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N Mottet

Publications and source records attributed to N Mottet.

At least 19 recordsLinked to original sources
PubMed2006

[Role of nephrectomy in metastatic renal cell carcinoma].

Metastatic kidney cancer is still a devastating disease but it represents a very heterogeneous situation. Some patients will have a median survival limited to some months, while others will live several years. If the initial diagnosis of kidney cancer at metastatic stage is quite uncommon, it raises the question of whether or not performing initial nephrectomy. The point was long debated as it was suggested that initial nephrectomy could result in a spontaneous metastase regression and protect against local complications (hematuria, local pain,...). Today, nephrectomy must not be systematic, as effective alternative treatments are often available. Furthermore spontaneous postoperative metastasis regression is unusual. Two recent prospective randomized trials clarified the impact of initial nephrectomy. It is now accepted that initial surgery prior to systemic immunotherapy results in 30% survival benefit. However this procedure should only be considered for highly selected cases: patients in otherwise good condition (ECOG 0-1), macroscopically complete local resection, no supra-hepatic caval thrombus, and patients suitable for systemic immunotherapy treatment. Several questions remain unanswered, such as lymph node dissection to be performed, and its real survival impact. Furthermore the definition of "suitable" patients for immunotherapy has to be clarified, based on the recent results from the Percy Quatro study. It would probably be more effective to consider only patients with an expected good survival benefit using immunotherapy, such as those classified as "good prognosis" based on the CRECY criteria. Finally the development of new drugs, targeting mainly the angiogenic pathway may lead to different future indications in this setting.

Carcinoma, Renal Cell↗
PubMed2005

Intermittent androgen castration: a biological reality during intermittent treatment in metastatic prostate cancer?

INTRODUCTION: To assess the effects of intermittent maximal androgen blockade (IMAB) on testosterone (T) levels during on- and off-treatment periods. MATERIALS AND METHODS: A total of 51 patients with metastatic prostate cancer underwent a 6-months period of continuous maximal androgen blockade (MAB) consisting of leuprorelin (3.75 mg at monthly intervals) plus flutamide (250 mg t.i.d.) followed by IMAB. During each cycle, the cut-off prostate-specific antigen (PSA) levels to stop and resume treatment were 4 and 10 ng/ml, respectively. IMAB continued until progression under treatment occurred. Monthly PSA and T measurements were performed in central laboratories. RESULTS: From the 51 patients included (mean age 67.6 years), 27, 16, 12, 8 and 5 underwent a second, third, fourth, fifth and sixth cycle, respectively (mean follow up: 17 months). Before treatment, 4 patients had a T lower than normal laboratory value but these recovered all to a normal T value at the end of the first cycle. During the 6 cycles, only 8 patients did not recover a normal T at least once during the off-treatment periods (OTP). The mean T values at the end of each OTP did not change during these 6 cycles (Anova test, p=0.621) with a mean stable recovery delay of 32-43 days (Anova test, p=0.722). CONCLUSION: IMAB protocol with an initial 6-month treatment period can result in an intermittent castration with the recovery of normal T levels in most patients during six consecutive cycles of treatment.

Aged↗
PubMed2003

Phase II study of oxaliplatin versus oxaliplatin combined with infusional 5-fluorouracil in hormone refractory metastatic prostate cancer patients.

