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Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF-RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.

Objectives: The Liver Imaging Reporting and Data System algorithm allows category downgrade in the presence of ancillary features (AFs) favoring benignity, even in observations categorized as LR-5. This study aims to assess the role of AFs favoring benignity in LR-5 observations and their impact on category downgrade., Methods: This study included high-risk patients with at least one LR-5 observation imaged with gadoxetate disodium MRI. Three readers with different experience levels independently evaluated the presence of AFs favoring malignancy (not hepatocellular carcinoma (HCC) in particular and HCC in particular) and AFs favoring benignity. Category downgrade was considered possible in the presence of ≥ 1 AF favoring benignity and no AF favoring malignancy. Correlation between observations size and number of AFs was assessed using Spearman's rank correlation coefficient. Cohen's kappa (k) test was used to assess inter-reader agreement., Results: The final study cohort included 162 LR-5 (mean size: 23 ± 16 mm) in 119 patients. AFs favoring benignity were reported in 9 (5.6%), 20 (12.3%), and 10 (6.2%) LR-5 observations by reader 1, reader 2, and reader 3, respectively. Hepatobiliary phase isointensity was observed in 6 (3.7%), 2 (1.2%), and 7 (4.3%) observations, respectively. Category downgrade was considered possible in only one (0.6%) observation by reader 1 and reader 3. There was a significant correlation between observation size and number of AFs favoring malignancy (p < 0.001), not HCC in particular (p ≤ 0.010), and favoring HCC in particular (p < 0.001). Inter-reader agreement of AFs favoring benignity was poor to moderate (k range: - 0.01, 0.43)., Conclusions: AFs favoring benignity are not uncommon in LR-5 observations, but category downgrade is exceptional., Key Points: • Ancillary features favoring benignity are encountered in 5.6-12.3% of observations categorized as LR-5. • Category downgrade of LR-5 observations is very rare (0.6% of observations) in the presence of AFs favoring benignity due to the high prevalence (98-99%) of ancillary features favoring malignancy in LR-5 observations. • The inter-reader agreement of ancillary features favoring benignity is poor to moderate (k range: - 0.01, 0.43) in readers with different levels of experience., (© 2021. European Society of Radiology.)

Objectives: To compare thulium laser enucleation of prostate (ThuLEP) versus laparoscopic trans-vesical simple prostatectomy (LSP) in the treatment of benign prostatic hyperplasia (BPH)., Materials and Methods: Data of patients who underwent surgery for "large" BPH (>80mL) at three Institutions were collected and analyzed. Two institutions performed ThuLEP only; the third institution performed LSP only. Preoperative (indwelling catheter status, prostate volume (PVol), hemoglobin (Hb), Qmax, post-voiding residual volume (PVR), IPSS, QoL, IIEF-5) and perioperative data (operative time, enucleated adenoma, catheterization time, length of stay, Hb-drop, complications) were compared. Functional (Qmax, PVR, %ΔQmax) and patient-reported outcomes (IPSS, QoL, IIEF-5, %ΔIPSS, %ΔQoL) were compared at last follow-up., Results: 80 and 115 patients underwent LSP and ThuLEP, respectively. At baseline, median PVol was 130 versus 120mL, p <0.001; Qmax 9.6 vs. 7.1mL/s, p=0.005; IPSS 21 versus 25, p <0.001. Groups were comparable in terms of intraoperative complications (1 during LSP vs. 3 during ThuLEP) and transfusions (1 per group). Differences in terms of operative time (156 vs. 92 minutes, p <0.001), Hb-drop (-2.5 vs. -0.9g/dL, p <0.001), catheterization time (5 vs. 2 days, p <0.001) and postoperative complications (13.8% vs. 0, p <0.001) favored ThuLEP. At median follow-up of 40 months after LSP versus 30 after ThuLEP (p <0.001), Qmax improved by 226% vs. 205% (p=0.5), IPSS decreased by 88% versus 85% (p=0.9), QoL decreased by 80% with IIEF-5 remaining almost unmodified for both the approaches., Conclusions: Our analysis showed that LSP and ThuLEP are comparable in relieving from BPO and improving the patient-reported outcomes. Invasiveness of LSP is more significant., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Background: Several studies described post-operative irritative symptoms after laser enucleation of prostate, sometimes associated with urge incontinence, probably linked to laser-induced prostatic capsule irritation, and potential for lower urinary tract infections We aimed to evaluate the efficacy of a suppository based on Phenolmicin P3 and Bosexil (Mictalase®) in control of irritative symptoms in patients undergoing thulium laser enucleation of prostate (ThuLEP)., Methods: In this single-center, prospective, randomized, open label, phase-III study, patients with indication to ThuLEP were enrolled (Dec2019-Feb2021-Institutional ethics committee STS CE Lazio approval no.1/N-726-ClinicalTrials.gov NCT05130918). The report conformed to CONSORT 2010 guidelines. Eligible patients were 1:1 randomized. Randomization defined Group A: patients who were administered Mictalase® suppositories twice a day for 5 days, then once a day for other 10 days; Group B: patients who did not receive Mictalase® ("controls"). Study endpoints were evaluated at 15 and 30 days postoperation. Primary endpoint included evaluation of effects of the suppository on irritative symptoms by administering IPSS + QoL questionnaire. Secondary endpoint included evaluation of effects on urinary tract infections by performance of urinalysis with urine culture., Results: 111 patients were randomized: 56 in Group A received Mictalase®. Baseline and perioperative data were comparable. At 15-days, no significant differences were found in terms of IPSS + QoL scores and urinalysis parameters. A significant difference in the rate of positive urine cultures favored Group A (p = 0.04). At 30-days follow-up, significant differences were found in median IPSS score (6 [IQR 3-11] versus 10 [5-13], Group A vs B, respectively, p = 0.02). Urinalysis parameters and rate of positive urine cultures were not significantly different., Conclusions: The present randomized trial investigated the efficacy of Mictalase® in control of irritative symptoms and prevention of lower urinary tract infections in patients undergoing ThuLEP. IPSS improvement 30-days postoperation was more pronounced in patients who received Mictalase®. Lower rate of positive urine culture favored Mictalase® group 15-days postoperatively., Trial Registration: The clinical trial has been registered on ClinicalTrials.gov on November 23rd, 2021-Registration number NCT05130918., (© 2022. The Author(s).)

