Procalcitonin and calcitonin gene-related peptide decrease LPS-induced tnf production by human circulating blood cells.

The pathogenesis of septic shock is mainly due to unregulated tumour necrosis factor-alpha (TNF-alpha) production. Procalcitonin (PCT) and calcitonin gene-related peptide (CGRP) are alternative transcription products of the calcitonin gene. Since high PCT levels have been described in human sepsis, and since CGRP inhibits TNF synthesis in rats, we examined the role of these peptides in the regulation of the inflammatory response during septic shock. LPS-induced TNF production was assessed using a human whole blood model. In this model, PCT (10(-7) M) and CGRP (10(-6) M) significantly inhibit TNF production by 27 and 24 % respectively. The effect of CGRP was reversed by CGRP 8-37 (10 microM), an antagonist of CGRP receptor. No effect on interleukin (IL)-1, IL-6 and IL-8 was found. This is the first description of an anti-inflammatory role for PCT and CGRP in humans.

Procalcitonin is not produced by circulating blood cells.

A large number of clinical studies has described procalcitonin (ProCT) as a marker of bacterial infection and a good predictor of disease severity and antibiotherapy efficacy. Nevertheless, the mechanism of ProCT synthesis remains unclear. The aim of this study was to demonstrate potential ProCT production by peripheral blood mononuclear cells as is the case for cytokines involved in sepsis. In a whole blood model, LPS (10 micrograms/ml) stimulation on blood samples from healthy volunteers (n = 14) was tested. Early (TNF-alpha and IL1-beta) and late (IL-6 and IL-8) cytokines were produced in large amounts in contrast to the absence of ProCT. Additional experiments with nitric oxide or detection of intra-cellular ProCT (cell lysis, flow cytometry) had negative results. It was concluded that ProCT is not produced in this model. Data are still needed to investigate the cellular origin of ProCT in order to better define its clinical usefulness.

Total androgen ablation: Canadian experience.

A multicenter randomized, double-blind trial comparing total androgen blockade obtained by the use of castration with a pure anti-androgen (nilutamide) with simple castration was begun. One hundred and five patients received the combined treatment and 103 the orchiectomy plus placebo. Several features were used to evaluate the efficacy. Bone pain responded better to combined treatment at 6 months (P = 0.042). The number of favorable responses, as evaluated by the NPCP criteria, was 61% with simple castration and 78% with the combined treatment (P = 0.013). There was no statistically significant difference between the two groups in time to progression (logrank test P = 0.462) or survival (logrank test P = 0.137) despite an increase in median survival of 5.4 months. All other measures showed no difference between the two treatments. With total androgen blockade, 50% of the patients had disease progression at 1 year, and 45% were dead at 2 years. A review of the results of similar reported studies suggests no improvement or very modest improvement with total androgen blockade over testicular androgen ablation alone.

A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma.

A randomized double-blind trial in patients with disseminated, previously untreated prostate cancer (Stage D2) was conducted in eight Canadian centers. All 203 patients enrolled in this study underwent bilateral orchiectomy and were randomized to receive either the nonsteroidal anti-androgen nilutamide or a placebo. Patient responses were graded according to the criteria of the National Prostatic Cancer Project (NPCP). Patients treated with nilutamide had a significantly greater number of positive objective responses (partial and complete regression) than did the patients treated with castration alone (46% versus 20%, P = 0.001). Progression-free survival was improved initially in the nilutamide group, but the median time to progression was 12 months for both groups. Despite an increase in the median length of survival from 18.9 to 24.3 months with the nilutamide, the survival time was not significantly longer in the nilutamide group (log = rank test, P = 0.048). Although minor side effects were frequent, adverse effects related to the medication and leading to discontinuation of treatment were observed in 9% of cases. These results suggest some benefit of the combined treatment (orchiectomy + nilutamide) over orchiectomy alone in the treatment of metastatic prostatic carcinoma.

Scintigraphic evaluation of renal function after extracorporeal shock-wave lithotripsy.

We evaluated renal function within 48 hours after extracorporeal shock-wave lithotripsy (ESWL) as well as 1 month and up to 6 months later employing technetium-99m dimercaptosuccinic acid and iodine-131-labelled ortho-iodohippurate. All 17 patients displayed abnormal renal function immediately after ESWL. The abnormalities identified included focal cortical lesions, diffuse reduction of renal function, increased kidney volume, and diffusely and focally increased parenchymal transit times. The follow-up scintigraphic studies indicated that the great majority of the lesions had been temporary.

The assessment of disease aggressivity in stage D2 prostate cancer patients (review).