BACKGROUND: A randomized, multicenter phase II study evaluating oxaliplatin alone (OXA) and oxaliplatin-5-fluorouracil combination (OXFU) in advanced hormone-refractory prostate cancer (HRPC) patients. PATIENTS AND METHODS: Metastatic, pathologically proven prostate carcinoma patients, progressing despite anti-androgen therapy, received intravenous OXA (130 mg/m(2 )over 2 h), alone or with 5-FU (1000 mg/m(2)/day, continuous intravenous infusion, days 1-4), every 3 weeks. OXA patients could receive OXFU after treatment failure. RESULTS: Fifty-four patients (26 OXA, 28 OXFU) from nine centers received 269 treatment cycles (106 OXA, 163 OXFU; median 3.5 OXA or 5 OXFU cycles per patient; range 1-10 or 1-14, respectively). Patient characteristics were similar in both arms. Three partial responses (PR) occurred in 21 evaluable OXA patients [14%; 95% confidence interval (CI) 1% to 30%], and in five of 26 evaluable OXFU patients (19%; 95% CI 7% to 39%). Clinical benefit response (pain, performance status and weight changes) was assessed in 20 OXA and 22 OXFU symptomatic patients, with more responders in the OXFU arm (39% compared with 12%). Median time to progression in the OXA and OXFU arms was 2.6 and 3.4 months, and median overall survival was 9.4 and 11.4 months, respectively. Hematotoxicity was common, but mostly mild to moderate. Neutropenia was more common in OXFU than OXA patients. After oxaliplatin failure, 12 patients received 46 cycles of OXFU and one of 11 evaluable patients had a PR. CONCLUSION: The objective response rate, palliation benefit, survival and manageable toxicity obtained in this heavily pretreated HRPC population with OXFU merit further study.

Adult↗
PubMed2003

Management of locally advanced prostate cancer: a European consensus.

This report summarises the findings of a European Consensus Group review of current standards of care in locally advanced prostate cancer defined as (a) untreated cancer extending clinically beyond the prostatic capsule in patients with no evidence of lymph node invasion or distant metastases, and (b) residual disease remaining after local treatment with positive surgical margins, seminal vesicle invasion, persistent prostate-specific antigen (PSA) and/or secondary PSA relapse. There was no overall consensus as to the standard of care in clinically apparent locally advanced prostate cancer. It was agreed, however, that hormonal therapy (e.g. with a gonadotrophin releasing hormone analogue [GnRHa]) represents a valid treatment in these patients. Treatment practices and regimens vary considerably between European countries, but GnRHa is widely used, either alone or in combination with antiandrogens. Hormonal therapy alone is a valid option, though the optimal modality, timing and duration of treatment remain to be defined. Adjuvant therapy with a GnRHa has been shown to improve survival in patients undergoing external beam radiotherapy. It is a viable option after prostatectomy in patients with persistent or secondary relapsing PSA. It was determined that optimal treatment will be different according to PSA, clinical staging and Gleason score, and the treatment of locally advanced disease should be individually tailored after discussion between physician and patient. In many instances, patients prefer and expect some form of treatment in preference to watchful waiting. Treatment nomograms such as the Kattan nomograms provide precise, comprehensive and invaluable tools for everyday use and may be used to predict outcomes and guide treatment decisions.

Androgen Antagonists↗
PubMed2001

Human prostatic cell line PNT1A, a useful tool for studying androgen receptor transcriptional activity and its differential subnuclear localization in the presence of androgens and antiandrogens.

The human immortalized prostatic cell line PNT1A has been proved to be a good model for analysis of cellular processes such as the prostatic epithelium proliferation in response to androgens and growth factors. Here we used this cell line for studying the transcriptional activity and trafficking of the androgen receptor (AR) by analyzing several actions of antiandrogens. Transient transfection experiments with PNT1A cells were performed with wild type human AR and an androgen-responsive gene reporter. We demonstrated that the transcription of reporter gene could be triggered by natural androgens (testosterone and dihydrotestosterone) in PNT1A cells as well as in the prostatic carcinoma cell line DU-145. With competitive experiments in the two cell lines, we observed no difference between the antagonistic capacity of cyproterone acetate (CPA) and hydroxyflutamide at 10(-7) M. At this concentration, bicalutamide antagonist activity was lower. In parallel, we compared the subcellular localization of the modified green fluorescent protein (EGFP)-AR in COS-7, PNT1A and DU-145 cell lines under fluorescence microscopy: we found different distributions between nucleus and cytoplasm, depending on the cell line and the culture medium. Androgen induced cluster formation within the nucleus of the PNT1A and DU-145 cells. However, the cytonuclear trafficking of androgen bound EGFP-AR in the same living cell and nuclear foci were easier to examine in the PNT1A cells. The antiandrogen capacity of bicalutamide was manifested by a slower androgen-dependent nuclear transfer of EGFP-AR and a homogeneous nuclear localization. A delayed advent of nuclear clusters was observed in presence of CPA. We conclude that the PNT1A cell line is a better model than the DU-145 cell line to analyze the trafficking of AR and the association of AR on the nuclear matrix, as well as to observe the action of antiandrogens on these critical steps in prostate cells.

