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Biomedical subjects

Philippe Mangin

Publications and source records attributed to Philippe Mangin.

At least 19 recordsLinked to original sources

Differential expression of 37 selected genes in hormone-refractory prostate cancer using quantitative taqman real-time RT-PCR.

Progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. The development of more effective treatments depends on our understanding of the molecular events associated with the hormone-refractory stage. We quantified, among 90 screened genes, the expression of 37 target genes, using real-time quantitative RT-PCR. Gene expression was studied in 13 samples of HPRC compared to 33 clinically localised cancers and normal prostate tissue. We identify 19 genes with significant differential expression in HRPC compared to localised prostate cancer. Genes with decreased expression included receptors for growth factors, MMR genes and the serine protease hepsin. Analysis of increased gene expression confirmed the importance of AR upregulation and highlighted genes not previously linked to HRPC, including enzymes involved in steroid synthesis and the antiapoptotic factor survivin. Progression of prostate cancer to the hormone-refractory state is associated with differential gene expression, which may prove useful for both understanding disease progression and the development of new therapeutic approaches.

Androgens↗

[Cystomanometric study of bladder sensation during sacral neuromodulation test].

PURPOSE: Prospective clinical and urodynamic study evaluating modification of bladder sensation during sacral neuromodulation (SNM). MATERIALS AND METHODS: 24 consecutive patients with non-neurological hyperactive bladder underwent an SNM test. Questioned about their symptoms before and during the test by the urinary handicap assessment scale, patients were divided into two groups: A (improved) and B (not improved). Group A consisted of patients obtaining 50% improvement of their symptoms with SNM followed by return of symptoms at the end of the test, while the other patients constituted group B. We then compared the cystomanometric results according to their clinical response. RESULTS: The mean age was 53 years: 10 patients with a good response constituted group A (n=10, i.e. 42%) and 14 patients with a poor response constituted group B (n=14, i.e. 58%). Clinically, in patients with a good response, SNM decreased urge incontinence by 100%, day-time frequency by 89% and protections by 55%. Urodynamic assessment in group A during the test demonstrated a significant increase of +23% of bladder capacity (p<0.01), +57% of the volume of onset of the first unstable contraction (p<0.004), +83% of bladder volume to the first urge to urinate BI (p<0.001) and +46% to urgency B3 (p<0.04). During SNM, cystometry revealed that 1 or 2 bladder filling volumes were increased at B1 and/or B3 in 100% of improved subjects. In contrast, 1 or 2 volumes decreased at B1 and/or B3 in 58% of non-improved subjects. No significant difference of intensity of unstable contractions was observed between the 2 groups during SNM (p=0.31). CONCLUSION: A significant correlation was observed between the two methods of clinical and urodynamic assessment. Our results suggest the use of the cystomanometric increase of bladder volume at B1 and B3 as selection criterion for candidates for SNM with non-neurological hyperactive bladder.

Aged↗

Expression in bladder transitional cell carcinoma by real-time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1-2: identification of 5 candidates tumor suppressor genes.

Frequent deletions on 9q34.1-2 were reported in bladder transitional cell carcinoma. High deletion mapping studies delimited a critical interval between markers D9S61 and D9S66, which is highly susceptible to contain a tumor suppressor gene. Expression level of the 65 genes localized in this region was analyzed by real-time quantitative RT-PCR, comparing tumor to normal urothelium. Five genes exhibited a significantly reduced expression level: C9orf9, KIAA0625, ABL1, LAMC3 and KIAA1857-netrin-G2, which exhibited the most significant downregulation (p=0.0007). KIAA1857-netrin-G2 belongs to the netrins and might then be a tumor suppressor gene in bladder cancer, as netrin1 receptor DCC has been implicated in tumorigenesis.

Carcinoma, Transitional Cell↗

Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer.

