Comparison of laparoscopic versus open simple nephrectomy in patients with xanthogranulomatous pyelonephritis: A singlecenter analysis of outcomes and predictors of surgical approaches and complications.

Background: The aim of this study was to compare the outcomes of open simple nephrectomy and laparoscopic simple nephrectomy in patients with xanthogranulomatous pyelonephritis (XGP) in a single-institutional retrospective study and to identify predictive factors of surgical approaches and complications. Materials and methods: We retrospectively analyzed the data of 67 consecutive patients with a histopathological diagnosis of XGP who underwent either open simple nephrectomy (ON) or laparoscopic simple nephrectomy (LN) from January 2014 to April 2020. The primary endpoint was the evaluation of perioperative outcomes and complications. Secondary endpoints were to define factors influencing the surgical approach and the likelihood of postoperative complications. Results: Overall, 44 out of 67 patients (65.67%) underwent ON, while 23 (34.33%) underwent LN. Patients in the ON group experienced more postoperative pain according to the visual analogic scale (p = 0.032). Moreover, time to deambulation and time to return to full daily activities, assessed according to the 12-Item Short Form Survey physical and mental component summary scores questionnaires, were significantly shorter in the LN group (p = 0.021, p < 0.001, and p < 0.001, respectively). Of note, there were no significant differences in intraoperative and postoperative complication rates among the groups (p = 0.258 and p = 0.317, respectively). No conversion to open surgery was described. Logistic regression analysis demonstrated that urgency (p = 0.025) was the only predictor associated with a higher risk of intraoperative complications. However, no independent factors associated with postoperative complications or with the surgical approach of choice were found. Conclusions: Based on our results, laparoscopic treatment of XGP represents a feasible alternative to ON, resulting in less postoperative pain and faster recovery. In skilled hands, LN should be considered as the treatment of choice for XGP.

Four dilation techniques in percutaneous nephrolithotomy: a single-institute comparative analysis.

BACKGROUND: The aim of this study was to compare four renal access techniques in percutaneous nephrolithotomy (PCNL). METHODS: A total of 437 patients who underwent PCNL at our center from January 2015 to December 2019 were included in the analysis. Telescopic metallic coaxial dilation (TMD) was used in 146 patients, single step balloon dilation (BD) in 98 patients, one-shot dilation with 30F Amplatz (OS 30F) in 106 patients, and one-shot dilation with 16F Amplatz (OS 16F) in 87 patients. Primary endpoints were perioperative outcomes and complications of the procedures. RESULTS: Similar baseline characteristics were observed in the four groups. Fluoroscopy time was significantly shorter in OS 30F and OS 16F groups (P<0.0001). The drop in hemoglobin level was not significantly different between TMD and BD groups, but it was significantly lower in OS 16F group versus the OS 30F group and lower in OS 30F group versus the BD Group (P<0.0001). Despite this, the rate of blood transfusion was similar across groups (P=0.837). Moreover, a smaller tract was associated with reduced postoperative morbidity including time to nephrostomy removal (P=0.001), hospital stay (P<0.0001), VAS scale (P<0.0001). There were no significant differences in postoperative complications (P=0.683), and Clavien-Dindo grade ≥3 complication rates (P=0.486) among the groups. Stone-free rates and number of auxiliary procedures required to achieve stone-free status were also similar among all groups (P=0.964 and 0.988, respectively). Multinomial logistic regression analysis showed that BMI (P=0.002), stone size (P=0.002) and previous PCNL (P=0.038) were predictive factors associated with the choice of OS 16 approach. CONCLUSIONS: Different dilation methods are equally effective and safe to use in a PCNL procedure for kidney stone treatment, allowing similar stone free rates and risk of complications. The OS dilation techniques seem to allow a shorter X-ray exposure time, which might be beneficial for both patients and operators. The use of a 16 F dilator can reduce the postoperative morbidity. Risk of sepsis should be always kept in mind.

Hyperbaric oxygen therapy reduces mortality in patients with Fournier's Gangrene. Results from a multi-institutional observational study.

