Single-cell Atlas of Penile Cancer Reveals TP53 Mutations as a Driver of an Aggressive Phenotype, Irrespective of Human Papillomavirus Status, and Provides Clues for Treatment Personalization.

BACKGROUND AND OBJECTIVE: TP53 loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV-) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC). Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status. METHODS: We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV- TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates. KEY FINDINGS AND LIMITATIONS: Patients with aberrant p53 staining fare much worse than patients with either HPV- or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV- TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed. CONCLUSIONS AND CLINICAL IMPLICATIONS: This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on TP53 and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC. PATIENT SUMMARY: Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the TP53 gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on TP53 gene mutations and human papillomavirus status of these tumors.

Effect of Sex on the Oncological Outcomes in Response to Immunotherapy and Antibody-drug Conjugates in Patients with Urothelial and Kidney Cancer: A Systematic Review and a Network Meta-analysis.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) herald a transformative era in metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) treatment, amid acknowledged sex-based disparities in these cancers. We conducted a systematic review and network meta-analysis (NMA) to identify sex-specific differences in the efficacy of ICI/ADC monotherapy or combination therapies for RCC and TCC survival, in metastatic and adjuvant settings. METHODS: A systematic search was conducted up to October 2023 for English articles on ICIs and ADCs as systemic therapies (ICIs in first-line and adjuvant treatment for RCC, ICIs and ADCs in first- and second-line treatment for TCC). Randomised clinical trials were considered. The primary objective was overall survival (OS) of ICIs and ADCs between males and females. The secondary outcomes included progression-free survival, overall response rate, disease-free survival, and recurrence-free survival. Treatment efficacy was evaluated by sex via odds ratios (ORs) and confidence intervals compared with controls. Log ORs were used for creating a frequentist NMA. This meta-analysis was registered on PROSPERO (CRD42023468632). KEY FINDINGS AND LIMITATIONS: Eighteen articles met the inclusion criteria. Females had an advantage for RCC-adjuvant treatment for atezolizumab (log OR [SE] = -0.57 ± 0.25, p = 0.024) in OS. Males showed a survival advantage in TCC second-line treatment for ADC-Nectin 4 (log OR [SE] = 0.65 ± 0.28, p = 0.02). No other significant results were shown. CONCLUSIONS AND CLINICAL IMPLICATIONS: The NMA revealed gender-specific variations in ICI and ADC responses for RCC and TCC, offering insights for personalised cancer care and addressing disparities in cancer care and outcomes. PATIENT SUMMARY: In this systematic review, we looked at the sex differences for metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) for antibody-drug conjugates and immune checkpoint inhibitors. In our analysis, female and male sex has better overall survival for adjuvant and second-line therapies for RCC and TCC, respectively. Urgent research on gender-specific cancer therapies is imperative.

Does the Timing of Cytoreductive Nephrectomy Impact Outcomes? Analysis of REMARCC Registry Data for Patients Receiving Tyrosine Kinase Inhibitor Versus Immune Checkpoint Inhibitor Therapy.

Background and objective: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been called into question on the basis of clinical trial data from the tyrosine kinase inhibitor (TKI) era. Comparative analyses of CN for patients treated with immuno-oncology (IO) versus TKI agents are sparse. Our objective was to compare CN timing and outcomes among patients who received TKI versus IO therapy. Methods: This was a multicenter retrospective analysis of patients who underwent CN using data from the REMARCC (Registry of Metastatic RCC) database. The cohort was divided into TKI versus IO first-line therapy groups. The primary outcome was all-cause mortality (ACM). Secondary outcomes included cancer-specific mortality (CSM). Multivariable analysis was used to identify factors predictive for ACM and CSM. The Kaplan-Meier method was used to analyze 5-yr overall survival (OS) and cancer-specific survival (CSS) with stratification by primary systemic therapy and timing in relation to CN. Key findings and limitations: We analyzed data for 189 patients (148 TKI + CN, 41 IO +CN; median follow-up 23.2 mo). Multivariable analysis revealed that a greater number of metastases (hazard ratio [HR] 1.06; p = 0.015), greater primary tumor size (HR 1.10; p = 0.043), TKI receipt (HR 2.36; p = 0.015), and initiation of systemic therapy after CN (HR 1.49; p = 0.039) were associated with worse ACM. A greater number of metastases at diagnosis (HR 1.07; p = 0.011), greater primary tumor size (HR 1.12; p = 0.018), TKI receipt (HR 5.43; p = 0.004), and initiation of systemic therapy after CN (HR 2.04; p < 0.001) were associated with worse CSM. Kaplan-Meier analyses revealed greater 5-yr rates for OS (51% vs 27%; p < 0.001) and CSS (83% vs 30%; p < 0.001) for IO +CN versus TKI + CN. This difference persisted in a subgroup analysis for patients with intermediate or poor risk, with 5-yr OS rates of 50% for IO + CN versus 30% for TKI + CN (p < 0.001). A subanalysis stratified by CN timing revealed better 5-yr rates for OS (50% vs 30%; p = 0.042) and CSS (90% vs 30%, p = 0.019) for delayed CN after IO therapy, but not after TKI therapy. Conclusions and clinical implications: For patients who underwent CN, systemic therapy before CN was associated with better outcomes. In addition, IO therapy was associated with better survival outcomes in comparison to TKI therapy. Our findings question the applicability of clinical trial data from the TKI era to CN in the IO era for mRCC. Patient summary: For patients with metastatic kidney cancer treated with surgery, better survival outcomes were observed for those who also received immunotherapy in comparison to therapy targeting specific proteins in the body (tyrosine kinase inhibitors, TKIs). Immunotherapy or TKI treatment resulted in better outcomes if it was received before rather than after surgery.

