Supplementation of Probiotic Butyricicoccus pullicaecorum Mediates Anticancer Effect on Bladder Urothelial Cells by Regulating Butyrate-Responsive Molecular Signatures

In bladder cancer, urothelial carcinoma is the most common histologic subtype, accounting for more than 90% of cases. Pathogenic effects due to the dysbiosis of gut microbiota are localized not only in the colon, but also in regulating bladder cancer distally. Butyrate, a short-chain fatty acid produced by gut microbial metabolism, is mainly studied in colon diseases. Therefore, the resolution of the anti-cancer effects of butyrate-producing microbes on bladder urothelial cells and knowledge of the butyrate-responsive molecules must have clinical significance. Here, we demonstrate a correlation between urothelial cancer of the bladder and Butyricicoccus pullicaecorum. This butyrate-producing microbe or their metabolite, butyrate, mediated anti-cancer effects on bladder urothelial cells by regulating cell cycle, cell growth, apoptosis, and gene expression. For example, a tumor suppressor against urothelial cancer of the bladder, bladder cancer-associated protein, was induced in butyrate-treated HT1376 cells, a human urinary bladder cancer cell line. In conclusion, urothelial cancer of the bladder is a significant health problem. To improve the health of bladder urothelial cells, supplementation of B. pullicaecorum may be necessary and can further regulate butyrate-responsive molecular signatures.

Animal Models in Bladder Cancer

Background: Bladder cancer (urothelial cancer of the bladder) is the most common malignancy affecting the urinary system with an increasing incidence and mortality. Mouse models of bladder cancer should possess a high value of reproducibility, predictability, and translatability to allow mechanistic, chemo-preventive, and therapeutic studies that can be furthered into human clinical trials. Objectives: To provide an overview and resources on the origin, molecular and pathological characteristics of commonly used animal models in bladder cancer. Methods: A PubMed and Web of Science search was performed for relevant articles published between 1980 and 2021 using words such as: “bladder” and/or “urothelial carcinoma” and animal models. Animal models of bladder cancer can be categorized as autochthonous (spontaneous) and non-autochthonous (transplantable). The first are either chemically induced models or genetically engineered models. The transplantable models can be further subclassified as syngeneic (murine bladder cancer cells implanted into immunocompetent or transgenic mice) and xenografts (human bladder cancer cells implanted into immune-deficient mice). These models can be further divided—based on the site of the tumor—as orthotopic (tumor growth occurs within the bladder) and heterotopic (tumor growth occurs outside of the bladder).

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

Incidence trends and survival prediction of urothelial cancer of the bladder: a population-based study

Background The aim of this study is to determine the incidence trends of urothelial cancer of the bladder (UCB) and to develop a nomogram for predicting the cancer-specific survival (CSS) of postsurgery UCB at a population-based level based on the SEER database. Methods The age-adjusted incidence of UCB diagnosed from 1975 to 2016 was extracted, and its annual percentage change was calculated and joinpoint regression analysis was performed. A nomogram was constructed for predicting the CSS in individual cases based on independent predictors. The predictive performance of the nomogram was evaluated using the consistency index (C-index), net reclassification index (NRI), integrated discrimination improvement (IDI), a calibration plot and the receiver operating characteristics (ROC) curve. Results The incidence of UCB showed a trend of first increasing and then decreasing from 1975 to 2016. However, the overall incidence increased over that time period. The age at diagnosis, ethnic group, insurance status, marital status, differentiated grade, AJCC stage, regional lymph nodes removed status, chemotherapy status, and tumor size were independent prognostic factors for postsurgery UCB. The nomogram constructed based on these independent factors performed well, with a C-index of 0.823 and a close fit to the calibration curve. Its prediction ability for CSS of postsurgery UCB is better than that of the existing AJCC system, with NRI and IDI values greater than 0 and ROC curves exhibiting good performance for 3, 5, and 8 years of follow-up. Conclusions The nomogram constructed in this study might be suitable for clinical use in improving the clinical predictive accuracy of the long-term survival for postsurgery UCB.

