Miniaturized percutaneous nephrolithotomy versus retrograde intrarenal surgery in the treatment of lower pole renal stones.

OBJECTIVES: Miniaturization of percutaneous nephrolithotomy techniques have led to their increased consideration for lower pole renal stones that can prove more challenging to reach using retrograde intrarenal surgery. The objectives of the present study were to evaluate and compare the outcomes of miniaturized percutaneous nephrolithotomy (miniPCNL) and retrograde intrarenal surgery (RIRS) for the treatment of lower pole renal stones. MATERIALS AND METHODS: A retrospective study was performed in two academic urology departments between January 2016 and June 2019. Patients presenting with one or multiple stones of the lower calyx and/or renal pelvis, between 10 and 40mm based on CT-scan treated by miniPCNL or RIRS were included. RESULTS: In all, 115 miniPCNL and 118 RIRS procedures were included. The rate of patients with no significant residual fragment (stone free rate) after the first procedure was higher in the miniPCNL group (69% vs. 52% P=0.01), especially for stones>20mm (63% vs. 24% respectively, P<0.001) and stones with a density≥1000HU (69% vs. 42% respectively, P=0.009). The higher stone free rate of miniPCNL was confirmed in multivariate analysis, adjusting for stone size and number of stones, OR 4.02 (95% CI 2.08-8.11, P<0.0001). The overall postoperative complication rate was higher in the miniPCNL group than in the RIRS group (23% vs. 11%, P=0.01). A second intervention for the treatment of residual fragments was necessary for 9.6% of patients in the miniPCNL group versus 30.5% of patients in the RIRS group (P<0.001). Pre-stenting rate and duration of ureteral drainage (2 [1-8] vs. 25 days [7-37], P<0.001) were lower in the miniPCNL group. CONCLUSIONS: The stone free rate was higher after miniPCNL, especially for stones>20mm and with a density>1000 HU, but was associated with a higher risk of postoperative complications and a longer hospital stay. RIRS resulted in fewer complications at the cost of a higher retreatment rate and longer ureteral stenting. LEVEL OF EVIDENCE: 3.

The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches.

BACKGROUND: In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. MATERIALS AND METHODS: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. RESULTS: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). CONCLUSION: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy.

Evaluation of the immunogenicity and protective efficacy of a recombinant CS6-based ETEC vaccine in an Aotus nancymaae CS6 + ETEC challenge model.

Colonization factors or Coli surface antigens (CFs or CS) are important virulence factors of Enterotoxigenic E. coli (ETEC) that mediate intestinal colonization and accordingly are targets of vaccine development efforts. CS6 is a highly prevalent CF associated with symptomatic ETEC infection both in endemic populations and amongst travelers. In this study, we used an Aotus nancymaae non-human primate ETEC challenge model with a CS6 + ETEC strain, B7A, to test the immunogenicity and protective efficacy (PE) of a recombinant CS6-based subunit vaccine. Specifically, we determined the ability of dscCssBA, the donor strand complemented recombinant stabilized fusion of the two subunits of the CS6 fimbriae, CssA and CssB, to elicit protection against CS6 + ETEC mediated diarrhea when given intradermally (ID) with the genetically attenuated double mutant heat-labile enterotoxin LT(R192G/L211A) (dmLT). ID vaccination with dscCssBA + dmLT induced strong serum antibody responses against CS6 and LT. Importantly, vaccination with dscCssBA + dmLT resulted in no observed diarrheal disease (PE = 100%, p = 0.03) following B7A challenge as compared to PBS immunized animals, with an attack rate of 62.5%. These data demonstrate the potential role that CS6 may play in ETEC infection and that recombinant dscCssBA antigen can provide protection against challenge with the homologous CS6 + ETEC strain, B7A, in the Aotus nancymaae diarrheal challenge model. Combined, these data indicate that CS6, and more specifically, a recombinant engineered derivative should be considered for further clinical development.

αvß8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus.

Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGFß-activating integrin αvß8 by cDC1. In contrast, αvß8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.

[Long-term follow-up of continent cystostomy with the Mitrofanoff procedure: 5 years later]. / Évaluation à long terme des cystostomies continentes de type Mitrofanoff chez l'adulte : résultats à 5 ans.