Cell therapy for male sexual dysfunctions: systematic review and position statements from the European Society for Sexual Medicine.

Background: Cell therapy (CT) is a form of regenerative medicine under investigation for the management of male sexual dysfunction (MSD). Aim: We sought to perform a systematic review of published information on CT for MSD and provide an official position statements for the European Society for Sexual Medicine. Methods: A comprehensive bibliographic search on the MEDLINE, Web of Science, Scopus, and Cochrane Library databases was conducted in February 2023. Articles were selected based on the Population, Intervention, Comparator, Outcome, Study design (PICOS) model if they included male patients (P) undergoing CT (I) with or without comparison with other treatments (C) and evaluated the impact of CT on sexual function (O). Quantitative data were reported as found in the original studies (S). Level of evidence and grade of recommendation according to the Oxford Centre for Evidence-Based Medicine were assigned to each statement. Outcomes: Outcomes were determined based on assessment of erectile function, ejaculatory function, orgasmic function, sexual desire, and penile curvature. Results: A total of 19 studies and 421 patients were included. Most articles (n = 12, 63%) were case series, whereas a minority of papers (n = 6, 32%) had a comparative group; only 2 articles reported randomized controlled trials (RCTs) and 1 article reported a post hoc analysis of RCTs. Most articles (16, 84%) investigated patients with erectile dysfunction (ED). Improvements in the International Index of Erectile Function-Erectile Function Domain (IIEF-EF) or the IIEF 5-item version (IIEF-5) were found in 11/15 (73%) studies, with mean increases in IIEF-EF, mean IIEF-5, and median IIEF-EF between 8 and 14 points, 2 and 9 points, and 4.5 and 6 points, respectively. Two papers (20%) evaluated men with Peyronie's disease (PD). In both ot these articles penile curvature improvement and plaque volume reduction were described in all patients (n = 16, 100%). Objective measurements were performed in 1 study, which showed 10°-120° (15%-100%) curvature improvement and 90%-100% plaque reduction. Mild transient adverse events at the donor or administration sites were found in 7/16 (44%) papers on ED. Priapism was reported in one case (20%) and mild penile skin complications were reported in the majority of patients after CT for PD. No severe adverse events were described. Clinical Implications: Although high-quality evidence is lacking, CT appears to have potential benefits from application in patients with ED or PD. Strengths and Limitations: This report is to our knowledge the most comprehensive and up-to-date systematic review on the topic of CT for the management of MSD, including the position statements of the European Society for Sexual Medicine. Overall the assessment of available studies demonstrated low quality and significant heterogeneity. Conclusion: Preliminary findings support potential efficacy and safety of CT in patients with ED or PD. Low-quality papers, high methodological heterogeneity, uncertainty about the magnitude of the beneficial effects, and lack of long-term data limit the available evidence.

Neoadjuvant Platinum-Based chemotherapy and lymphadenectomy for penile cancer: an international, Multi-Institutional, Real-World study.