Checkpoint inhibitors in BCG-unresponsive nonmuscle invasive bladder cancer: can they help spare the bladder?

Intravesical BCG therapy has been for years, the standard of care in nonmuscle-invasive bladder cancer. But upon recurrence/relapse, radical cystectomy is imposed, due to the paucity of other therapeutic options. Immunotherapy has been revolutionizing cancer treatment, and its indications continue to broaden. It has been approved for the treatment of advanced urothelial cancer of the bladder, mainly as a second-line therapy. Its activity is being studied in nonmuscle-invasive bladder cancer that is not responsive to BCG; we herein report the trials investigating these checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab) in this particular setting.

Modification in the Oncology Field during COVID-19 Pandemic

Background: COVID-19 outbreak impacted all healthcare specializations including the oncology field. Objective: To discuss in detail the varied effects of COVID-19 on the oncology field. Methods: For this narrative review, the researchers relied only on accredited and peer-reviewed resources. As such, the references of this paper were mostly taken from Google Scholar and online repositories, such as PubMed, which hosts the National Center for Biotechnology Information (NCBI), Science Direct, JSTOR, and The Lancet. Results: COVID-19 and the necessity of physical distancing have significantly changed the practice in the oncology field. The use of telehealth is widely adopted, physicians are recommended to consider other forms of treatment, and decisions on immediate cancer treatment depend on the level of risk of progression with cancer care delay. Cancer treatment delay is causing the highest mortality rate for patients who are suffering from cancer of the bladder, lungs, ovary, stomach, and esophagus. COVID-19 has shifted the focus of healthcare professionals away from other life-threatening diseases, like cancer. In the United Kingdom, it has been projected that there is at least a 20% increase in the expected cancer-related mortality rate. This is due to abrupt changes in diagnosing and treating cancer patients, physical distancing protocols, economic downfall, as well as the public's behavior in opting for medical assistance. Conclusion: With the spread of COVID-19, the situation has become more difficult for cancer patients. The mortality rate for cancer patients has worsened during COVID-19. Health professionals working in the oncology field are also devastated by COVID-19.

Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial.

4504 Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR > 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2-yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr ≥3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr ≥3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151.

Do females have worse surgical outcomes after radical cystectomy? Impact of gender on 30-day complications in a national cohort.

402 Background:: Men have higher rates of bladder cancer and are more likely to undergo cystectomy than women, yet women seem to have worse oncologic outcomes. This is attributed to biologic factors including adverse histologic variants and social factors including delay in diagnosis. There is early evidence that women also have worse surgical outcomes. We further examined the role of gender in 30-day perioperative outcomes following radical cystectomies in a national cohort. Methods: We examined the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2012 to 2016. The database was searched for CPT codes reflecting radical cystectomy and a diagnosis of “cancer of the bladder.” Frailty was estimated by the modified frailty index (functional status, diabetes, chronic obstructive pulmonary disorder, history of chronic heart failure, and hypertension requiring medication.) To compare demographic and perioperative characteristics between genders, Chi-Square analyses were performed for categorical variables, student’s t test to compare averages, and the Wilcoxon rank sum test for operative time and length of stay (LOS). Results: 4,681 radical cystectomies were identified including 842 (18.0%) females. Of the female cohort, average age was 68.6 (+/-11.2 years), 77.3% was Caucasian and 278 (33%) had a BMI of at least 30. There were no differences appreciated between genders with regards to age, average ASA score, frailty, or minimally-invasive approach (all p=NS). Compared to males, female gender was associated with longer operative time (350 vs. 336 min, p<0.009), length of stay (LOS) (8 vs 7, p<0.001) and lower rates of discharge to home (79.9% vs 87.0%, p<0.0001). Reoperation (4.8% vs. 6.0%), readmission (22.2% vs 20.6%), and death within 30 days (1.9% vs. 2.0%) were similar. Clavien 3 or greater was also similar among gender (Table). Conclusions: Female patients comprise a minority of radical cystectomies with slightly longer LOS and less home discharge than men, yet 30-day major complications, reoperation and mortality appear similar. [Table: see text]