Simplified urethral score system for predicting complex anterior urethroplasty.

OBJECTIVE: To assess U-score individual values as urethral complex surgery predictors. METHODS: Cross-sectional study including patients who received anterior urethroplasty from 2011 to 2019. U-score (etiology (1-2 points), number of strictures (1-2 points), anatomic location (1-2 points) and length (1-3 points)) was measured individually and globally. Surgical complexity was defined as low (anastomotic, buccal mucosal graft, and augmented anterior urethroplasty), and high complexity (double buccal mucosal graft, flap, and graft/flap combination). U-score components were included as complex surgery predictor and as main variable with individual probability values estimations and comparisons. Risk complex surgery probability groups were established. RESULTS: 654 patients were included. Mean age was 57.2 years. Low complexity surgery was performed in 464 patients (259 anastomotic, 144 graft, 61 augmented anterior urethroplasty) and high complexity was done in 190 (53 double buccal mucosa graft, 27 flap, 110 graft/flap comb.). In multivariate analysis length, number of strictures and location were predictors of complexity. Introducing U-Score as only variable in univariate model predicted an OR 8.52 (95%CI 6.1-11). Simplified U-score grouping set obtained by complex probability was: low risk (4-5 points), medium risk (6 points) and high risk of complexity (7-9 points) Predicted risk of complex surgery probability (95%CI) for low, median and high risk group were 1.6 (0-2.9), 19.1 (13.8-25.9) and 77.9 (61.6-88.7), respectively. CONCLUSIONS: U-score can be used as a tool to predict complex urethral surgery. We present a simplified U-score risk tool to assess individual complex anterior urethroplasty probability.

Safety and efficacy of urethroplasty based on age groups.

OBJECTIVE: To analyze the results and complications after urethroplasty based on patient age groups. As secondary objective, we analyzed the impact of operative complexity on each age group. MATERIAL AND METHODS: This is a retrospective cohort study that include male patients who underwent urethroplasty between January 2011 and December 2018. Data was obtained from the patients' electronic health records. Patients were grouped as follows: <60 years, 60-79 years and >80 years. Variables evaluated were history, comorbidities, previous surgeries and operative complexity. Restenosis-free survival and complications presented in each group were determined according to the Clavien-Dindo classification system. The SPSS® program was used for statistical analysis. RESULTS: A total of 783 patients were included, and the mean follow-up was 19 months. The estimated 2-year restenosis-free survival in the population under 60, 60-79 and over 80 years was 87, 87 and 93.9% (IC 95%), respectively. Univariate analysis showed that the age group was not a predictor of restenosis. Complex surgery is the only predictor of recurrence, increasing the risk by 60% (HR 1.64, 95% CI 1.05-2.56, p = 0.029). There was an overall complication rate of 30.8%, and 62% of these were Clavien ≤ II. We found no association between the frequency of complications and age. CONCLUSIONS: Urethroplasty is safe and effective regardless of age group. There are no statistically significant differences in outcomes and complications shown by the age group comparison. There were no significant differences when analyzing the impact of complex surgeries among the different age groups. The data indicate that age alone should not be taken as an absolute exclusion criterion for patients needing urethral reconstruction.

Safety and efficacy of urethroplasty based on age groups. / Seguridad y eficacia de la uretroplastia según grupos etarios.

OBJECTIVE: To analyze the results and complications after urethroplasty based on patient age groups. As secondary objective, we analyzed the impact of operative complexity on each age group. MATERIAL AND METHODS: This is a retrospective cohort study that include male patients who underwent urethroplasty between January 2011 and December 2018. Data was obtained from the patients' electronic health records. Patients were grouped as follows: < 60 years, 60-79 years and > 80 years. Variables evaluated were history, comorbidities, previous surgeries and operative complexity. Restenosis-free survival and complications presented in each group were determined according to the Clavien-Dindo classification system. The SPSS® program was used for statistical analysis. RESULTS: A total of 783 patients were included, and the mean follow-up was 19 months. The estimated 2-year restenosis-free survival in the population under 60, 60-79 and over 80 years was 87, 87 and 93.9% (IC 95%), respectively. Univariate analysis showed that the age group was not a predictor of restenosis. Complex surgery is the only predictor of recurrence, increasing the risk by 60% (HR 1.64, 95% CI 1.05-2.56, p = 0.029). There was an overall complication rate of 30.8%, and 62% of these were Clavien ≤ II. We found no association between the frequency of complications and age. CONCLUSIONS: Urethroplasty is safe and effective regardless of age group. There are no statistically significant differences in outcomes and complications shown by the age group comparison. There were no significant differences when analyzing the impact of complex surgeries among the different age groups. The data indicate that age alone should not be taken as an absolute exclusion criterion for patients needing urethral reconstruction.

