Isolated continent cystostomy on neurologic native bladder: Functional results.

INTRODUCTION: Continent cutaneous urinary diversion (CCUD) is proposed to patients suffering from chronic neurologic retention and undergoing intermittent self-catheterization (ISC). In case of neurogenic detrusor overactivity (NDO), augmentation enterocystoplasty is often required. The aim was to identify the prevalence of urinary stomal and/or urethral leakage in patients who had not undergone enlargement. METHODS: Monocentric, retrospective study of patients who underwent CCUD surgery in a neuro-urological context. Mitrofanoff's, Monti's or Casale's channels were performed. Patients selected had an underactive, stable, or stabilized bladder under adjuvant therapy with proper cystomanometric capacity. Prior or concomitant enterocystoplasty were excluded. Failure was defined as the occurrence of clinical leakage whatever it is through urinary stomal, or urethral. Urodynamic parameters were also reported. RESULTS: Thirty-one patients underwent surgery. Nine women had a concomitant bladder neck sling and 1 urethral closure. The mean follow-up was 7 years. 8/31 (26%) had stomal leakage and 9 urethral leakage (29%). Five spinal cord injured patients (n=14) had stomal leakage (36%) and 6 urethral leakage (43%). Of the 25 postoperative urodynamic parameters, cystomanometric bladder capacity was 419mL (vs. 514mL) and 2 additional patients had de novo NDO (9 vs. 7). DISCUSSION: The morbidity of augmentation enterocystoplasty is weighed against the presence of a well-controlled bladder preoperatively. Our study shows the appearance of leakage in some patients despite a well-balanced bladder, a decrease in mean cystomanometric capacity and an increase in the rate of NDO postoperatively. Good selection criteria for an isolated CCUD should be carefully revised and defined. LEVEL OF EVIDENCE: Grade C - retrospective study.

Educational program in onco-urology for young urologists: What are their needs?

PURPOSE: The emergence of new communication media such as digital contents are progressively replacing more traditional medias in the field of educational programs. Our purpose was to assess urologist in training aspirations regarding urological education. METHODS: Members of a national urologist in training association were sent an anonymous online questionnaire regarding their medical formation in the field of urology. Responders interest for urological sub-specialty or education support (new tools and traditional support) were evaluated through a 5-point Likert scale. RESULTS: Overall, 109 young urologists (26%) responded to the survey. Most of the respondents worked during their training in an academic hospital (n=89, 82%). The three favorite tools for training chosen by the responders were: videos, workshop or masterclass, and podcasts (responders very interested were respectively n=64 (58.7%), n=50 (45.9%), and n=49 (45%)). E-mail newsletters were reported as the less useful educational tool by participants (n=38, 34.9%). Participants were very interested in improving their surgical skills and their radiological knowledge. Responders who were the most attracted by PCa were much more looking to improve their systemic treatment and radiological knowledges. CONCLUSIONS: Urologic-oncology was a priority regarding education for urologists in training. A majority of participants expressed a lack in their surgical education, revealing a reduced OR access and underlining utilization of new tools such as simulation. New digital contents such as social media or podcast achieved high interest for the participants, instead of more traditional media. There is a need that educational content evolve and uses new digital media. LEVEL OF EVIDENCE: 3.

Residents and patients benefit from surgical simulation on a live porcine model, could we consider it as ethical?

INTRODUCTION: The objective was to evaluate, by self-questionnaire, the feeling of participants in surgical training sessions on a live porcine model. METHODS: A computerized questionnaire (GoogleForm ©) was sent to the members of the French Association of Urologists-in-Training (AFUF) (fellows and residents). Only questionnaires from Urologists-in-training who had participated in surgical training sessions were included. The sessions consisted of performing surgeries such as laparoscopic nephrectomies or laparoscopic cystectomies. RESULTS: Overall, 198 met the inclusion criteria. A total of 36.4% (72/198) of the participants were fellows and 63.6% (126/198) were residents. According to the participants, the main interest of sessions was to be able to train for emergency situations. A total of 79.8% (158/198) of the participants wanted surgical simulation to become compulsory. To their opinion, the main advantage of surgical simulation on a live porcine model was: technical progress in 87.4% (173/198) of cases. A total of 13.1% (26/198) of the participants found it was unethical to perform the first technical procedures on live animal models. A total of 65.7% (130/198) of the participants considered that there is currently no system of substitution. CONCLUSION: For the participants, surgical training on a live porcine model allows technical progress while training for serious emergency situations. Surgeons and patients could benefit from this risk-free mock surgical scenario. LEVEL OF EVIDENCE: 3.

