[Cancers of the external genital organs of male in Hérault: Results from the Hérault tumor register (RTH) over a period of 30 years (1987-2016)]. / Le cancer des organes génitaux externes de l'homme dans le département de l'Hérault: résultats de 30 ans d'enregistrement du registre des tumeurs de l'Hérault (1987­2016).

AIM: The objective of this study is to present the history of cancers of the external genital organs of male in Hérault using data from the Hérault tumor register (RTH) over a period of 30 years. PATIENTS AND METHODS: Using the RTH database, we studied the development of testicular germ cell tumors (TGCT) and penile cancer (PC) over 30 years, from 1987 to 2016. We analyzed the incidence and mortality data for these tumors. We compared these results to French, European and global data. RESULTS: In 30 years of registration we have recorded 725 cases of TGCT and 175 cases of PC. The age standardized incidence rate (ASR) of TGCT has doubled between 1987 and 2016 (4.2 per 100,000 in 1987 and 9.3 per 100,000 in 2016). It was multiplied by 2.63 in the population of patients aged 30 to 44. There is a decrease of the mortality rate with a ASR of 0.8 deaths per 100,000 in 1987, and 0.4/100 000 in 2016. The PC incidence ASR was stable between 1987 and 2016 (0.4-0.9/100,000). Mortality is stable with a ASR between 0.1 and 0.3 deaths per 100,000 between 1987 and 2016. CONCLUSION: The incidence of TGCT has increased sharply in the Hérault over the past 30 years, while a decrease in mortality has been observed. The proportion of seminomas is increasing; it has gone from 53 % to 60 % in 30 years in the Hérault. The incidence and mortality of PC shows a stability in the Hérault over the past 30 years.

[RHESOU (Registry in HErault Specialized in Onco-Urology) : the first French Registry specialized in Onco-Urology. One-year experience]. / RHESOU (Registre de l'Hérault spécialisé en onco-urologie) : le premier registre français spécialisé en onco-urologie. Un outil méthodologique de recueil de données en onco-urologie. Bilan de faisabilité sur un an d'expérience.

PURPOSE: In 2016, the Herault tumor registry collected 1961cancers in urology (21.4 % from all Herault cancers this year). RHESOU was created to complete RTH' data with specific parameters in onco-urology. The aim of this study is to describe RHESOU and to give some examples with our first results. MATERIAL AND METHODS: In November 2018, RHESOU (Registry HErault Specialised in Onco-Urology) was founded with the same registry recommendations. It collects specific oncologic parameters and also complete RTH's data. For each urological cancer, a specific survey with different choices was performed to collect a maximum of data which could be present in patients' file. These surveys were used for urological cancers cases that live in Herault in 2017. RESULTS: In 2017, we collected 970 prostate cancers, 581 bladder cancers, 212 kidney cancers, 51 upper excretory tract cancers, 28 testicle cancers and 9 penil cancers. Our urological data collection gives many possibilities to create many requests for detailed analysis in urological cancers. In this article, we reported data from kidney, bladder and prostate cancers. CONCLUSIONS: RHESOU is a new tool opened to the different urologic corporations (urologists, pathologists, oncologists, radiotherapists, radiologists) that permits an overview in urological cancers in Herault. Finally, one important aim is that this tool will be adapted when new treatments or new important parameters appear in the years ahead. LEVEL OF EVIDENCE: 3.

[Results of surgical revisions for ureteral complications after renal transplantation]. / Résultats des reprises chirurgicales pour complications urétérales après transplantation rénale.

