Lynch Syndrome: Its Impact on Urothelial Carcinoma.

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.

Organ-sparing surgery of penile cancer: higher rate of local recurrence yet no impact on overall survival.

PURPOSE: To report on the oncological outcome of organ-sparing surgery (OSS) compared to (total or partial) penectomy regarding recurrence patterns and survival in squamous cell carcinoma (SCC) of the penis. METHODS: This was a retrospective study of all patients with penile SCC and eligible follow-up data of at least 2 years at our institution. Patients with tumors staged ≥ pT1G2 underwent invasive lymph node (LN) staging by dynamic sentinel-node biopsy or modified inguinal lymphadenectomy. Radical inguinal lymphadenectomy was performed when LNs were palpable at diagnosis and in those with a positive LN status after invasive nodal staging. Follow-up visits were assessed, and local, regional and distant recurrences were defined and analyzed. RESULTS: 55 patients were identified with a mean follow-up of 63.7 months. Surgical management was OSS in 26 patients (47.2%) and partial or total penectomy in 29 cases (52.8%). Histopathological staging was: pTis (12.7%), pTa (16.3%), pT1a (18.2%), pT1b (5.5%), pT2 (29.1%) and pT3 (18.2%), respectively. Patients in the penectomy group were significantly older (mean 68 vs. 62 years; p = 0.026) with a higher rate of advanced tumor stage (≥ pT2: 44.8% vs. 11.5%; p = 0.002). The local recurrence rate was 42.3% (n = 11) following OSS compared to 10.3% (n = 3) after penectomy (p = 0.007). Kaplan-Meier curves showed no significant differences between the two groups regarding metastasis-free and overall survival. CONCLUSIONS: OSS is associated with a higher local recurrence rate compared to penectomy, yet it has no negative impact on overall and metastasis-free survival.

Real-World Evidence of Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer: An Austrian Multicenter Study.

INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.

Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study.

Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.

Rare, but Severe: Vasculitis and Checkpoint Inhibitors.

In the last years, immunotherapy has become a mainstay of cancer treatment. Owing to its increasing application in clinical practice, novel and rare, but severe, immune-related adverse events such as vasculitis are now being described more frequently. Vasculitis occurs as part of a primary immune disorder but might be induced additionally by substances such as checkpoint inhibitors, which boost the immune system, and thus can also appear as an immune-related adverse event. Several lines of evidence indicate that checkpoint proteins such as programmed death-1 (PD-1) play a major role in the pathophysiology of vasculitis. Such immune checkpoints serve to prevent autoimmunity and to maintain tolerance. We present a case of pronounced vasculitis in a patient with metastatic urothelial carcinoma who received pembrolizumab, and discuss potential pathomechanisms regarding how checkpoint inhibitors can mediate immune-related vascular toxicity. PATIENT SUMMARY: In this report, we looked at potential interactions between checkpoint inhibitors and immune-associated vascular adverse events. Immunotherapy-induced changes of the immune status can favor the occurrence of vascular disease, being fatal in most cases. We conclude that the risk of progressive vascular damage and identification of patients with pre-existing vascular disease should always be borne in mind when treating patients with immunotherapy.

Brunn's Cyst Inducing Persistent Lower Urinary Tract Symptoms in a Young Man: A Case Report.

Background: Lower urinary tract symptoms (LUTS) are mostly caused by hyperplasia of the prostate in the elderly generation or are the consequence of a urethral stricture in young men. Proliferated Brunn's cell nests forming cysts at the bladder neck can likewise result in similar symptoms and can, therefore, often be overlooked. Case Presentation: The case describes a 46-year-old man presenting with the typical LUTS of urgency and pathologic residual urine volume of 350 mL. Sonographic and cystoscopic diagnostics showed a cystic lesion located at the bladder neck, acting as a ball valve mechanism. Transurethral deroofing and resection of the cyst resulted in an immediate resolution of LUTS and a symptom-free patient with no residual urine at follow-up. Conclusion: The presence of a Brunn's cyst is rare but should be kept in mind as a differential diagnosis of LUTS in young men.