Postoperative urinary extravasation does not impact anterior urethroplasty surgical outcomes: a Latin American large cohort study.

OBJECTIVE: To determine the prevalence of postoperative urinary extravasation (POUE) following anterior urethroplasty, to analyze factors associated with its occurrence, and to study the impact of POUE on surgical success. MATERIALS AND METHODS: Retrospective cohort study including all male patients who have undergone a urethroplasty at our center between 2011 and 2018. Subjects with posterior location stricture, those who did not undergo routine radiographic follow-up, or patients with inadequate follow-up were excluded. Urinary extravasation was defined as presence of evident contrast extravasation on the postoperative voiding cystourethrogram (VCUG). Impact was determined as "need-for-reoperation". Uni- and multivariate analysis were performed to determine clinical and demographic variables associated with occurrence of extravasation and postoperative stricture. RESULTS: A total of 783 men underwent a urethroplasty and 630 fulfilled inclusion criteria. Urinary extravasation prevalence was 12.2%, and there was a "need-for-reoperation" in 1.1% of cases. On uni- and multivariate analysis, greatest stricture length (HR: 1.07 (1-1.2), p = 0.05) and penile urethral location (HR: 2.29 (1.1-4.6), p = 0.021) showed to be POUE predictors. POUE did not show to be a risk factor for postoperative stricture (HR: 1.57, 95% CI (0.8-3), p = 0.173). However, reoperation group  showed to be a risk factor (HR: 6.6, 95% CI 1.4-31, p = 0.019). CONCLUSIONS: Prevalence of POUE was 12.2%. Stricture length and penile urethral strictures were POUE predictors. POUE occurrence with successful conservative management did not appear to have impact on urethroplasty outcomes as it did not predict re-stricture. POUE was reoperation cause in 1.1% of total cases.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Pelvic exenteration for gynecologic malignancies: Postoperative complications and oncologic outcomes. / Exenteración pélvica para neoplasias ginecológicas: Complicaciones postoperatorias y resultados oncológicos.

INTRODUCTION AND OBJECTIVE: To evaluate complications, morbidity and oncologic outcomes of pelvic exenteration as treatment for gynecologic malignancies. MATERIALS AND METHODS: Between 2008 and 2015, a total of 35 patients underwent pelvic exenteration, due to recurrence of gynecological cancer. Surgical outcomes, early and late postoperative complications, and recurrence/survival outcomes were assessed. RESULTS: Mean patient age was 53.8 years. Anterior exenteration was done in 20 patients, while 15 were total exenterations. Ileal conduit was done in 24 patients, while 8 received a neobladder and 3 a cutaneous ureterostomy. Postoperative complications were divided in 2groups, early (<30 days) and late complications (>30 days). A total of 25 patients (71.4%) had one or more early complications; 16 (45.7%) had fever due to a urinary tract infection, pyelonephritis or intra-abdominal collection; 2 (5.7%) developed a vesicovaginal fistula; 4 (11.4%) a rectovaginal fistula; 3 (8.5%) acute kidney failure and one (2.85%) uronephrosis. Regarding to late complications, 8patients (22.8%) had fever. Six (17%) presented with uronephrosis, and 5 (14.2%) with ureteral-pouch stricture. Five patients (14.2%) had acute renal insufficiency, 3 (8,6%) rectovaginal fistula and one (2.85%) urinary fistula. Mean follow up time was 20.3 month (2-60). A total of 22patients (62.8%) were free of disease. Another 13 (37.1%) patients relapsed. Only 4 (11.4%) patients died after pelvic exenteration due to underlying disease. CONCLUSION: Pelvic exenteration has a high rate of complications and morbidity, but can be the last curative opportunity in patients with recurrent or persistent gynecologic malignancies. This procedure should be performed by multidisciplinary, experienced teams in a tertiary medical center.

Surgical approach to vesicourethral anastomotic stricture following radical prostatectomy.

INTRODUCTION: Vesicourethral anastomotic stricture following prostatectomy is uncommon but represents a challenge for reconstructive surgery and has a significant impact on quality of life. The aim of this study was to relate our experience in managing vesicourethral anastomotic strictures and present the treatment algorithm used in our institution. PATIENTS AND METHODS: We performed a descriptive, retrospective study in which we assessed the medical records of 45 patients with a diagnosis of vesicourethral anastomotic stricture following radical prostatectomy. The patients were treated in the same healthcare centre between January 2002 and March 2015. Six patients were excluded for meeting the exclusion criteria. The stricture was assessed using cystoscopy and urethrocystography. The patients with patent urethral lumens were initially treated with minimally invasive procedures. Open surgery was indicated for the presence of urethral lumen obliteration or when faced with failure of endoscopic treatment. Urinary continence following the prostatectomy was determinant in selecting the surgical approach (abdominal or perineal). RESULTS: Thirty-nine patients treated for vesicourethral anastomotic stricture were recorded. The mean age was 64.4 years, and the mean follow-up was 40.3 months. Thirty-three patients were initially treated endoscopically. Seventy-five percent progressed free of restenosis following 1 to 4 procedures. Twelve patients underwent open surgery, 6 initially due to obliterative stricture and 6 after endoscopic failure. All patients progressed favourable after a mean follow-up of 29.7 months. CONCLUSIONS: Endoscopic surgery is the initial treatment option for patients with vesicourethral anastomotic strictures with patent urethral lumens. Open reanastomosis is warranted when faced with recalcitrant or initially obliterative strictures and provides good results.

