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.

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.

European Association of Urology-American Society of Clinical Oncology Collaborative Guideline on Penile Cancer: 2023 Update.

CONTEXT: Penile cancer is a rare disease but has a significant impact on quality of life. Its incidence is increasing, so it is important to include new and relevant evidence in clinical practice guidelines. OBJECTIVE: To provide a collaborative guideline that offers worldwide physician and patient guidance for the management of penile cancer. EVIDENCE ACQUISITION: Comprehensive literature searches were performed for each section topic. In addition, three systematic reviews were conducted. Levels of evidence were assessed, and a strength rating for each recommendation was assigned according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. EVIDENCE SYNTHESIS: Penile cancer is a rare disease but its global incidence is increasing. Human papillomavirus (HPV) is the main risk factor for penile cancer and pathology should include an assessment of HPV status. The main aim of primary tumour treatment is complete tumour eradication, which has to be balanced against optimal organ preservation without compromising oncological control. Early detection and treatment of lymph node (LN) metastasis is the main determinant of survival. Surgical LN staging with sentinel node biopsy is recommended for patients with a high-risk (≥pT1b) tumour with cN0 status. While (inguinal) LN dissection remains the standard for node-positive disease, multimodal treatment is needed in patients with advanced disease. Owing to a lack of controlled trials and large series, the levels of evidence and grades of recommendation are low in comparison to those for more common diseases. CONCLUSIONS: This collaborative penile cancer guideline provides updated information on the diagnosis and treatment of penile cancer for use in clinical practice. Organ-preserving surgery should be offered for treatment of the primary tumour when feasible. Adequate and timely LN management remains a challenge, especially in advanced disease stages. Referral to centres of expertise is recommended. PATIENT SUMMARY: Penile cancer is a rare disease that significantly impacts quality of life. While the disease can be cured in most cases without lymph node involvement, management of advanced disease remains challenging. Many unmet needs and unanswered questions remain, underlining the importance of research collaborations and centralisation of penile cancer services.

What Is the Most Effective Management of the Primary Tumor in Men with Invasive Penile Cancer: A Systematic Review of the Available Treatment Options and Their Outcomes.

Context: The primary lesion in penile cancer is managed by surgery or radiation. Surgical options include penile-sparing surgery, amputative surgery, laser excision, and Moh's micrographic surgery. Radiation is applied as external beam radiotherapy (EBRT) and brachytherapy. The treatment aims to completely remove the primary lesion and preserve a sufficient functional penile stump. Objective: To assess whether the 5-yr recurrence-free rate and other outcomes, such as sexual function, quality of life, urination, and penile preserving length, vary between various treatment options. Evidence acquisition: The EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED), Google Scholar, and ClinicalTrials.gov were searched for publications from 1990 through May 2021. Randomized controlled trials, nonrandomized comparative studies (NRCSs), and case series (CSs) were included. Evidence synthesis: The systematic review included 88 studies, involving 9578 men from 16 NRCSs and 72 CSs. The cumulative mean 5-yr recurrence-free rates were 82.0% for penile-sparing surgery, 83.9% for amputative surgery, 78.6% for brachytherapy, 55.2% for EBRT, 69.4% for lasers, and 88.2% for Moh's micrographic surgery, as reported from CSs, and 76.7% for penile-sparing surgery and 93.3% for amputative surgery, as reported from NRCSs. Penile surgery affects sexual function, but amputative surgery causes more appearance concerns. After brachytherapy, 25% of patients reported sexual dysfunction. Both penile-sparing surgery and amputative surgery affect all aspects of psychosocial well-being. Conclusions: Despite the poor quality of evidence, data suggest that penile-sparing surgery is not inferior to amputative surgery in terms of recurrence rates in selected patients. Based on the available information, however, broadly applicable recommendations cannot be made; appropriate patient selection accounts for the relative success of all the available methods. Patient summary: We reviewed the evidence of various techniques to treat penile tumor and assessed their effectiveness in oncologic control and their functional outcomes. Penile-sparing as well as amputative surgery is an effective treatment option, but amputative surgery has a negative impact on sexual function. Penile-sparing surgery and radiotherapy are associated with a higher risk of local recurrence, but preserve sexual function and quality of life better. Laser and Moh's micrographic surgery could be used for smaller lesions.

Case of bilateral hydronephrosis and spontaneous ureteral rupture as a rare complication of prostate biopsy.

