Publications by authors named "Nicola Longo"

207 Publications

MRI index lesion radiomics and machine learning for detection of extraprostatic extension of disease: a multicenter study.

Eur Radiol 2021 Apr 1. Epub 2021 Apr 1.

Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples, Italy.

Objectives: To build a machine learning (ML) model to detect extraprostatic extension (EPE) of prostate cancer (PCa), based on radiomics features extracted from prostate MRI index lesions.

Methods: Consecutive MRI exams of patients undergoing radical prostatectomy for PCa were retrospectively collected from three institutions. Axial T2-weighted and apparent diffusion coefficient map images were annotated to obtain index lesion volumes of interest for radiomics feature extraction. Data from one institution was used for training, feature selection (using reproducibility, variance and pairwise correlation analyses, and a correlation-based subset evaluator), and tuning of a support vector machine (SVM) algorithm, with stratified 10-fold cross-validation. The model was tested on the two remaining institutions' data and compared with a baseline reference and expert radiologist assessment of EPE.

Results: In total, 193 patients were included. From an initial dataset of 2436 features, 2287 were excluded due to either poor stability, low variance, or high collinearity. Among the remaining, 14 features were used to train the ML model, which reached an overall accuracy of 83% in the training set. In the two external test sets, the SVM achieved an accuracy of 79% and 74% respectively, not statistically different from that of the radiologist (81-83%, p = 0.39-1) and outperforming the baseline reference (p = 0.001-0.02).

Conclusions: A ML model solely based on radiomics features demonstrated high accuracy for EPE detection and good generalizability in a multicenter setting. Paired to qualitative EPE assessment, this approach could aid radiologists in this challenging task.

Key Points: • Predicting the presence of EPE in prostate cancer patients is a challenging task for radiologists. • A support vector machine algorithm achieved high diagnostic accuracy for EPE detection, with good generalizability when tested on multiple external datasets. • The performance of the algorithm was not significantly different from that of an experienced radiologist.
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http://dx.doi.org/10.1007/s00330-021-07856-3DOI Listing
April 2021

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies.

Diagnostics (Basel) 2021 Feb 20;11(2). Epub 2021 Feb 20.

Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy.

Bladder cancer (BCa) is an endocrine-related tumour and the activation of androgen signalling pathways may promote bladder tumorigenesis. We summarized the available preclinical and clinical evidence on the implications of the manipulation of androgen signalling pathways on the outcomes of BCa therapies. A systematic review was performed in December 2020. We included papers that met the following criteria: original preclinical and clinical research; evaluating the impact of androgen signalling modulation on the outcomes of BCa therapies. Six preclinical and eight clinical studies were identified. The preclinical evidence demonstrates that the modulation of androgen receptor-related pathways has the potential to interfere with the activity of the Bacillus Calmette Guerin, doxorubicin, cisplatin, gemcitabine, and radiotherapy. The relative risk of BCa recurrence after transurethral resection of the bladder tumour (TURBT) is significantly lower in patients undergoing therapy with 5 alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT) (Relative risk: 0.50, 95% CI: 0.30-0.82; = 0.006). Subgroup analysis in patients receiving 5-ARIs revealed a relative risk of BCa recurrence of 0.46 (95% CI: 0.22-0.95; = 0.040). A significant negative association between the ratio of T1 BCa patients in treated/control groups and the relative risk of BCa recurrence was observed. Therapy with 5-ARIs may represent a potential strategy aimed at reducing BCa recurrence rate, mainly in patients with low stage disease. Further studies are needed to confirm these preliminary data.
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http://dx.doi.org/10.3390/diagnostics11020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923424PMC
February 2021

Hypogonadism in Patients with Prader Willi Syndrome: A Narrative Review.

Int J Mol Sci 2021 Feb 17;22(4). Epub 2021 Feb 17.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", 80131 Naples, Italy.

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder related to the lack of a functional paternal copy of chromosome 15q11-q13. Several clinical manifestations are reported, such as short stature, cognitive and behavioral disability, temperature instability, hypotonia, hypersomnia, hyperphagia, and multiple endocrine abnormalities, including growth hormone deficiency and hypogonadism. The hypogonadism in PWS is due to central and peripheral mechanisms involving the hypothalamus-pituitary-gonadal axis. The early diagnosis and management of hypogonadism in PWS are both important for physicians in order to reach a better quality of life for these patients. The aim of this study is to summarize and investigate causes and possible therapies for hypogonadism in PWS. Additional studies are further needed to clarify the role of different genes related to hypogonadism and to establish a common and evidence-based therapy.
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http://dx.doi.org/10.3390/ijms22041993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922674PMC
February 2021

SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review.

J Med Virol 2021 May 1;93(5):3133-3142. Epub 2021 Mar 1.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy.

PubMed, Scopus, and ISI Web of Knowledge databases were searched to identify studies published up to December 2020 on the involvement of urinary and male genital systems in COVID-19. Sixteen studies involving a total of 575 patients (538 males and 37 females) were included in this systematic review. The COVID-19 phase was available for 479 patients: 426 in the acute and 53 in the recovery phase. De novo lower urinary tract symptoms (LUTS) were observed in 43 patients and deterioration of pre-existing LUTS in 7. Bladder hemorrhage was observed in three patients and acute urinary retention in one. Regarding the male genital system, scrotal discomfort was observed in 8 patients, swelling in 14, pain in 16, and erythema in 1; low flow priapism was observed in 2 patients. Ultrasound examination identified acute orchitis in 10 patients, acute epididymitis in 7, and acute epididymo-orchitis in 16. A case-control study reported that patients with moderate COVID-19 show a significant reduction in sperm concertation, the total number of sperms per ejaculate, progressive motility, and complete motility. In contrast to what is known from the first studies on the subject, this review also includes subsequent studies that give evidence of the involvement of the lower urinary tract and male genital system in COVID-19.
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http://dx.doi.org/10.1002/jmv.26883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013185PMC
May 2021

Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study.

Clin Nutr ESPEN 2021 Feb 25;41:293-298. Epub 2020 Dec 25.

Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA, USA.