Active Transport, Cell Nucleus↗
PubMed2001

The COOH-terminal Src kinase Csk is a tumor antigen in human carcinoma.

The cytoplasmic tyrosine kinase cSrc is involved in the regulation of many important cellular functions including cell growth and transformation, and its activity is down-regulated by phosphorylation of the Tyr530 residue by the COOH-terminal Src tyrosine kinase, Csk. Because cSrc was previously found overexpressed, activated, and in some cases mutated in carcinoma, we investigated whether it could act as a tumor antigen. We show that whereas no autoantibodies were found against cSrc or its relative Fyn, up to 20% of patients with carcinoma had high-affinity autoantibodies against Csk. Immunity mainly resulted from a secondary response, as indicated by the presence of IgG1 in the sera. Antibodies were linked to the cancer because they were not detected in healthy subjects nor in patients with unrelated diseases, and their levels decreased in the sera of patients after surgical resection. Furthermore, they behaved as early markers of epithelial transformation because they were present in sera of patients with early-stage tumors and precancerous lesions such as colorectal polyps and in sera of patients that were scored negative for other cancer serological markers (CEA, CA15-3, CA19-9, p53 antibodies). Finally the presence of these antibodies was attributed, at least in part, to a substantial elevation of Csk protein levels in the corresponding tumors. However a strong increase in Src activity was also observed in these tissues, which suggested that Csk cannot regulate Src-like activity in carcinoma. Taken together, these data demonstrate that Csk acts as an autoantigen, and the detection of anti-Csk antibodies may have potential diagnostic usefulness in the early detection and postoperative follow-up of patients with carcinoma.

Adenocarcinoma↗
PubMed2001

The use of an artificial urinary sphincter in women with type III incontinence and a negative Marshall test.

PURPOSE: We evaluate the efficacy of the AMS 800 artificial urinary sphincter in women with type III incontinence. MATERIALS AND METHODS: We enrolled 207 women with genuine stress incontinence due to intrinsic sphincter deficiency. Primary inclusion criterion was a negative Marshall test. A modified surgical procedure was used to implant the AMS 800 through an abdominal approach, with placement of the cuff around the bladder neck between the periurethral fascia and vagina. Followup data were available for 206 women, including 179 with nonneurogenic and 27 with neurogenic bladders (mean followup 3.9 years). RESULTS: There were 12 (5.9%) explantations due to the prosthesis either through an erosion, extrusion or both that were necessary. The only significant risk factor for explantation was perioperative injury. This injury resulted in 8 explantations in 49 patients compared with 4 in 155 who did not have such injuries (p = 0.0016). Of the 190 patients with working devices continence was achieved in 88.7% (49 of 168) and 81.8% (18 of 22) of those with nonneurogenic and neurogenic bladders, respectively. Social continence (slight leakage but no pad use) was reported by 7.7% (13 of 168) and 9.1% (2 of 22) of patients in the nonneurogenic and neurogenic groups, respectively. The remaining patients reported leakage and pad use. CONCLUSIONS: The AMS 800 can be used successfully to treat women with genuine stress incontinence due to intrinsic sphincter deficiency. The modified surgical approach resulted in fewer perioperative injuries and, consequently, a low explantation rate. Women with genuine stress incontinence, a low urethral closure pressure and negative Marshall test indicating severe intrinsic sphincter deficiency are potential candidates for artificial urinary sphincter implantation.

Adult↗
PubMed2000

Deregulation of the cytoplasmic tyrosine kinase cSrc in the absence of a truncating mutation at codon 531 in human bladder carcinoma.