OBJECTIVE: To assess the adherence to an annual PSA screening program conducted over 3 years in first-degree relatives of a sample of men with prostate cancer, and to identify characteristics of men who failed to undergo the full screening process. PATIENTS AND METHODS: Out of 747 candidates that were eligible for the screening program (asymptomatic brothers and sons aged between 40 and 70 years of men diagnosed with prostate cancer) 640 were contacted. The screening program entailed annual serum PSA testing over a 3-year period, during which every candidates attendance was recorded. At the outset, each candidate was requested to complete a questionnaire regarding their socio-professional characteristics, their level of anxiety and their attitude towards genetic susceptibility. RESULTS: 442 (69%) candidates agreed to enter the study and 420 filled out the questionnaire. During the 3-year period, 50 candidates (12%) who had accepted the first year screening refused to undergo subsequent PSA tests. These men were younger ( p=0.015), more anxious (p=0.037 ) and to have more than one affected first-degree relative ( p=0.028 ). CONCLUSIONS: The crucial and challenging step in the adherence to a screening program was the initial recruitment. Once recruited, adherence rate after 3 years was very high (88%). Identifying factors that help predict men who might leave the screening process may provide us means of improving their compliance in the future.

Adult↗

Molecular profiling of benign prostatic hyperplasia using a large scale real-time reverse transcriptase-polymerase chain reaction approach.

PURPOSE: Benign prostatic hyperplasia (BPH) is characterized by a hyperplastic growth of epithelial and stromal cells in the prostate. Despite the high prevalence of the disease little is known regarding the molecular etiology of BPH. Therefore, a comparison of gene expression patterns between normal prostate, BPH and prostate cancer could provide insights into the pathogenic mechanisms of the disease and identify candidate genes that could be targeted for therapeutic use. MATERIALS AND METHODS: Prostate tissue specimen were obtained from 30 patients undergoing adenomectomy for BPH. Adenoma weight was less than 60 gm in 15 patients and more than 60 gm in the remainder. Normal prostate tissue was obtained from 15 patients undergoing radical prostatectomy for cancer from areas selected for absent tumor and BPH. Two pools of organ confined prostate cancer were also analyzed. We quantified in the 5 pools of tissues the expression of 327 genes using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: A total of 23 genes showed increased expression in BPH with a fold change of at least 2.5 between normal prostate and the 2 BPH groups, of which most were normal or down-regulated in prostate cancer. Seven genes showed decreased expression in BPH with a fold change of at least 3.5 between normal prostate and BPH. Most of them were also normal or down-regulated in prostate cancer. CONCLUSIONS: We identified a set of genes up-regulated in BPH compared to normal prostate tissue and often prostate cancer, including genes previously implicated in BPH and others not previously linked to this disease to our knowledge. Further investigations are now warranted to determine the clinical relevance and therapeutic potential of these genes.

Aged↗

Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion.

BACKGROUND: Loss of heterozygosity (LOH) on chromosome arm 13q14 is one of the most consistent genetic alterations in sporadic prostate cancer. This alteration may be involved in prostate oncogenesis through inactivation of one or more tumor suppressor genes (TSGs). Candidate gene expression is an approach to focus the search for TSGs in this region. METHODS: We tested 41 human sporadic prostate tumors for 13q14 LOH by using seven polymorphic markers overlapping the critical region and used a real-time quantitative RT-PCR assay to study the same tumors for expression of the 31 genes located in this genomic region (localized by the Human Genome Project Working Draft). RESULTS: Allelic loss on at least one locus was found in 18 (41%) of the 41 tumor DNAs. Only four genes (ITM2B, CHC1L, KIAA0970, and LOC51131), located in the region most frequently deleted in prostate carcinoma, showed a significant difference in expression between normal and neoplastic prostate tissues. CONCLUSIONS: Given their location in the LOH hotspot, as indicated by our genomic analysis, ITM2B, CHC1L, KIAA0970, and LOC51131 are candidate tumor suppressor genes in this region. ITM2B that showed a significant association (P < 0.005) between expression and LOH at the corresponding locus could, furthermore, be the main target of the observed LOH at 13q in prostate tumors.