There is a growing interest in exploiting Antarctic fisheries for human consumption. However, information on how the nutritional qualities of these resources will respond to the predicted seawater warming in the region for the next century is poor. The present research investigates changes in various nutritional indices of dietary importance (e.g. the ratio polyunsaturated to saturated fatty acids, the atherogenicity index, the thrombogenicity index, the hypo-cholesterolemic to hyper-cholesterolemic index, the health-promoting index, the flesh lipid quality and the ratio omega-3 to omega-6 index) by determining the fatty acid composition in muscle of Trematomus bernacchii (an Antarctic fish species) in its natural habitat (-1.87 °C) and warmer temperatures (0.0, 1.0, 2.0 °C). Comparison of the estimated nutritional indices at -1.87 °C with those at warmer temperatures revealed that seawater warming caused changes in the nutritional indices in the range of -12%<Δ < 30%. The observed changes were not statistically significant and ascribed to biological variability. Therefore, the nutritional values of T. bernacchii muscle were preserved after increasing the temperature of its natural habitat by + 4 °C. The present research is the first report describing the nutritional quality indices for an Antarctic fish species and the consequences of seawater warming on the nutritional value of T. bernacchii., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Adalimumab (ADA) is a human anti-tumor necrosis factor (TNF-α) monoclonal antibody used in inflammatory bowel diseases, such as Crohn's disease (CD). Vitamin-D (VD) is important for biological functions, such as the modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. ADA trough levels were associated with VD concentrations in patients with IBD, but no data are present in the literature concerning VD pathway-related gene single-nucleotide polymorphisms (SNPs) in affecting clinical outcomes. For this reason, the aim of this study was to evaluate the ability of VD-related genetics to predict clinical remission at 3 and 12 months in patients affected by CD treated with ADA. Patients affected by CD were included in this study. SNPs in CYP27B1 , CYP24A1 , GC , and VDR genes were analyzed through real-time PCR. A total of 63 patients were enrolled. Calprotectin, hemoglobin, and C-reactive protein levels were influenced by SNPs in VDR , CYP27B1 , and GC genes. After 3 months of therapy, clinical remission was predicted by smoke, systemic steroids, and VDR BsmI, whereas at 12 months by GC 1296AA/AC and VD supplementation. This study reports the association between VD pathway-related genetics and ADA treatment. Further studies are needed to confirm these promising data.

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.

Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or osteoarticular infections, treated either with one or two 1500 mg doses of dalbavancin. A liquid chromatography-tandem mass spectrometry method was used to measure total dalbavancin concentrations in plasma samples. The results were analyzed through a non-compartmental analysis (NCA). Breakpoint minimum inhibitory concentration (MIC) was used to calculate AUC/MIC and T > MIC parameters, adjusted by 93% protein binding. A total of 14 patients were enrolled, 11 with osteoarticular infection and 3 with ABSSSI. Long-term pharmacokinetics showed median T > MIC (0.125 mg/L) of 11.9 and 13.7 weeks for single and dual dose, respectively. Similarly, median AUC 0-2w /MIC ratios of 20,590 and 31,366 were observed for single and dual dose regimens, respectively. No adverse events were observed, and treatment success was achieved in 12/14 patients. Failure was associated with the worst clinical conditions, bone infections, and single dose. The results of this study show that dalbavancin exposure exceeds previously suggested pharmacodynamic targets. Optimization of these targets is needed for the osteoarticular setting.

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved.