Background & Aims: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive disorders that lead to energy depletion and major clinical events (MCEs), such as acute metabolic crises of hypoglycemia, cardiomyopathy, and rhabdomyolysis. The aim of this study was to report a post hoc analysis of diet diary data from the phase 2 UX007-CL201 study (NCT01886378).

Methods: In the single-arm, open-label, phase 2 UX007-CL201 study, the safety and efficacy of 78 weeks of treatment with triheptanoin, an odd-carbon, medium-chain triglyceride consisting of three 7-carbon fatty acids on a glycerol backbone, was investigated in subjects with LC-FAOD versus a retrospective 78-week period when subjects were optimally managed under published dietary guidelines. Subject dietary reports were collected to analyze the relationship between diet, triheptanoin treatment, and MCEs. Referring metabolic physicians completed a survey on patient management and clinical outcomes before and after initiation of triheptanoin. Before initiating triheptanoin, subjects received a mean daily caloric intake (DCI) of 17.4% from medium-chain triglycerides (MCT). During the study, subjects received a mean of 27.5% DCI from triheptanoin. Protein (13.7% vs 14.5% DCI), long-chain fat (13.1% vs 10.5% DCI), and carbohydrate (55.3% vs 47.1% DCI) intake were consistent between the pre-triheptanoin and triheptanoin treatment periods, respectively.

Results: Following 78 weeks of treatment, mean annualized MCE rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028). A weak association existed between improvement in annualized MCE rate and change in percent DCI from MCT (Spearman rank correlation: r = -0.38; 95% CI: -0.675, 0.016). However, there was large variability in the association and no specific pattern of change for larger or smaller changes in dose. Seventy-two percent of physicians reported that triheptanoin had a clinically meaningful benefit on medical management of their patients.

Conclusions: Treatment with triheptanoin at the protocol-specified dose decreased the rate of MCEs in patients with LC-FAOD independently from other dietary changes between the pre-triheptanoin and triheptanoin treatment periods.

Trial Registration: ClinicalTrials.gov identifier: NCT01886378.
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http://dx.doi.org/10.1016/j.clnesp.2020.11.018DOI Listing
February 2021

Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis.

Mol Genet Metab 2021 02 13;132(2):119-127. Epub 2021 Jan 13.

Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. Electronic address:

Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was -0.5768 with a lower limit of the 95% confidence interval (CI) of -1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of -3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120-360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.
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http://dx.doi.org/10.1016/j.ymgme.2021.01.001DOI Listing
February 2021

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders.

Mol Genet Metab 2021 01 23;132(1):19-26. Epub 2020 Dec 23.

University of Minnesota, Minneapolis, MN, USA.

Background/aims: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.

Methods: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.

Results: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.

Conclusions: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
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http://dx.doi.org/10.1016/j.ymgme.2020.12.002DOI Listing
January 2021

Focus on Silodosin: Pros and Cons of Uroselectivity.

Res Rep Urol 2020 23;12:669-672. Epub 2020 Dec 23.

Department of Urology, Luigi Vanvitelli University of Naples, Naples, Italy.

Medical management of lower urinary tract symptoms related to benign prostatic obstruction engages healthcare professionals worldwide. Currently, alpha-1 adrenergic antagonists are strongly recommended as first-line therapy for patients with moderate to severe symptoms because of their safety, efficacy and good tolerability. These agents are highly heterogeneous in terms of pharmacological selectivity for the adrenergic receptor subtypes with silodosin being the agent characterized by the highest α/α affinity ratio. This property has been proposed to confer to silodosin advantages in terms of bladder outlet obstruction improvement and lower incidence of cardiovascular side effects at the cost of a higher incidence of ejaculatory dysfunction. These aspects should be carefully taken in consideration when personalizing medical therapy for lower urinary tract symptoms related to benign prostatic obstruction.
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http://dx.doi.org/10.2147/RRU.S287129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767706PMC
December 2020

Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists.

Arch Ital Urol Androl 2020 Dec 17;92(4). Epub 2020 Dec 17.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples.

Objective: We aimed to assess the attitudes and perceptions towards multiparametric magnetic resonance imaging (mpMRI) of the prostate among Italian urologists.

Material And Methods: A national, web-based survey was performed. A questionnaire composed of 18 multiple choice questions was e-mailed to 941 currently active urologists, members of the Italian Society of Urology. Preserving anonymity, respondents' demographics were collected (e.g. geographic region, type of workplace, prostate procedures performed) as well as data concerning their attitudes and perceptions towards mpMRI (e.g. indications deemed appropriate, degree of confidence in mpMRI results). Data were expressed as raw numbers and percentages of survey answers.

Results: In total, 98 responses were received (participation rate = 10.4%). Respondents mostly worked in urban areas (96%) and primarily in hospital settings (89%), while 48% of them worked in southern Italy. 97% of respondents considered mpMRI useful to detect Prostate Cancer (PCa) in patients with prior negative biopsy, 64% in biopsy-naïve patients and 60% for PCa pre-operatory staging. About half (42%) of the participants declared that mpMRI results frequently lead them to change PCa management strategy. Standardization of mpMRI acquisition and reporting was partially unsatisfactory. Reported waiting time for mpMRI scans was longer than 4 weeks for 51% of respondents. The major limitation of this survey includes the small number of participants.

Conclusions: Prostate mpMRI is used by Italian urologists mainly for detection and for pre-operative staging of PCa. Further improvements in terms of mpMRI availability and report standardization are required.
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http://dx.doi.org/10.4081/aiua.2020.4.291DOI Listing
December 2020

Outcomes of Renal Stone Surgery Performed Either as Predonation or Ex Vivo Bench Procedure in Renal Grafts from Living Donors: A Systematic Review.

Biomed Res Int 2020 27;2020:6625882. Epub 2020 Nov 27.

Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Aims: We aimed to summarize available evidence about intraoperative and postoperative donors' and recipients' outcomes following stone surgery in renal grafts from living donors performed either before donation or as ex vivo bench surgery at the time of living-donor nephrectomy.

Methods: A systematic review of PubMed, ISI Web of Knowledge, and Scopus databases was performed in September 2020. We included full papers that met the following criteria: original research, English language, human studies, and describing the results of stone surgery in renal grafts from living donors performed either before transplantation or as ex vivo bench surgery.