INTRODUCTION: This study investigated the efficacy and safety of neoadjuvant chemotherapy (NAC) for locally advance penile squamous cell carcinoma (PSCC), for which current evidence is lacking. METHODS: Included patients had locally advanced PSCC with clinical lymph node metastasis treated with at least one dose of NAC prior to planned consolidative lymphadenectomy. Objective response rates (ORR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events (trAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: 209 patients received NAC for locally advanced and clinically node-positive PSCC.The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 TrAEs occurred in 35 (17%) patients, and no treatment related mortality was observed. 201 (97%) completed planned consolidative lymphadenectomy. During follow up, 106 (52.7%) patients expired, with a median OS of 37.0 months (95% CI 23.8-50.1), and median PFS of 26.0 months (95% CI 11.7-40.2). ORR was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to NAC had a longer median OS (73.0 vs 17.0 months, p < .01) compared to those who did not. The lymph-node pathologic complete response rate (ypN0) was 24.8% in the cohort. CONCLUSION: NAC with lymphadenectomy for locally advanced PSCC is well tolerated and active to reduce the disease burden and improve long term survival outcomes.

New EAU/ASCO guideline recommendations on sentinel node biopsy for penile cancer and remaining challenges from a nuclear medicine perspective.

INTRODUCTION: The European Association of Urology (EAU) and the American Society of Clinical Oncology (ASCO) recently issued updated guidelines on penile cancer, emphasising dynamic sentinel node biopsy (DSNB) as the preferred method for surgical staging among patients with invasive penile tumours and no palpable inguinal lymphadenopathy. This paper outlines the rationale behind this new recommendation and describes remaining challenges, as well as strategies for promoting DSNB worldwide. MAIN TEXT: DSNB offers high diagnostic accuracy with the lowest postoperative complications compared to open or minimally invasive inguinal lymph node dissection (ILND), prompting its preference in the new guidelines. Nevertheless, despite its advantages, there are challenges hampering the widespread adoption of DSNB. This includes the false-negative rate associated with DSNB and the potential negative impact on patient outcome. To address this issue, improvements should be made in several areas, including refining the timing and interpretation of the lymphoscintigraphy and the single photon emission computed tomography/computed tomography images. In addition, the quantity of tracer employed and choice of the injection site for the radiopharmaceutical should be optimised. Finally, limiting the removal of nodes without tracer activity during surgery may help minimise complication rates. CONCLUSION: Over the years, DSNB has evolved significantly, related to the dedicated efforts and innovations in nuclear medicine and subsequent clinical studies validating its efficacy. It is now strongly recommended for surgical staging among selected penile cancer patients. To optimise DSNB further, multidisciplinary collaborative research is required to improve SN identification for better diagnostic accuracy and fewer complications.

International case series of metastasis to penis.

Objectives: To evaluate clinical characteristics associated with survival in patients with metastases to the penis. Methods: After approval by the IRB, records of collaborating centres in Leuven, London, Rostock, Amsterdam and Tampa were screened for men presenting with metastatic disease to penis. Multivariate logistic regression analyses were used to identify covariables associated with survival. We analysed clinical data on 34 patients. Results: Primary sites were most frequently prostate (n = 14, 41%) and bladder (n = 9, 26%). Twenty-eight of 34 (82%) presented with metachronous penile metastases, and 11 (32%) patients had penile metastases as the sole metastatic site. Penile metastatic locations were most frequently in the corpora (n = 18; 53%). Seven (21%) patients with penile metastases had priapism on presentation. Systemic therapy was frequent and variable (chemotherapy n = 12; immunotherapy n = 5; hormones n = 3). Local management included either surgery (n = 10) or RT (n = 8). Twelve- and 24-month overall survival rate were 67% and 35%, respectively. No clinical parameter including primary histology, synchronous or metachronous metastases or priapism showed statistical survival benefit or detriment. Conclusion: Metastasis to penis arises most frequently from pelvic primaries. Priapism does not appear to correlate with survival in this large, well-defined series.

Management of Lymph Node-positive Penile Cancer: A Systematic Review.