INTRODUCTION: This study analyzed long-term functional outcome of continent catheterizable channels with the Mitrofanoff procedure, their continence, complications and the satisfaction of the patients. MATERIAL AND METHOD: Data from patients who underwent a Mitrofanoff procedure at our institution from June 1997 to March 2015 were retrospectively collected. All patients were contacted at the end of the study, a survey was submitted to them. RESULTS: Sixty-seven patients underwent a continent cystostomy with the Mirtrofanoff procedure. Forty-five patients had the inclusion criteria: 18 years old or older, no previous urinary diversion with a minimum of 6 months of follow-up. The cohort comprised mainly neurologic bladder (84 %) with spinal cord injuries (54 %) or spina-bifida patients (15 %). Median age was 35 years old [22-49]. Median follow-up was 64months [39-90]. The surgical procedure used an appendicular channel: 30 patients (67 %) or a continent ileal plasty: 15 patients (33 %). At the end of follow-up: 88 % patients have a full cystostomy continence, 89 % full uretral continence. Twenty-nine patients had one (41 %) or more reinterventions. Reasons for the 58 reinterventions were: stomal stenosis (31 %), uretral incontinence (29 %), cystostomy incontinence (15 %), lithiasis (9 %). Those reinterventions were done with a local surgery (31 %) or an endoscopic surgery (35 %). Overall early adverse events (<30days) or delayed (>30days) adverse events were similar (P=0.93) in appendicovesicostomy group or continent ileal plasty group. Ninety-four percent patients described a satisfactory urinary comfort. The cystostomy was considered esthetic by 71 %, its realization allowed an improvement of the quality of life for 89 % of them. CONCLUSION: Continent channels in adults demonstrate favorable long-term outcomes even if reinterventions could be necessary to maintain a continent and catheterizable channel. Despite reinterventions, patients remain satisfied by the Mitrofanoff procedure which facilitate the process of clean intermittent catheterization. LEVEL OF EVIDENCE: 4.

Open prostatectomy versus 180-W XPS GreenLight laser vaporization: Long-term functional outcome for prostatic adenomas>80 g.

INTRODUCTION: GreenLight photoselective vaporisation of the prostate (PVP) offers an endoscopic alternative to open prostatectomy (OP) for treatment of large adenomas. This study compares long-term functional outcome of both techniques in patients with Benign prostatic obstruction (BPO)>80g. MATERIAL AND METHOD: Data from patients who underwent surgical treatment for BPO>80g from January 2010 to February 2015 at our institution were retrospectively collected and compared according to surgical technique. Patient's demographics, surgeon's experience, operative data and long-term functional results were analyzed, using IPSS and International continence society (ICS) male questionnaire associated with Quality of life scores (IPSS-QL and ICS-QL). Predictors of long-term outcome were also assessed. RESULTS: In total, 111 consecutive patients, 57 PVP and 54 OP, were included in the study with a mean follow-up of 24 and 33 month respectively. Patient's age, Charlson score, preoperative IPSS and urinary retention rates were similar. Mean prostatic volume was superior in the OP group (142 versus 103g, P<0.001). Transfusion rate was lower after PVP (P=0.02), despite a more frequent anticoagulant use. Length of hospital stay and urinary catheterization were shorter after PVP (P<0.001), with however a higher rate of recatheterization (RR=4.74) and rehospitalization (RR=10.42). Long-term scores were better after OP for IPSS (1 versus 5, P<0.001), IPSS-QL, ICS, ICS-QL. On multivariate analysis, prostatic residual volume was the only predictor of long-term IPSS but not ICS. CONCLUSION: Long-term functional outcome are better after OP compared to PVP. However, PVP offers good results, allowing to safely operate patients taking anticoagulants, regardless of prostatic volume. Endoscopic enucleation may the compromise between both techniques. LEVEL OF EVIDENCE: 4.

[The Allium ureteral stent in the management of ureteral stenoses, a retrospective, multicenter study]. / Stent Allium urétéral dans la prise en charge des sténoses urétérales. Étude rétrospective multicentrique.