OBJECTIVE: To analyze the results of surgical revision for ureteral complication (ureteric stenosis or urinary leakage) after renal transplantation over a period of 10 years. MATERIALS AND METHODS: We performed a retrospective study on 1313 consecutive kidney transplantations carried out in a University Hospital Center between 2005 and 2014. The data of the patients who developed a ureteral stenosis or a urinary leakage secondary to a renal transplantation were analyzed. Combined organ transplantations (kidney-liver and kidney-pancreas), as well as pediatric transplantations were excluded. RESULTS: Seventy-six patients (5.8%) had ureteric stenosis or urinary leakage after renal transplantation. Forty-six patients (3.5%) underwent surgical revision: 27 for ureteral stenosis, 19 for urinary leakage. Early success was achieved in 26 patients (56.5%), including 14 ureteric stenosis (51.9%) and 12 urinary leakage (63.2%) (P=0.45). After a complementary endoscopic or surgical treatment, the final success rate was increased to 73.1% (34 patients): 20 ureteric stenosis (74.1%) and 14 urinary leakage (73.7%) (P=0.98). There were 2 graft losses (4.3%) and one death (2.2%). The mean glomerular filtration rate estimated by the MDRD was 44.58mL/min/1.73m2 (±14.7) before surgery and 45.37mL/min/1.73m2 (±16.5) 6 months after surgery (P=0.92). CONCLUSION: Although frequently challenging, surgical revisions for ureteral complications after renal transplantation give good results, with a low rate of graft loss and mortality. LEVEL OF EVIDENCE: 4.

Overall survival and oncological outcomes after partial nephrectomy and radical nephrectomy for cT2a renal tumors: A collaborative international study from the French kidney cancer research network UroCCR.

BACKGROUND: Partial nephrectomy (PN) is recommended as first-line treatment for cT1 stage kidney tumors because of a better renal function and probably a better overall survival than radical nephrectomy (RN). For larger tumors, PN has a controversial position due to lack of evidence showing good cancer control. The aim of this study was to compare the results of PN and RN in cT2a stage on overall survival and oncological results. METHOD: A retrospective international multicenter study was conducted in the frame of the French kidney cancer research network (UroCCR). We considered all patients aged≥18 years who underwent surgical treatment for localized renal cell carcinoma (RCC) stage cT2a (7.1-10cm) between 2000 and 2014. Cox and Fine-Gray models were performed to analyze overall survival (OS), cancer specific survival (CSS) and cancer-free survival (CFS). Comparison between PN and RN was realized after an adjustment by propensity score considering predefined confounding factors: age, sex, tumor size, pT stage of the TNM classification, histological type, ISUP grade, ASA score. RESULTS: A total of 267 patients were included. OS at 3 and 5 years was 93.6% and 78.7% after PN and 88.0% and 76.2% after RN, respectively. CSS at 3 and 5 years was 95.4% and 80.2% after PN and 91.0% and 85.0% after RN. No significant difference between groups was found after propensity score adjustment for OS (HR 0.87, 95% CI: 0.37-2.05, P=0.75), CSS (HR 0.52, 95% CI: 0.18-1.54, P=0.24) and CFS (HR 1.02, 95% CI: 0.50-2.09, P=0.96). CONCLUSION: PN seems equivalent to RN for OS, CSS and CFS in cT2a stage kidney tumors. The risk of recurrence is probably more related to prognostic factors than the surgical technique. The decision to perform a PN should depend on technical feasibility rather than tumor size, both to imperative and elective situation. LEVEL OF EVIDENCE: 4.

The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment.

BACKGROUND: Human Leucocyte Antigen- E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to the presence of intratumoural natural killer (NK) cells and cytotoxic T cells (CTLs). METHODS: Tissue microarrays (TMAs) of endometrial tumours were used for immunohistochemical staining of parameters of interest. The combined impact of clinical, pathological and immune parameters on survival was analysed using log rank testing and Cox regression analyses. RESULTS: Upregulation of HLA-E was associated with an improved disease-free and disease-specific survival in univariate analysis (HR 0.58 95% CI 0.37-0.89; HR 0.42 95% CI 0.25-0.73, respectively). In multivariate analysis, the presence of NK cells predicts survival with a hazard ratio (HR) 0.28 (95% confidence interval (CI) 0.09-0.91) when HLA-E expression is upregulated; but it is associated with a worse prognosis when HLA-E expression is normal (HR 13.43, 95% CI 1.70-106.14). By contrast, the prognostic benefit of T cells was not modulated by HLA-E expression. CONCLUSIONS: Taken together, we demonstrate that the prognostic benefit of NK cells, but not T-cells, is influenced by HLA-E expression in endometrial cancer (EC) and propose a model to explain our observations.