Objectives: To assess if the lockdown period (March-April 2020) during the coronavirus disease-19 outbreak in Italy influenced the number, presentation, and treatment of urgent admissions to the emergency department for ureteral lithiasis, and to evaluate the same variables during the reopening phase (May-June 2020)., Methods: We performed a retrospective analysis of patients admitted to the emergency department of three different hospitals (two coronavirus disease-19 hubs). Demographics and data on acute pyelonephritis, acute kidney injury, urinoma, hematuria, inpatient admission/discharge home, and type of treatment were gathered and compared with the same periods in 2019., Results: A total of 516 patients were admitted during the study period, of whom 62.4% were male. Their mean age was 58.86 ± 16.24 years. The number of admissions decreased significantly, by 51.25% (P = 0.003), during lockdown compared to 2019 (78 vs 160 admissions). The number of admissions in the reopening phase (May-June 2020) was in line with that in 2019 (n = 138). The number of hospitalizations (P = 0.005), acute obstructive pyelonephritis (P = 0.019), and complications (P = 0.02) was statistically significantly higher during lockdown compared to 2019. The increase in the rate of surgical procedures nearly reached significance (P = 0.059). The odds of having complications and being hospitalized were almost fivefold (odds ratio 4.68, 95% confidence interval 1.98-11.07) and twofold greater (odds ratio 2.39, 95% confidence interval 1.29-4.43) compared to the same period in 2019. No difference was noted between May-June 2020 and 2019., Conclusion: The coronavirus disease-19 lockdown period provoked a meaningful reduction in symptomatic ureteral lithiasis admission. Most patients presented with complicated disease, which required an increased rate of interventional procedures compared to the equivalent period in 2019. Admissions reverted to normal levels during the reopening phase., (© 2021 The Japanese Urological Association.)

Transurethral resection of bladder tumor (TURBT) is still the gold standard for the diagnosis, treatment, and staging of nonmuscle invasive bladder cancer. En bloc resection of bladder tumor (EBRT) has been recently introduced to overcome the limitations of conventional TURBT. EBRT potential advantages are (1) complete resection, (2) a more precise and controlled resection (potentially fewer complications), (3) better sample orientation for histopathology analysis, (4) presence of detrusor in the specimen, and (5) less tumor seeding on normal urothelium by tumor fragments. This article aimed to present a step-by-step technique of conventional TURBT and EBRT with thulium laser support. We also aimed to provide tips and tricks for a correct surgical procedure and postoperative patient care. Finally, clinical outcomes of TURBT versus EBRT were reviewed.

Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration-effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines' requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF.

Recently, large-scale screening for COVID-19 has presented a major challenge, limiting timely countermeasures. Therefore, the application of suitable rapid serological tests could provide useful information, however, little evidence regarding their robustness is currently available. In this work, we evaluated and compared the analytical performance of a rapid lateral-flow test (LFA) and a fast semiquantitative fluorescent immunoassay (FIA) for anti-nucleocapsid (anti-NC) antibodies, with the reverse transcriptase real-time PCR assay as the reference. In 222 patients, LFA showed poor sensitivity (55.9%) within two weeks from PCR, while later testing was more reliable (sensitivity of 85.7% and specificity of 93.1%). Moreover, in a subset of 100 patients, FIA showed high sensitivity (89.1%) and specificity (94.1%) after two weeks from PCR. The coupled application for the screening of 183 patients showed satisfactory concordance (K = 0.858). In conclusion, rapid serological tests were largely not useful for early diagnosis, but they showed good performance in later stages of infection. These could be useful for back-tracing and/or to identify potentially immune subjects.

Background and Purpose: This is an observational study to evaluate the safety of magnetic resonance imaging (MRI) to localize subdural grids and depth electrodes in patients with refractory epilepsy using a 1.5 Tesla MR scanner., Methods: We implemented an optimized MRI protocol providing adequate image quality for the assessment of subdural grids and depth electrodes, while minimizing the specific absorption rate (SAR). We reviewed all MRI studies performed in patients with subdural grids and depth electrodes between January 2010 and October 2018. Image quality was graded as acceptable or nonacceptable for the assessment of intracranial device positioning. We reviewed the medical record and any imaging obtained after intracranial implant removal for adverse event or complication occurring during and after the procedure., Results: Ninety-nine patients with refractory epilepsy underwent MRI scans using a magnetization-prepared rapid acquisition of gradient echo sequence and a transmit-receive head coil with depth electrodes and subdural grids in place. Two patients underwent two separate depth electrode implantations for a total of 101 procedures and MRI scans. No clinical adverse events were reported during or immediately after imaging. Image quality was graded as acceptable for 97 MRI scans. Review of follow-up CT and MRI studies after implant removal, available for 70 patients, did not demonstrate unexpected complications in 69 patients., Conclusion: In our experience, a low SAR MRI protocol can be used to safely localize intracranial subdural grids and depth electrode in patients with refractory epilepsy., (© 2021 American Society of Neuroimaging.)

Primary central nervous system posttransplant lymphoproliferative disorder is a rare complication of solid organ transplantation, with increasing incidence in children given a steady rise in pediatric solid organ transplants. Given similar imaging appearance to many opportunistic infections, a high degree of awareness is required for prompt and early diagnosis. We report a case of primary central nervous system posttransplant lymphoproliferative disorder presenting as a single rim enhancing lesion with central restricted diffusion mimicking an intracranial abscess., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

In this study, we present the management of an intra-articular fracture in a 13-year-old boy with WAGR syndrome, an extremely rare genetic disorder. The goal of this study was to provide possible solutions to the complex pain management requirements presenting in the setting of trauma to the right lower extremity. Given the scarcity of literature available with regard to this condition, we aim to not only increase awareness of the disease but also provide insight into trauma management and expected outcomes.