Adenocarcinoma↗

Kidney warming during transplantation.

The objective of the present study was to describe kidney temperature variations during transplantation and to identify the factors responsible for kidney warming. Kidney temperature was recorded steadily during transplantation. Kidney weight, body mass index (BMI), second warm ischemia time (t), and kidney temperature at the time of being placed in the recipient were analyzed so that we could evaluate their influence on kidney temperature and on kidney warming during transplantation. Kidney temperature at the time of removal from the container was 1.6 degrees C and 6. 3 degrees C when the kidney was placed in the recipient. Kidney temperature in the recipient depended on kidney temperature after serum washing (P<0.0001), but was independent of kidney preparation time (P=0.94). Then, kidney temperature (T) increased according to the logarithmic curve given in the following equation: T=7.2 ln(t)-0.6. Kidney temperature at the end of anastomosis was 26.7 degrees C. Kidney warming speed was 0.48 degrees/min and was dependent on the length of time of vascular anastomosis (P<0.0001). Kidney weight decreased the kidney warming speed (P=0.02). In conclusion, kidney warming increases slowly during ex vivo preparation. Kidney temperature stays below the damaging ischemic temperature of 18 degrees C. Because of its major impact on kidney warming, it is desirable that vascular anastomosis time be reduced, and, consequently, ex vivo kidney preparation needs to be meticulous.

Adolescent↗

Quantification of expression of netrins, slits and their receptors in human prostate tumors.

Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over-expressed either Slit genes or their receptors, Robo.

Adenocarcinoma↗

Laparoscopic robotic-assisted ileal conduit urinary diversion in a quadriplegic woman.

Urinary diversion is a therapeutic option in quadriplegic patients with poor lower urinary tract conditions, but it is an invasive procedure. Laparoscopic techniques are less invasive, but are technically demanding, and only a few surgical teams are able to complete such a complex procedure endoscopically. Robotics bring an unprecedented control of surgical instruments, shorten the learning curve, and allow open surgeons to apply more easily their technical skill to the laparoscopic approach. This complex case of laparoscopic ileal conduit in a quadriplegic woman was completed by our team with the Da Vinci system after 6 months of clinical experience in robotic surgery.

Cervical Vertebrae↗

Familial prostate cancer cases before and after radical prostatectomy do not show any aggressiveness compared with sporadic cases.

OBJECTIVES: To compare the clinical and biologic features at diagnosis between sporadic and familial clinically localized prostate cancer (CaP), and to compare the prognosis of familial with that of sporadic cases after radical prostatectomy in southwestern Europe. METHODS: Eighty-five sporadic (one case of CaP) and 37 familial (two or more CaP cases in the family) patients with clinically localized CaP undergoing radical prostatectomy were compared regarding preoperative (mean age, clinical status, mean prostate-specific antigen level, and mean Gleason score at diagnosis) and postoperative (pT, pN, and pathologic Gleason score) parameters using the Student t test, Fisher's exact test, and the chi-square test. The biochemical relapse-free survival for each group was compared using the Kaplan-Meier method and the log-rank test. RESULTS: The mean follow-up was about 51.8 months (range 1 to 156) in the sporadic group and 35 months (range 1 to 96) in the familial group. No specific preoperative and postoperative clinical or biologic feature was associated with familial CaP. Biochemical relapse occurred in 40.5% (15 of 37) of cases when the proband had a positive family history of CaP versus 32.9% (28 of 85) in the sporadic cases (P = 0.42). Biochemical relapse-free survival curves did not display any difference (P = 0.46) between familial and sporadic CaP. CONCLUSIONS: In this population, the outcome after radical prostatectomy is similar in those with and without a family history. Thus, the natural history of CaP seems to follow the same path whether the triggering point is inherited or acquired for this subset of patients during this period.

Follow-Up Studies↗

Association study of polymorphisms in the human estrogen receptor alpha gene and prostate cancer risk.