Influence of dissolved gases on sonochemistry and sonoluminescence in a flow reactor.

In the present work, the influence of gas addition is investigated on both sonoluminescence (SL) and radical formation at 47 and 248 kHz. The frequencies chosen in this study generate two distinct bubble types, allowing to generalize the conclusions for other ultrasonic reactors. In this case, 47 kHz provides transient bubbles, while stable ones dominate at 248 kHz. For both bubble types, the hydroxyl radical and SL yield under gas addition followed the sequence: Ar>Air>N2>>CO2. A comprehensive interpretation is given for these results, based on a combination of thermal gas properties, chemical reactions occurring within the cavitation bubble, and the amount of bubbles. Furthermore, in the cases where argon, air and nitrogen were bubbled, a reasonable correlation existed between the OH-radical yield and the SL signal, being most pronounced under stable cavitation at 248 kHz. Presuming that SL and OH originate from different bubble populations, the results indicate that both populations respond similarly to a change in acoustic power and dissolved gas. Consequently, in the presence of non-volatile pollutants that do not quench SL, sonoluminescence can be used as an online tool to qualitatively monitor radical formation.

Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor.

We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.

Is it possible to improve the breaking bad news skills of residents when a relative is present? A randomised study.

BACKGROUND: Although patients with cancer are often accompanied by a relative during breaking bad news (BBN) consultations, little is known regarding the efficacy of training programmes designed to teach residents the communication skills needed to break bad news in a triadic consultation. METHODS: Residents were randomly assigned to a 40-h dyadic and triadic communication skills training programme (n=48) or a waiting list (n=47). A simulated BBN triadic consultation was audiotaped at baseline, and after training for the training group, and 8 months after baseline for the waiting list group. Transcripts were analysed using content analysis software (LaComm). A coder determined the moment of bad news delivery and the relative's first turn of speech regarding the bad news. A generalised estimating equation was used to evaluate residents' communication skills, BBN timing, and the relative's inclusion in the consultation. RESULTS: Ninety-five residents were included. After training, the duration of the pre-delivery phase was found to be longer for the trained residents (relative risk (RR)=3.04; P<0.001). The simulated relative's first turn of speech about the bad news came more often during the pre-delivery phase (RR=6.68; P=0.008), and was more often initiated by the trained residents (RR=19.17; P<0.001). Trained residents also used more assessment (RR=1.83; P<0.001) and supportive utterances (RR=1.58; P<0.001). CONCLUSION: This study demonstrates that a training programme that focuses on the practice of dyadic and triadic communication skills can improve the communication skills of the participating residents in a BBN triadic consultation. Such a training should be included in resident curriculum.

Is it possible to improve residents breaking bad news skills? A randomised study assessing the efficacy of a communication skills training program.

BACKGROUND: This study aims to assess the efficacy of a 40-h training programme designed to teach residents the communication skills needed to break the bad news. METHODS: Residents were randomly assigned to the training programme or to a waiting list. A simulated patient breaking bad news (BBN) consultation was audiotaped at baseline and after training in the training group and 8 months after baseline in the waiting-list group. Transcripts were analysed by tagging the used communication skills with a content analysis software (LaComm) and by tagging the phases of bad news delivery: pre-delivery, delivery and post-delivery. Training effects were tested with generalised estimating equation (GEE) and multivariate analysis of variance (MANOVA). RESULTS: The trained residents (n=50) used effective communication skills more often than the untrained residents (n=48): more open questions (relative rate (RR)=5.79; P<0.001), open directive questions (RR=1.71; P=0.003) and empathy (RR=4.50; P=0.017) and less information transmission (RR=0.72; P=0.001). The pre-delivery phase was longer for the trained (1 min 53 s at baseline and 3 min 55 s after training) compared with the untrained residents (2 min 7 s at baseline and 1 min 46 s at second assessment time; P<0.001). CONCLUSION: This study shows the efficacy of training programme designed to improve residents' BBN skills. The way residents break bad news may thus be improved.