We report herein the longest-lasting study of SARS-CoV-2 antibody profile in pregnancy, from first trimester-infection to delivery. Seventeen out of 164 pregnant women tested positive for COVID-19. Throughout pregnancy, the neutralizing antibody titer remained stable, whilst a significant decline in the non-neutralizing antibodies was observed after 16 weeks of gestation. All the newborns of women who developed IgG antibodies showed the presence of the same antibodies in arterial cord blood. Knowledge on the longevity and type of SARS-CoV-2 antibody response may help to guide vaccination strategies in pregnancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The treatment of drug-sensitive tuberculosis (TB) is highly effective; however, many patients have suboptimal drug exposure, which possibly explains treatment failures and selection of resistance. This study aimed to describe the prevalence and determinants of suboptimal maximal concentrations (C max ) for anti-TB drugs., Methods: An observational study was conducted in patients receiving first-line anti-TB treatment. At two early time points (T1 and T2), blood samples were withdrawn 2 hours post-dose (C max ) and drug concentrations were measured. Data were expressed as medians (interquartile ranges)., Results: The study included 199 participants: 72.9% were male and the median age was 39.8 years (27.5-51.4). The median C max at T1 and T2 were 7950 ng/mL and 7122 ng/mL (rifampicin), 3260 ng/mL and 3185 ng/mL (isoniazid), 4210 ng/mL and 5742 ng/mL (ethambutol), and 31 008 ng/mL and 30 352 ng/mL (pyrazinamide), respectively. Higher doses/kg and other variables (being born in Italy and female gender for rifampicin, older age and proton pump inhibitor use for isoniazid, female gender and older age for pyrazinamide) were identified by multivariate linear regression analysis. Participants with a higher body mass index received lower doses/kg of all anti-TB drugs. Suboptimal C max at T1 and T2 were observed in 60% and 66% (rifampicin), 54% and 55% (isoniazid), 33% and 39% (ethambutol), 20% and 11% (pyrazinamide) of patients. Despite 21% of patients at T1 and 24% at T2 showing two or more drugs with suboptimal exposure, no effect on treatment outcome was observed., Discussion: The majority of patients receiving first-line anti-TB drugs had low isoniazid and rifampin C max . Increased doses or the use of therapeutic drug monitoring in selected patients may be advised., (Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Thermography is a non-invasive diagnostic method commonly used to monitor changes of the body surface temperature potentially induced by different conditions such as fever, inflammation, trauma, or changes of tissue perfusion. Capacitive-resistive diathermy therapy (such as energy transfer capacitive and resistive-Tecar) is commonly used in rehabilitation due to its diathemic effect secondary to blood circulation increase that could accelerate the healing process. The aim of this study was to monitor by thermal camera the diathermic effects induced by Tecar on the surface of the region of application. The investigation was conducted on six dogs referred for Tecar therapy to treat muscle contractures (three dogs) or osteoarthritis (three dogs). Eleven anatomical treated regions were recorded. Thermographic images and relative measurements were obtained by each region immediately before (T0), at conclusion (T1), and sixty seconds after the Tecar application (T2). Data were recorded and statistically analyzed. A comparison of temperature differences (maximum, minimum and mean values) between T0 and T1, T0 and T2, and T1 and T2 was performed by ANOVA test with Bonferroni post hoc ( p ≤ 0.05). Statistically significant differences were detected for mean temperature between T0 (32.42 ± 1.57 °C) and T1 (33.36 ± 1.17 °C) ( p = 0.040) and between T1 and T2 (32.83 ± 1.31 °C) ( p = 0.031). Furthermore, there was no significant difference between the mean temperature at T0 and T2, demonstrating that superficial diathermic effect exhausted within 60 s.

Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2-8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3-5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.

Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies.