Results: We identified 11 studies involving 106 patients aged between 22 and 72 years. Predonation and bench stone surgery was performed in 9 (8.5%) and 96 (90.6%) patients, respectively. Predonation stone surgery involved extracorporeal shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy in 8, 1, and 1 patient, respectively. The overall success rate of predonation stone surgery was 78%, and the complication rate was 0%. Bench stone surgery involved ureteroscopy, pyelolithotomy, or a combination of both in 79 (82.3%), 10 (10.4%), and 7 (7.3%) cases, respectively, with an overall success rate of 95.8% and an overall complication rate of 9.37%.

Conclusions: Predonation and bench stone surgery in grafts from living donors represents efficacious and safe procedures. Further studies on wider series with a longer follow-up are required.
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http://dx.doi.org/10.1155/2020/6625882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723480PMC
November 2020

How Can the COVID-19 Pandemic Lead to Positive Changes in Urology Residency?

Front Surg 2020 24;7:563006. Epub 2020 Nov 24.

Department of Urology, IEO European Institute of Oncology IRCCS, Milan, Italy.

The COVID-19 outbreak, in a few weeks, overloaded Italian hospitals, and the majority of medical procedures were postponed. During the pandemic, with hospital reorganization, clinical and learning activities performed by residents suffered a forced remodulation. The objective of this study is to investigate how urology training in Italy has been affected during the COVID-19 era. In this multi-academic study, we compared residents' training during the highest outbreak level with their previous activity. Overall 387 (67.1%) of the 577 Italian Urology residents participated in a 72-h anonymous online survey with 36 items sent via email. The main outcomes were clinical/surgical activities, social distancing, distance learning, and telemedicine. Clinical and learning activity was significantly reduced for the overall group, and after categorizing residents as those working only in COVID hospitals, both "junior" and "senior" residents, and those working in any of three geographical areas created (Italian regions were clustered in three major zones according to the prevalence of COVID-19). A significant decrease in outpatient activity, invasive diagnostic procedures, and endoscopic and major surgeries was reported. Through multivariate analysis, the specific year of residency has been found to be an independent predictor for all response modification. Being in zone 3 and zone 2 and having "senior" resident status were independent predictors associated with a lower reduction of the clinical and learning activity. Working in a COVID hospital and having "senior" resident status were independent predictors associated with higher reduction of the outpatient activity. Working in zone 3 and having "senior" resident status were independent predictors of lower and higher outpatient surgical activity, respectively. Working in a COVID hospital was an independent predictor associated with robotic surgical activity. The majority of residents reported that distance teaching and multidisciplinary virtual meetings are still not used, and 44.8% reported that their relationships with colleagues decreased. The COVID-19 pandemic presents an unprecedented challenge, including changes in the training and education of urology residents. The COVID era can offer an opportunity to balance and implement innovative solutions that can bridge the educational gap and can be part of future urology training.
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http://dx.doi.org/10.3389/fsurg.2020.563006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732553PMC
November 2020

Incidence and Survival Rates of Contemporary Patients with Invasive Upper Tract Urothelial Carcinoma.

Eur Urol Oncol 2020 Dec 5. Epub 2020 Dec 5.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada.

Background: Contemporary incidence and mortality rates of upper tract urothelial carcinoma (UTUC) are unavailable.

Objective: To describe contemporary UTUC incidence and mortality rates in the USA.

Design, Setting, And Participants: Within the Surveillance, Epidemiology and End Results (SEER) database (2004-2016), we identified 13 075 UTUC patients. Of all, 9208 (70.4%) harbored nonmetastatic UTUC and were treated with radical nephroureterectomy versus 1174 (9.0%) who harbored metastatic UTUC.

Outcome Measurements And Statistical Analysis: Age-standardized incidence rates per 100 000 person years were calculated. Kaplan-Meier curves and multivariable Cox regression models addressed cancer-specific and overall mortality.

Results And Limitations: Overall UTUC age-standardized incidence rates decreased from 1.3 to 1.1 cases per 100 000 person years (average annual percentage change: -1.32%, p = 0.002). Moreover, age-standardized incidence rates decreased for TNM (average annual percentage change: -2.77%, p < 0.001) but increased for TNM stage (average annual percentage change: +2.87%, p < 0.01). In nonmetastatic UTUC treated with radical nephroureterectomy, stage, grade, age, and sex (p < 0.001) were independent predictors in multivariable Cox regression models focusing on cancer-specific mortality. In metastatic UTUC, chemotherapy administration, radical nephroureterectomy treatment, and ureteral primary were independent predictors of lower overall mortality in multivariable Cox regression models.

Conclusions: Although overall incidence of UTUC decreased, the incidence of metastatic UTUC increased over the study period. The majority of nonmetastatic UTUC harbored TNM stage. However, TNM, TNM, and TNM stages, respectively, affected 28.9%, 4.6%, and 10.0% of all incident cases. In metastatic UTUC, both chemotherapy and radical nephroureterectomy use exerted an important protective effect on overall mortality, and ureteral primaries exhibited more favorable survival.

Patient Summary: From 2004 to 2016, the incidence of upper tract urothelial carcinoma decreased in the USA. However, more advanced stages are on the rise.
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http://dx.doi.org/10.1016/j.euo.2020.11.005DOI Listing
December 2020

Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy.

A high percentage of patients with metastatic renal cell carcinoma (mRCC) require a second-line option. We aimed to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. A systematic review was performed in August 2020. We included papers that met the following criteria: original research; English language; human studies; enrolling mRCC patients entering a second-line therapy. Twenty-nine studies enrolling 7650 patients (73.5% male, mean age: 55 to 70 years) were included. Clear cell histology was reported in 74.4% to 100% of cases. Tyrosine kinase inhibitors, immunotherapy, bevacizumab, mTOR inhibitors, and chemotherapy were adopted as first line option in 68.5%, 29.2%, 2.9%, 0.6%, and 0.2% of patients, respectively. Discontinuation of first-line therapy was due to progression and toxicity in 18.4% to 100% and in 17% to 48.8% of patients, respectively. Eastern Cooperative Oncology Group performance status score was 0 or 1 in most cases. Most prevalent prognostic categories according to the International Metastatic RCC Database Consortium and Memorial Sloan-Kettering Cancer Centre score were intermediate and good. About 77.8% of patients harboured ≥2 metastatic sites. In conclusion, patients who enter a second-line therapy are heterogeneous in terms of a clinical-pathological profile. Tailoring of second-line treatment strategies is strongly advocated.
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http://dx.doi.org/10.3390/cancers12123634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761871PMC
December 2020