CONTEXT: Lymph node (LN) involvement in penile cancer is associated with poor survival. Early diagnosis and management significantly impact survival, with multimodal treatment approaches often considered in advanced disease. OBJECTIVE: To assess the clinical effectiveness of treatment options available for the management of inguinal and pelvic lymphadenopathy in men with penile cancer. EVIDENCE ACQUISITION: EMBASE, MEDLINE, the Cochrane Database of Systematic Reviews, and other databases were searched from 1990 to July 2022. Randomised controlled trials (RCTs), nonrandomised comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: We identified 107 studies, involving 9582 patients from two RCTs, 28 NRCSs, and 77 CSs. The quality of evidence is considered poor. Surgery is the mainstay of LN disease management, with early inguinal LN dissection (ILND) associated with better outcomes. Videoendoscopic ILND may offer comparable survival outcomes to open ILND with lower wound-related morbidity. Ipsilateral pelvic LN dissection (PLND) in N2-3 cases improves overall survival in comparison to no pelvic surgery. Neoadjuvant chemotherapy in N2-3 disease showed a pathological complete response rate of 13% and an objective response rate of 51%. Adjuvant radiotherapy may benefit pN2-3 but not pN1 disease. Adjuvant chemoradiotherapy may provide a small survival benefit in N3 disease. Adjuvant radiotherapy and chemotherapy improve outcomes after PLND for pelvic LN metastases. CONCLUSIONS: Early LND improves survival in nodal disease in penile cancer. Multimodal treatments may provide additional benefit in pN2-3 cases; however, data are limited. Therefore, individualised management of patients with nodal disease should be discussed in a multidisciplinary team setting. PATIENT SUMMARY: Spread of penile cancer to the lymph nodes is best managed with surgery, which improves survival and has curative potential. Supplementary treatment, including the use of chemotherapy and/or radiotherapy, may further improve survival in advanced disease. Patients with penile cancer with lymph node involvement should be treated by a multidisciplinary team.

A clinical guide to rare male sexual disorders.

Conditions referred to as 'male sexual dysfunctions' usually include erectile dysfunction, ejaculatory disorders and male hypogonadism. However, some less common male sexual disorders exist, which are under-recognized and under-treated, leading to considerable morbidity, with adverse effects on individuals' sexual health and relationships. Such conditions include post-finasteride syndrome, restless genital syndrome, post-orgasmic illness syndrome, post-selective serotonin reuptake inhibitor (SSRI) sexual dysfunction, hard-flaccid syndrome, sleep-related painful erections and post-retinoid sexual dysfunction. Information about these disorders usually originates from case-control trials or small case series; thus, the published literature is scarce. As the aetiology of these diseases has not been fully elucidated, the optimal investigational work-up and therapy are not well defined, and the available options cannot, therefore, adequately address patients' sexual problems and implement appropriate treatment. Thus, larger-scale studies - including prospective trials and comprehensive case registries - are crucial to better understand the aetiology, prevalence and clinical characteristics of these conditions. Furthermore, collaborative efforts among researchers, health-care professionals and patient advocacy groups will be essential in order to develop evidence-based guidelines and novel therapeutic approaches that can effectively address these disorders. By advancing our understanding and refining treatment strategies, we can strive towards improving the quality of life and fostering healthier sexual relationships for individuals suffering from these rare sexual disorders.

Impact of the Standardization of Penile Cancer Care on the Quality of Care, Outcomes, and Academic-driven Centralization in a Single eUROGEN Referral Center.

BACKGROUND: Penile cancer (PeCa) represents a diagnostic and therapeutic challenge given the low patient volume, which may result in inadequate physician expertise and poor guideline adherence. Since 2015, we have developed a specific care pathway for PeCa in our tertiary referral center. OBJECTIVE: To evaluate the impact of a dedicated PeCa care pathway on patient management, the adequacy of pathological reporting, and oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively queried our institutional registry (S-66482) to identify patients who were surgically treated for PeCa between January 1989 and April 2022. The patient numbers were evaluated within a broader national context. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared patient, surgery, tumor, and pathological data before and after 2015. Kaplan-Meier analysis was used to compare local and regional recurrence rates and cancer-specific survival (CSS). RESULTS AND LIMITATIONS: Overall, 313 patients were included, of whom 204 (65.1%) were surgically treated after 2015. The median number of patients treated yearly was significantly higher after 2015 (26 vs 5; p < 0.01). Patients treated after 2015 more frequently had no palpable lymph nodes at diagnosis, despite similar primary tumor stage. After adoption of the PeCa care pathway, organ-sparing surgery (OSS) was more commonly performed (79.9% vs 57.8%; p < 0.01) despite local staging being similar and without observing a significant increase in positive margins. Surgical staging in patients with European Association of Urology intermediate- or high-risk tumors was conducted more frequently after 2015 (90% vs 41%; p < 0.01). Pathology reporting was standardized, and there was more frequent reporting of p16 staining status (81.4% vs 8.3%; p < 0.01), lymphovascular invasion (93.8% vs 44.3%; p < 0.01), and perineural invasion (92.4% vs 44.3%; p < 0.01) following implementation. CONCLUSIONS: Implementation of a standardized care pathway for PeCa resulted in higher rates of OSS and pathological nodal staging and more complete pathology reports. Considering that these changes were associated with an increase in the number of patients treated, academic-driven centralization may play a role in optimizing the management of these patients. PATIENT SUMMARY: We evaluated the impact of a care pathway for patients with penile cancer on patient management, the completeness of pathology reporting, and cancer control. We found that implementation of this pathway was associated with an increase in the number of patients treated, higher rates of organ-sparing surgery and lymph node staging, and more complete pathology reports. Centralization of care may play a role in optimizing the management of penile cancer.