Introduction and Objectives: We aimed to evaluate how the corona virus disease of 2019 (COVID-19) outbreak influenced emergency department (ED) admissions for urolithiasis, hospitalizations and clinical management of the hospitalized patients., Patients and Methods: We conducted a multicentric retrospective analysis of ED admissions in three high volume urology departments (one directly involved in COVID-19 patients management and two not involved) in Rome - Italy between March and April 2020 and in the same period of 2019. Statistical analysis was conducted on the number of admissions for urolithiasis, rate of complications, hospitalization and the type of treatment received., Results: 304 patients were included in the analysis. A significant reduction in the global number of patients admitted to ED for urolithiasis between 2019 and 2020 (48.8%) was noted. Moreover, regarding the choice of treatment of hospitalized patients, a statistically significant increase of stone removal procedures versus urinary drainage was reported in 2020 (p = 0.015)., Conclusions: During the COVID-19 pandemic in Rome there has been a significant reduction of emergency admissions for urolithiasis. Patients admitted to ED had more complications, more frequently need hospitalization and regarding clinical management early stone removal was preferred over urinary drainage only. All the urologists should be aware that in the next months they could face an increased number of admissions for urolithiasis and manage more complicated cases., (Copyright © 2020 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: This exploratory retrospective analysis examined any potential prognostic role of preoperative neutrophil lymphocyte ratio (NLR) for progression-free survival (PFS) and time to endoscopically verified upper tract or bladder recurrence-free survival (RFS) in upper tract urothelial cancer (UTUC) patients selected for endoscopic treatment with subsequent endosurveillance. Patients and Methods: Eligibility criteria were natural orifice endoscopically retrogradely treated low-risk and imperative UTUC patients treated between 2005 and 2019, with biopsy confirmed diagnosis and 12 months minimum follow-up. For PFS, optimal NLR cutoff value was derived by log-rank test. Subsequently, both PFS and RFS were assessed for differences using Kaplan-Meier survival curves and log-rank test. Multivariate proportional Cox regression analysis adjusted for clinicopathologic variables was performed to examine end points for NLR-independent prognostic significance. Results: There were 100 eligible patients (63 truly low risk and 37 imperative cases). The optimal PFS log-rank test NLR cutoff value was 2.7. NLR ≥2.7 was significantly associated with shorter PFS ( p  = 0.01), and shorter upper tract RFS ( p  = 0.03), but not with bladder RFS ( p  = 0.90). Only positive high-grade cytology (hazard ratio [HR] 5.92, 95% confidence interval [CI] 2.140-16.35, p  = 0.002) and NLR ≥2.7 (HR 4.28, 95% CI 1.34-13.72, p  = 0.014) independently predicted PFS in multivariate analysis. Recurrence and progression were not significantly linked in the low-risk subset. Conclusions: This exploratory analysis showed that baseline NLR evaluation before first endoscopic UTUC treatment may be a valuable predictor and prognosticator of defined disease progression and of upper tract recurrence risk. In conjunction with high-grade urine cytology, NLR may improve risk stratification to optimize future individualized management.

Therapeutic drug monitoring (TDM) of immunosuppressive drugs is crucial in organ-transplanted patients to prevent rejection or toxic effects due to inadequate dosage. Mycophenolic acid (MPA) is a commonly used immunosuppressant in this setting. Nowadays, MPA concentrations are monitored by Enzyme Multiplied Immunoassay Technology (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Tandem Mass Spectrometry (LC-MS/MS). This study evaluates the concordance between TDM results for MPA obtained through CE-IVD EMIT and LC-MS/MS assays in plasma samples. LC-MS/MS quantification was based on a commercial kit and the analytical performance in terms of accuracy was tested through external proficiency tests and inter-laboratory comparison with a home-made HPLC-UV method. Both these evaluations confirmed the reliability of the LC-MS/MS method (1.6 % and 9.0 % of bias, respectively). Conversely, the comparison between EMIT and LC-MS/MS showed overestimation by EMIT of 33.5 %. This bias resulted concentration-dependent, ranging from 46.4 % in the concentration range of 1-2 mg/L, to 21.4 % over 4 mg/L. Considering the theoretical clinical impact of this overestimation, a fraction comprised between 12.4 % and 31.4 % of samples which resulted over three different minimum effective concentration values by EMIT (no indication for dose adjustment) had discordant indications by LC-MS/MS (dose adjustment needed). Concluding, this study highlights a clinically relevant systematic overestimation of MPA concentration by EMIT, supporting the switch to LC-MS/MS techniques for TDM purpose. However, further prospective studies are needed in order to evaluate the clinical impact of switching the TDM activity from EMIT to LC-MS/MS in a larger cohort in a long period., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification., Objectives: The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma., Methods: Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines., Results: Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety., Conclusions: This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Objectives: The broad-spectrum triazole antifungal agent, voriconazole, is widely used in the treatment of invasive fungal infections. Its treatment efficacy and the occurrence of adverse events are associated with plasma drug concentration, rendering inconsistent or inadequate dosing in many patients. The aim of this study was to evaluate the effect of gender, age, body mass index, ethnicity, serum creatinine and drug dose on voriconazole trough concentration., Methods: A fully validated chromatographic method was used to quantify voriconazole concentration in plasma collected from adult patients at the end of dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney U test was used to probe the influence of categorical variables on continuous ones., Results: In a cohort of 330 Italian patients treated with voriconazole, males reported a significantly higher drug concentration than females, with values higher than 1000 ng/mL. Moreover, in the univariate analysis, a significant correlation was found between trough concentration and increasing age., Conclusion: Increasing age and gender could influence voriconazole trough concentrations.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic, epigenetic and environmental factors. The discovery of new gene polymorphisms and their association with disease susceptibility have added new elements to better clarify RA pathogenesis. In the last year, important elements have been added to the current knowledge of mechanisms regulating innate and adaptive immunity in RA, leading to discovering new targets for the development of disease-modifying therapies. Thus, in this review we summarise the new insights resulting from a literature research data published in the last year.

