Prostate Cancer in Latin America: Challenges and Recommendations.

Prostate cancer (PCa) is the most frequent tumor among Latin American (LATAM) men. The incidence of de novo metastatic PCa is higher in LATAM than other parts of the world, and demographic changes in the region have increased disease burden. However, region-specific information regarding prevalence, progression, and treatment effectiveness is not currently available for nonmetastatic, castration-resistant PCa (nmCRPC). Nonmetastatic, castration-resistant PCa is a heterogeneous disease with varying potential to develop metastasis with limited treatments available, until recently. New clinical trials with promising results have allowed second-generation antiandrogen drugs to be used as first-line treatments, rendering guidelines outdated. As a result, this panel of experts reviewed the current status and challenges and developed recommendations for nmCRPC diagnosis and management in LATAM. The Americas Health Foundation (AHF) conducted a literature review and identified LATAM scientists and clinicians who have published in the field of PCa since 2012. The AHF convened a panel of 7 chosen experts urologists and medical oncologists from the region. The AHF developed specific questions relating to nmCRPC, which were answered by the experts prior to the multiday meeting. Each narrative was discussed and edited by the panel, through numerous rounds of discussion until a consensus was reached in a final manuscript. The panel proposes specific and realistic recommendations for improving access to diagnosis and management of PCa in LATAM. No treatment has yet shown improvement in overall survival; however, when including metastasis-free survival as an end point, second-generation antiandrogen drugs have emerged as effective treatment options and are currently included as first-line treatment. Although nmCRPC is a specific disease that represents a small percentage of patients with PCa, effective diagnostic and treatment strategies can contribute toward increasing quality of life and survival rates of patients with PCa in LATAM.

Should continuous bladder irrigation be recommended when single instillation of intravesical chemotherapy cannot be used after transurethral resection in low-risk non-muscle invasive bladder cancer?

Reducing the recurrence rate in patients with low-risk non-muscle invasive bladder cancer patients is a critical concern in the urologic community. The gold standard treatment is single instillation (SI) of intravesical chemotherapy after transurethral resection of bladder tumor (TURBT), but unfortunately, it is underused. Continuous bladder irrigation (CBI) after TURBT is an alternative strategy to SI for the prevention of bladder tumor implantation and recurrence. The aim of this review was to present the evidence that supports CBI after TURBT when SI is not possible.

The Impact of Dose Reduction of Bacillus Calmette-Guerin on Oncological Outcomes and Toxicity in Non-Muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard adjuvant treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) following transurethral resection of the bladder (TURB). However, the optimal dose, strain, and schedule of BCG remain unclear. OBJECTIVE: To evaluate the impact of BCG dose reduction on oncological outcomes and toxicity in patients with non-muscle invasive bladder cancer. METHODS: We performed a systematic review of the literature in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Selected studies were analyzed for Meta Analysis using PRISMA criteria. The study focused on disease recurrence, progression, and toxicity. We also compared the oncological outcomes of the different BCG strains. RESULTS: A total of 2963 patients in 13 randomized controlled trials were included. In recurrence analysis, we found a non-significant difference between the full dose and any dose reduction of BCG (RR = 1.17, [1.06-1.28], I2 = 0%, p = 0.7). In terms of progression, the difference was also non-statistically significant (RR: 1.12 [0.89 - 1.41], I2 = 0%, p = 0.93). In the toxicity analysis, there were more local (RR: 0.81 [0.67-0.99] I2 = 76%; p < 0.01) and systemic (RR: 0.53 [0.34-0.82] I2 = 83%; p < 0.01) side effects in the full dose group than in the dose reduction group. There were no statistically significant differences in oncological outcomes between the analyzed BCG strains. CONCLUSIONS: Dose reduction did not affect the oncological outcomes of patients with NMIBC who received adjuvant therapy with BCG. On the other hand, dose reduction showed a significant trend towards fewer systemic and local side effects. Further studies comparing oncological and toxicity outcomes using different strains are needed.

A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study.

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (p = 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (p = 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a pre-existing Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.

Post-Transurethral Resection of Bladder Tumor Bladder Perforation Resulting in Mitomycin C Extravasation, Pudendal Neuralgia, and Ureterohydronephrosis.

Background: Mitomycin C (MMC) extravasation after transurethral resection of bladder tumor (TURBT) is a rare and highly morbid complication. Management of these cases may require a multidisciplinary approach with strategies ranging from conservative management to surgical intervention. Case Presentation: We present a 48-year-old woman who received a TURBT for a 5 mm bladder tumor. Procedure was uneventful and no bladder perforation was noticed. A single dose of instillation of MMC was performed after surgery resulting in extravasation, consequent ipsilateral pudendal neuralgia, and ureterohydronephrosis. Treatment included a second TURBT, Double-J stent placement, and multiple pain management schemes. After 8 months the patient had complete resolution of pain and ureterohydronephrosis. Conclusion: Perioperative chemotherapy is the standard of care in low-risk bladder cancer. Extravasation of MMC, although rare, can produce severe complications, sometimes irreversible. Other treatment options, such as gemcitabine, are less frequently used despite being less irritant and having similar efficacy. Further studies are needed to compare single-dose instillation regimens.

Histologic changes after urethroplasty using small intestinal submucosa unseeded with cells in rabbits with injured urethra.

OBJECTIVE: To determine whether small intestine submucosa has the same regenerative capacity when urethroplasty is performed in injured urethras. METHODS: Our experiment was conducted in 30 New Zealand male rabbits, all of which had urethral injury. One month after the injury, the animals were randomized into a control group or a group with onlay urethroplasty with small intestine submucosa. The animals were euthanized at 2, 4, 12, 24, and 36 weeks after urethroplasty, and their urethras were removed for histologic and immunohistochemical examination. Before the scheduled euthanasia, urethrography and cystoscopy were performed. RESULTS: After 2 weeks, there was evidence of a continuous monolayer of stratified epithelial cells and absence of smooth muscle fibers. One month later, the epithelium showed no changes from the previously observed features, but some smooth muscle fibers (representing newly formed vessels) became apparent. After 3 months, the graft showed increased concentration of smooth muscle fibers. After 6 and 9 months, the density of smooth muscle cells remained unchanged. Fiber arrangement was irregular, particularly at the anastomosis site. Epithelial and smooth muscle phenotypes were confirmed by immunohistochemistry using anti-pan-citokeratin (AE1/AE3) antibodies and anti-α-smooth muscle actin, respectively. CONCLUSION: Small intestine submucosa promotes regeneration in traumatized urethras, with slightly delayed epithelialization and abnormal distribution of smooth muscle. Urethral damage caused by trauma interferes with the normal healing process.