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which is mainly due to its high risk of metastatic dissemination. One critical point of this process is the ability of cancer cells to detach from the primary tumor and migrate through the extracellular matrix; however, the underlying molecular mechanisms are not yet fully understood. In the present study, we identified the small GTPase RhoB as a key regulator of bronchial cell morphology in a three-dimensional (3D) matrix. RhoB loss, which is frequently observed during lung cancer progression, induced an epithelial-mesenchymal transition (EMT) characterized by an increased proportion of invasive elongated cells in 3D. The process was mediated by Slug induction and E-cadherin repression. In addition, downregulation of RhoB induced Akt1 activation, which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement. Further, we provide evidence that RhoB interacted with and positively regulates phosphatase PP2A through the recruitment of its regulatory subunit B55, which was found to be crucial for Akt dephosphorylation. B55 inhibition completely suppressed RhoB-mediated PP2A regulation. Finally, we show that PP2A inactivation, by targeting either its catalytic or its regulatory B55 subunit, completely reversed RhoB-dependent morphological changes and also fully prevented the ability of RhoB to decrease the invasiveness of bronchial cells. Altogether, these results highlight a novel signaling axis and describe new molecular mechanisms that could explain the tumor suppressor role of RhoB in lung cancer. Therefore, we propose that RhoB could be responsible for early metastatic prevention by inhibiting the EMT-derived invasiveness of lung cells through the control of PP2A activity.

Tender Nesting Polypore (Hapalopilus rutilans) poisoning: report of two cases.

INTRODUCTION: Only four cases of Hapalopilus rutilans poisoning have been previously published. We report two new cases. CASE REPORTS: A father and his 13-year-old daughter picked mushrooms identified as Fistulina hepatica specimens and ate an unknown quantity (Hour 0). At Hour 12 post-ingestion, both subjects complained of abdominal pain, then nausea, vomiting, anorexia, asthenia, diplopia, and blurred vision. The father also had visual hallucinations. On Day 2 post-ingestion, clinical examination showed multidirectional nystagmus. The father also had balance disorders and both subjects emitted purple urine. Laboratory tests showed elevated serum creatinine and blood urea levels, proteinuria and leukocyturia in both subjects, and mild elevation of hepatic enzymes in the father. Urine color returned to normal on Day 2 and Day 7 post-ingestion in the girl and her father, respectively. Complete clinical and biochemical recovery was obtained within one week in both cases. DISCUSSION: Signs and symptoms are similar to those previously reported after H. rutilans ingestion. This mushroom can be easily confused with F. hepatica. Purple discoloration of the urine after ingestion of a polyporic mushroom is highly suggestive of H. rutilans poisoning. Polyporic acid is probably the active toxin.

Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis.

Of critical importance in the stress response is the post-transcriptional control of the expression of important genes involved in the control of cell survival and apoptosis. Here we report that miR-19, an oncogenic component of the miR-17-92/Oncomir-1 microRNA polycistron, regulates the expression of Ras homolog B (RhoB) in keratinocytes upon exposure to ultraviolet (UV) radiation. Strikingly, we could not find any evidence for deregulated expression of miR-19 during UV treatment. However, we show that miR-19-mediated regulation of antiapoptotic RhoB expression requires the binding of human antigen R (HuR), an AU-rich element binding protein, to the 3'-untranslated region of the rhoB mRNA. We propose that the loss of the interdependent binding between HuR and miR-19 to the rhoB mRNA upon UV exposure relieves this mRNA from miR-19-dependent inhibition of translation and contributes to the apoptotic response.

Tumor incidence in related hematopoietic stem cell donors.