Background: Recent studies have reported contrasting results of the effects of laser therapy on post-operative intervertebral disk herniation, with a lack of evidence-based advantages of this modality within a rehabilitation protocol. The aim of this study was to report the clinical effects of photobiomodulation therapy within a post-operative rehabilitation protocol in dogs submitted to surgery for thoracolumbar disk extrusion. Twenty-four dogs were included in the study (12 dogs treated with laser therapy and rehabilitation protocol and 12 dogs treated with same rehabilitation protocol but without laser therapy)., Results: All dogs treated with laser therapy showed improved neurological status (Modified Frankel Score more than 3 within 30 days of physiotherapy starting) if deep nociception on admission was maintained (P = 0.04). However, Kaplan-Meier analysis did not show any statistical difference in time to regain ambulatory ability, although there was a tendency for a shorter mean time of 14.2 ± 8.55 days in the laser group versus 24 ± 18.49 days in the no laser group., Conclusions: The use of laser therapy in the post-operative rehabilitation of dogs affected by intervertebral disc extrusion and submitted to surgery for spinal decompression could help improve their neurological status.

Although arterio-venous grafts (AVGs) represent the second choice as permanent vascular access for hemodialysis, this solution is still affected by a relevant failure rate due to graft thrombosis, and development of neointimal hyperplasia (IH) at the distal vein. As a key role in these processes has been attributed to the abnormal hemodynamics establishing in the distal vein, the optimization of AVGs design aimed at minimizing flow disturbances would reduce AVG hemodynamic-related risks. In this study we used computational fluid dynamics to investigate the impact of alternative AVG designs on the reduction of IH and thrombosis risk at the distal venous anastomosis. The performance of the newly designed AVGs was compared to that of commercially available devices. In detail, a total of eight AVG models in closed-loop configuration were constructed: two models resemble the commercially available straight conventional and helical-shaped AVGs; six models are characterized by the insertion of a flow divider (FD), straight or helical shaped, differently positioned inside the graft. Unfavorable hemodynamic conditions were analyzed by assessing the exposure to disturbed shear at the distal vein. Bulk flow was investigated in terms of helical blood flow features, potential thrombosis risk, and pressure drop over the graft. Findings from this study clearly show that using a helically-shaped FD located at the venous side of the graft could induce beneficial helical flow patterns that, minimizing flow disturbances, reduce the IH-related risk of failure at the distal vein, with a clinically irrelevant increase in thrombosis risk and pressure drop over the graft., Competing Interests: Declaration of Competing Interest The authors state no conflict of interest for the study object of the manuscript. The research was not supported financially by private companies. None of the authors has a financial agreement with peoples or organisations that could inappropriately influence their work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Larvae of Tenebrio molitor L. (Coleoptera: Tenebrionidae) are particularly suitable as novel food for the human consumption; nevertheless, there are some potential safety risks linked with insect consumption. In this study we investigated the presence of Cd, Pb, Ni, As, Hg in new feeding substrates coming from solid residues generated by olive fruits processing, called olive-pomace, and their influence on the metal content in larvae of T. molitor . Morover, bioaccumulation factor and the mercury-selenium balance were evaluated. Analyses were carried out via graphite furnace atomic absorption spectrophotometry for Cd, Pb, Ni, As and Se, and via Direct Mercury Analyzer for Hg. All metal concentrations found in feeding substrates were below the legal limit of undesirable substances in animal feed (2002/32/EC). Concentrations in larvae were in the range (mg kg -1 wet weight): Cd 0.008-0.016, Pb 0.063-0.079, Ni 0.03-0.63, As 0.021-0.023, Hg 0.12 × 10 -3 -0.49 × 10 -3 , and Se 0.057-0.085. Statistically significant correlation between metal content in feeding substrates and in larvae was evidenced only for Hg, which bioaccumulates. Se protects from mercury toxicity, with a Selenium Health Benefit Value (HVB Se ) of > 0. Overall, our results indicate that the risk of exposure to metals from consumption of mealworm larvae is relatively low and in compliance with European Union regulations.

Introduction and Objectives: To evaluate ablative safety and efficacy of thulium-holmium:YAG (TL-HL:YAG) duo laser in renal conserving retrograde intrarenal surgery (RC-RIRS) in upper tract urothelial carcinoma (UTUC). Materials and Methods: A retrospective study was performed on 178 consecutive patients referred for consideration of RC-RIRS UTUC-eLA (endoscopic laser ablation) in a tertiary center (January 2005 to December 2018). Key data were recorded using a standardized study proforma. Results: After endodiagnostic procedure, 42 declined rigorous endosurveillance protocol and went elsewhere for alternative treatment, leaving 136 patients, of whom 35 patients dropped out (25.7%) after undergoing primary radical nephroureterectomy (RNU) (unsuitable for renal preservation). This was left with 101 candidates who continued UTUC conservative management (intention-to-treat [ITT] population). Mean follow-up (FU) for these 101 patients was 28.7 months. At last FU (range 3-144 months), 70 patients (69.3%) were recurrence free, 22 (21.8%) had endoscopically treated recurrences, and a further 9 (8.9%) had undergone RNU. In the ITT population, kidney-preserving rate was 91%, whereas in imperative indications, it was 87.5%. Clavien-Dindo grade I complications only (self-limiting hematuria) were reported in 10%. Conclusions: Over a 13-year period, RC-RIRS UTUC treatment with the TL-HL:YAG duo laser was safe and oncologically noninferior to alternative combination laser energy technologies used for this indication.