The involvement of the cytoplasmic tyrosine kinase cSrc was investigated in human bladder carcinogenesis. Kinase activity was determined in tissue lysates from bladder transitional cell carcinoma (TCC) relative to normal epithelia. Strong kinase activation was observed at all stages of carcinogenesis with a peak at the stage pT1, where tumor cells disrupt the basement membrane and invade the submucosa. In agreement with a role for cSrc in cell invasion, immunocytochemistry analysis showed a strong staining of invading cells. An increase in cSrc protein level were also found in most tumor samples, however, it did not correlate with an increase in activity (r = 0.44) suggesting that cSrc is deregulated in these tumors. Indeed, high Src activity was affinity-purified from a column (IRSVSSDGHE(p)YIYVDP-Affigel 10) that specifically retains active Src. Enzymatic regulation involves the C-terminus, recently found mutated at codon 531 in a subset of advanced human colon cancers. However, no such mutations were detected in TCC, suggesting the existence of other mechanisms for kinase activation.

Base Sequence↗
PubMed2000

Pharmacokinetics of enoxacin and its oxometabolite after multiple oral dosing and penetration into prostatic tissue.

The objective of this study was to determine the concentrations of enoxacin and its oxo-metabolite in human prostatic tissue after multiple oral doses (400 mg bd) in 13 patients. On the first day of treatment, elimination half-lives were 6.8 h for enoxacin and 7.1 h for its metabolite; they were increased on day 4 (10.3 and 13.2 h, respectively). The ratios of drug concentration in prostatic tissue and plasma averaged 2.2 for enoxacin and 1.4 for its metabolite. In conclusion, concentrations of enoxacin achieved within the prostatic tissue were higher than plasma concentrations suggesting that there was an active transport mechanism.

Administration, Oral↗
PubMed2000

[Testicular cancer and male fertility].

Disorders of fertility after treatment of testicular cancer constitute important sequelae. Almost one half of patients initially present decreased fertility. Chemotherapy, radiotherapy and surgery each exert their specific harmful effects. Although the desire for subsequent paternity is often satisfied spontaneously, some patients remain permanently sterile. Systematic semen storage, designed to palliate this sterility, when necessary, must be systematically part of the therapeutic contract. It is best performed before or immediately following castration. It also plays a psychological role, projecting the patient into his future cure. The limits of freezing have been considerably reduced with progress in vitro fertilization and ICSI. In the case of radiotherapy or chemotherapy, effective contraception must be recommended for 2 years after starting treatment. The long-term teratogenicity of the various treatments used is still very poorly known.

Antineoplastic Agents↗
PubMed2000

[Simultaneous radio-chemotherapy for infiltrating bladder carcinoma. What is new since 1997?].

Concomitant radiotherapy-chemotherapy is increasingly used in urology in the treatment of invasive bladder tumours. In 1997, the outcome of 552 patients was reported in the international literature. Two years later, another 617 patients had been treated according to various modalities. The initial complete response rate ranged from 56 to 87% (median: 70%). 5-year overall survival rates were between 55 and 68% for T2 tumours. The metastasis rate was between 22 and 35% for the overall treated population. Concomitant radiotherapy-chemotherapy using a platinum salt represents a possible therapeutic modality in some patients, but it cannot be considered to be equivalent to total cystectomy, which remains the reference treatment in operable patients with an operable tumour, achieving a 63 to 80% 5-year survival for pT2 tumours.

Clinical Trials as Topic↗
PubMed1999

High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy. Pathologist Multi Center Study Group.