[Venous thromboembolism and urological cancer: Epidemiology and therapeutically management]. / Maladie thromboembolique veineuse et cancers urologiques : épidémiologie et prise en charge thérapeutique.

INTRODUCTION: Active cancer is a risk factor in the occurrence of venous thromboembolism (VTE). This is the second cause of death for these patients. In onco-urology, some cancers are associated with an increased risk of VTE. The aim of this study was to propose a focus of epidemiology and VTE therapy management. MATERIAL AND METHODS: A systematic analysis of the PubMed® database was performed through the PRISMA methodology using the followings keywords : "neoplasm", "venous thromboembolism", "prophylaxis", "pulmonary embolism", "urology". The original papers were included with a priority on: meta-analyzes, literature reviews, randomized controlled trials and good-level proof cohort studies. Only publications in English or French have been selected. RESULTS: The incidence of VTE was more important in case of renal carcinomas (3.5%/year). When surgery was proposed cystectomy was the riskiest procedure (2.6 to 11.6% VTE). Chemotherapy alone was an important risk factor increasing by a factor of six the occurrence of VTE. Hormonotherapy also increased this risk by induced hypogonadism. The curative treatment for VTE associated with cancers has to be performed through the injection of low molecular weight heparin. The implantation of a prophylactic treatment was not systematic among patients diagnosed with urological cancer. CONCLUSION: The understanding of mechanisms associated with the occurrence of VTE among these patients has enabled to improve patient management, especially those suffering from urological cancer. Undeniably, frequency of VTE is probably underestimated by urologists during clinical practice.

Towards (99m)Tc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study.

Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = (99m)Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the (99m)Tc compounds are prospective imaging agents.

Generation of coherent 19- and 38-nm radiation at a free-electron laser directly seeded at 38 nm.

Initiating the gain process in a free-electron laser (FEL) from an external highly coherent source of radiation is a promising way to improve the pulse properties such as temporal coherence and synchronization performance in time-resolved pump-probe experiments at FEL facilities, but this so-called "seeding" suffers from the lack of adequate sources at short wavelengths. We report on the first successful seeding at a wavelength as short as 38.2 nm, resulting in GW-level, coherent FEL radiation pulses at this wavelength as well as significant second harmonic emission at 19.1 nm. The external seed pulses are about 1 order of magnitude shorter compared to previous experiments allowing an ultimate time resolution for the investigation of dynamic processes enabling breakthroughs in ultrafast science with FELs. The seeding pulse is the 21st harmonic of an 800-nm, 15-fs (rms) laser pulse generated in an argon medium. Methods for finding the overlap of seed pulses with electron bunches in spatial, longitudinal, and spectral dimensions are discussed and results are presented. The experiment was conducted at FLASH, the FEL user facility at DESY in Hamburg, Germany.

Circadian variation of rectal sensitivity and gastrointestinal peptides in healthy volunteers.

The aim of our study was to identify diurnal variation of perception of rectal distension and the release of gastroenteropancreatic hormones. In 12 healthy male volunteers (25 years, range 22-32), a rectal balloon distension was performed. Rectal perception thresholds (minimal, urge and pain) and rectal compliance were double-measured with a computer-controlled barostat at seven standardized time points during the day (from 16.00 to 14.00 hours the following day). Blood samples were taken 30 min before and after each rectal distension procedure to determine plasma levels of cholecystokinin (CCK), pancreatic polypeptide (PP) and motilin. Sensory thresholds for urge and pain varied significantly with the time of day, with higher threshold levels in the evening than in the morning hours. Bowel wall compliance showed as well-significant variance at pain threshold and was higher during daytime than in the evening or at night. In contrast to motilin, release of CCK and PP also showed a significant variation depending on daytime. Perception of rectal distension stimuli as well as compliance was independent of intake of food and peptide hormone levels, but CCK and PP levels increased with food, and PP levels decreased with rectal distension. Significant differences in the perception of rectal distension stimuli for urge and pain depending on daytime were found, but the release of gastrointestinal peptides seemed not to be involved. This circadian variation needs to be taken into account in patients and volunteer studies.

Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples.

The purpose of this study was to analyze the drug interactions of paclitaxel (PTX) with epirubicin (EPI), carboplatin (CBDCA), gemcitabine (GEM) and vinorelbine (VIN) in human breast cancer cells and compare the cytotoxic activity of each drug combination in primary breast cancer samples. These experiments were intended to identify the most active agents in combination with PTX, and to provide a preclinical rational for future clinical investigations in breast cancer. Multiple drug effect/combination index (CI) isobologram analysis was applied to combinations of PTX with either CBDCA, EPI, GEM or VIN in MCF-7, MDA-MB-231 and SK-BR-3 human breast cancer cell lines. Drug concentrations were limited to the ranges achievable in humans in vivo, and the drugs were applied simultaneously at fixed molar ratios for each drug combination. Interactions were assessed at multiple effect levels (IC10-IC90). Additionally, the cytotoxic activity of these combinations was assessed in tumor samples of 50 primary breast cancer patients, utilizing the ATP-tumorchemosensitivity assay (ATP-TCA). Drug interactions were shown to be strongly dose-related in the human breast cancer cell lines investigated. At clinically relevant concentrations, CBDCA/PTX demonstrated synergistic (MCF-7) or additive (MDA-MB-231, SK-BR-3) interactions, and EPI/PTX showed additive (SK-BR-3, MCF-7) and antagonistic (MDA-MB-231) interactions. GEM/PTX and VIN/PTX, however, demonstrated antagonism over multiple dose effect levels at clinically relevant drug concentrations in all three cell lines tested. At plasma peak concentrations, EPI/PTX, CBDCA/PTX, GEM/PTX and VIN/PTX achieved > or = 90% tumor growth inhibition in 93, 86, 63 and 50%, respectively, of primary breast cancer samples investigated with the ATP-TCA. Cumulative dose-response plots of primary breast cancer tumor cells responding in vitro with > or = 90% growth inhibition showed a strong dose dependence for both EPI/PTX and CBDCA/PTX. In conclusion, the current data indicate favorable drug interactions for CBDCA/PTX at clinically relevant drug concentrations in breast cancer cells, and demonstrate superior in vitro cytotoxicity of EPI/PTX and CBDCA/PTX compared to GEM/PTX and VIN/PTX in primary breast cancer cultures.

Her-2/neu and urokinase-type plasminogen activator and its inhibitor in breast cancer.

PURPOSE: Recent studies suggest that HER-2/neu specifically promotes the invasive capacity of tumor cells by up-regulating secretion of the proteolytic enzyme, urokinase-type plasminogen activator (uPA), or its inhibitor, plasminogen activator inhibitor-1 (PAI-1), in colon and gastric cancer. It was the purpose of this study to: (a) evaluate the association between HER-2/neu and uPA and PAI-1 expression in a large primary breast cancer cohort; (b) perform the first multivariate analysis, including HER-2/neu, uPA, and PAI-1 in breast cancer; and (c) define the effect of HER-2/neu overexpression on uPA and PAI-1 expression in breast cancer cells. EXPERIMENTAL DESIGN: HER-2/neu, uPA, and PAI-1 were measured as continuous variables by ELISA in primary breast cancer tissue extracts from 587 patients with clinical follow-up and analyzed for correlations with clinical outcome. Furthermore, a full-length human HER-2/neu cDNA was introduced into five human breast cancer cell lines to define the effects of HER-2/neu overexpression on uPA and PAI-1 expression. In addition, we tested whether HER-2/neu antibodies could reverse any given alteration of uPA and PAI-1 levels. RESULTS: Our findings indicate a weak positive association between HER-2/neu and uPA (r = 0.147; P < 0.001) and no association between HER-2/neu and PAI-1 (r = 0.07; P = 0.085). HER-2/neu overexpression (> or =400 fmol/mg) and high levels of uPA/PAI-1 (> or =5.5 ng/mg and/or > or =14 ng/mg, respectively) were significantly associated with shorter disease-free survival (DFS; P < 0.001 and P = 0.003) and metastasis-free survival (MFS; P = 0.015 and P < 0.001). Multivariate analysis revealed prognostic independence between HER-2/neu and the uPA/PAI-1 axis for DFS and MFS. Both uPA and PAI-1 had no significant discriminatory effect among HER-2/neu-positive patients for DFS. The prognostic value of HER-2/neu overexpression for MFS, however, was significantly enhanced by elevated uPA expression (P = 0.053). Stable transfection of the HER-2/neu gene into multiple human breast cancer cell lines resulted in consistent down-regulation of uPA or PAI-1 expression. In addition, anti-HER-2/neu antibodies did not significantly affect uPA or PAI-1 expression in human cancer cell lines naturally overexpressing HER-2/neu. CONCLUSIONS: The present findings suggest that the invasive phenotype elicited by HER-2/neu overexpression in breast cancer is not a direct effect of uPA or PAI-1 expression. HER-2/neu and the uPA/PAI-1 axis have been shown to affect the invasive capacity of breast cancer independently. Determination of uPA can provide significant additional prognostic information for MFS in HER-2/neu-positive and -negative patients.

HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer.

Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25-200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC90) at significantly lower PPC values, using the CB11 (p = 0.048), TAB250 (p = 0.007) and AO485 (p < or =0.01) antibodies, and showed 50% growth inhibition (IC50) at significantly lower PPC values, using the CB11 antibody (p = 0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p = 0.044) and AO485 (p = 0.032) antibodies, but not with the CB11 antibody (p =0.8) at the IC90 level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.

Correlation of drug response with the ATP tumorchemosensitivity assay in primary FIGO stage III ovarian cancer.

OBJECTIVE: Our purpose was to: (a) study the in vitro chemosensitivity of primary epithelial ovarian cancer to drug combinations with cisplatin (CDDP), carboplatin (CBDCA), paclitaxel (PTX), epirubicin (EPI), or cyclophosphamide (CTX) utilizing the ATP tumorchemosensitivity assay (ATP-TCA); (b) correlate the test results with clinical response in patients with FIGO stage III ovarian cancer; and (c) analyze the most useful parameters for interpretation of test results. METHODS: CBDCA/CTX, CBDCA/PTX, CDDP/PTX, and EPI/PTX were tested in 93 fresh human primary epithelial ovarian cancer specimens. Correlations of in vitro drug sensitivity/resistance and clinical response were performed in 38 patients with FIGO stage III disease utilizing Fisher's exact test and by comparison of progression-free (PFS) and overall survival (OS) between those testing as sensitive or resistant. A progression-free interval of more than 12 months following surgery was classified as clinical response. ATP-TCA results were analyzed using the median effective dose, area under the curve, or a defined sensitivity index. RESULTS: Evaluable test results were achieved in 83 of 93 patients (89%). EPI/PTX had the highest in vitro activity (P < 0.001). In the clinical correlation, 29 of 38 patients (76%) were classified as in vitro sensitive (sensitivity index [SI] <250) and 9 patients as in vitro resistant (SI >250). The SI was superior for interpretation of test results. Patients testing as chemosensitive had a significantly longer mean PFS (28.5 vs 12.6 months, P = 0.033) and OS (46.1 vs 17.6, P = 0.03) compared to those patients predicted to be resistant. The assay demonstrated a sensitivity, specificity, and positive and negative predictive value of 95, 44, 66, and 89%, respectively (Fisher's exact test, P = 0. 007). CONCLUSION: The observed in vitro efficacy of EPI/PTX in primary epithelial ovarian cancer specimens warrants further clinical evaluation. The high evaluability rate and the observed correlation with PFS and OS, within the limitations of a nonrandomized study, support the use of the ATP chemosensitivity assay in future prospective assay-directed trials.

Rare activation of ras oncogenes in radiation induced rat skin tumors.