Suppression of androgen levels in blood of stage D2 prostate cancer patients has been the prominent treatment for advanced prostate cancer. However, the duration of hormone sensitivity of prostate tumor is variable. The type of initial response to hormonal treatment, the length of response and patient's survival are in direct association with disease aggressiveness. Recently, an arithmetic formula expressing disease aggressivity was computed using pretreatment values of prostatic acid phosphatase (P.A.P.), alkaline phosphatase (A.P.), degree of tumor differentiation and number of bone metastases. This aggressiveness score was related to disease response and patients outcome receiving hormonal treatments. The use of an arithmetic formula to express disease aggressivity could result in a subdivision of the disease. The identification of the subgroup of stage D2 patients destined not to benefit from hormonal manipulation could change the strategies employed up until today for the treatment of advanced prostate cancer.

[Lithotripsy of biliary calculi: evaluation of ultrasonography as a method to guide treatment by extracorporeal shock waves]. / Lithotripsie des calculs biliaires: évaluation de l'ultrasonographie comme moyen de diriger le traitement par ondes de choc extracorporelles.

Extracorporeal shock-wave lithotripsy is a procedure recently introduced to treat gallstone disease. According to the literature, 15% to 25% of symptomatic persons will be candidates for this procedure if it proves effective. Currently, sonography is one of the best methods for monitoring the performance of lithotripsy. The authors have confirmed this. They have designed an in-vitro model which allows comparison between what is actually happening during gallstone lithotripsy and what is being seen by real-time sonography. The sonographic characteristics of the different phases of gallstone lithotripsy are presented.

Total androgen blockade for metastatic cancer of the prostate.

This randomized, double-blind study comparing orchiectomy plus placebo to orchiectomy plus a nonsteroid antiandrogen (Anandron) shows that total androgen blockade for metastatic cancer of the prostate provides a significantly better early objective response when compared to castration alone. This response, however, is less apparent at 18 months. The study also suggests a longer survival for the patients with total androgen blockade.

Objective response and disease outcome in 59 patients with stage D2 prostatic cancer treated with either Buserelin or orchiectomy. Disease aggressivity and its association with response and outcome.

A comparative study was done in 59 recently diagnosed Stage D2 prostatic cancer patients treated with either long-term GnRH-A (Buserelin) (N = 42) or with orchiectomy (N = 17) and followed up for three years. The suppressed limits of plasma testosterone and estradiol levels after eight-week follow-up as well as the objective clinical response and disease outcome were found to be similar with either treatment. Hot flushes and loss of libido were noticed in both groups throughout the follow-up period; however, there were no other side effects. Analysis of Stage D2 patients based on their time of death enables us to identify nonhormonal variables which, in the form of an aggressiveness score, correlated well with both clinical response and disease outcome. These data confirm that (1) Buserelin is an effective and safe alternative to orchiectomy in advanced prostatic cancer, and (2) in clinical studies a multifactor aggressiveness score is useful for analyzing clinical efficacy data. Prospective application of that score may enable predictability of patient response and influence patient management.

[Quantitative evaluation of low-flow rate hemodialysis with sequential use of 2 membranes of differing permeability]. / Evaluation quantitative de l'hémodialyse à bas débit avec utilisation séquentielle de deux membranes de perméabilité différente.

Although the "low flow" dialysis has not gained large clinical experience, recent long term clinical investigation indicate that it can be an interesting alternative in the treatment of uremia. This method permits a reduction in treatment cost without impairing the quality of therapy. The interest of this 12 months cross-over and comparative study with 2 types of dialyzers (H12-10/DISCAP 110) and 2 dialysate flow regiments is twofold: it confirms the lack of morbidity linked to the low flow stage; it gives quantitative data on "dose therapy" changes during the two consecutive stages. The 50% reduction of conventional dialysate flow has a lowering effect of 11 to 18% on urea and creatinine clearances depending on which type of dialyzer used. The use of H12-10 was associated in this case with a more pronounced clearance reduction. The reduction of performances was accompanied by a significant rise in urea and creatinine plasma level without changes in protein catabolic rate while it masks a decrease in creatinine generation rate.

Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma.

