A Novel Risk Calculator Incorporating Clinical Parameters, Multiparametric Magnetic Resonance Imaging, and Prostate-Specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Risk Stratification Before Transperineal Prostate Biopsy.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa. Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy. Design setting and participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores. Outcome measurements and statistical analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis. Results and limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 (p = 0.02) for overall PCa and 0.805 (p = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa. Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone. Patient summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies.

US Food and Drug Administration Warning Regarding Finasteride and Suicidal Ideation: What Should Urologists Know?

Finasteride competitively inhibits 5α-reductase (5-AR) isoenzymes, which blocks dihydrotestosterone (DHT) production, thereby reducing DHT. Finasteride is used in the management of benign prostatic hyperplasia (BPH) and androgenic alopecia. Amid patient reports of suicidal ideation (SI), the Post Finasteride Syndrome advocacy group has petitioned for either a stop to selling of the drug or advertisement of stronger warnings. The US Food and Drug Administration recently added SI to the adverse effects listed for finasteride. Here we provide a brief but comprehensive review of the literature on the psychological side effects of 5-AR inhibitors (5-ARIs) to provide an opinion to help in guiding treating urologists. Most of the current evidence, obtained from the literature on dermatology, suggests that 5-ARI users experience a higher rate of depressive symptoms. However, given the lack of comprehensive randomised studies, the causal link between finasteride and SI remains unclear. Urologists prescribing 5-ARIs should be aware of the recent addition of suicide and SI risk to the list of side effects. A mental health screen should be performed and appropriate resources provided to patients commencing treatment. Furthermore, a review should be arranged with the general practitioner to assess new-onset mental health or SI symptoms. Patient summary: We provide recommendations for urologists who prescribe finasteride for the treatment of benign prostate enlargement. Urologists should be aware of the recent addition of suicidal ideation to the list of side effects for this drug. Finasteride prescription should be continued; however, we recommend a detailed medical history to screen for prior mental health and personality disorders, with discontinuation of the medication in patients with new onset of depression or suicidal symptoms. Close liaison with the patient's general practitioner is vital for management of depressive or suicidal symptoms.

Recent developments in the diagnosis and management of N1 penile cancer.

PURPOSE OF REVIEW: This article presents a critical review of the current literature to provide a brief update on the contemporary advances in diagnosing and managing N1 penile cancer. RECENT FINDINGS: Penile squamous cell carcinoma (pSCC) has evolved from being an orphan field for cancer innovation. Advances in the understanding tumour biology have enabled sophisticated diagnostics and predictive modelling to better characterize inguinal disease. Minimally invasive inguinal lymph node dissection is emerging as a technique that reduces morbidity while maintaining oncological safety. Furthermore, robust clinical trials are underway ,which will provide level one evidence to guide treatment decisions. Exciting advances in the field of immune-oncology offer promise as adjuvant therapies. International collaboration and centralisation of care will be essential to driving translational research and equitable evidence-based care. SUMMARY: Improving outcomes for men with pSCC remains a global challenge. Radical inguinal lymph node dissection remains the gold standard for diagnosing and curing N1 disease. Although many promising developments are on the horizon, high-level evidence is required to guide therapy.

Modern paradigms for prostate cancer detection and management.

Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states.

Interrogating the Impassable: A Case Series and Literature Review of Unilateral SPECT-CT Groin Visualization in Men With Penile Cancer.

Penile squamous cell carcinoma (SCC) is a rare malignancy, which is known to invade local inguinal lymph nodes prior to progressing to the pelvis. Dynamic sentinel lymph node biopsy (DSLNB) is a standard for the minimally invasive assessment of lymphadenopathy in patients with subclinical groin metastasis. Hybrid 99mTc Single-Photon Emission Computed Tomography (SPECT-CT) has been shown to increase the accuracy of identifying first draining "sentinel" nodes (SN). Unilateral inguinal visualization on SPECT-CT is a rare presentation, which may increase the likelihood of a false negative SN biopsy. Retrospective analysis from three-penile cancer uro-oncologists in Melbourne, Australia identified 78 groins undergoing DSLNB for intermediate/high risk primary disease. Unilateral SPECT-CT results were observed in four patients suggesting a functional pattern of lymph diversion. Analysis confirmed malignancy (n = 2), sarcoidosis (n = 1), and evidence of local inflammation in SPECT-CT negative groins. Findings re-iterate the role of SPECT-CT a pre-operative adjunct. Experienced multimodal groin assessment using palpation, SPECT-CT, lymphoscintigraphy, and blue dye tracking remains paramount. Unilateral SN on pre-operative SPECT-CT in men with intermediate/high-risk penile SCC should elicit a higher degree of clinical suspicion. We recommend a low threshold for recommending radical inguinal lymph node dissection (ILND) for groins refractory to minimally invasive assessment.