Effect of various additives and polymers on lysozyme release from PLGA microspheres prepared by an s/o/w emulsion technique.

Incomplete protein release from PLGA-based microspheres due to protein interactions with the polymer is one of the main issues in the development of PLGA protein-loaded microspheres. In this study, a two-dimensional adsorption model was designed to rapidly assess the anti-adsorption effect of formulation components (additives, additives blended with the polymer or modified polymers). Lysozyme was chosen as a model protein because of its strong, non-specific adsorption on the PLGA surface. This study showed that PEGs, poloxamer 188 and BSA totally inhibited protein adsorption onto the PLGA37.5/25 layer. Similarly, it was emphasised that more hydrophilic polymers were less prone to protein adsorption. The correlation between this model and the in vitro release profile was made by microencapsulating lysozyme with a low loading in the presence of these excipients by a non-denaturing s/o/w encapsulation technique. The precipitation of lysozyme with the amphiphilic poloxamer 188 prior to encapsulation exhibited continuous release of active lysozyme over 3 weeks without any burst effect. To promote lysozyme release in the latter stage of release, a PLGA-PEG-PLGA tribloc copolymer was used; lysozyme was continuously released over 45 days in a biologically active form.

[Current indications and ongoing clinical trials with CyberKnife stereotactic radiotherapy in France in 2009]. / Indications du CyberKnife et essais cliniques en cours en 2009.

Image-guided frameless fractionated stereotactic radiotherapy can be performed with millimetric accuracy using the CyberKnife (Accuray Inc. Sunnyvale, USA) equipped with an integrated tracking system for intra- and extracranial lesions. Highly conformal hypofractionated irradiation has been used to treat lesions with curative or palliative intent. It is advantageous for radioresistant tumors, re-irradiating lesions, boosting small volumes and treating tumors that move with respiration. It also limits travel costs and improves the quality of life. Over 60,000 patients have been treated worldwide using CyberKnife including 600 patients in the three French cancer centres of Nice, Nancy and Lille. These expert Cyberknife centres follow quality assurance programs and work together with the "Haute Autorité de santé" and the French National Cancer Institute (INCa) to promote clinical developments. The CyberKnife has been used to treat intracranial lesions including (but not limited to) meningiomas, acoustic schwannomas, brain oligometastases, as well as skull base tumors like chordomas, or para- or intraspinal tumors, and extracranial tumors such as lung cancers. Currently, extracranial stereotactic radiotherapy is particularly attractive for tumors moving with respiration and is being evaluated in liver, prostate and re-irradiation including head and neck tumors.

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab.

Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody whose activity is related to the inhibition of EGFR downstream signaling pathways. P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been reported to control the functionality of PI3K/AKT signaling. In this study we evaluated whether reintroducing P53 using non-viral gene transfer enhances PTEN-mediated inhibition of PI3K/AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations. Signaling phosphoproteins expression was analyzed using Bio-Plex phosphoprotein array and western blot. Apoptosis induction was evaluated from BAX expression, caspase-3 activation and DNA fragmentation analyses. The results presented show that p53 and pten gene transfer additionally mediated cell growth inhibition and apoptosis induction by restoral of signaling functionality, which enabled the control of PI3K/AKT and MAPKinase signaling pathways by cetuximab in PC3 cells. These results highlight the interest of the analysis of signaling phosphoproteins expression as molecular predictive markers for response to cetuximab and show that p53 and pten mutations could be key determinants of cell response to cetuximab through the functional impact of these mutations on cell signaling.

Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells.

