) patients.

Univariate and multivariate analyses were performed on data from 370 5-fluorouracil (5-FU)-resistant advanced colorectal cancer patients treated with oxaliplatin (Eloxatin)/5-FU+/-folinic acid (FA) to identify prognostic factors for oxaliplatin-based treatment. The response rate was 14.6% (95% confidence interval (CI): 11.0-18.2%), median time to progression was 4.3 months (95% CI: 3.9-4.7), and median overall survival 9.7 months (95% CI: 8.5-10.8). Multivariate analysis indicated < 2 prior chemotherapy regimens, bi-weekly treatment administration schedule (versus tri-weekly) and continuous chronomodulated delivery (CCM) as significantly associated (P < 0.05) with a higher overall response rate. Performance status (PS) < 2, having only one involved organ, biweekly schedule and CCM were associated (P < 0.05) with a longer time to progression. Good PS, one involved organ, low alkaline phosphatase (AP) serum levels, bi-weekly schedule and CCM were significantly correlated with longer overall survival, while confirming the efficacy of oxaliplatin/5-FU+/-FA in this indication.

Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT. Association pour le Traitement des Tumeurs Intra Thoraciques.

The aim of this phase II study was to determine the antitumour activity and safety of trans-1-diaminocyclohexane-platinum (oxaliplatin) in previously untreated advanced non-small cell lung cancer (NSCLC) patients. 33 patients with unresectable and measurable NSCLC were entered into this phase II study between January 1992 and January 1994. Patients had either locoregional disease with performance status 2 (19 patients) or a stage IV disease (14 patients). Oxaliplatin (130 mg/m2) was given on an out-patient basis (2-h infusion, every 21 days) without hydration. Response was assessed after every two courses. One hundred courses were administered, with a mean of three courses per patient (range 1-12). All patients were evaluable for response; 1 had a complete response, and 4 a partial response (overall response rate 15%, 95% confidence interval 5.1-31.9%). The median response duration was 5.9 months. All cycles (n = 100) were evaluable for toxicity assessment. Transient reversible, cold-related finger dysesthesias occurred in 29 patients, but were mild, and disappeared in most cases within a few days. We observed brief episodes of pharyngolaryngeal discomfort (8 patients, 11 episodes) accompanied in 4 cases (3 patients), by transient episodes of inspiratory stridor, leading 2 patients to treatment withdrawal. We conclude that oxaliplatin has activity in poor-prognosis NSCLC and that this treatment is feasible in out-patients; the absence of renal and haematological toxicity makes this drug a good candidate for further evaluation in NSCLC.

Pharmacokinetics and safety profile of oxaliplatin.

In early clinical trials, oxaliplatin has demonstrated significant activity against colorectal cancer, both as a single agent and in combination with 5-fluorouracil (5-FU) and folinic acid (FA). Oxaliplatin differs from cisplatin in its lack of nephrotoxicity and from carboplatin in its hematologic toxicity being mild. The most constant acute side effect of oxaliplatin observed in clinical trials was a transient peripheral neuropathy manifesting as paresthesia and dysesthesia in the extremities, triggered or enhanced by exposure to cold. The neurosensory phenomena, dependent on the cumulative dose of oxaliplatin, affect all patients who receive doses > or = 540 mg/m2 over four cycles or more of therapy. This neurologic toxicity is also highly reversible, with 82% of patients having their neuropathy regress within 4 to 6 months and 41% experiencing complete recovery within 6 to 8 months. With these considerations in mind, the currently recommended dosing schedules for oxaliplatin are 130 mg/m2/d as a 2- to 6-hour infusion or 175 mg/m2/d as a chronomodulated infusion over 5 days, both of which are administered every 3 weeks. Oxaliplatin rapidly disappears from the plasma and is rapidly transformed into putative active species. 5-Fluorouracil and folinic acid, often used in combination with oxaliplatin, do not affect its pharmacokinetics. The favorable pharmacokinetics and safety profile of oxaliplatin contribute to its tolerability, particularly in pretreated cancer patients with reduced renal function. The reversible nature of its dose-limiting neurotoxicity and its synergistic action with 5-FU/FA make oxaliplatin an interesting agent for the treatment of colorectal cancer and for other potential indications.

Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences.

UNLABELLED: The influence of oxaliplatin (OXA) on 5-fluorouracil (5-FU) plasma clearance was investigated. PATIENTS AND METHODS: A group of 29 patients with advanced colorectal cancer refractory to prior weekly 8-h 5-FU infusion plus bolus folinic acid (FA), received the same combination plus OXA at 130 mg/m(2) every 3 weeks, OXA plus 5-FU plus FA on day 1, and 5-FU plus FA on days 8 and 15. Steady-state 5-FU concentrations in plasma were measured weekly and 5-FU clearance was calculated. Both before and after the addition of OXA, the 5-FU dose was individually adjusted according to the pharmacokinetic follow-up (target steady-state plasma concentrations 2.5-3 mg/l). RESULTS AND DISCUSSION: A total of 122 OXA-containing infusions and 338 5-FU plus FA infusions were given and the median number of infusions per patient was 4 (2-9) and 10 (5-28), respectively. 5-FU plasma clearance was significantly decreased on days 8 and 15 when compared with the value on day 1 and with the values before OXA introduction using a direct paired comparison (2.36 and 2.31 l/min, respectively, vs 3.12 and 3.05 l/min; P<10(-5)). Of 25 evaluable patients, 6 had an objective response after the introduction of OXA (24% objective response rate, 95% confidence interval 9.4-45%). CONCLUSION: OXA reduces 5-FU plasma clearance for 15 days. This may be a factor in the synergy between the two drugs. It is not linked to dihydropyrimidine dehydrogenase inhibition. Implications for drug schedules in clinical practice are discussed.

Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function.

PURPOSE: The pharmacokinetics (PK) of platinum was investigated and compared in patients with normal (NRF) and impaired renal function (IRF), after they had received oxaliplatin at the recommended dose and delivery modality. METHODS: Oxaliplatin was administered at 130 mg/m(2) as a 2-h infusion without hydration. Patients were recruited and classified according to their creatinine clearance (CrCl > or < 60 ml/min), calculated using the Cockcroft and Gault formula. Blood was taken for PK analysis during and after the infusion. Twenty-three patients were included in the PK analysis (13 NRF and 10 IRF). At inclusion, the median CrCls were 70.5 ml/min (range 63-136) for the NRF group and 42 ml/min (range 27-57) for the IRF group. Three patients underwent a second course of treatment and additional blood sampling for analysis. Platinum levels in the plasma, ultrafiltrate and red blood cells (RBCs) were measured using flameless atomic absorption spectrophotometry (FAAS). RESULTS: Following the administration of oxaliplatin, platinum binding to plasma proteins and RBCs was rapid and extensive; at the end of the 2-h infusion, 27% of the platinum in the plasma remained free (40% bound to RBCs, 33% bound to plasma proteins). Neither the mean maximal concentration (C(max)) of total platinum in the plasma, the mean C(max) of ultrafilterable platinum in the plasma, nor the maximal platinum content in the RBCs differed significantly between the two groups (2.59 vs 2.58 microg/ml, 1.09 vs 1.28 microg/ml and 2. 06 vs 2.17 microg/ml, respectively, for patients with NRF vs IRF). After the end of the infusion, levels of total and free (ultrafilterable) platinum in the plasma declined biexponentially. The plasma clearance of both total and free platinum as well as the area under the curve (AUC) of the free platinum fraction correlate with the calculated CrCl (P=9 x 10(-3), P=3.1 x 10(-5) and P=9 x 10(-6), respectively). After a single course of oxaliplatin, toxicities reported in the two groups of patients were similar. CONCLUSIONS: Our results are in agreement with the in vitro data concerning the extensive binding of oxaliplatin to plasma proteins and RBCs. They also reveal a strong negative correlation between free drug plasma availability and renal function, with a corresponding positive correlation between clearance of the plasmatic platinum and renal function. Thus, renal impairment entails a greater overall exposure to platinum in the plasma. However, this study failed to elicit any relationship between moderate renal impairment and the acute toxicity associated with oxaliplatin.

From methodology to ethics and from ethics to methodology.

This editorial criticizes certain ethical and scientific deficiencies, the statistical manipulation of patients' rights and the misuse of the Social Security budget in human experimentation and therapeutics.

Retrospective study correlating clinical infectious history and peripheral blood T-cell subpopulations in cancer, GvH and HIV+ patients.

The CD4+ CD8- inducer helper cell and the CD4- CD8+ cytotoxic/suppressor cell absolute numbers were measured in the peripheral blood of patients with various pathological conditions: with leukemia-lymphomas or solid tumors, patients with bone marrow grafts suffering from GvH, HIV-1 asymptomatic carriers, ARC and AIDS patients. The study was carried out during observation periods when they were not suffering from opportunistic infections and were untreated. In all the groups a decrease of the CD4+ CD8- cell absolute number was observed. In the leukemia-lymphoma and solid tumor bearing patients the CD4- CD8+ absolute value was lower than normal, while in the GvH- and HIV-infected patients, it was significantly higher. The clinical follow-up of each group indicates that GvH, ARC and AIDS patients developed infection in 40-68% of the cases, ie the only groups at risk of infection are those in which the CD4- CD8+ absolute values are high: we suggest that the balance CD4+ versus CD8+ should be considered rather the absolute CD4+ when discussing appropriate use of immuno-regulators.

A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service.

Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunomodulating properties of bestatin in cancer patients. A phase II trial.

Thirty-four patients with cancer (30) or ARC (4) with severe T cell defect or imbalance persisting a long time after completion of any cytostatic treatment were treated by bestatin 30 mg/day 3 days per week during three weeks. The drug has no toxicity of any kind. Reassessment of T cell subsets after completion of bestatin therapy showed a significant improvement of the absolute number of CD4 cells in peripheral blood. CD8 subsets wether initially increased or decreased were modified towards normalisation but the modification reached statistical significance only in the subgroup with initial absolute defect of CD8 cells. CD4/CD8 ratio was significantly increased whether considering all cycles of therapy, or all those given to patients with initially high or normal CD8 subsets. Bestatin appears to have immunomodulating properties which might be useful in cancer patients.

Oxalato-platinum or 1-OHP, a third-generation platinum complex: an experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum.

A new platinum complex, oxalatoplatin or l-OHP, which, at the same metal dose in experimental tests is as efficient as cisplatin, and is more so at a lower metal dose than carboplatin; which is as efficient in human tumors of the testis and ovary as these other analogs, and more so in melanoma and breast cancer; which is not nephrotoxic, cardiotoxic or mutagenic, and hardly hematotoxic and neurotoxic, is described and compared with the above-mentioned platinum complexes. Combined with 5Fu, it induces a high number of remissions in colorectal cancer, and has brought about cures in inoperable gastric cancers. Combined with carboplatin, it has resulted in a high proportion of cures in L1210-carrying mice, which no other two-by-two combination of these complexes has achieved.