We have used the paradoxical antigonadal effects of LHRH agonists as a chemical castration in advanced prostatic cancer. We report early results of a phase II study on the clinical efficacy of the LHRH agonist D-Ser (TBU)6, des-Gly-NH2(10) LHRH administered to patients with stage D prostatic carcinoma. Following dose-range finding studies using either intranasal (IN) (200 micrograms twice/day or 500 micrograms twice/day) or subcutaneous (SC) administration (50 micrograms once/day, we developed a sequential combination of SC (500 micrograms three times/day for seven days) and IN regimen that was administered for 3 to 16 months to a group of 23 patients with stage D prostatic carcinoma. Initiation of therapy was associated with a clinical flare in one patient during the first week of treatment. Mean serum testosterone levels were already decreasing at one week and remained inhibited to levels inferior to 1 ng/ml after the first four weeks of treatment. Overall assessment shows that within the first six months of treatment, 26% patients were improved, 39% were stabilized, and 35% were nonresponders. Fourteen patients were followed during the next six months: 29% continued to respond, 29% escaped, 21% remained stable, and 21% were nonresponders. Histologic studies from castrated patients showed changes in spermatogenesis correlating to the degree and duration of suppression of testicular steroidogenesis without signs of toxicity. Preliminary observations on the combination of the pure antiandrogen RU 23908 with Buserelin (n = 5) or castration (n = 3) suggest that the addition of an antiandrogen does not seem to improve the patients nonresponding to other hormonal suppressive therapy (Buserelin) administered before (n = 3) or concomitantly with the antiandrogen (n = 2). Three relapsing castrate patients responded to the antiandrogen, but the response was temporary in two (eight to nine months of therapy). No side effects other than hot flashes and decreased potency are related to LHRH agonist alone or to the low-dose antiandrogen. Multicenter trials will be necessary to delineate the place of LHRH agonist alone or LHRH agonist combined with an antiandrogen in the treatment of prostatic cancer.

Inhibition of serum androgen levels by chronic intranasal and subcutaneous administration of a potent luteinizing hormone-releasing hormone (LH-RH) agonist in adult men.

The effect of chronic treatment with the luteinizing hormone-releasing hormone (LH-RH) agonist Buserelin (Hoechst AG, Frankfurt/Main, West Germany) ([D-Ser(TBU)6,des-Gly-NH2(10)]LH-RH ethylamide) administrered by nasal spray (200 or 500 micrograms, twice daily) or subcutaneously (50 micrograms daily) for periods of 1 to 8 months was studied on serum sex steroids and LH levels in 18 patients with cancer of the prostate. Basal serum testosterone concentration decreases to 71.1 +/- 18.3 (NS) and 28.6 +/- 9.3%, (P less than 0.01) of control in patients receiving the 200-micrograms and 500-micrograms dose by nasal spray, respectively. In patients treated subcutaneously, a more rapid inhibition of serum testosterone levels to 19.6 +/- 6.4% of control (P less than 0.01) is observed. The finding of decreased levels of 17-OH-progesterone, testosterone, and dihydrotestosterone in the presence of unchanged pregnenolone concentration indicates that the decrease in androgen biosynthesis induced by Buserelin treatment is due to a blockage at the level of 17-hydroxylase and 17,20-desmolase activities. The present data indicate that chronic administration of Buserelin could be a safe and effective means of reducing serum androgens in patients with cancer of the prostate.

[Myocardial protection of the homograft. III - Evaluation of ventricular fibrillations with hypothermic coronary perfusion (author's transl)]. / Protection myocardique de l'homogreffe. III - Evaluation de la fibrillation ventriculaire avec perfusion coronarienne hypothermique.

The homotransplanted heart is in severe failure in the immediate post-operative period, secondary to ischemia inherent to the technic of orthotopic transplantation. The present work was carried out to investigate if ventricular fibrillation followed by cold coronary perfusion could protect the homograft during implantation by evaluating the post-operative cardiac performance. In the control group, 7 hearts were excised, immediately immersed in physiological saline at 5 degrees C, and homotransplanted. In a second group of 4 grafts, ventricular fibrillation was induced and the coronary bed was perfused immediately with cold (5 degrees C) extracellular solution for a period of 10 minutes before orthotopic implantation. All animals were prepared at the end of surgery for hemodynamic studies to be carried out 3, 24 and 48 hours post-operatively in the resting state. In group I, the myocardial temperature dropped to 13.5 degrees C in 14.5 minutes. In group II, the hypothermia by perfusion was more rapid and deeper (11 degrees C within 10 minutes). Three hours post-operatively, cardiac function of group II was superior to that of group I as demonstrated by the increase of cardiac index (39%), stroke volume index (41%) mean systolic ejection rate index (44%), maximum systolic flow index (58%), maximum acceleration index (36%), stroke power index (88%), stroke work index (67%). Twenty-four and forty-eight hours post-operatively the cardio-vascular function improved in both groups but remained superior in group II. These results demonstrate that ventricular fibrillation followed by cold coronary perfusion increases protection of the homograft during the initial period of implantation.