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Authors:
Laura Bryant Dong Li Samuel G Cox Dylan Marchione Evan F Joiner Khadija Wilson Kevin Janssen Pearl Lee Michael E March Divya Nair Elliott Sherr Brieana Fregeau Klaas J Wierenga Alexandrea Wadley Grazia M S Mancini Nina Powell-Hamilton Jiddeke van de Kamp Theresa Grebe John Dean Alison Ross Heather P Crawford Zoe Powis Megan T Cho Marcia C Willing Linda Manwaring Rachel Schot Caroline Nava Alexandra Afenjar Davor Lessel Matias Wagner Thomas Klopstock Juliane Winkelmann Claudia B Catarino Kyle Retterer Jane L Schuette Jeffrey W Innis Amy Pizzino Sabine Lüttgen Jonas Denecke Tim M Strom Kristin G Monaghan Zuo-Fei Yuan Holly Dubbs Renee Bend Jennifer A Lee Michael J Lyons Julia Hoefele Roman Günthner Heiko Reutter Boris Keren Kelly Radtke Omar Sherbini Cameron Mrokse Katherine L Helbig Sylvie Odent Benjamin Cogne Sandra Mercier Stephane Bezieau Thomas Besnard Sebastien Kury Richard Redon Karit Reinson Monica H Wojcik Katrin Õunap Pilvi Ilves A Micheil Innes Kristin D Kernohan Gregory Costain M Stephen Meyn David Chitayat Elaine Zackai Anna Lehman Hilary Kitson Martin G Martin Julian A Martinez-Agosto Stan F Nelson Christina G S Palmer Jeanette C Papp Neil H Parker Janet S Sinsheimer Eric Vilain Jijun Wan Amanda J Yoon Allison Zheng Elise Brimble Giovanni Battista Ferrero Francesca Clementina Radio Diana Carli Sabina Barresi Alfredo Brusco Marco Tartaglia Jennifer Muncy Thomas Luis Umana Marjan M Weiss Garrett Gotway K E Stuurman Michelle L Thompson Kirsty McWalter Constance T R M Stumpel Servi J C Stevens Alexander P A Stegmann Kristian Tveten Arve Vøllo Trine Prescott Christina Fagerberg Lone Walentin Laulund Martin J Larsen Melissa Byler Robert Roger Lebel Anna C Hurst Joy Dean Samantha A Schrier Vergano Jennifer Norman Saadet Mercimek-Andrews Juanita Neira Margot I Van Allen Nicola Longo Elizabeth Sellars Raymond J Louie Sara S Cathey Elly Brokamp Delphine Heron Molly Snyder Adeline Vanderver Celeste Simon Xavier de la Cruz Natália Padilla J Gage Crump Wendy Chung Benjamin Garcia Hakon H Hakonarson Elizabeth J Bhoj

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth.

Mol Genet Metab 2020 12 18;131(4):380-389. Epub 2020 Nov 18.

Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA; Department of Pathology, University of Utah, Salt Lake City, UT, USA.. Electronic address:

Background: Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition.

Methods: Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables.

Results: Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (-1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal.

Values: All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms.

Discussion: Patients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749858PMC
December 2020

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

J Inherit Metab Dis 2021 Jan 1;44(1):178-192. Epub 2020 Dec 1.

Department of Pediatrics Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
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http://dx.doi.org/10.1002/jimd.12332DOI Listing
January 2021

Is partial nephrectomy safe and effective in the setting of frail comorbid patients affected by renal cell carcinoma? Insights from the RECORD 2 multicentre prospective study.

Urol Oncol 2021 01 27;39(1):78.e17-78.e26. Epub 2020 Oct 27.

Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy. Electronic address:

Background: To investigate the perioperative and morbidity outcomes after partial nephrectomy (PN) in patients with short life expectancy (SLE) (≥95% 10-year expected mortality (10y-EM)), to assess the main predictors of outcomes in this population and to compare these results with those of a group at the opposite upper range with long LE (LLE, ≤5% 10y-EM) relying on a multicenter Italian prospective registry of kidney surgery (the RECORD 2 project).

Methods: Clinical data of 4,325 patients undergone kidney surgery were collected at 26 urological Italian Centers from 2013 to 2016. SLE was defined as a ≥95% 10y-EM (assessed using the age-adjusted Charlson comorbidity index [CCI]). A multivariable logistic regression for overall postoperative complications, acute kidney injury (AKI), positive surgical margins (SM) and ∆ estimated glomerular filtration rate (eGFR) ≥25% at 2 years from surgery was performed in patients with SLE including clinically relevant variables. Adjusted outcomes reported as mean (SD) of the 2 groups were generated using separate multivariable logistic regression models and compared.

Results: Overall, 559 patients with SLE were selected. Patients had an ASA score ≥3 in 58.4% of cases. A clinical T1a, T1b, and T2 stage was found in 412 (74.5%), 124 (22.4%), and 17 (3.1%) patients. The median PADUA score was 7 (6-8). Surgical and medical postoperative complication rates were registered in 14.8% and 6% cases. Postoperative AKI was reported in 27.3% cases, positive surgical margins (PSM) in 9.3% cases. In this subgroup of patients, ASA score, cerebrovascular disease, surgery in low volume centers, and open surgery were independent predictors of overall complications. ASA and PADUA scores, renal clamping, resection technique and lower eGFR at baseline were independent predictors of AKI. PADUA score, open approach and resection technique were independent predictors of PSM. Cardiovascular disease, hilar clamping, and resection technique were independent predictors of eGFR decrease >25% at 2 years from surgery. Patients with SLE were compared with those with LLE (n = 302). All analyzed parameters at baseline were significantly different among the groups with the exception of cancer laterality. After adjusting for several clinical variables, the SLE group had a significantly higher risk rate of adjusted overall postoperative complication rate compared to the LLE group (20.6% ± 0.36 vs. 9.9% ± 0.65, P < 0.0001), while the overall intraoperative complications (4.1% ±0.13 vs. 2.3% ± 0.23), overall postoperative major complications (3.8% ± 0.09 vs. 1.9% ± 0.14) adjusted AKI (24.2% ± 0.37 vs. 22.6% ± 0.92), positive surgical margins (8% ± 0.22 vs. 6.4% ± 0.49), and 2-year RF loss (13.4% ± 0.17 vs. 12.4% ± 0.74).