OBJECTIVES: To assess the prognostic value of prostatic stromal inflammation in surgically treated localized prostate carcinoma for biochemical recurrence-free survival. METHODS: Stromal prostatic inflammation grading was studied in 161 patients who underwent radical prostatectomy for prostate cancer without involvement of the lymph nodes and who did not receive preoperative or postoperative radiotherapy or hormonal therapy until recurrence occurred. Inflammation was graded as high-grade inflammation if confluence of inflammatory cell infiltrate and/or glandular epithelium disruption associated with interstitial inflammatory infiltrate were present and as low-grade inflammation otherwise. Each specimen was graded separately first in the stroma surrounding nonmalignant glands and second in the stroma surrounding malignant glands. Biochemical recurrence based on serum prostate-specific antigen (PSA) level was defined as two successive PSA measurements greater than 1 ng/mL. RESULTS: Malignant tissue was significantly less involved in high-grade inflammation than benign adjacent tissue (9.3% and 19.9%, respectively; P <0.01). In a univariate Kaplan-Meier analysis, the 5-year recurrence-free survival rate for patients with high-grade and low-grade classified prostates was 61.0% and 66.7% in benign tissue and 27.0% and 65.3% in malignant tissue, respectively, with a significant difference between grades only in malignant tissue (P <0.02). In a multivariate analysis controlling for Gleason grade, preoperative serum PSA, pathologic stage, and inflammation grade in malignant tissue, the latter factor remained significantly predictive of biochemical recurrence (P = 0.03). CONCLUSIONS: Patients with high-grade inflammation surrounding malignant glands in radical prostatectomy specimens had significantly more postoperative biochemical recurrence than patients with low-grade inflammation.

Aged↗
PubMed1999

Randomized comparison of transurethral electroresection and holmium: YAG laser vaporization for symptomatic benign prostatic hyperplasia.

OBJECTIVE: To evaluate the safety and efficacy of holmium:YAG laser vaporization v transurethral electroresection (TURP) for benign prostatic hyperplasia. PATIENTS AND METHODS: Thirty-six patients were randomized. Two laser procedures (60 to 80 W) were performed for one TURP. Symptom Score, peak flow rate, potency, and ejaculation status were measured at baseline and at 1, 3, 6, and 12 months. RESULTS: The mean operative time was 75 minutes for laser and 56 minutes for TURP (P = 0.0407). With a mean laser energy delivered of 103.6 kJ, hemostasis was satisfactory during vaporization. The mean catheterization time was 1.7 and 2.1 days in the laser and TURP group, respectively. For the laser and TURP groups, the mean AUA Score improved from 20 preoperatively to 7 and from 24.1 to 5, respectively, at 12 months. The mean peak flow increased from 8.4 to 19.5 mL/sec and from 7.6 to 16.8 ml/sec, respectively, at 12 months. These results are not statistically different. No significant initial dysuria occurred. No significant difference between the groups appeared in potency or ejaculatory status during the follow-up. One patient in the laser group (Day 5) and two in the TURP group (2nd and 6th month) had to undergo a second procedure to relieve obstruction. CONCLUSION: Although taking slightly longer to accomplish, holmium:YAG laser vaporization of BPH provides early results very similar to those of TURP with a shorter catheterization time and no initial dysuria or pain.

Aged↗
PubMed1999

[Autonomic nervous system and prostatic physiology. Specific features of the alpha-adrenergic system].

A better understanding of the rich autonomic innervation of the prostate allows more effective treatment of voiding disorders secondary to benign prostatic hyperplasia. The glandular contingent possesses mainly cholinergic innervation (M2 muscarinic receptors). Smooth muscle cells are richly supplied with alpha and beta catecholaminergic receptors, involved in muscle contraction and muscle relaxation, respectively, but they may also be involved in growth. These alpha receptors, divided into 2 families (alpha 1 and alpha 2), belong to the family of G protein-coupled seven membrane-spanning helix receptors. The genes, followed by the recombinant proteins of 3 subtypes of alpha 1 receptors have been described: alpha 1-a, -b, -d. In the prostate, these receptors are predominantly located in the stroma, mainly in the centroprostatic region. The mRNA present mainly code for the alpha 1a subtype. The use of specific agonists and antagonists shows that these receptors control smooth muscle contraction according to a mechanism initially considered to be of the alpha 1a type. However, their low affinity for prazosin and the development of new alpha 1 blocking agents is in favour of the involvement of a different functional subtype: alpha 1L. This difference could be explained by a different conformation of the receptor or by different coupling mechanisms. The subtype involved in prostatic smooth muscle contraction has yet to be characterized.

Autonomic Nervous System↗