Evaluating the Protective Effect of Intravesical Bacillus Calmette-Guerin against SARS-CoV-2 in Non-Muscle Invasive Bladder Cancer Patients: A Multicenter Observational Trial

Simple Summary The transurethral resection of bladder tumors followed by intravesical Bacillus Calmette-Guerin (BCG) instillations represents the standard treatment for high-risk and selected intermediate-risk non-muscle invasive bladder cancer (NMIBC) patients. We hypothesized that intravesical BCG might be protective against symptomatic SARS-CoV-2 infection, especially in those patients who experienced systemic adverse events during BCG treatment. We tested our hypothesis in a large multicenter cohort of NMIBC patients treated with adjuvant intravesical BCG in the year preceding the first and second waves of the SARS-CoV-2 pandemic at two tertiary urological centers in Northern Italy. We aim to evaluate the potential protective role of intravesical Bacillus Calmette-Guerin (BCG) against SARS-CoV-2 in patients with non-muscle invasive bladder cancer (NMIBC). Patients treated with intravesical adjuvant therapy for NMIBC between January 2018 and December 2019 at two Italian referral centers were divided into two groups based on the received intravesical treatment regimen (BCG vs. chemotherapy). The study's primary endpoint was evaluating SARS-CoV-2 disease incidence and severity among patients treated with intravesical BCG compared to the control group. The study's secondary endpoint was the evaluation of SARS-CoV-2 infection (estimated with serology testing) in the study groups. Overall, 340 patients treated with BCG and 166 treated with intravesical chemotherapy were included in the study. Among patients treated with BCG, 165 (49%) experienced BCG-related adverse events, and serious adverse events occurred in 33 (10%) patients. Receiving BCG or experiencing systemic BCG-related adverse events were not associated with symptomatic proven SARS-CoV-2 infection (p = 0.9) nor with a positive serology test (p = 0.5). The main limitations are related to the retrospective nature of the study. In this multicenter observational trial, a protective role of intravesical BCG against SARS-CoV-2 could not be demonstrated. These results may be used for decision-making regarding ongoing and future trials.

Evaluating the Protective Effect of Intravesical Bacillus Calmette-Guerin against SARS-CoV-2 in Non-Muscle Invasive Bladder Cancer Patients: A Multicenter Observational Trial.

We aim to evaluate the potential protective role of intravesical Bacillus Calmette-Guerin (BCG) against SARS-CoV-2 in patients with non-muscle invasive bladder cancer (NMIBC). Patients treated with intravesical adjuvant therapy for NMIBC between January 2018 and December 2019 at two Italian referral centers were divided into two groups based on the received intravesical treatment regimen (BCG vs. chemotherapy). The study's primary endpoint was evaluating SARS-CoV-2 disease incidence and severity among patients treated with intravesical BCG compared to the control group. The study's secondary endpoint was the evaluation of SARS-CoV-2 infection (estimated with serology testing) in the study groups. Overall, 340 patients treated with BCG and 166 treated with intravesical chemotherapy were included in the study. Among patients treated with BCG, 165 (49%) experienced BCG-related adverse events, and serious adverse events occurred in 33 (10%) patients. Receiving BCG or experiencing systemic BCG-related adverse events were not associated with symptomatic proven SARS-CoV-2 infection (p = 0.9) nor with a positive serology test (p = 0.5). The main limitations are related to the retrospective nature of the study. In this multicenter observational trial, a protective role of intravesical BCG against SARS-CoV-2 could not be demonstrated. These results may be used for decision-making regarding ongoing and future trials.

Impact of chronic exposure to 5-alpha reductase inhibitors on the risk of hospitalization for COVID-19: a case-control study in male population from two COVID-19 regional centers of Lombardy, Italy.

BACKGROUND: There are sex differences in vulnerability to Coronavirus disease 2019 (COVID-19). The coronavirus S protein mediates viral entry into target cells employing the host cellular serine protease TMPRSS2 for S-protein priming. The TMPRSS2 gene expression is responsive to androgen stimulation and it could partially explain sex differences. We hypothesized that men chronically exposed to 5-alpha reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) have a lower risk of hospitalization for COVID-19. METHODS: This is a population-based case-control study on consecutive patients positive for SARS-CoV-2 virus who required hospitalization for COVID-19 (cases), age-matched to beneficiaries of the Lombardy Regional Health Service (controls). Data were collected by two high-volume COVID-19 regional centers of Lombardy (Italy). The primary outcome was to compare the prevalence of patients chronically exposed to 5ARIs, who required hospitalization for COVID-19, with the one of controls. RESULTS: Overall, 943 males were enrolled; 45 (4.77%) were exposed to 5ARI. COVID-19 patients aged >55 years under 5ARI treatment were significantly less than expected on the basis of the prevalence of 5ARI treatment among age-matched controls (5.57 vs. 8.14%; P=0.0083, 95% CI: 0.75-3.97%). This disproportion was higher for men aged >65 (7.14 vs. 12.31%; P=0.0001, 95% CI: 2.83-6.97%). Eighteen 5ARIs-patients died; the mean age of men who died was higher than those who did not: 75.98±9.29 vs. 64.78±13.57 (P<0.001). Cox-regression and multivariable models did not show correlation between 5ARIs exposure and protection against intensive care unit admission/death. CONCLUSIONS: Men exposed to 5ARIs might be less vulnerable to severe COVID-19, supporting its use in disease prophylaxis.

The Impact of SARS-CoV-2 Pandemic on Time to Primary, Secondary Resection and Adjuvant Intravesical Therapy in Patients with High-Risk Non-Muscle Invasive Bladder Cancer: A Retrospective Multi-Institutional Cohort Analysis.