Conclusion: In selected patients with SLE, PN is feasible with an acceptable safety profile that is overall comparable to patients with no LE limitations. While a robotic approach and surgery performed in high volume centers could reduce the risk of complications, an off-clamp approach and a SE surgical technique may decrease the risk of postoperative AKI and of longer term eGFR decrease.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.022DOI Listing
January 2021

Tamsulosin plus a new complementary and alternative medicine in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results from a retrospective comparative study.

Arch Ital Urol Androl 2020 Oct 1;92(3). Epub 2020 Oct 1.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II. Naples.

Background: We aimed to compare the efficacy of tamsulosin 0.4 mg once a day alone and the combination therapy involving tamsulosin 0.4 mg once a day plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid L-Glutamine bid in patients with lower urinary tract symptoms related to benign prostatic hyperplasia (LUTS/BPH).

Methods: We performed a retrospective matched paired comparison. The clinical records of LUTS/BPH patients who underwent medical therapy with tamsulosin 0.4 mg/day plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid L-Glutamine bid between January 2019 to September 2019 were reviewed (Group 1). These patients were compared in a 1:1 fashion with LUTS/BPH patients who underwent therapy with tamsulosin 0.4 mg/day alone (Group 2). Total, storage, voiding and Quality of Life (QoL) international prostate symptom (IPSS) score, as well as overactive bladder (OAB)-v8 score and treatment- related adverse events recorded at 40 days follow-up in both groups were compared.

Results: At 40 days follow-up mean total, storage, voiding and QoL IPSS sub-scores as well as OAB-v8 score significantly improved in both groups. Intergroup comparison showed statistically significant lower mean total IPSS score (11.6 vs 12.4, p = 0.04) mean storage IPSS sub-score (6.5 vs 7.5, p = 0.01), and mean OAB v8 score (16.7 vs 18.8, p = 0.03) in patients in the Group 1.

Conclusions: The combination of tamsulosin 0.4 mg/die plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid LGlutamine bid provides statistically significant advantages in terms of storage LUTS improvements in patients with LUTS/BPH compared to tamsulosin 0.4 mg/day alone. These findings are preliminary and further prospective studies on a greater number of patients are needed to confirm it.
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http://dx.doi.org/10.4081/aiua.2020.3.173DOI Listing
October 2020

Comparison of Mexican-American vs Caucasian prostate cancer active surveillance candidates.

Urol Oncol 2021 01 17;39(1):74.e1-74.e7. Epub 2020 Sep 17.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada.

Background: We compared upgrading and upstaging rates in low risk and favorable intermediate risk prostate cancer (CaP) patients according to racial and/or ethnic group: Mexican-Americans and Caucasians.

Methods: Within Surveillance, Epidemiology and End Results database (2010-2015), we identified low risk and favorable intermediate risk CaP patients according to National Comprehensive Cancer Network guidelines. Descriptives and logistic regression models were used. Furthermore, a subgroup analysis was performed to test the association between Mexican-American vs. Caucasian racial and/or ethnic groups and upgrading either to Gleason-Grade Group (GGG II) or to GGG III, IV or V, in low risk or favorable intermediate risk CaP patients, respectively.

Results: We identified 673 (2.6%) Mexican-American and 24,959 (97.4%) Caucasian CaP patients. Of those, 14,789 were low risk (434 [2.9%] Mexican-Americans vs. 14,355 [97.1%] Caucasians) and 10,834 were favorable intermediate risk (239 [2.2%] Mexican-Americans vs. 10,604 [97.8%] Caucasians). In low risk CaP patients, Mexican-American vs. Caucasian racial and/or ethnic group did not result in either upgrading or upstaging differences. However, in favorable intermediate risk CaP patients, upgrading rate was higher in Mexican-Americans than in Caucasians (31.4 vs. 25.5%, OR 1.33, P = 0.044), but no difference was recorded for upstaging. When comparisons focused on upgrading to GGG III, IV or V, higher rate was recorded in Mexican-American relative to Caucasian favorable intermediate risk CaP patients (20.4 vs. 15.4%, OR 1.41, P = 0.034).

Conclusion: Low risk Mexican-American CaP patients do not differ from low risk Caucasian CaP patients. However, favorable intermediate risk Mexican-American CaP patients exhibit higher rates of upgrading than their Caucasian counterparts. This information should be considered at treatment decision making.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.012DOI Listing
January 2021

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.

J Inherit Metab Dis 2021 Jan 14;44(1):253-263. Epub 2020 Sep 14.

Ultragenyx Pharmaceutical Inc., Novato, California, USA.

Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7-carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC-FAOD. CL202 is an open-label, long-term extension study evaluating triheptanoin (Dojolvi) safety and efficacy in patients with LC-FAOD. Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin-naïve (naïve); or had participated in investigator-sponsored trials/expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy-five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other. In the rollover group, mean annualized MCE rate decreased from 1.76 events/year pre-triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre-triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdominal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Triheptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.
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http://dx.doi.org/10.1002/jimd.12313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891391PMC
January 2021

Transperitoneal vs retroperitoneal minimally invasive partial nephrectomy: comparison of perioperative outcomes and functional follow-up in a large multi-institutional cohort (The RECORD 2 Project).

Surg Endosc 2020 Aug 27. Epub 2020 Aug 27.

Division of Urology, Department of Oncology- School of Medicine, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy.

Background: Aim of this study was to evaluate and compare perioperative outcomes of transperitoneal (TP) and retroperitoneal (TR) approaches in a multi-institutional cohort of minimally invasive partial nephrectomy (MI-PN).