OBJECTIVE: To evaluate the performance of the Allium ureteral stent in the management of patients initially treated with double J stents for the long-term treatment of stenoses. MATERIALS AND METHODS: We performed a retrospective multicenter study involving 36 patients who received 37 Allium ureteral stents (metallic 24 Fr) between September 2011 and January 2015 in one of three French teaching hospital centers. The mean age of the patients was 63.8 years (min-max: 33-88 years) and most were women (70%). Of these patients, 5.6% had ureteral fistulae and 94.4% stenoses. Mean stenosis length was 4.15cm (min-max: 0.5-12cm). All analyses were two-tailed with an alpha risk of 0.05. Statistical significance was set at P<0.05. Results were expressed as hazard ratios (HR) with 95% confidence intervals and P-values. RESULTS: During the follow-up period, 37% of the stents were removed due to migration (complication occurring in 18.9% of the studied population), infection (10.8%) or intolerance (8.1%). The other stents were removed after 1 year. Clinical effectiveness, defined as a lack of stenosis or fistula recurrence, was 52.8% after a mean follow-up of 7.1 months. CONCLUSION: Clinically effective in more than 50% of cases, the Allium ureteral stent appears to be an alternative to indwelling double J stents. LEVEL OF EVIDENCE: 4.

[Renal transplantation using a Maastricht category III non-heartbeating donor: First French experience and review of the literature]. / Transplantation rénale à partir d'un donneur décédé par arrêt circulatoire Maastricht III : première expérience française et revue de la littérature.

In 2015, Annecy Hospital was the first French hospital to perform non-heartbeating organ donation from a Maastricht category III donor (patient awaiting cardiac arrest after withdrawal of treatment). Non-heartbeating organ donation (NHBD), performed in France since 2006, had initially excluded this category, due to ethical questions concerning end of life and treatment withdrawal, as well as technical specificities linked to this procedure. Grenoble University Hospital and Edouard-Herriot Hospital in Lyon then performed the first kidney transplants, with satisfactory outcomes in both recipients. This article presents the details and results of this new experience, challenging both on a deontological and organizational level. Functional outcomes of kidney grafts from NHBD are now well known in the literature and confirm their benefit for patients, with similar results to those from heartbeating donors (HBD). International experiences concerning specifically Maastricht category III NHBD are encouraging and promising.

[Biochemical recurrence after curative treatment for localized prostate cancer: Performance of choline PET/CT in the assessment of local recurrence]. / Récidive biochimique après traitement curatif d'un adénocarcinome prostatique localisé: intérêt de la TEP à la choline dans l'évaluation de la récidive locale.

OBJECTIVE: To establish 18 fluorocholine-positron emission tomography/computed tomography (F-PET/CT) performances for the detection of local recurrence in a population of patients with biochemical failure after primary curative treatment for localized prostate carcinoma. MATERIAL AND METHOD: From February 2011 to February 2014, 55 patients underwent a F-PET/CT for biochemical relapse after primary radical therapy for prostate cancer localized or locally advanced. Primary therapies for prostate cancer were 19 radical prostatectomy, 18 radiotherapy, 13 radiotherapy with hormonal treatment, 3 brachytherapy. The median age was 65 years (50-79). The initial staging was 17 T1, 23 T2 and 15 T3, 52 were N0 and N1 3. The median PSA was 12 (3-127). The Gleason score was less than 7, equal to 7 and greater than 7 at 21, 25 and 9 patients respectively. The average time to recurrence was 69.5 months (8-147) with a median PSA of 2.9 ng/mL (0.48-41). RESULTS: In 42 cases, F-PET/CT showed uptake, suggesting a recurrence, metastatic (6), nodal (26) or local isolated (10). The focal uptake in PET commissioned in 5 cases prostate biopsy, confirming the histological recurrence of prostate cancer in 4 cases. Among the 10 patients with isolated local recurrence, 8 underwent salvage radiotherapy. Of the 13 cases where the (F-PET/CT) showed no recurrence, 7 multiparametric MRI were performed. The MRI showed a local recurrence in 3 patients, the diagnoses were confirmed with prostate biopsy for two of them. CONCLUSION: In our study, for the patients with biochemical relapse of prostate adenocarcinoma localized or locally advanced, (F-PET/CT) was able to detect local recurrence isolated in nearly half the cases but did not show sufficient sensitivity to exclude recurrence local if negative. It does not replace MRI or additional prostate biopsy.

Cellular and molecular portrait of eleven human glioblastoma cell lines under photon and carbon ion irradiation.