Systematic Review and Meta-analysis of Minimally Invasive Procedures for Surgical Inguinal Nodal Staging in Penile Carcinoma.

CONTEXT: There are several procedures for surgical nodal staging in clinically node-negative (cN0) penile carcinoma. OBJECTIVE: To evaluate the diagnostic accuracy, perioperative outcomes, and complications of minimally invasive surgical procedures for nodal staging in penile carcinoma. EVIDENCE ACQUISITION: A systematic review of the Medline, Embase, and Cochrane controlled trials databases and ClinicalTrials.gov was conducted. Published and ongoing studies reporting on the management of cN0 penile cancer were included without any design restriction. Outcomes included the false negative (FN) rate, the number of nodes removed, surgical time, and postoperative complications. EVIDENCE SYNTHESIS: Forty-one studies were eligible for inclusion. Four studies comparing robot-assisted (RA-VEIL) and video-endoscopic inguinal lymphadenectomy (VEIL) to open inguinal lymph node dissection (ILND) were suitable for meta-analysis. A descriptive synthesis was performed for single-arm studies on modified open ILND, dynamic sentinel node biopsy (DSNB) with and without preoperative inguinal ultrasound (US), and fine-needle aspiration cytology (FNAC). DSNB with US + FNAC had lower FN rates (3.5-22% vs 0-42.9%) and complication rates (Clavien Dindo grade I-II: 1.1-20% vs 2.9-11.9%; grade III-V: 0-6.8% vs 0-9.4%) in comparison to DSNB alone. Favourable results were observed for VEIL/RA-VEIL over open ILND in terms of major complications (2-10.6% vs 6.9-40.6%; odds ratio [OR] 0.18; p < 0.01). Overall, VEIL/RA-VEIL had lower wound-related complication rates (OR 0.14; p < 0.01), including wound infections (OR 0.229; p < 0.01) and skin necrosis (OR 0.16; p < 0.01). The incidence of lymphatic complications varied between 20.6% and 49%. CONCLUSIONS: Of all the surgical staging options, DSNB with inguinal US + FNAC had the lowest complication rates and high diagnostic accuracy, especially when performed in high-volume centres. If DSNB is not available, favourable results were also found for VEIL/RA-VEIL over open ILND. Lymphatic-related complications were comparable across open and video-endoscopic ILND. PATIENT SUMMARY: We reviewed studies on different surgical approaches for assessing lymph node involvement in cases with penile cancer. The results show that a technique called dynamic sentinel node biopsy with ultrasound guidance and fine-needle sampling has high diagnostic accuracy and low complication rates. For lymph node dissection in penile cancer cases, a minimally invasive approach may offer favourable postoperative outcomes.

Could a Risk-adapted Approach Support Shared Decision-making Regarding Eligibility for Adjuvant Pembrolizumab for Patients with Clear Cell Renal Cell Carcinoma at High Risk of Recurrence? A Multicentre Cohort Study.

The KEYNOTE-564 randomised controlled trial showed a disease-free survival benefit of adjuvant pembrolizumab (aPZB) in comparison to placebo for patients with clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. Despite its recommendation by the European Association of Urology guidelines, the ultimate value of aPZB has recently been questioned. Arguably, patients who might benefit the most from aPZB are those whose probability of RCC recurrence outweighs their probability of dying from other causes over a reasonable timeframe after surgery. To assess the potential impact of this hypothesis on "eligibility" for aPZB, we queried our prospectively collected multi-institutional database for consecutive patients undergoing surgery for nonmetastatic renal masses (cT1-4 N0-1 M0) between 2015 and 2021 to identify ccRCC cases meeting the KEYNOTE-564 criteria. We stratified the patients using the risk-adapted model proposed by Stewart-Merrill et al (whereby stopping follow-up is warranted when the estimated risk of other-cause mortality [OCM] outweighs the estimated risk of RCC recurrence). Then we explored the proportion of patients whose follow-up could theoretically be stopped at 2, 5, 10, or 20 yr, for whom "eligibility" for aPZB might be more controversial. Overall, 1745 patients with ccRCC were included, of whom 419 (24%) met the KEYNOTE-564 criteria. The proportion of patients "not eligible" for aPZB because of higher probability of OCM than of RCC recurrence would have been 81%, 66%, 43%, and 29% at "recommended" follow-up of ≤2.0, ≤5, ≤10, and ≤20 yr, respectively. To the best of our knowledge, this is the first study providing insights to support shared decision-making regarding eligibility for aPZB for patients with nonmetastatic ccRCC with a focus on patient-related factors beyond tumour-driven prognostic scores. PATIENT SUMMARY: An immunotherapy drug call pembrolizumab given after surgery for nonmetastatic kidney cancer may benefit some patients who have a high risk of disease recurrence, but it can have immune-related side effects. We found that comparing the risk of death from other causes and the risk of cancer recurrence could help in reducing overtreatment of patients who might not benefit from this drug.