A desirable goal of the aquaculture sector is to replace most of fish meal and fish oil with more sustainable, cost-effective, and environmental friendly ingredients ensuring fish health and welfare standards. Due to minimal environmental impact, compared with most conventional feed commodities, insects deserve a growing attention as candidate ingredients for aquafeeds. The present study investigated, for the first time, the possible application of a 100% insect diet in zebrafish larval rearing. Through a multidisciplinary approach, the major biological responses of fish to the new diets were assessed. Results of biometry, fatty acid composition, expression of genes involved in fish growth, stress response, lipid metabolism, chitinolytic activity, gut inflammation, and liver macromolecular composition suggested a possible application of insect larvae for zebrafish larval rearing. However, further studies are necessary to better understand the use of this insect species in the rearing of fish.

Materials and Methods: The study was conducted from December 2011 to December 2012 on 95 patients between the ages of 20 and 65 years: 44 of which had been undergoing dialysis for over a year and 51 of whom had undergone kidney transplants more than 6 months before. Comorbidities were carefully recorded, erectile function was evaluated the with IIEF5 questionnaire and serum levels of total testosterone / free and prolactin were tested at early morning (7 AM). To assess the relationship between erectile dysfunction (ED) and clinical laboratory tests, Student's t-test statistical (quantitative variables), chi-square (qualitative variables), the uni and multivariate analysis were used., Results: In patients undergoing dialysis and in recently transplanted patients a higher instance of ED was found (70% and 65% of cases respectively). Amongst dialyzed patients, patients aged over 50 suffer from ED more frequently. Patients aged over 50s represent 61% of the total number of patients suffering from ED, and just 31% of patients not suffering from ED, (p = 0.006); Hyperprolactinemia was found in 23% and 20% of both groups respectively. Fifty nine % of the dialyzed patients presented values of testosterone serum levels of less than 250 ng/dl with a significant difference between those who were suffering from ED and those who were not (65% of ED patients vs. 46%,of patients not affected from ED p = 0.019). This was found in only 37% of transplanted patients and there does not appear to be a statistically significant correlation with the onset of ED (p = 0.12). In patients over the age of 50, diabetes and a condition of hypotestosteronemia were significantly correlated with ED at univariate and multivariate analyses., Conclusions: The ED in patients with end stage chronic kidney failure (CKF) continues to have a strong prevalence, either in the patients who are undergoing dialysis or in those who have received transplants. In literature this issue is not sufficiently considered if not at all. Hypotestosteronemia is a risk factor for the onset of ED in end stage CKF patients. A significantly lower prevalence of hypogonadism among dialyzed patents and transplant recipients suggests that renal transplantation may be protective for the sexual capabilities of these patients.

Curative treatments, including liver transplantation, surgical resection and percutaneous treatments, are the recommended therapies in BCLC-0 (Barcelona Clinic of Liver Cancer) or BCLC-A hepatocellular carcinoma (HCC). This review provides an overview of some issues of clinical importance concerning curative treatments in HCC.

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.

Background and Purpose: Parallel imaging facilitates the acquisition of echo-planar images with a reduced TE, enabling the incorporation of an additional image at a later TE. Here we investigated the use of a parallel imaging-enhanced dual-echo EPI sequence to improve lesion conspicuity in diffusion-weighted imaging., Materials and Methods: Parallel imaging-enhanced dual-echo DWI data were acquired in 50 consecutive patients suspected of stroke at 1.5T. The dual-echo acquisition included 2 EPI for 1 diffusion-preparation period (echo 1 [TE = 48 ms] and echo 2 [TE = 105 ms]). Three neuroradiologists independently reviewed the 2 echoes by using the routine DWI of our institution as a reference. Images were graded on lesion conspicuity, diagnostic confidence, and image quality. The apparent diffusion coefficient map from echo 1 was used to validate the presence of acute infarction. Relaxivity maps calculated from the 2 echoes were evaluated for potential complementary information., Results: Echo 1 and 2 DWIs were rated as better than the reference DWI. While echo 1 had better image quality overall, echo 2 was unanimously favored over both echo 1 and the reference DWI for its high sensitivity in detecting acute infarcts., Conclusions: Parallel imaging-enhanced dual-echo diffusion-weighted EPI is a useful method for evaluating lesions with reduced diffusivity. The long TE of echo 2 produced DWIs that exhibited superior lesion conspicuity compared with images acquired at a shorter TE. Echo 1 provided higher SNR ADC maps for specificity to acute infarction. The relaxivity maps may serve to complement information regarding blood products and mineralization., (© 2014 by American Journal of Neuroradiology.)