Material And Methods: All consecutive patients undergone MI-PN for clinical T1 renal tumors at 26 Italian centers (RECORd2 project) between 01/2013 and 12/2016 were evaluated, collecting the pre-, intra-, and postoperative data. The patients were then stratified according to the surgical approach, TP or RP. A 1:1 propensity score (PS) matching was performed to obtain homogeneous cohorts, considering the age, gender, baseline eGFR, surgical indication, clinical diameter, and PADUA score.

Results: 1669 patients treated with MI-PN were included in the study, 1256 and 413 undergoing TP and RP, respectively. After 1:1 PS matching according to the surgical access, 413 patients were selected from TP group to be compared with the 413 RP patients. Concerning intraoperative variables, no differences were found between the two groups in terms of surgical approach (lap/robot), extirpative technique (enucleation vs standard PN), hilar clamping, and ischemia time. Conversely, the TP group recorded a shorter median operative time in comparison with the RP group (115 vs 150 min), with a higher occurrence of intraoperative overall, 21 (5.0%) vs 9 (2.1%); p = 0.03, and surgical complications, 18 (4.3%) vs 7 (1.7%); p = 0.04. Concerning postoperative variables, the two groups resulted comparable in terms of complications, positive surgical margins and renal function, even if the RP group recorded a shorter median drainage duration and hospital length of stay (3 vs 2 for both variables), p < 0.0001.

Conclusions: The results of this study suggest that both TP and RP are feasible approaches when performing MI-PN, irrespectively from tumor location or surgical complexity. Notwithstanding longer operative times, RP seems to have a slighter intraoperative complication rate with earlier postoperative recovery when compared with TP.
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http://dx.doi.org/10.1007/s00464-020-07919-4DOI Listing
August 2020

Parkes Weber syndrome associated with two somatic pathogenic variants in .

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Pathology, University of Utah, Salt Lake City, Utah 84108, USA.

Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in consistent with the c.934_938del, p.(Glu312Argfs*14) and the c.2925del, p.(Asn976Metfs*20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the gene in DNA from a vascular lesion.
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http://dx.doi.org/10.1101/mcs.a005256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476407PMC
August 2020

A case of incidentally discovered solitary fibrous tumor of the kidney: A case study.

Mol Clin Oncol 2020 Oct 10;13(4):39. Epub 2020 Aug 10.

Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, I-80123 Naples, Italy.

Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin. The kidney represents an unusual location for SFT and the diagnosis and treatment of renal SFT remains challenging. The present study reports the case of a right kidney SFT incidentally discovered in a 52-year old woman. Radiological findings from computed tomography and magnetic resonance imaging were not specific but highly suspect for a malignant neoplasm. The definitive diagnosis relied on histological examination and immunohistochemical staining for CD34 and signal transducer and activator of transcription
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http://dx.doi.org/10.3892/mco.2020.2109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439114PMC
October 2020

Perioperative and Mid-term Oncological and Functional Outcomes After Partial Nephrectomy for Complex (PADUA Score ≥10) Renal Tumors: A Prospective Multicenter Observational Study (the RECORD2 Project).

Eur Urol Focus 2020 Aug 15. Epub 2020 Aug 15.

Department of Urology, University of Florence, Unit of Oncologic Minimally Invasive Urology and Andrology, Careggi Hospital, Florence, Italy. Electronic address:

Background: Partial nephrectomy (PN) for complex renal masses has a non-negligible risk of perioperative complications. Furthermore, late functional and oncological outcomes of patients submitted to these challenging surgeries still remain to be determined.

Objectives: To report the perioperative and mid-term oncological and functional outcomes of PN for complex masses (Preoperative Aspects and Dimensions Used for an Anatomical [PADUA] score≥10) in a large multicenter prospective observational study.

Design, Setting, And Participants: We prospectively evaluated patients treated with PN for complex renal tumors at 26 urological centers (Registry of Conservative and Radical Surgery for Cortical Renal Tumor Disease [RECORD2] project).

Outcome Measurements And Statistical Analysis: Multivariate logistic regression analyses explored the predictors of surgical complications. Multivariable Cox regression analyses estimated the hazard of renal function loss and disease recurrence. Kaplan-Meier estimates assessed the probability of survival.

Results And Limitations: In total, 410 patients who underwent PN for complex masses were evaluated. Clinical T1b and T2 tumors accounted for 43.2% and 9.8% of the cases. Overall, 45.9%, 18.8%, and 35.4% of patients underwent open, laparoscopic, and robotic PN, respectively. Intraoperative complications occurred in 15 (3.6%) patients, while postoperative surgical complications were recorded in 76 (18.5%) patients. At multivariable analysis, preoperative hemoglobin (odds ratio [OR]: 0.67; p<0.001) and open (OR: 3.91; p<0.001) versus robotic surgical approach were found to be the only predictors of surgical complications. An estimated glomerular filtration rate drop of >25% from baseline was observed in 30.2% and 17.6% of patients at 1st month and 2 yr after surgery, respectively. Two-year recurrence-free survival was 97.1%; positive surgical margins (hazard ratio [HR]: 3.35; p=0.009), nucleolar grading (HR: 5.61; p<0.001), and tumor stage (HR: 2.62; p=0.05) were associated with recurrence.

Conclusions: In a large series, PN for complex renal masses was a safe technique with an acceptable rate of perioperative complications and excellent mid-term oncological and functional results.

Patient Summary: In this study, we evaluated peri- and postoperative outcomes of patients treated with partial nephrectomy for complex renal masses. Open surgery was associated with higher complications than the robotic approach. Some histological features were found to be associated with disease recurrence.
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http://dx.doi.org/10.1016/j.euf.2020.07.004DOI Listing
August 2020

Granulomatous prostatitis mimicking prostate cancer in a patient with psoriatic arthritis: a case report.

Future Sci OA 2020 Jun 17;6(7):FSO591. Epub 2020 Jun 17.

Department of Neuroscience, Reproductive Sciences & Odontostomatology, University of Naples Federico II, Naples, Italy.