Development of bilateral hydronephrosis and ureteric rupture has never been reported in the published literature so far. We describe a case of 51years old gentleman who developed this complication aftertrans-rectal ultrasound guided prostate biopsy. The patient was treated with bilateral double-J stent insertion, intravenous antibiotic therapy and recovered completely. There have been reports of hydronephrosis with or without ureteric rupture in the world literature. The causes reported have been such as malignancy, stones, retroperitoneal fibrosis, iatrogenic manipulation, trauma, degenerative kidney conditions and spontaneous causes. This could lead to development of retroperitoneal urinoma, urosepsis, abscess formation, infection and renal impairment.

Morphological and functional alterations of the prostate tissue during clinical progression in hormonally-naïve, hormonally-treated and castration-resistant patients with metastatic prostate cancer.

Since commony used tools in oncological practice for the diagnosis of castration-resistent prostatic acinar adenocarcinoma are based on clinical criteria, such as castrate testosterone level, continuous rise in serum prostate-specific antigen, progression of preexisting disease or appearance of new metastases, it is important to identify reliable histopathological markers for the identification of this disease. Therefore, the aim of the present study was to determine the association between results from histological analysis, ultrastructural analysis and apoptosis in the prostate of patients with metastatic acinar prostatic adenocarcinoma (mPC). Patients were treated with androgen deprivation therapy (ADT), abiraterone acetate (Abi) therapy or received no treatment. Prostate tissue samples were divided into four groups as follows: i) Group 1, tissues from patients with benign prostatic hyperplasia (adenocarcinoma negative); ii) group 2, tissues from patients with metastatic hormone naïve prostate cancer; iii) group 3, tissues from patients with mPC treated with ADT; and iv) group 4, tissues from patients with metastatic castration-resistant prostate cancer treated with ADT and Abi. Immunohistochemical, terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling (TUNEL) and ultrastructural assays using light, fluorescence and transmission electron microscopy, respectively, were used to analyze prostate tissue samples. The results demonstrated that ADT and Abi therapy caused histological and ultrastructural changes in prostate tissues. In groups 3 and 4, benign and malignant tissues were affected by the hormonal therapy. Histologically, the malignant epithelium after ADT therapy in groups 3 and 4 presented with a loss of glandular architecture, nuclear and nucleolar shrinkage, chromatin condensation and cytoplasmic clearing. At the ultrastructural level, compact hypertrophic and hyperchromatic nuclei with numerous invaginations were observed in groups 2, 3 and 4. In addition, the incidence of abnormal mitochondria in malignant cells of these groups was high. Group 4 was characterized by the presence of malignant mesenchyme-like cells in the prostatic stroma, arranged in small groups surrounded by collagen fibrils. Furthermore, the cytoplasm of these cells contained filaments. A decrease in the number of apoptotic cells using TUNEL assays in the examined samples was observed with increasing disease progression. The findings from the present study suggest that the duration of treatment with ADT and progression of the disease were associated with apoptosis dysregulation.

Reprint - Medical and surgical interventions for the treatment of urinary stones in children: A Cochrane Review.

INTRODUCTION: We performed systematic review to assess the effects of different medical and surgical management of urinary stones in children. METHODS: We performed a comprehensive search using multiple databases (MEDLINE, EMBASE, Cochrane Register of Controlled Trials), trials registries (World Health Organization International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov), and abstract proceedings of major urological and pediatric urology meetings, with no restrictions on the language of publication or publication status, up until December 2017. We included all randomized controlled trials (RCTs) and quasi-RCTs. Two review authors independently assessed the eligibility of studies for inclusion, extracted data, and assessed risk of bias in accordance with the Cochrane "Risk of bias" tool. We performed statistical analyses using a random-effects model and assessed the quality of the evidence according to GRADE. RESULTS: We included 14 studies with a total of 978 randomized participants in our review, informing seven comparisons with shock wave lithotripsy, percutaneous nephrolithotripsy, ureterorenoscopy (regardless of the type of lithotripsy), open stone surgery, and medical expulsive therapy. There was very low quality of evidence in the most comparisons with regards to the effectiveness and adverse events for the treatment of pediatric upper renal tract stone disease. CONCLUSIONS: Based on mostly very low-quality evidence for most comparisons and outcomes, we are uncertain about the effect of nearly all medical and surgical interventions to treat stone disease in children. There is a critical need for better-quality trials assessing patient-important outcomes in children with stone disease to inform future guidelines on the management of this condition.

Medical and surgical interventions for the treatment of urinary stones in children.