Infertility is defined as the inability of a couple to conceive after 12 months of unprotected intercourse and affects 15% of couples with male component of 50%. The failure of spermatogenesis can result from hypothalamic, pituitary or testicular disorders although in the majority of cases it remains idiopathic. The diagnostic process includes medical history, semen analysis, hormonal studies, genetic studies and radiological evaluation.Targeted hormonal therapies are available for patients whose infertility is caused by altered levels of androgens, prolactin, or TSH. Main treatments aim to restore normal sexual function by administering testosterone and to increase spermatogenesis with pulsatile GnRH.Fertility in men suffering from hypogonadotrophic hypogonadism can be restored through hormone therapy using GnRH or with the use of gonadotropins when there is hypothalamic failure. In the past, treatment options for the factors of idiopathic male infertility were mainly based on the use of anti-estrogens that cause an increased secretion of FSH and LH and therefore of testosterone.Oxytocin promotes the progression of the sperm and increases the conversion of testosterone into dihydrotestosterone. The aromatase's inhibitors decrease the conversion of androgens to estrogens, increasing serum levels of androgens, resulting in an increased release of gonadotropins.Two areas showed interesting future perspectives for the treatment of infertility: gene therapy and transplantation of spermatogonial stem cells.

Radical orchiectomy is the standard treatment of testicular neoplasia causing androgen insufficiency, infertility and psychological stress. Focal surgery allows the preservation of fertility, endocrine function and integrity of the genital anatomy, with preservation of the image of the male body. The EAU guidelines suggest focal surgery in case of synchronous bilateral tumors, metachronous contralateral tumours, tumour in solitary testis with normal pre-operative testosterone levels, when the tumor volume less than 30% of the testicular volume. There are two focal surgical techniques: tumorectomy and polar resection, followed by biopsies and frozen section of the resection bed. In case of benign tumours, the treatment is often curative. In case of malignancy, carcinoma in situ is frequently found in the surrounding tissues. Adjuvant treatment with chemotherapy or radiotherapy is performed with a fair success rate. These adjuvant treatments reduce or delete the functional benefits achieved by conservative surgery. The evidence of the literature suggests that focal surgery is a valid option for all patients with testicular tumours that are not palpable and small sized, with the advantage of avoiding unnecessary radical orchiectomy in most cases. Therefore, the selection criteria for focal surgery are the mass size (less than 25 mm) and a safety distance of the tumor from the rete testis, in order to preserve testicular vascularization. A close follow-up with ultrasound, testicular markers and radiological examinations is mandatory in case of germ cell neoplasia treated conservatively in patients with indications for conservative surgery.

Introduction: Radical surgery is the "gold standard" for treatment of invasive penile carcinoma but very poor aesthetic, functional and psychological outcomes have been reported. Our purpose was to assess the impact of organ potency-sparing surgery in locally confined carcinoma of the penis., Materials and Methods: We evaluated retrospectively 42 patients with early penile cancer (Ta,T1,T2), treated with glandulectomy and glanduloplasty with urethral mucosa and sparing of cavernosal apexes, or glandulectomy and limited apical resection in cases of Stage T2. Sexual function, ejaculation and libido were evaluated with an IIEF-15 questionnaire before the appearance of neoplasia (about three months before the surgery) and six months after surgery. Quality of life was evaluated by the Bigelow-Young questionnaire. The scores relating to two weeks prior to the surgery have been compared to those obtained six months after surgery. The statistical analysis was conducted using t-Student for repeated measures and analysis of variance., Results: Six months after surgery 73% of patients reported spontaneous rigid erections, 60% coital activity while 76% of the group treated with urethral glanduloplasty reported normal ejaculation and orgasm, regained an average of 35 days after surgery. The average IIEF-15 scores reported in the entire series in the domains of erection, libido and coital activity of the pre-cancer period were not statistically different than those recorded six months after surgery. In the group treated with glandular reconstruction, pre-and postoperative IIEF-15 mean scores related to ejaculation and orgasm domains were not significantly different. Mean scores of Bigelow-Young questionnaires related to sexual pleasure, familial, social and professional relationships showed significant improvement after surgery., Conclusions: Potency sparing-sparing surgical treatments have a positive impact on a wide spectrum of the patient's life including family relationships, and social and working conditions.

A systematic review of the current treatment options and of the outcomes of penile carcinoma has been performed with special focus on controversial issues. A MedLine search using specified search terms was done during the period 1988 - January 2013. Demolitive surgery is considered as the "gold standard" treatment of invasive penile carcinoma staged higher than T2, but negative psychological outcomes were reported. On the other hand, conservative surgical techniques have been associated with higher recurrence rates. Potency-sparing technique (glansectomy and apexes sparing) preserves penile length: the reconstruction of glans anatomy and function is a key point to restore anatomy and sexual functions. Techniques such as glanduloplasty have given satisfactory anatomic, functional and sexual outcomes. Lymphadenectomy is indicated in any case of inguinal palpable nodes that persist after a course of antibiotic therapy, but also in all the cases staged T2 or higher, or in any high-grade penile cancer. It is still being debated the extension of inguinal lymphadenectomy for penile cancer: unilateral, bilateral, and extended to pelvic lymph nodes. Due to the specific radioresistance of penile cancer, radiation therapy is currently indicated in case of unresectable penile cancers with palliative intent. Chemotherapy is indicated as adjuvant therapy for stage T1-T3, N1-3, M0, or as neo-adjuvant therapy in the event of extensive pelvic and inguinal lymphadenopathies, or as palliative treatment in patients with unresectable or metastatic cancers. New chemotherapy agents such as Cis - platinum and Taxanes have shown promising results in early trials.