Granulomatous prostatitis (GP) is an unusual and benign inflammatory condition of the prostate, where autoimmunity has been recognized as a key factor in the pathogenesis of GP in a subset of patients. Clinically, GP poses diagnostic challenges as it may strongly mimic prostate cancer from a clinical, biochemical and radiological point of view. The occurrence of GP in patients suffering from psoriasis, a systemic autoimmune disease, has never been investigated. We describe the case of GP in a patient with psoriatic arthritis presenting with an increased prostate specific antigen level, and evidence of a nodular lesion visualized by prostate multiparametric magnetic resonance imaging, which was highly suspicious for aggressive prostate cancer.
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http://dx.doi.org/10.2144/fsoa-2020-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421716PMC
June 2020

Perceptions, Expectations, Preferences, and Attitudes Toward Premature Ejaculation, Its Diagnosis and Topical Treatment with Fortacin™ Spray: Results from an Expert Panel Discussion.

Res Rep Urol 2020 2;12:211-216. Epub 2020 Jul 2.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy.

Introduction: Premature ejaculation (PE) represents the most prevalent male sexual issue. Before beginning treatment, it is essential to discuss the patient's expectations thoroughly.

Methods: Herein, we report the results of an expert panel discussion about perceptions, expectations, preferences, and attitudes towards PE, its diagnosis and treatment. The panel took place in October 2019 and involved 30 Italian urologists experienced in the management of male sexual dysfunction. It aimed at investigating physicians' points of view about selected aspects of PE management which emerged during the counselling of PE patients over the previous two years. Treatment-related questions were mainly focused on topical treatment with Fortacin™.

Results: Overall, 83.3% of those interviewed declared that most of their patients perceive PE as a bother rather than a disease. The percentage of urologists interviewed perceived that improved subjective control over ejaculation and prolonged intravaginal ejaculatory latency time (IELT) as the main benefit expected by the majority of their patients was 56.5% and 10%, respectively. Eighty percent of urologists reported on-demand regimen as the dosage modality preferred by the majority of their patients and half of them reported the topical route to be the way of administration preferred in most cases. Moreover, 73.3% of urologists reported that adherence to treatment was higher in patients undergoing topical treatment. Finally, 80% of urologists perceived Fortacin to be efficacious in patients with acquired PE and 70% of them perceived its efficacy to be independent from IELT.

Discussion: Most patients perceive PE as a bother rather than a disease and mainly advocate an improved control over ejaculation. Fortacin is perceived as efficacious in patients with acquired PE, and independent from IELT.
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http://dx.doi.org/10.2147/RRU.S250301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337443PMC
July 2020

Short- and Long-Term Evaluation of Renal Function after Radical Cystectomy and Cutaneous Ureterostomy in High-Risk Patients.

J Clin Med 2020 Jul 11;9(7). Epub 2020 Jul 11.

Urologic Section, Department of Neurosciences, Sciences of Reproduction, and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy.

Deterioration of renal function has been reported after radical cystectomy (RC) with urinary diversion. We investigated renal function changes in elderly bladder cancer (BCa) patients who underwent RC with cutaneous ureterostomy (CU) urinary diversion. We performed a retrospective, observational study. BCa patients aged ≥75 with an American Society of Anesthesiologists (ASA) class greater than II were included. Glomerular filtration rate (GFR) was the main outcome measure. GFR values were recorded preoperatively, at discharge, at 6-month follow-up, and yearly up to 60 months. A total of 70 patients with a median age of 78.0 years were identified. Median preoperative GFR was 74.3 mL/min/1.73 m and declined significantly to 54.6 mL/min/1.73 m after 6 months ( < 0.001). A gradual GFR decline was observed thereafter, reaching a median value of 46.2 after 60 months. Preoperative GFR and acute kidney injury were significant predictors of fast deterioration of GFR and of 25% deterioration of GFR after 12 months. Elderly BCa patients with high comorbidity rates undergoing RC with CU should be carefully informed about the risk of GFR deterioration and the need for adequate monitoring.
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http://dx.doi.org/10.3390/jcm9072191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408808PMC
July 2020

Toward Individualized Approaches to Partial Nephrectomy: Assessing the Correlation Between Ischemia Time and Patient Health Status (RECORD2 Project).

Eur Urol Oncol 2020 Jul 6. Epub 2020 Jul 6.

Department of Urology, University of Florence, Unit of oncologic minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy. Electronic address:

Background: Ischemia time during partial nephrectomy (PN) is among the greatest determinants of acute kidney injury (AKI). Whether this association is affected by the preoperative risk of AKI has never been investigated.

Objective: To assess the effect of the interaction between the preoperative risk of AKI and ischemia time on the probability of AKI during PN.

Design, Setting, And Participants: Data of 944 patients treated with on-clamp PN for cT1 renal tumors were extracted from the Registry of Conservative and Radical Surgery for Cortical Renal Tumor Disease (RECORD2) database, a prospective multicenter project.

Outcome Measurements And Statistical Analysis: We estimated the preoperative risk of AKI (defined according to the risk/injury/failure/loss/end-stage [RIFLE] criteria) according to age, baseline renal function, clinical stage, preoperative aspects and dimensions used for an anatomical (PADUA) score, and surgical approach. Classification and regression tree (CART) analysis identified patients at "high" and "low" risk of AKI. Finally, we plotted the probability of AKI over ischemia time stratified by the preoperative risk of AKI.

Results And Limitations: Overall, 235 (25%) patients experienced AKI after surgery. At multivariable analysis, older patients, those with more complex tumors, those with higher baseline function, and those treated with open surgery had an increased risk of AKI (all p ≤ 0.011). According to the first split at CART analysis, patients were categorized as those with "high" and "low" risk of AKI having a probability of >40% or <40%. For low-risk patients, the probability of AKI in case of <10 versus >20 min of ischemia was 13% versus 28% (absolute risk increase 15%). The risk of AKI for high-risk patients who had <10 versus >20 min of ischemia was 31% versus 77%. This corresponds to an absolute risk increase of 45%. Limitations include retrospective data analyses and lack of surgeons' prior experience.

Conclusions: Ischemia time during PN has different implications for patients with different health status. Clamp time seems less clinically relevant for patients in good conditions who may endure prolonged ischemia with a mild increase in the risk of AKI, whereas frail patients seem to be more vulnerable to ischemic damage even for short clamp time. For individualized intra- and postoperative management, duration of ischemia needs to be questioned in the context of the individual health status.