BACKGROUND: Urolithiasis is a condition where crystalline mineral deposits (stones) form within the urinary tract. Urinary stones can be located in any part of the urinary tract. Affected children may present with abdominal pain, blood in the urine or signs of infection. Radiological evaluation is used to confirm the diagnosis, to assess the size of the stone, its location, and the degree of possible urinary obstruction. OBJECTIVES: To assess the effects of different medical and surgical interventions in the treatment of urinary tract stones of the kidney or ureter in children. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid) as well as the World Health Organization International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. We searched reference lists of retrieved articles and conducted an electronic search for conference abstracts for the years 2012 to 2017. The date of the last search of all electronic databases was 31 December 2017 and we applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs looking at interventions for upper urinary tract stones in children. These included shock wave lithotripsy, percutaneous nephrolithotripsy, ureterorenoscopy, open surgery and medical expulsion therapy for upper urinary tract stones in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to Cochrane guidance. Two review authors independently searched and assessed studies for eligibility and conducted data extraction. 'Risk of bias' assessments were completed by three review authors independently. We used Review Manager 5 for data synthesis and analysis. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 14 studies with a total of 978 randomised participants in our review, informing eight comparisons. The studies contributing to most comparisons were at high or unclear risk of bias for most domains.Shock wave lithotripsy versus dissolution therapy for intrarenal stones: based on one study (87 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on stone-free rate (SFR), serious adverse events or complications of treatment and secondary procedures for residual fragments.Slow shock wave lithotripsy versus rapid shock wave lithotripsy for renal stones: based on one study (60 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures for residual fragments.Shock wave lithotripsy versus ureteroscopy with holmium laser or pneumatic lithotripsy for renal and distal ureteric stones: based on three studies (153 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures.Shock wave lithotripsy versus mini-percutaneous nephrolithotripsy for renal stones: based on one study (212 participants), SWL likely has a lower SFR (RR 0.88, 95% CI 0.80 to 0.97; moderate quality evidence); this corresponds to 113 fewer stone-free patients per 1000 (189 fewer to 28 fewer). SWL may reduce severe adverse events (RR 0.13, 95% CI 0.02 to 0.98; low quality evidence); this corresponds to 66 fewer serious adverse events or complications per 1000 (74 fewer to 2 fewer). Rates of secondary procedures may be higher (RR 2.50, 95% CI 1.01 to 6.20; low-quality evidence); this corresponds to 85 more secondary procedures per 1000 (1 more to 294 more).Percutaneous nephrolithotripsy versus tubeless percutaneous nephrolithotripsy for renal stones: based on one study (23 participants) and consistently very low quality evidence, we are uncertain about the effects of percutaneous nephrolithotripsy on SFR, serious adverse events or complications of treatment and secondary procedures.Percutaneous nephrolithotripsy versus tubeless mini-percutaneous nephrolithotripsy for renal stones: based on one study (70 participants), SFR are likely similar (RR 1.03, 95% CI 0.93 to 1.14; moderate-quality evidence); this corresponds to 28 more per 1,000 (66 fewer to 132 more). We did not find any data relating to serious adverse events. Based on very low quality evidence we are uncertain about secondary procedures.Alpha-blockers versus placebo with or without analgesics for distal ureteric stones: based on six studies (335 participants), alpha-blockers may increase SFR (RR 1.34, 95% CI 1.16 to 1.54; low quality evidence); this corresponds to 199 more stone-free patients per 1000 (94 more to 317 more). Based on very low quality evidence we are uncertain about serious adverse events or complications and secondary procedures. AUTHORS' CONCLUSIONS: Based on mostly very low-quality evidence for most comparisons and outcomes, we are uncertain about the effect of nearly all medical and surgical interventions to treat stone disease in children.Common reasons why we downgraded our assessments of the quality of evidence were: study limitations (risk of bias), indirectness, and imprecision. These issues make it difficult to draw clinical inferences. It is important that affected individuals, clinicians, and policy-makers are aware of these limitations of the evidence. There is a critical need for better quality trials assessing patient-important outcomes in children with stone disease to inform future guidelines on the management of this condition.

Medical and surgical interventions for the treatment of urinary stones in children.