Corporal Skip Metastases in Penile Squamous Cell Carcinoma: An Unknown and Distinct Pattern of Spread with Poor Prognosis.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is characterised by stepwise lymphatic dissemination. Skip metastases (SkMs) are rare metastases in the corpus cavernosum or spongiosum without continuity to the primary tumour or its resection site. OBJECTIVE: To assess the distinct pattern of spread in SkM+ patients and the effect of SkM on prognosis. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of patients with SkM+ PSCC at ten high-volume international referral centres between January 2006 and May 2022. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated histopathological data, primary lymph node (LN) staging, and metastatic spread. We included a cohort of patients matched for pT stage, LN status, and grade who did not have SkM (SkM-) to compare the SkM prognosis and predictive value for cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Among the 63 SkM+ patients who met our inclusion criteria, the SkM diagnosis was synchronous in 54.0% and metastases were mostly located in the corpus cavernosum. SkM was symptomatic in 14% of cases, was detected on imaging in 32%, and was found incidentally on pathological examination in 27%. Fifty-one patients (81%) presented with positive LNs and 28 (44%) developed distant metastases. Seven patients (11%) presented with or developed distant metastasis without displaying any LN involvement. The 2-yr cancer-specific survival estimates were 36% (95% confidence interval [CI] 25-52%) for SkM+ and 66% (95% CI 55-80%) for matched SkM- patients (p < 0.001). On multivariable Cox regression analysis, SkM presence was an independent predictor for higher CSM (hazard ratio 2.05, 95% CI 1.06-4,12; p = 0.03). CONCLUSIONS: PSCC-related SkM is associated with aggressive disease behaviour and poor survival outcomes. Palpation of the entire penile shaft is essential, and distant staging is recommended in patients suspected of having SkM owing to the tendency for distant metastatic spread. PATIENT SUMMARY: We investigated outcomes for patients with cancer of the penis who had metastases in the tissues responsible for erection. We found that metastases in this location were associated with poor prognosis, even in the absence of more typical spread of cancer via the lymph nodes.

Morbidity of elective surgery for localized renal masses among elderly patients: A contemporary multicenter study.

BACKGROUND: The aging population and the incidence of renal cell carcinoma (RCC) are increasing worldwide. Over 25% of newly diagnosed LRM (localized renal masses) occur in patients over the eighth decade of life. The decision-making and treatment approach to LRM in this population represents a clinical dilemma due to inherited decreased functional reserve and competing mortality risks. Current literature reports conflicting evidence regarding age as a risk factor for worst surgical outcomes. As such, we aimed to evaluate the contemporary morbidity of elective surgery for LRM among elderly patients, focusing on intraoperative and postoperative complications. METHODS: After Ethical Committee approval, we queried our prospectively maintained databases to identify patients with preoperative eGFR ≥60 ml/min/1.73 m [(David and Bloom, 2022) 22 and a normal contralateral kidney who underwent partial or radical nephrectomy (PN or RN) for a single cT1-T2N0M0 LRM between 1/2015-12/2021 at four high-volume European Academic Institutions. Patients were categorized by age groups: <50 yrs (young) vs. 50-75 (middle-aged) yrs vs.> 75 yrs (elderly). Postoperative complications were recorded according to Clavien-Dindo (CD) classification. The primary objectives were the proportion of patients experiencing intraoperative (IOC), any grade (AGC), and high-grade postoperative complications (HGC), defined as CD grade 3-5. RESULTS: Overall, 2469/3076 (80.2%) patients met the inclusion criteria. Of these, 363 (14.7%) were young, 1682 (68.1%) were middle-aged, and 424 (17.2%) were elderly. Compared to middle-aged and young patients, elderly patients had a higher median Charlson Comorbidity Index (6 vs. 4 vs. 0, p < 0.01) and a higher proportion of cT1 renal mass (87.6% vs. 93.0% vs. 93.6%, p < 0.01). No differences among the study groups were found regarding surgical approach (open vs. minimally-invasive) and type of surgery (PN vs. RN). We found that older patients experienced similar IOC (4.5% vs. 4.2% vs. 3.3%, p = 0.7) and AGC (23.1% vs. 20.0% vs. 21.5%, p = 0.4) compared to middle-aged and young patients, respectively. Similarly, there were no significant differences in HGC between the study cohorts (0.7% vs. 1.4% vs. 1.7%, p = 0.8). At multivariable analysis, open approach and PN significantly predicted the occurrence of AGCs, while only the open surgical approach was associated with the occurrence of HGCs. CONCLUSION: In kidney cancer tertiary referral centers, the risk of IOC and postoperative HGC after PN or RN for localized renal masses (LRM) is low, despite a non-negligible risk of AGC, especially in elderly patients. Further efforts should focus on identifying multidisciplinary strategies to select patients most likely to benefit from surgery among elderly candidates with LRMs and decrease the morbidity of surgery in this specific setting.