Dynamic Sentinel Lymph Node Biopsy for Penile Cancer: Accuracy is in the Technique.

OBJECTIVES: To demonstrate an operative standard for dynamic sentinel lymph node biopsy (DSLNB). Long-term survival in men with penile squamous cell carcinoma (SCC) depends on accurately staging lymph node metastases. European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines recognize DSLNB as a standard for staging men with intermediate to high-risk tumors and clinically absent inguinal lymphadenopathy. DSLNB accuracy has been linked with pre-operative planning and surgical technique, yet no peer-reviewed video exists to establish an operative standard. Here we present a narrated video of our technique and discuss the accuracy of this approach using retrospective patient data. METHODS: Ethics approval and patient consent was obtained. Retrospective analysis was performed on patients undergoing DSLNB for inguinal lymph node staging of histologically proven penile SCC. Data was included from 2 experienced uro-oncologists with subspecialty training in penile cancer working in Victoria, Australia between January 2015 and July 2021. Variables collected included Primary tumour histology, DSLNB pathology, progression to radical inguinal lymph node dissection (RILND) and recurrence patterns. DSLNB sensitivity and proportion of groins spared RILND is calculated. RESULTS: DSLNB was performed on 127 groins (64 patients) during the study period. Within the cohort, 44% (n = 28) of patients had a pre-operative lymphoscintigraphy with single-photon emission computed tomography (SPECT/CT). Analysis of primary tumor intervention demonstrates that 82.8% (n = 53) of men underwent penile sparing surgery. Tumor histology in 88% of patients (n = 56) demonstrated pT1-pT2 disease. Overall n = 19 groins undergoing DSLNB were positive for malignancy and n = 108 were negative. 36 groins progressed to RILND during a mean follow up of 29 months. Only 2 groins that previously had a negative DSLNB were positive on RILND, one in the groin and one in the pelvis. We observed a false negative rate of 1.9% and a sensitivity of 90.5%. In our cohort DSLNB allowed 71.7% of groins to proceed for surveillance instead of prophylactic radical ILND. CONCLUSIONS: DSLNB is a safe and accurate method for assessing inguinal lymphadenopathy in men with intermediate to high-risk penile SCC and impalpable groins. This video study establishes an operative standard for DSLNB with oncological outcomes are consistent with international expectations. Standardized use of DSLNB by an experienced team will reduce morbidity while maintaining oncological safety for men with intermediate to high-risk penile cancer and cN0 disease.

Mesenteric metastases from mature teratoma of the testis: A case report.

Metastatic spread of testicular cancer has been well documented, with 95% of cases involving para-aortic retroperitoneal lymph nodes. Mesenteric lymphatic basins do not lie within the canonical drainage pathway of the testes and represent a rare site of metastasis. Various mechanisms of spread to the mesentery have been described, including direct extension and haematogenous dissemination. We present a case of a previously-well 43-year-old man who presented with right scrotal discomfort and intermittent lower back pain, who was found to have mesenteric metastases from a non-seminomatous germ cell tumour of the testis. Managing lymphadenopathy that lies outside of standard resection templates remains a complex surgical challenge. Here we present the first case in the English medical literature with co-existing supradiaphragmatic axillary and mediastinal nodal disease.

Reporting and ideal testosterone levels in men undergoing androgen deprivation for prostate cancer-time for a rethink?

BACKGROUND: This study aims to review current laboratory reporting strategies across Australia and New Zealand with a view to propose a more useful template for reporting serum testosterone in the context of prostate cancer. MATERIALS AND METHODS: Registered pathology laboratories in Australia and New Zealand were enrolled into the current study. An electronic or a phone survey was utilized to collect data from each participating laboratory. Obtained information included assay utilized, units reported, reference intervals, lowest reported value, and lowest detectable value. To identify recommendations for testosterone testing, a systematic search was performed across Web of Science (including MEDLINE), EMBASE, and Cochrane libraries. RESULTS: Assessment of national pathology laboratories identified significant heterogeneity in the reporting methods. Reports typically used a "normal healthy male of 35 years of age" as a comparator but did not refer to optimal castrate levels, the lowest level that their assay was able to detect, nor did they include appended clinical guidelines relating to the prostate cancer patient cohort. CONCLUSIONS: Across Australia and New Zealand, various methods for testing and reporting serum testosterone exist, while international guidelines remain vague. The fashion in which serum testosterone levels are displayed should be re-evaluated to address the relevant clinical population and reflect an agreed-upon castrate threshold in patients undergoing androgen deprivation therapy.

Three dimensional models in uro-oncology: a future built with additive fabrication.