BACKGROUND: To investigate the impact of COVID-19 outbreak on the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC). METHODS: A retrospective analysis was performed using an Italian multi-institutional database of TURBT patients with high-risk urothelial NMIBC between January 2019 and February 2021, followed by Re-TURBT and/or adjuvant intravesical BCG. RESULTS: A total of 2591 patients from 27 institutions with primary TURBT were included. Of these, 1534 (59.2%) and 1056 (40.8%) underwent TURBT before and during the COVID-19 outbreak, respectively. Time between diagnosis and TURBT was significantly longer during the COVID-19 period (65 vs. 52 days, p = 0.002). One thousand and sixty-six patients (41.1%) received Re-TURBT, 604 (56.7%) during the pre-COVID-19. The median time to secondary resection was significantly longer during the COVID-19 period (55 vs. 48 days, p < 0.0001). A total of 977 patients underwent adjuvant intravesical therapy after primary or secondary resection, with a similar distribution across the two groups (n = 453, 86% vs. n = 388, 86.2%). However, the proportion of the patients who underwent maintenance significantly differed (79.5% vs. 60.4%, p < 0.0001). CONCLUSIONS: The COVID-19 pandemic represented an unprecedented challenge to our health system. Our study did not show significant differences in TURBT quality. However, a delay in treatment schedule and disease management was observed. Investigation of the oncological impacts of those differences should be advocated.

Oncology and complications.

This collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. Case 1: A case of uretero-arterial fistula in a patient with long-term ureteral stenting for ureteral oncological stricture and a second case associated to retroperitoneal fibrosis were described. Abdominal CT, pyelography, cystoscopy were useful to show the origin of the bleeding. Angiography is useful for confirming the diagnosis and for subsequent positioning of an endovascular prosthesis which represents a safe approach with reduced post-procedural complications. Case 2: A case of patient who suffered from interstitial pneumonitis during a cycle of intravesical BCG instillations for urothelial cancer. The patient was hospitalized for more than two weeks in a COVID ward for a suspected of COVID-19 pneumonia, but he did not show any evidence of SARS-CoV-2 infection during his hospital stay. Case 3: A case of a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. Case 4: A case of a 61 year old male suffering from muscle invasive bladder cancer who was admitted for a radical cystectomy and on the eighth postoperative day developed microangiopathic hemolytic anemia and thrombocytopenia, which clinically defines thrombotic microangiopathy.

Overview of the italian experience in surgical management of bladder cancer during first month of COVID-19 pandemic.

OBJECTIVE: Overview of bladder cancer (BC) management in Italy during the first month of the COVID-19 pandemic (March 2020) with head to head comparison of the data from March 2019, considered "usual activity" period. The aim is to analyze performance of different Italian Centers in North, Center and South, with a special eye for Lombardy (the Italian epicenter). PATIENTS AND METHODS: During April 2020, a survey containing 14 multiple-choice questions focused on general staffing and surgical activity related to BC during the months of March 2019 and March 2020 was sent to 32 Italian Centers. Statistical analysis was performed using IBM SPSS Statistics (v26) software. A Medline search was performed, in order to attempt a comparative analysis with published papers. RESULTS: 28 Centers answered, for a response rate of 87.5%. Most of the urology staff in the Lombardy region were employed in COVID wards (p = 0.003), with a statistically significant reduction in the number of radical cystectomies (RC) performed during that time (p = 0.036). The total amount of RC across Italy remained the same between 2019 and 2020, however there was an increase in the number of surgeries performed in the Southern region. This was most likely due to travel restrictions limiting travel the North. The number of Trans-Urethral Resection of Bladder Tumors (TURBT) (p = 0.046) was higher in Academic Centers (AC) in 2020 (p = 0.037). CONCLUSIONS: The data of our survey, although limited, represents a snap shot of the management of BC during the first month of the COVD-19 pandemic, which posed a major challenge for cancer centers seeking to provide care during an extremely dynamic clinical and political situation which requires maximum flexibility to be appropriately managed.

SARS-CoV-2 Infection and High-Risk Non-Muscle-Invasive Bladder Cancer: Are There Any Common Features?

BACKGROUND: The new severe acute respiratory syndrome virus (SARS-CoV-2) outbreak is a huge health, social and economic issue and has been declared a pandemic by the World Health Organization. Bladder cancer, on the contrary, is a well-known disease burdened by a high rate of affected patients and risk of recurrence, progression and death. SUMMARY: The coronavirus disease (COVID-19 or 2019-nCoV) often involves mild clinical symptoms but in some cases, it can lead to pneumonia with acute respiratory distress syndrome and multiorgan dysfunction. Factors associated with developing a more severe disease are increased age, obesity, smoking and chronic underlying comorbidities (including diabetes mellitus). High-risk non-muscle-invasive bladder cancer (NMIBC) progression and worse prognosis are also characterized by a higher incidence in patients with risk factors similar to COVID-19. Immune system response and inflammation have been found as a common hallmark of both diseases. Most severe cases of COVID-19 and high-risk NMIBC patients at higher recurrence and progression risk are characterized by innate and adaptive immune activation followed by inflammation and cytokine/chemokine storm (interleukin [IL]-2, IL-6, IL-8). Alterations in neutrophils, lymphocytes and platelets accompany the systemic inflammatory response to cancer and infections. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for example have been recognized as factors related to poor prognosis for many solid tumors, including bladder cancer, and their role has been found important even for the prognosis of SARS-CoV-2 infection. Key Messages: All these mechanisms should be further analyzed in order to find new therapeutic agents and new strategies to block infection and cancer progression. Further than commonly used therapies, controlling cytokine production and inflammatory response is a promising field.