BACKGROUND: Evidence about the clinical benefits of Hyperbaric Oxygen Therapy (HBOT) in patients with Fournier's Gangrene (FG) is controversial and inconclusive. We aimed to compare the mortality related to FG between patients undergoing surgical debridement and/or standard antibiotic therapy alone or in combination with HBOT. METHODS: We performed a retrospective multi-institutional observational case-control study. All patients admitted with diagnosis of FG from June 2009 to June 2019 were included into the study. Patients received surgical debridement and/or standard antibiotic therapy alone or in combination with HBOT. Factors associated with FG related mortality were assessed with uni-and multivariate analyses. The main outcome measure was FG related mortality. RESULTS: A total of 161 patients with diagnosis of FG were identified. Mean FG Severity Index was 8.6±4.5. All patients had broad-spectrum parenteral antibiotic therapy. An aggressive debridement was performed in 139 (86.3%) patients. A total of 72 patients (44.7%) underwent HBOT. Mortality due to FG was observed in 32 (36.0%) of patients who do not underwent HBOT and in 14 (19.4%) of patients who underwent HBOT (P=0.01). At the multivariate analysis, surgical debridement and HBOT were independent predictors of lower mortality while higher FG Severity Index was independent predictor of higher mortality. CONCLUSIONS: HBOT and surgical debridement are independent predictors of reduced FG related mortality.

Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors.

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20-25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

New combinatorial strategies to improve the PARP inhibitors efficacy in the urothelial bladder Cancer treatment.

BACKGROUND: Novel therapeutic strategies are urgently needed for the treatment of metastatic Urothelial Bladder Cancer. DNA damaging repair (DDR) targeting has been introduced in cinical trials for bladder cancer patients that carry alterations in homologous DNA repair genes, letting to envisage susceptibility to the Poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors. MAIN BODY: PARP inhibition, by amplifying the DNA damage, augments the mutational burden and promotes the immune priming of the tumor by increasing the neoantigen exposure and determining upregulation of programmed death ligand 1 (PD-L1) expression. Thus, the combination of PARP-inhibition and the PD/PD-L1 targeting may represent a compelling strategy to treat bladder cancer and has been introduced in recent clinical trials. The targeting of DDR has been also used in combination with epigenetic drugs able to modulate the expression of genes involved in DDR, and also able to act as immunomodulator agents suggesting their use in combination with immune-checkpoint inhibitors. CONCLUSION: In conclusion, it may be envisaged the combination of three classes of drugs to treat bladder cancer, by targeting the DDR process in a tumor context of DDR defect, together with epigenetic agents and immune-checkpoint inhibitors, whose association may amplify the effects and reduce the doses and the toxicity of each single drug.

CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer.

BACKGROUND: The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells. METHODS: The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis. RESULTS: P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels. CONCLUSIONS: In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients.

A comparison of hexaminolevulinate (Hexvix(®)) fluorescence cystoscopy and white-light cystoscopy for detection of bladder cancer: results of the HeRo observational study.

BACKGROUND: To date, no study has presented results of photodynamic diagnosis (PDD) cystoscopy compared with white-light cystoscopy (WLC) in daily practice. The aim of the present study is to evaluate the diagnostic accuracy of hexylaminolevulinate hydrochloride (Hexvix(®)) PDD cystoscopy compared with standard WLC used in daily practice. METHODS: An observational, open-label, comparative, controlled (within patient), multicenter study was carried out on 96 consecutive patients with suspected or confirmed bladder cancer. All patients had standard WLC followed by blue-light cystoscopy (BLC). Positive lesions detected using WLC and BLC were recorded. Biopsies/resection of each positive lesion were taken after the bladder was inspected. Sensitivity, specificity, positive predictive value, and negative predictive value with each method were calculated. RESULTS: Overall, 234 suspicious lesions were detected; 108 (46.2%) were histologically confirmed to be bladder tumors/carcinoma in situ (CIS). The sensitivity of BLC biopsies was significantly higher than for WLC technique (99.1 vs 76.8%; p < 0.00001). The relative sensitivity of BLC versus WLC was 1.289, showing superiority of BLC of 28.9%. The specificity of BLC biopsies was not significantly different compared with WLC (36.5 vs 30.2%). Positive predictive value for BLC- and WLC-guided biopsies was 54.9 and 50.9%, respectively. Negative predictive value per biopsy for BLC- and WLC-guided biopsies was 97.4 and 64.8%, respectively. BLC and WLC reached the correct diagnosis in 97.9 and 88.5% of patients, respectively. This difference was statistically significant (p = 0.0265). The lack of a random biopsy protocol was the major limitation of the study. CONCLUSIONS: Hexvix(®) PDD cystoscopy used in daily practice enhances the diagnostic accuracy of standard cystoscopy with higher negative predictive value, potentially permitting an improvement in patient prognosis.