The present study investigates the relationship between the subcellular localisation of Foscan and intrinsic apoptotic pathway post Foscan-based photodynamic therapy (PDT). With this purpose, mammary carcinoma MCF-7 cells were incubated with Foscan for 3 or 24 h and then subjected to equitoxic light doses. Fluorescence microscopy revealed very good Foscan co-localization to endoplasmic reticulum (ER) and Golgi apparatus after 3 h incubation with MCF-7 cells. Progressive increase in incubation time shows leakage of Foscan from Golgi apparatus. Twenty-four hours incubation yielded a fluence-dependent enhanced induction of the ER-resident glucose-regulated protein 78 (Bip/GRP78), along with a weak mitochondrial damage, thus underscoring the ER as the main site of photodamage after prolonged incubation. Analysis of events implicated in apoptotic pathway after 24 h incubation demonstrated photodamage to Bcl-2 protein in total cellular extract, but not in the mitochondrial fraction. We further determined an increase in caspases-7 and -6 activation, which was strongly related to the expression of GRP78. The above findings demonstrate that Foscan localisation in ER improves the photoactivation of the caspase-7 apoptotic pathway, which is poorly related to mitochondrial damage.

Factors that influence cancer patients' anxiety following a medical consultation: impact of a communication skills training programme for physicians.

BACKGROUND: No study has yet assessed the impact of physicians' skills acquisition after a communication skills training programme on the evolution of patients' anxiety following a medical consultation. This study aimed to compare the impact, on patients' anxiety, of a basic communication skills training programme (BT) and the same programme consolidated by consolidation workshops (CW), and to investigate physicians' communication variables associated with patients' anxiety. PATIENTS AND METHODS: Physicians, after attending the BT, were randomly assigned to CW or to a waiting list. The control group was not a non-intervention group. Consultations with a cancer patient were recorded. Patients' anxiety was assessed with the State Trait Anxiety Inventory before and after a consultation. Communication skills were analysed according to the Cancer Research Campaign Workshop Evaluation Manual. RESULTS: No statistically significant change over time and between groups was observed. Mixed-effects modelling showed that a decrease in patients' anxiety was linked with screening questions (P = 0.045), physicians' satisfaction about support given (P = 0.004) and with patients' distress (P < 0.001). An increase in anxiety was linked with breaking bad news (P = 0.050) and with supportive skills (P = 0.013). No impact of the training programme was observed. CONCLUSIONS: This study shows the influence of some communication skills on the evolution of patients' anxiety. Physicians should be aware of these influences.

The powerful high pressure tool for protein conformational studies.

The pressure behavior of proteins may be summarized as a the pressure-induced disordering of their structures. This thermodynamic parameter has effects on proteins that are similar but not identical to those induced by temperature, the other thermodynamic parameter. Of particular importance are the intermolecular interactions that follow partial protein unfolding and that give rise to the formation of fibrils. Because some proteins do not form fibrils under pressure, these observations can be related to the shape of the stability diagram. Weak interactions which are differently affected by hydrostatic pressure or temperature play a determinant role in protein stability. Pressure acts on the 2 degrees, 3 degrees and 4 degrees structures of proteins which are maintained by electrostatic and hydrophobic interactions and by hydrogen bonds. We present some typical examples of how pressure affects the tertiary structure of proteins (the case of prion proteins), induces unfolding (ataxin), is a convenient tool to study enzyme dissociation (enolase), and provides arguments to understand the role of the partial volume of an enzyme (butyrylcholinesterase). This approach may have important implications for the understanding of the basic mechanism of protein diseases and for the development of preventive and therapeutic measures.