Predicting Limited Survival Following Inguinal Lymph Node Dissection in Penile Cancer: Should We Revisit the Goals of Care?

OBJECTIVE: Patients with advanced penile squamous cell cancer have a poor prognosis and can benefit from early palliative care consultation. We built a model to identify those patients most likely to benefit. METHODS: Patients with penile squamous cell cancer undergoing inguinal lymph node dissection were identified from the National Cancer Database (NCDB) and a multi-institutional international dataset (INT). A multivariable Cox proportional hazards model for overall survival (OS) was developed using the NCDB and applied to the INT dataset. Parameters were used to make receiver operating characteristic (ROC) curves. ROC-related criteria were optimized to identify a predictive probability cut point and dichotomize patients from INT into risk groups for limited OS of <6 and <12 months. RESULTS: NCDB had 860 deaths; 105 (5%) at 6 months and 296 (15%) at 12 months. INT had 257 deaths; 56 (8%) at 6 months and 124 (18%) at 12 months. Limited OS was associated with older age, greater T and N stage, and fewer lymph nodes removed. Optimized ROC criteria using the OS <6 months curve best dichotomized INT patients into high-risk group with median OS of 24 months (95% CI 18-34) and low-risk group with median OS of 174 months (95% CI 120-NE). CONCLUSION: We developed a simple model that could be used as a screening tool for early palliative care referral.

Penile metastasis in prostate cancer patients: Two case reports, surgical excision technique, and literature review.

Two cases of penile metastasis from primary prostate cancer in a single center are presented, along with a literature review and description of the excision technique. Despite its rich vascularization, penile metastasis is rare, with 72 new cases from September 2006 to March 2021. There is a wide variety of diagnoses, treatments, and prognoses for penile metastatic lesions. Ga-68 prostatespecific membrane antigen positron emission tomography/computed tomography is the most sensitive imaging tool for detecting metastasis from primary prostate cancer. Magnetic resonance imaging of the penis is the most reliable technique for differentiating penile lesions. Histological diagnosis is mostly performed using fine-needle biopsy aspiration. Metastasis-directed treatment is not considered to contribute to prolonged survival. Local treatment is feasible and can be offered to symptomatic patients. Owing to a heterogeneous group, defining overall survival is difficult. Survival until 46months after detecting penile metastases is described.

New-onset Chronic Kidney Disease After Surgery for Localised Renal Masses in Patients with Two Kidneys and Preserved Renal Function: A Contemporary Multicentre Study.