PURPOSE: Three-dimensional (3D) printing was invented in 1983 but has only just begun to influence medicine and surgery. Conversion of digital images into physical models demonstrates promise to revolutionize multiple domains of surgery. In the field of uro-oncology, researchers and clinicians have recognized the potential of this technology and are working towards making it an integral part of urological practice. We review current literature regarding 3D printing and other 3D technology in the field of urology. METHOD: A comprehensive assessment of contemporary literature was performed according to a modified PRISMA analysis for the purposes of this narrative review article. Medical databases that were searched included: Web of Science, EMBASE and Cochrane databases. Articles assessed were limited only to English-language peer-reviewed articles published between 1980 and 2017. The search terms used were "3D", "3-dimensional", "printing", "printing technology", "urology", "surgery". Acceptable articles were reviewed and incorporated for their merit and relevance with preference given for articles with high impact, original research and recent advances. RESULTS: Thirty-five publications were included in final analysis and discussion. CONCLUSIONS: The area of 3D printing in Urology shows promising results, but further research is required and cost reduction must occur before clinicians fully embrace its use. As costs continue to decline and diversity of materials continues to expand, research and clinical utilization will increase. Recent advances have demonstrated the potential of this technology in the realms of education and surgical optimization. The generation of personalized organs using 3D printing scaffolding remains the 'holy grail' of this technology.

Blueprint unknown: a case for multidisciplinary management of advanced penile mycosis fungoides.

A 64-year-old man presented with a 2 week history of progressive phimosis and painful ulcer on his penile meatus. He underwent penile preserving excision, and subsequent pathological examination confirmed T-cell non-Hodgkin lymphoma with immunohistochemical features of large cell transformation of mycosis fungoides. The penis was further treated with local external beam radiotherapy consisting of 27 Gy in 15 fractions and systemic mini-CHOP chemotherapy. An organ-preserving tissue response has since been achieved. This case is the first of its kind in the literature and firmly highlights the role of multidisciplinary management for this rare malignancy.

Atypical Small Acinar Proliferation and High-grade Prostatic Intraepithelial Neoplasia in the Era of Multiparametric Magnetic Resonance Imaging: A Contemporary Review.

Multiparametric magnetic resonance imaging (mpMRI) has added to the armamentarium for the diagnosis and surveillance for organ-confined prostate cancer. Atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia (HGPIN) are premalignant prostatic lesions. The management of such lesions remains contentious, and the addition of mpMRI introduces further uncertainty, given its ability to pick up indolent lesions and its use in targeted biopsy. We aimed to perform a comprehensive review of current evidence regarding atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and mpMRI to ascertain a consensus for a current management algorithm.

Penile Cancer: Contemporary Lymph Node Management.

PURPOSE: In penile cancer, the optimal diagnostics and management of metastatic lymph nodes are not clear. Advances in minimally invasive staging, including dynamic sentinel lymph node biopsy, have widened the diagnostic repertoire of the urologist. We aimed to provide an objective update of the recent trends in the management of penile squamous cell carcinoma, and inguinal and pelvic lymph node metastases. MATERIALS AND METHODS: We systematically reviewed several medical databases, including the Web of Science® (with MEDLINE®), Embase® and Cochrane databases, according to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines. The search terms used were penile cancer, lymph node, sentinel node, minimally invasive, surgery and outcomes, alone and in combination. Articles pertaining to the management of lymph nodes in penile cancer were reviewed, including original research, reviews and clinical guidelines published between 1980 and 2016. RESULTS: Accurate and minimally invasive lymph node staging is of the utmost importance in the surgical management of penile squamous cell carcinoma. In patients with clinically node negative disease, a growing body of evidence supports the use of sentinel lymph node biopsies. Dynamic sentinel lymph node biopsy exposes the patient to minimal risk, and results in superior sensitivity and specificity profiles compared to alternate nodal staging techniques. In the presence of locoregional disease, improvements in inguinal or pelvic lymphadenectomy have reduced morbidity and improved oncologic outcomes. A multimodal approach of chemotherapy and surgery has demonstrated a survival benefit for patients with advanced disease. CONCLUSIONS: Recent developments in lymph node management have occurred in penile cancer, such as minimally invasive lymph node diagnosis and intervention strategies. These advances have been met with a degree of controversy in the contemporary literature. Current data suggest that dynamic sentinel lymph node biopsy provides excellent sensitivity and specificity for detecting lymph node metastases. More robust long-term data on multicenter patient cohorts are required to determine the optimal management of lymph nodes in penile cancer.

Discovery of Ibomycin, a Complex Macrolactone that Exerts Antifungal Activity by Impeding Endocytic Trafficking and Membrane Function.

Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis. Chemogenomic profiling coupled with cell biological assays link ibomycin bioactivity to membrane function. The preferential activity of ibomycin toward C. neoformans is due to the ability of the compound to selectively permeate its cell wall. These results delineate a novel antifungal agent that is produced by one of the largest documented biosynthetic clusters to date and underscore the fact that there remains significant untapped chemical diversity of natural products with application in antimicrobial research.

The comprehensive antibiotic resistance database.

The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.