The powerful high pressure tool for protein conformational studies

The pressure behavior of proteins may be summarized as a the pressure-induced disordering of their structures. This thermodynamic parameter has effects on proteins that are similar but not identical to those induced by temperature, the other thermodynamic parameter. Of particular importance are the intermolecular interactions that follow partial protein unfolding and that give rise to the formation of fibrils. Because some proteins do not form fibrils under pressure, these observations can be related to the shape of the stability diagram. Weak interactions which are differently affected by hydrostatic pressure or temperature play a determinant role in protein stability. Pressure acts on the 2°, 3° and 4° structures of proteins which are maintained by electrostatic and hydrophobic interactions and by hydrogen bonds. We present some typical examples of how pressure affects the tertiary structure of proteins (the case of prion proteins), induces unfolding (ataxin), is a convenient tool to study enzyme dissociation (enolase), and provides arguments to understand the role of the partial volume of an enzyme (butyrylcholinesterase). This approach may have important implications for the understanding of the basic mechanism of protein diseases and for the development of preventive and therapeutic measures.

High pressure, an alternative approach to understand protein misfolding diseases.

Protein folding is essential for the flow of genetic information to biological activity. A failure in this process can result in disease, by causing cell damage and sometimes death. The misfolding of proteins often induces their aggregation, initiating the fibril formation seen in a range of human and animal diseases. Because misfolding and aggregation are of fundamental importance in vivo, there is currently great interest in understanding their mechanisms. To gain insight into the folding and unfolding processes of proteins, for nearly a century, an original biophysical approach has been successfully used: the application of high hydrostatic pressure combined with various spectroscopic and kinetic techniques. Because high pressure provides new insight into protein structure and folding which cannot be obtained by other techniques, the conformations of pressure-induced unfolding intermediates and species involved in the initial states of aggregation of proteins associated with specific diseases are currently being investigated. Our contention is that by exploring folding kinetics, misfolding pathways and stability under pressure, it will be possible to understand the mechanisms of amyloidogenesis, with the ultimate goal to design therapeutic strategies to prevent progression of the disease.

Characterization of a complex formed between human plasminogen and recombinant sheep prion: pressure and thermal sensitivity of complex formation.

Scrapie is thought to be caused by one or more conformations of a proteinacious particle called a prion. The infectious form(s) is referred to as the scrapie form of the prion protein (PrPsc) whereas a benign form, the cellular conformer, is referred to as PrPC. The cellular conformation of the sheep prion protein formed a 1:1 complex with human plasminogen. The complex precipitated at 0 degrees C (Ksp = 17* 10(-12) M2). This precipitation reaction was sensitive to both temperature and pressure. When subjected to hydrostatic pressure the precipitate dissolved. At 25 degrees C the complex was soluble with a dissociation constant of about 10(-7) M as determined by isothermal titration calorimetry. Absorption, fluorescence and circular dichroism spectroscopy showed that neither protein, in the complex, underwent a detectable structural change so long as proteolytic inhibitors were present. In the absence of proteolytic inhibitors, plasminogen slowly cleaved the prion protein.

Modality of cell death induced by Foscan-based photodynamic treatment in human colon adenocarcinoma cell line HT29.

Apoptosis induced by photodynamic therapy (PDT) is considered to be an important factor defining the treatment outcome. Nevertheless, the relevance of apoptotic events in overall cell death should be established for every given photosensitizer. The present study addresses the contribution of Foscan-(meta-tetra(hydroxyphenyl)chlorine; mTHPC) photosensitized apoptosis in overall cell death in a model of cultured HT29 adenocarcinoma cells. Early events of cell death were assessed by the evaluation of mitochondrial response to mTHPC-mediated PDT, cytochrome c release and membrane depolarization. Apoptosis was measured through the activity of caspase-3 and the binding of the fluorescent conjugate Ca2+-dependent protein Annexin-V on membrane externalized phosphatidylserine at 2, 4, and 24 h post-PDT. Immediately after mTHPC-PDT, from 28 to 57% cells exhibited cytochrome c release concomitantly with mitochondrial membrane depolarization for light doses inducing more than 90% overall cell death. The maximum of caspase-3 activation (12-fold more than control) was reached 24 h after irradiation at fluence inducing 90% cell death (LD(90)). The corresponding measurement of apoptotic cells (12% of Annexin-V bound cells) confirmed the mild and delayed apoptotic response of HT29 cells to mTHPC-PDT.