Background: There is a lack of evidence on acute kidney injury (AKI) and new-onset chronic kidney disease (CKD) after surgery for localised renal masses (LRMs) in patients with two kidneys and preserved baseline renal function. Objective: To evaluate the prevalence and risk of AKI and new-onset clinically significant CKD (csCKD) in patients with a single renal mass and preserved renal function after being treated with partial (PN) or radical (RN) nephrectomy. Design setting and participants: We queried our prospectively maintained databases to identify patients with a preoperative estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and a normal contralateral kidney who underwent PN or RN for a single LRM (cT1-T2N0M0) between January 2015 and December 2021 at four high-volume academic institutions. Intervention: PN or RN. Outcome measurements and statistical analysis: The outcomes of this study were AKI at hospital discharge and the risk of new-onset csCKD, defined as eGFR <45 ml/min/1.73 m2, during the follow-up. Kaplan-Meier curves were used to examine csCKD-free survival according to tumour complexity. A Multivariable logistic regression analysis assessed the predictors of AKI, while a multivariable Cox regression analysis assessed the predictors of csCKD. Sensitivity analyses were performed in patients who underwent PN. Results and limitations: Overall, 2469/3076 (80%) patients met the inclusion criteria. At hospital discharge, 371/2469 (15%) developed AKI (8.7% vs 14% vs 31% in patients with low- vs intermediate- vs high-complexity tumours, p < 0.001). At the multivariable analysis, body mass index, history of hypertension, tumour complexity, and RN significantly predicted the occurrence of AKI. Among 1389 (56%) patients with complete follow-up data, 80 events of csCKD were recorded. The estimated csCKD-free survival rates were 97%, 93% and 86% at 12, 36, and 60 mo, respectively, with significant differences between patients with high- versus low-complexity and high- versus intermediate-complexity tumours (p = 0.014 and p = 0.038, respectively). At the Cox regression analysis, age-adjusted Charlson Comorbidity Index, preoperative eGFR, tumour complexity, and RN significantly predicted the risk of csCKD during the follow-up. The results were similar in the PN cohort. The main limitation of the study was the lack of data on eGFR trajectories within the 1st year after surgery and on long-term functional outcomes. Conclusions: The risk of AKI and de novo csCKD in elective patients with an LRM and preserved baseline renal function is not clinically negligible, especially in those with higher-complexity tumours. While baseline nonmodifiable patient/tumour-related characteristics modulate this risk, PN should be prioritised over RN to maximise nephron preservation if oncological outcomes are not jeopardised. Patient summary: In this study, we evaluated how many patients with a localised renal mass and two functioning kidneys, who were candidates for surgery at four referral European centres, experienced acute kidney injury at hospital discharge and significant renal functional impairment during the follow-up. We found that the risk of acute kidney injury and clinically significant chronic kidney disease in this patient population is not negligible, and was associated with specific baseline patient comorbidities, preoperative renal function, tumour anatomical complexity, and surgery-related factors, in particular the performance of radical nephrectomy.

Accuracy of dynamic sentinel lymph node biopsy for inguinal lymph node staging in cN0 penile cancer.

BACKGROUND: Penile cancer is characterized by an early lymphatic dissemination. In intermediate and high-risk primary tumors without palpable inguinal lymph nodes, there is a 6-30% risk of micro-metastatic disease. Invasive lymph node staging in these patients is performed using dynamic sentinel lymph node biopsy (DSNB). In this study, the role of DSNB in cN0 penile cancer was studied, evaluating features of sentinel lymph node (SN) visualization and outcome parameters. Patients with penile cancer without inguinal lymph node metastases who were referred for DSNB at our center between January 2015 and May 2021 and had a follow-up period of at least 18 months, were retrospectively included. After injection of 85 ± 20 MBq [99mTc]Tc-nanocolloid peritumorally, dynamic, static planar and SPECT/CT imaging was performed. Primary endpoints were sensitivity of the diagnostic procedure, disease-free survival and DSNB-related adverse events. Secondary endpoints were SN detection rate, number of SNs and the number of counts of the most active SN. RESULTS: Seventy-seven penile DSNB procedures in 75 patients (67 ± 11 years) were included. The detection rate of DSNB was 91% and 96% per procedure and groin, respectively. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were 79%, 100%, 97% and 100%, respectively. More SNs were seen on SPECT/CT than on static planar imaging (1.33 vs. 1.17, p = 0.001). The mean counts per SN on static planar imaging was lower compared to SPECT/CT (1343 vs. 5008; p < 0.0001). There was a positive correlation between the total counts of the SN on the static planar image and the SPECT/CT (r = 0.79, p < 0.0001). Only one out of seventy-five patients (1%) experienced DSNB-related adverse events. After 18 months, 58 patients remained disease free (77%), 13 developed local recurrence (17%), and 4 developed lymphatic or distant metastases (5%). CONCLUSION: DNSB is a safe diagnostic procedure with a good detection rate and in particular high negative predictive value. It can therefore prevent overtreatment of patients with negative inguinal groins on clinical examination and DSNB examination. Finally, DSNB enables an early detection of occult metastases which would not be visualized with standardized imaging modalities.