Late malignancies have been discussed as a potential risk for growth factor mobilized donors of hematopoietic stem cells. Little is known about the incidence and potential risk factors. This single center retrospective cohort study evaluated all HLA-identical sibling pairs with hematopoietic stem cell transplantation (HSCT) for a hematological malignancy, treated from 1974 to 2001 at the University Hospital of Basel. Three hundred eighteen pairs were identified, 291 donors (92%) could be contacted. Median observation time was 13.8 years (range 5-32 years). Sixteen (5%) donors had developed a total of 18 tumors, 17 recipients a secondary tumor. According to the age- and sex-adapted cancer incidence, 3.3 tumors in male and 6.8 in female donors were expected, 3 (relative risk (RR): 0.91, 95% confidence interval: 0.19-2.66) and 4 (RR: 0.58, 95% confidence interval: 0.16-1.48), respectively, were found in donors between 0 and 49 years. Between 50 and 69 years, 4.5 tumors in males and 4.8 in females were expected, 5 (RR: 1.11, 95% confidence interval: 0.36-2.59) and 6 (RR: 1.23, 95% confidence interval: 0.45-2.67), respectively, were observed. Tumors do occur in donors of hematopoietic stem cells at least at the rate as expected in a normal population; whether incidence exceeds expected rates needs to be determined in larger international cohorts.

Epstein-Barr virus-associated hepatic leiomyosarcoma after renal transplantation: case report.

The incidence of neoplastic complications after solid organ transplantation is increasing tremendously probably as the consequence of long term immunosuppression. Beside usual risk factors, the oncogenic role of some viruses like Epstein-Barr virus is well established. We report a case of a primitive EBV-induced liver leiomyosarcoma after renal transplantation.

High duty factor plasma generator for CERN's Superconducting Proton Linac.

CERN's Linac4 is a 160 MeV linear accelerator currently under construction. It will inject negatively charged hydrogen ions into CERN's PS-Booster. Its ion source is a noncesiated rf driven H(-) volume source directly inspired from the one of DESY and is aimed to deliver pulses of 80 mA of H(-) during 0.4 ms at a 2 Hz repetition rate. The Superconducting Proton Linac (SPL) project is part of the luminosity upgrade of the Large Hadron Collider. It consists of an extension of Linac4 up to 5 GeV and is foreseen to deliver protons to a future 50 GeV synchrotron (PS2). For the SPL high power option (HP-SPL), the ion source would deliver pulses of 80 mA of H(-) during 1.2 ms and operate at a 50 Hz repetition rate. This significant upgrade motivates the design of the new water cooled plasma generator presented in this paper. Its engineering is based on the results of a finite element thermal study of the Linac4 H(-) plasma generator that identified critical components and thermal barriers. A cooling system is proposed which achieves the required heat dissipation and maintains the original functionality. Materials with higher thermal conductivity are selected and, wherever possible, thermal barriers resulting from low pressure contacts are removed by brazing metals on insulators. The AlN plasma chamber cooling circuit is inspired from the approach chosen for the cesiated high duty factor rf H(-) source operating at SNS.

Sideroblastic changes of the bone marrow can be predicted by the erythrogram of peripheral blood.

The diagnosis of sideroblastic anemia is based on bone marrow aspiration, and the detection of ring sideroblasts (RS) in iron staining. The finding of laboratory parameters to approach this diagnosis still remains a great challenge. In this study, we analyzed the value of a specific erythrogram pattern from peripheral blood, produced by the ADVIA120 cell counter, to predict sideroblastic changes in the bone marrow. In a two step-design study, we first showed that 32/38 consecutive patients reporting > or =15% RS had such a pattern in the erythrogram. In the second step, we prospectively identified over a period of 32 months 21 patients with this typical erythrogram; 20/21 had > or =15% RS in the bone marrow. Hence, by this validation, we confirm that the erythrogram is highly predictive of RS in the bone marrow. The interpretation of the erythrogram should become daily practice in hematology to improve the efficacy to detect sideroblastic changes.

Serum protein signature may improve detection of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is part of a spectrum of preinvasive lesions that originate within normal breast tissue and progress to invasive breast cancer. The detection of DCIS is important for the reduction of mortality from breast cancer, but the diagnosis of preinvasive breast tumors is hampered by the lack of an adequate detection method. To identify the changes in protein expression during the initial stage of tumorigenesis and to identify the presence of new DCIS markers, we analysed serum from 60 patients with breast cancer and 60 normal controls using mass spectrometry. A 23-protein index was generated that correctly distinguishes the DCIS and control groups with sensitivities and specificities in excess of 80% in two independent cohorts. Two candidate peptides were purified and identified as platelet factor 4 (PF-4) and complement C3a(desArg) anaphylatoxin (C3a(desArg)) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In an independent serum set of 165 patients, PF-4 and C3a(desArg) were significantly upregulated in DCIS compared with non-cancerous controls, as validated using western blot and enzyme-linked immunosorbent assay. We conclude that our serum protein-based test, used in conjunction with image-based screening practices, could improve the sensitivity and specificity of breast cancer detection.