This study aimed to examine the cellular and molecular long-term responses of glioblastomas to radiotherapy and hadrontherapy in order to better understand the biological effects of carbon beams in cancer treatment. Eleven human glioblastoma cell lines, displaying gradual radiosensitivity, were irradiated with photons or carbon ions. Independently of p53 or O(6)-methylguanine-DNA methyltransferase(1) status, all cell lines responded to irradiation by a G2/M phase arrest followed by the appearance of mitotic catastrophe, which was concluded by a ceramide-dependent-apoptotic cell death. Statistical analysis demonstrated that: (i) the SF2(2) and the D10(3) values for photon are correlated with that obtained in response to carbon ions; (ii) regardless of the p53, MGMT status, and radiosensitivity, the release of ceramide is associated with the induction of late apoptosis; and (iii) the appearance of polyploid cells after photon irradiation could predict the Relative Biological Efficiency(4) to carbon ions. This large collection of data should increase our knowledge in glioblastoma radiobiology in order to better understand, and to later individualize, appropriate radiotherapy treatment for patients who are good candidates.

Comparison of the efficacy of rotavirus VLP vaccines to a live homologous rotavirus vaccine in a pig model of rotavirus disease.

Rotavirus-like particles (VLPs) have shown promise as rotavirus vaccine candidates in mice, rabbits and pigs. In pigs, VLP vaccines reduced rotavirus shedding and disease but only when used in conjunction with live attenuated human rotavirus. Using a porcine rotavirus pig model, rotavirus antigen shedding was reduced by up to 40% after vaccination with VLPs including the neutralizing antigens VP7 and VP8* when used in combination with the adjuvant polyphosphazene poly[di(carbozylatophenoxy)phoshazene] (PCPP). In contrast, complete protection from rotavirus antigen shedding and disease was induced by vaccination with the virulent porcine rotavirus PRV 4F. This is the first study to demonstrate some post-challenge reductions in rotavirus antigen shedding in a pig model of rotavirus disease after vaccination with VLPs without combining with infectious rotavirus.

Amount of maternal rotavirus-specific antibodies influence the outcome of rotavirus vaccination of newborn mice with virus-like particles.

In presence of low or high levels of rotavirus-specific maternal antibodies, the ability of newborn mice to respond to immunization with rotavirus RF 8*-2/6/7 VLPs, was evaluated. After parenteral vaccination, 100% of offspring born to low-antibody-titer dams developed rotavirus-specific IgG antibodies (n=7). In contrast, only 25% of offsprings born to high-antibody-titer dams responded to parenteral immunization (n=12). When comparing parenteral versus oral immunization in offspring to low-antibody-titer dams only 45% responded after oral immunization (n=6). In conclusion, the response to parenteral immunization was not hampered by the presence of low levels of maternal antibodies induced by a natural infection while oral immunization was impaired. However, high levels of maternal antibodies impaired the response to parenteral immunization.

Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis.

The accumulation of Ca2+ in the mitochondrial matrix can stimulate oxidative phosphorylation, but can also, at high Ca2+ concentrations, transmit and amplify an apoptotic signal. Here, we characterized the capacity of physiological stimuli (for example, histamine and inositol-1,4,5-triphosphate) and inducers of endoplasmic reticulum (ER) stress (for example, A23187, thapsigargin and tunicamycin) to release Ca2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines. Sustained Ca2+ accumulation in the mitochondrial matrix induced by ER stress triggered signs of proapoptotic mitochondrial alteration, namely permeability transition, dissipation of the electrochemical potential, matrix swelling, relocalization of Bax to mitochondria and the release of cytochrome c and apoptosis-inducing factor from mitochondria. In contrast, rapid and transient accumulation of Ca2+ induced by physiological stimuli failed to promote mitochondrial permeability transition and to affect cell viability. The specificity of this apoptosis pathway was validated in cells using a panel of pharmacological agents that chelate Ca2+ (BAPTA-AM) or inhibit inositol-1,4,5-trisphosphate receptor (IP(3)R; 2-aminoethoxydiphenyl borate), voltage-dependent anion channel (VDAC) (4,4'-diisothiocyanatostilbene-2,2'-disulfonate, NADH), the permeability transition pore (cyclosporin A and bongkrekic acid), caspases (z-VAD-fmk) and protein synthesis (cycloheximide). Finally, we designed an original cell-free system in which we confronted purified mitochondria and ER vesicles, and identified IP(3)R, VDAC and the permeability transition pore as key proteins in the ER-triggered proapoptotic mitochondrial membrane permeabilization process.

Structure-function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA.

The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X(L). In contrast to Bcl-X(L), however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an alpha-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membrane-inserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Bax-binding function. We found that Delta131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIADelta131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIADelta131-147 suggest that vMIA forms homo-oligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.