BACKGROUND: Urolithiasis is a condition where crystalline mineral deposits (stones) form within the urinary tract. Urinary stones can be located in any part of the urinary tract. Affected children may present with abdominal pain, blood in the urine or signs of infection. Radiological evaluation is used to confirm the diagnosis, to assess the size of the stone, its location, and the degree of possible urinary obstruction. OBJECTIVES: To assess the effects of different medical and surgical interventions in the treatment of urinary tract stones of the kidney or ureter in children. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid) as well as the World Health Organization International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. We searched reference lists of retrieved articles and conducted an electronic search for conference abstracts for the years 2012 to 2017. The date of the last search of all electronic databases was 31 December 2017 and we applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs looking at interventions for upper urinary tract stones in children. These included shock wave lithotripsy, percutaneous nephrolithotripsy, ureterorenoscopy, open surgery and medical expulsion therapy for upper urinary tract stones in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to Cochrane guidance. Two review authors independently searched and assessed studies for eligibility and conducted data extraction. 'Risk of bias' assessments were completed by three review authors independently. We used Review Manager 5 for data synthesis and analysis. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 14 studies with a total of 978 randomised participants in our review, informing eight comparisons. The studies contributing to most comparisons were at high or unclear risk of bias for most domains.Shock wave lithotripsy versus dissolution therapy for intrarenal stones: based on one study (87 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on stone-free rate (SFR), serious adverse events or complications of treatment and secondary procedures for residual fragments.Slow shock wave lithotripsy versus rapid shock wave lithotripsy for renal stones: based on one study (60 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures for residual fragments.Shock wave lithotripsy versus ureteroscopy with holmium laser or pneumatic lithotripsy for renal and distal ureteric stones: based on three studies (153 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures.Shock wave lithotripsy versus mini-percutaneous nephrolithotripsy for renal stones: based on one study (212 participants), SWL likely has a lower SFR (RR 0.88, 95% CI 0.80 to 0.97; moderate quality evidence); this corresponds to 113 fewer stone-free patients per 1000 (189 fewer to 28 fewer). SWL may reduce severe adverse events (RR 0.13, 95% CI 0.02 to 0.98; low quality evidence); this corresponds to 66 fewer serious adverse events or complications per 1000 (74 fewer to 2 fewer). Rates of secondary procedures may be higher (RR 2.50, 95% CI 1.01 to 6.20; low-quality evidence); this corresponds to 85 more secondary procedures per 1000 (1 more to 294 more).Percutaneous nephrolithotripsy versus tubeless percutaneous nephrolithotripsy for renal stones: based on one study (23 participants) and consistently very low quality evidence, we are uncertain about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures.Percutaneous nephrolithotripsy versus tubeless mini-percutaneous nephrolithotripsy for renal stones: based on one study (70 participants), SFR are likely similar (RR 1.03, 95% CI 0.93 to 1.14; moderate-quality evidence); this corresponds to 28 more per 1,000 (66 fewer to 132 more). We did not find any data relating to serious adverse events. Based on very low quality evidence we are uncertain about secondary procedures.Alpha-blockers versus placebo with or without analgesics for distal ureteric stones: based on six studies (335 participants), alpha-blockers may increase SFR (RR 1.34, 95% CI 1.16 to 1.54; low quality evidence); this corresponds to 199 more stone-free patients per 1000 (94 more to 317 more). Based on very low quality evidence we are uncertain about serious adverse events or complications and secondary procedures. AUTHORS' CONCLUSIONS: Based on mostly very low-quality evidence for most comparisons and outcomes, we are uncertain about the effect of nearly all medical and surgical interventions to treat stone disease in children.Common reasons why we downgraded our assessments of the quality of evidence were: study limitations (risk of bias), indirectness, and imprecision. These issues make it difficult to draw clinical inferences. It is important that affected individuals, clinicians, and policy-makers are aware of these limitations of the evidence. There is a critical need for better quality trials assessing patient-important outcomes in children with stone disease to inform future guidelines on the management of this condition.

Identification of novel genes in Hirschsprung disease pathway using whole genome expression study.

AIM: This study aims to identify new genes not described previously that may be relevant in the etiology or pathophysiology of patients with Hirschsprung disease (HD). This was done by identifying differences in gene expression between normal and abnormal segments of bowel in HD patients compared with controls. METHODS: Full-thickness colonic tissue samples were taken from HD patients, both from the diseased (Ds) and normal segment of the colon (Nr), and from controls (Ct). Samples were further dissected into mucosa (MUC) and muscle (MUS). RNA was extracted and analyzed on Affymetrix Gene Chip Human Gene 1.0 ST arrays. Statistical analyses using ANOVA with a fold change cut off of 2 was applied to detect a number of differentially expressed genes. Selected genes were revalidated by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: Thirty-four samples (18 MUS and 16 MUC) were analyzed. MUC (1.64 ± 0.46 µg/mg) and MUS (0.83 ± 0.48 µg/mg) showed good RNA extraction yield and quality. Of the 24,987 filtered on expression genes, MUS showed 220 genes with expression difference of 2-fold, out of which 120 genes were significant with P ≤ .05. Similarly, MUC demonstrated 206 genes with 2-fold changes and 9 had P ≤ .05. Some genes showing differential expression between groups and therefore subject to further analysis were RELN, GAL, GAP43, NRSN1, and GABRG2. CONCLUSION: Analyzed data showed significant differences in expression of above sets of genes with up- and down-regulation, which has not been described before in HD and could have a role in pathogenesis of this condition.