Patient Summary: Functional sequelae related to ischemia time during partial nephrectomy depend on baseline health status. The correlation between the duration of ischemia and baseline health status should be taken into account toward individualized intra- and postoperative management.
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http://dx.doi.org/10.1016/j.euo.2020.05.009DOI Listing
July 2020

Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up.

Mol Genet Metab 2020 08 16;130(4):239-246. Epub 2020 Jun 16.

Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, 12605 E 16th St, Aurora, CO 80045, United States of America. Electronic address:

Background: Phenylketonuria (PKU) is characterized by a deficiency in phenylalanine hydroxylase (PAH) that may lead to elevated blood phenylalanine (Phe) and significant neurocognitive and neuropsychological comorbidities. Pegvaliase (PALYNZIQ®, BioMarin Pharmaceutical Inc.) is a PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), which converts Phe to trans-cinnamic acid and ammonia, and was approved in May 2018 in the United States and in May 2019 in the European Union for decreasing blood Phe levels in adults with PKU with blood Phe levels >600 μmol/L. The efficacy and safety of pegvaliase was assessed in two phase 2 dose-finding studies in adults with PKU (PAL-002, NCT00925054, and PAL-004, NCT01212744). Participants completing these studies could enroll in a long-term extension study (PAL-003, NCT00924703).

Methods: Participants in PAL-002 received pegvaliase 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for 8 weeks, then continued treatment for a further 8 weeks with dose and/or frequency adjusted to achieve blood Phe concentrations of 60 to 600 μmol/L. Participants in PAL-004 received pegvaliase 0.001 to 0.4 mg/kg 5 days/week for 13 weeks, with modifications made to the starting dose in response to safety and/or efficacy, followed by 3 additional weeks of follow-up assessments. The maximum allowable daily dose in both studies was 1.0 mg/kg/day (5.0 mg/kg/week). Participants who completed any of the phase 2 studies (PAL-002; PAL-004; or a third phase 2 study, 165-205) were eligible to enroll in an open-label, multicenter, long-term extension study (PAL-003, NCT00924703).

Results: Thirty-seven of the 40 enrolled participants completed PAL-002 and 15 of the 16 enrolled participants completed PAL-004. Mean blood Phe at baseline was 1311.0 (standard deviation [SD] 354) μmol/L in PAL-002 and 1482.1 (SD 363.5) μmol/L in PAL-004. Mean blood Phe did not substantially decrease with pegvaliase treatment in PAL-002 (-206.3 [SD 287.1] μmol/L at Week 16) or PAL-004 (-410.8 [SD 653.7] μmol/L at Week 13). In PAL-004, mean blood Phe dropped from baseline by 929.1 μmol/L (SD 691.1) by Week 2; subsequent to dose modifications and interruptions, this early decrease in mean Phe level was not sustained. With increased pegvaliase dose and duration in PAL-003, mean blood Phe levels steadily decreased from baseline, with mean reductions by Week 120 of 68.8% (SD 44.2%) in PAL-002 participants and 75.9% (SD 32.4%) in PAL-004 participants. All participants in PAL-002 and PAL-004 reported ≥1 adverse event (AE), with higher exposure-adjusted event rates in PAL-004. The majority of AEs were mild (87.2% in PAL-002, 86.7% in PAL-004) or moderate (12.4% in PAL-002, 13.3% in PAL-004). The most commonly reported AEs in PAL-002 were injection site reaction (50.0% of participants), headache (42.1%), injection site erythema (36.8%), nausea (34.2%), and arthralgia (29.0%), and in PAL-004 were arthralgia (75.0%), headache (62.5%), dizziness (56.3%), injection site erythema (56.3%), and injection site reaction (50.0%).

Conclusions: In two phase 2 dose-finding studies, pegvaliase did not lead to substantial blood Phe reductions. Higher and more frequent pegvaliase dosing in PAL-004 led to a substantial initial drop in blood Phe, but an increase in the number of hypersensitivity AEs and dose reductions or interruptions. With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized. Together, these studies led to the development of an induction-titration-maintenance regimen that has been approved for pegvaliase, with patients starting at a low weekly dose that gradually increases in dose and frequency until they achieve a standard non-weight-based daily maintenance dose. This regimen has been tested in a third phase 2 study, as well as in two successful phase 3 studies of pegvaliase.
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http://dx.doi.org/10.1016/j.ymgme.2020.06.006DOI Listing
August 2020

Laboratory evaluation of homocysteine remethylation disorders and classic homocystinuria: Long-term follow-up using a cohort of 123 patients.

Clin Chim Acta 2020 Oct 10;509:126-134. Epub 2020 Jun 10.

Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States.

The homocystinurias, caused by defects of remethylation and cystathionine-beta-synthase (CBS) deficiency, are characterized by elevated homocysteine and abnormal methionine levels. Various treatments, including injectable hydroxycobalamin and oral betaine, aim to reduce homocysteine toxicity and normalize methionine, but only limited biochemical data has been reported assessing biochemical response to treatment. We analyzed laboratory results in 812 plasma samples from 56 patients with remethylation disorders and 67 patients with CBS deficiency. Total plasma homocysteine (tHcys) decreased with therapy, but rarely normalized regardless of treatment, with highest levels seen in CBS (116 ± 79 μmol/L) and MTHFR (102 ± 56 μmol/L) deficiencies. In CBS deficiency, tHcys correlated positively with methionine (rs = 0.51, p < 0.0001) and inversely with cystine (rs = -0.57, p < 0.0001) consistent with a metabolic block downstream of homocysteine. In patients with remethylation disorders, methionine was mostly normal on therapy, and inversely correlated with tHcys (rs = -0.57, p < 0.0001) demonstrating effectiveness of hydroxycobalamin and/or betaine in stimulating tHcys remethylation. Betaine also significantly increased sarcosine from its pre-treatment level on average 19-fold in remethylation disorders and 3-fold in CBS deficiency, with sarcosine > 5 μmol/L being 97% sensitive and 95% specific for betaine therapy. These results show that existing therapies improve sulfur amino acid metabolism without completely normalizing it and that sarcosine can determine compliance to betaine supplementation.
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http://dx.doi.org/10.1016/j.cca.2020.06.014DOI Listing
October 2020