OBJECTIVES: Prostate cancer is a very common hormone-related malignancy in Western countries. It is initially dependent on androgen stimulation but in vitro growth of prostate cancer cells are also dependent on estrogen. Our goal was to elucidate if some polymorphisms of estrogen receptor alpha gene might be associated with the risk of prostate cancer. METHODS: Using DHPLC techniques, each coding exon of the estrogen receptor alpha gene was screened for new polymorphisms in germline DNA from 96 healthy controls and 96 sporadic prostate cancer cases. Identified polymorphisms were then genotyped and their distribution compared between the two populations. RESULTS: Thirteen polymorphisms were identified. A difference was found in the distribution of one newly identified polymorphism, namely a GGGA repeat located in the first intron of the gene. The common wild type genotype consisted of two alleles with five GGGA repetitions (5/5 genotype). Indeed this 5/5 genotype was found in 294/296 controls (99.3%) and 285/294 patients (96.9%; OR, 4.6; 95% CI, 0.99-21.67). Among the nine patients with a different genotype, one was 4/5, seven were 5/6 and one was 6/6. CONCLUSION: These results suggest that variants of the GGGA polymorphism from the estrogen receptor alpha gene may be associated with an increased risk of developing prostate cancer.

Adult↗

[Prostate cancer screening].

Prostate cancer has become the most frequent cancer and the second cause of cancer mortality in men. This public health problem is becoming increasingly important due to the increasing life expectancy. At the present time, prostate cancer will be discovered in one in every eight men during their lifetime. Prostate cancer represents 25% of all new cases of male cancers. Prostate cancer screening is designed to detect early stage, asymptomatic prostate cancer, as the patient's chances of cure are higher when the cancer is diagnosed at an early stage. The conclusions of the ANAES evaluation in 1998 did not recommend mass screening for prostate cancer. Several international prospective randomized studies based on serum PSA assay, sometimes associated with digital rectal examination, are currently underway. France is participating in the European ERSPC study (European Randomized Study of Screening for Cancer Prostate) and is organizing a national study on high-risk populations. While waiting for the final results of these studies, a recommendation needs to be proposed to inform general practitioners and specialists about optimal use of the currently available tests. Based on the conclusions of its oncology committee (composed of urologists, medical oncologists, radiotherapists, pathologists and radiologists), the Association Française d'Urologie proposes a recommendation concerning prostate cancer screening and defines its modalities, especially concerning the target population, screening tests and the information given to men before screening. The Association Française d'Urologie recommends prostate cancer screening by PSA assay (prostate specific antigen) and digital rectal examination annually between the ages of 50 and 75 years, and from the age of 45 years in men with a family or ethnic risk. If total PSA is above the normal value of the test or if digital rectal examination is abnormal, referral to a urologist is recommended. Information concerning the limits, benefits and risks of screening and the available treatment options must be given before performing these examinations.

Humans↗

[Evaluation of the accuracy of four-channel multidetector CT for investigation of the renal arterial blood supply].

OBJECTIVE: To evaluate the accuracy of four-channel multidetector CT for investigation of the proximal and distal renal arterial blood supply. MATERIAL AND METHOD: Four-channel multidetector CT was performed in 51 patients prior to nephrectomy (3 bilateral nephrectomies). The anatomy of the renal pedicle was described intraoperatively and arteriography of the nephrectomy specimen was performed immediately postoperative. Preoperative CT data were compared to intraoperative anatomical findings and arteriography findings on 54 nephrectomy specimens. Concordance analysis (determination of the kappa coefficient) was based on 4 criteria: number of renal arteries, position of the artery with respect to the vein, the intra-sinus or extra-sinus situation of the division of the artery and the number of first order branches. RESULTS: The concordance between CT and intraoperative anatomical findings was good for number of renal arteries (kappa = 0.78) and moderate for the position of the artery with respect to the vein (kappa = 0.65). The concordance between CT and arteriography was poor for the intra-sinus or extra-sinus situation of the division of the renal artery (kappa = 0.5) and for the number of first order branches of the renal artery (kappa = 0.41). CONCLUSION: Four-channel multidetector CT precisely visualizes the proximal renal arterial blood supply, but remains less accurate than arteriography for investigation of the distal arterial blood supply.