We examined a large panel of radiation induced rat skin tumors for activation of the H- or K-ras oncogenes. Using oligonucleotide hybridization analysis of tumor DNA we found that only 1 out of 96 tumors tested had an activated K-ras gene, and none of the 78 tumors examined for H-ras mutations were positive. Tumors were induced by high and low LET, and included lesions of various sizes and histologic type. DNA sequencing of tumors and NIH3T3 transfectants from a previous study gave results consistent with a rare occurence of ras activation in this system.

DNA fingerprinting analysis of radiation-induced rat skin tumors.

DNA fingerprinting analysis was performed on rat skin tumors induced by high linear energy transfer neon ion radiation. Most of these tumors (13/15) showed DNA-fingerprint variability between independently isolated tumors from the same animal. These changes include multiple band shifts and extra bands. Comparisons of DNA fingerprints were also made on successive biopsy samples from the same tumor. Each of 3 neon-induced tumors and 2 of 8 electron (low LET) induced tumors showed progressive loss of amplified sequences, gain of amplified sequences, deletions, band shifts, and the appearance of extra bands in progressive biopsies. These results provide evidence for LET-specific effects on genomic instability in radiation-induced rat skin tumors.

[Spinal metastasis from ovarian granulosa cell tumor--after 23 years]. / Granulosasejtes ováriumtumor spinális metastasisa--23 év után.

On admission, the 63-year-old patient suffered from spinal chord compression at the level of D. IV. vertebra. 23 years earlier she had undergone a total uterus exstirpation for ovarian tumor, with bilateral adnexectomy. The microcellular granular cell tumor potentially regarded as malignant, gave a spinal metastasis after 23 years of "dormancy". Half a year after the second spinal surgery, the growth again reached compression-size, requiring reoperation. On discussing the case, the authors also deal with the clinical signs of ovarian tumors as well as their prognosis and treatment modalities.

Amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of linear energy transfer and dose.

The c-myc oncogene was previously shown to be amplified in large, later-stage carcinomas of the rat skin induced by 0.8-MeV electrons. In a panel of 70 tumors induced by neon ions (45 keV/microns), c-myc amplification was rare, and in contrast to the data for tumors induced by low-linear-energy transfer (LET) (0.3 keV/microns) radiation, showed no correlation with tumor size, growth period, or time, but was associated with radiation dose. The tissue specificity for c-myc amplification seen in tumors induced by electrons was not seen in tumors induced by neon ions. These results suggest that quite distinct molecular mechanisms operate even in late stages of carcinogenesis that depend on the LET of the inducing radiation. Furthermore, the results suggest that c-myc amplification observed in tumors induced by low-LET radiation is not a general property of rat skin carcinomas, but is linked mechanistically to the inducing radiation, even though it is not detectable until many months after exposure and tumor appearance.

Amplification of the c-myc oncogene during progression of radiation-induced rat skin tumors.

Evaluation of a large panel of radiation-induced rat skin tumors of diverse size and histological type revealed a correlation between c-myc copy number and tumor size. Both the frequency and degree of c-myc gene amplification were increased in large compared to small carcinomas, but none of the sarcomas examined showed c-myc amplification. Serial biopsies of individual tumors exhibited similar trends of increasing c-myc copy number in later biopsies. In one regressing tumor, the c-myc gene copy number paralleled the growth rate of the tumor during growth and regression. The average time required from tumor appearance to significant gene amplification was close to the average period between tumor appearance and the onset of rapid growth. The data suggest that, rather than being a target gene for the direct early effects of ionizing radiation, c-myc functions as a late-stage progression-related oncogene in this model system.

Detection of novel non-ras oncogenes in rat nasal squamous cell carcinomas.

Rat nasal squamous cell carcinomas induced by inhalation of three direct-acting alkylating agents yielded DNA containing activated oncogenes with no homology to any member of the ras family. The novel NIH 3T3 transforming oncogenes from tumors induced by beta-propiolactone and methylmethane sulfonate are distinct from each other based on restriction analysis. The gene isolated from beta-propiolactone-induced tumors is between 6 and 9 kb in size. None of the tumors induced by dimethylcarbamyl chloride contained positive DNA in the NIH 3T3 focus assay or in the nude mouse cotransfection assay. The rat nasal tumor model is apparently ideally suited for analysis of the roles of carcinogen and tissue specificity in oncogene activation, especially related to novel (non-ras) transforming oncogenes.