Adult↗

Down-regulation of (IIIb) and (IIIc) isoforms of fibroblast growth factor receptor 2 (FGFR2) is associated with malignant progression in human prostate.

BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) have a critical function in the cellular stroma/epithelium interaction for the development and homeostasis of human prostate. Imbalance in expression of these factors is associated with malignancy in several cancers. METHODS: To quantify the expression of fibroblast growth factor receptor isoforms FGFR2(IIIb), FGFR2(IIIc), FGFR1(IIIc), and fibroblast growth factors FGF2 and FGF7 in normal and tumoral human prostate tissues, and human prostatic epithelial cell lines, we used quantitative real-time polymerase chain reaction. RESULTS: The expression of FGFR2(IIIb) mRNA is down-regulated in 60% of the tumors studied (P < 0.0001). Furthermore, FGFR2(IIIb) is significantly reduced in androgen-independent tumors (AI) compared with androgen-responsive tumors (AD) (P = 0.02). A significant reduction in FGFR2(IIIc) expression is also observed in 80% of tumors (P = 0.001). However, unlike FGFR2(IIIb), the down-regulation of FGFR2(IIIc) is not related to the androgen-independent status (P = 0.09). On the other hand, neither FGFR1(IIIc) nor FGF2 and FGF7 have shown any significant variation in expression between normal and cancerous specimens. CONCLUSIONS: These findings propose that decreased expression of not only FGFR2(IIIb) but also FGFR2(IIIc) isoforms may be a critical step in prostate cancer progression and furthermore suggest that FGFR2(IIIb) expression could be used as a marker for prostate cancer evolution from androgen-dependent to androgen-independent status.

Cell Line↗

CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer.

Loss of heterozygosity (LOH) at chromosome 13q14 is one of the most recurrent anomalies observed in sporadic prostate tumors. This LOH is believed to unmask recessive mutations that inactivate a tumor-suppressor gene(s) which otherwise regulates normal cell growth and suppresses abnormal cell proliferation. Identification of potential tumor-suppressor genes within the deleted region is a way of indicating putative pathways of prostate cancer development and progression. The main target that disappears or is downregulated as a result of 13q14 loss remains to be identified. Therefore, our first concern was to find a gene located in the 13q14 region whose transcription is reduced. CHC1-L, for chromosome condensation 1-like, is mapped to the smallest common deleted region. CHC1-L expression is significantly reduced in prostate tumors compared to normal prostate tissues (p = 0.0002). In 21 of 36 (58%) primary prostate tumors studied, CHC1-L expression was reduced at least 2-fold, as measured by real-time quantitative RT-PCR; 18 of the tumors (50%) showed 13q14 LOH for at least 1 of the 5 polymorphic markers that we studied in the region, and 14 (78%) of these were among the tumors underexpressing CHC1-L. CHC1-L is alternatively spliced at its 5' end to produce 2 isoforms, of 551 and 526 aa. Analyses of CHC1-L integrity and of the quantitative expression of its variants indicate that the observed underexpression in prostate tumors is related to reduced expression of the 551 aa isoform. Although CHC1-L is not the obvious candidate given its only known homology, to RCC1, a guanine nucleotide exchange factor for the Ras-related GTPase Ran, the frequent significant decrease observed in its expression in prostate cancer associated with the difference in frequency of CHC1-L variant isoforms between normal and neoplastic prostate tissues places it in a pivotal role or possibly adjacent to a gene that has that role in prostate cancer evolution.

Alleles↗

Worry and attitude of men in at-risk families for prostate cancer about genetic susceptibility and genetic testing.

BACKGROUND: The aim of this study was to evaluate worry about genetic susceptibility and the attitude of men with family history of prostate cancer (CaP) toward genetic testing. METHODS: Three hundred seventy-five eligible first-degree relatives (FDR) of men with CaP, were asked to participate in a screening and to fill out a survey covering the worry about genetic susceptibility and interest in genetic testing. RESULTS: Of the 375 candidates contacted, 277 completed the survey, and had undergone PSA measurement. Sixty-four percent worried a little or not at all about inherited predisposition to CaP, while the remainder worried a lot or extremely. The candidates who worried a lot or extremely were men with high levels of durable anxiety disposition (STAI trait), who had undergone a previous screening procedure and men with sons. Ninety-eight percent of men expressed their interest in undergoing genetic testing. The most motivated candidates to have the test done were men with several relatives with CaP. CONCLUSIONS: The level of worry about genetic susceptibility was low and there was a concrete interest in genetic testing in FDR of men with CaP. This interest increased with the number of CaP in the family.

Adult↗

Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives.

PURPOSE: Targeted screening for prostate cancer in high risk families is generally suggested by ages 40 to 45 years in first degree relatives. We support this concept by reporting higher risk and earlier onset of the disease in these families. MATERIALS AND METHODS: We proposed serum prostate specific antigen (PSA) testing in 40 to 70-year-old first degree relatives of 435 patients with prostate cancer treated between July 1994 and June 1997. A previous systematic genealogical analysis allowed us to define the familial prostate cancer status of each patient as sporadic or familial. RESULTS: Of the 747 potential candidates 442 (59%) accepted into the study have been screened, including 240 who were 40 to 49 years old (mean age 44.8) and 202 who were 50 to 70 years old (mean age 57.4). Two of the 240 subjects (0.8%) had PSA greater than 4 ng./ml. in the 40 to 49-year-old group. Prostate biopsies were negative in 1 relative but diagnostic for prostate cancer in the other. In the 50 to 70-year-old group 25 of 202 subjects (12.4%) had a PSA of greater than 4 ng./ml. Prostate cancer was diagnosed in 9 individuals (4.5%), 9 had negative biopsy results, 1 died before biopsy and 6 refused biopsy. The proportion of relatives with PSA greater than 4 ng./ml. and prostate cancer detection was not different according to familial status (sporadic or familial) but it was significantly higher in first degree relatives with early onset prostate cancer in the family at ages younger than 65 years (p = 0.037 and 0.012, respectively). CONCLUSIONS: Our results emphasize the usefulness of PSA screening in high risk families, including those without obvious hereditary features. Furthermore, early onset prostate cancer is a significant risk factor for prostate cancer in first degree relatives.

Adult↗

Impact of prostate cancer screening on health-related quality of life in at-risk families.

OBJECTIVES: To describe the impact of prostate-specific antigen (PSA) screening on the health-related quality of life (HRQOL) and anxiety of men with a family history of prostate cancer. METHODS: We asked 334 brothers or sons of men with prostate cancer who agreed to undergo PSA testing to fill out HRQOL questionnaires. The questionnaires were the RAND SF-36 (generic HRQOL) and State-Trait Anxiety Inventory (anxiety-specific). Participants completed the questionnaires at the time of screening, while waiting for the results, and after receiving normal results. Sociodemographic and HRQOL variables were entered into a logistic regression model to identify factors associated with the deterioration of HRQOL, defined as a decrease of at least one standard error of measurement. Only men with normal PSA results were considered. RESULTS: Among 334 candidates, 273 underwent PSA measurement and 220 candidates with a PSA of 4 ng/mL or less returned completed questionnaires. Of these, in 20% their anxiety moderately deteriorated and in 20% their HRQOL minimally deteriorated during the screening process. Factors associated with HRQOL deterioration included age between 50 and 60 years, having more than two relatives with prostate cancer, an anxious personality, a high level of education, and having no children presently living at home. CONCLUSIONS: Screening with normal PSA results is accompanied by a minimally to moderate deterioration of HRQOL in some subjects. The identification of such individuals before screening provides opportunities to improve their HRQOL during the screening process.

Adult↗