Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis.

Apoptosis culminates in secondary necrosis due to lack of ATP. Cancer stem cells form spheres after apoptosis by evoking the blebbishield emergency program. Hence, determining how blebbishields avoid secondary necrosis is crucial. Here we demonstrate that N-Myc and VEGFR2 control transformation from blebbishields, during which oligomers of K-Ras, p27, BAD, Bax, and Bak boost glycolysis to avoid secondary necrosis. Non-apoptotic cancer cells also utilize oligomers to boost glycolysis, which differentiates the glycolytic function of oligomers from their apoptotic action. Smac mimetic in combination with TNF-α or TRAIL but not in combination with FasL abrogates transformation from blebbishields by inducing secondary necrosis. Thus blebbishield-mediated transformation is dependent on glycolysis, and Smac mimetics represent potential candidates to abrogate the blebbishield emergency program.

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis.

Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called 'blebbishields'. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2(High) cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

Management of bladder cancer.

Bladder cancer is the fourth most common cancer in men and is increasing in incidence in women as well. Bladder cancer has a broad range of behavior and presentations, with different prognoses and treatments. Laboratory research has made strides in elucidating pathways of this cancer, and identifying novel therapeutic targets. This short review provides a summary of the current knowledge of the management of bladder cancer.

Immunotherapy for bladder cancer.

The primary role of immunotherapy for bladder cancer is to treat superficial transitional cell carcinomas (ie, carcinoma in situ, Ta, and T1). Immunotherapy in the form of bacille Calmette-Guérin (BCG), interferon, bropirimine, keyhole limpet hemocyanin, and gene therapy is intended to treat existing or residual tumor, to prevent recurrence of tumor, to prevent progression of disease, and to prolong survival of patients. Presently, BCG is commonly used and is the most effective immunotherapeutic agent against superficial transitional cell carcinoma. Data support that BCG has a positive impact on tumor recurrence, disease progression, and survival. Proper attention to maintenance schedules, route of administration, dosing, strains, and viability is essential to obtain the maximum benefits of BCG immunotherapy. This review highlights and summarizes the recent advances concerning immunotherapy, with special emphasis on BCG therapy for transitional cell carcinoma.

Diet and nutrition in urologic cancer.

Cancer is a major cause of mortality and morbidity throughout the world and is projected to become the leading cause of death in the United States and other developed countries in the next few years. There is a large body of evidence linking diet and nutrition with the development of urologic cancers. This is an area where intervention and education can have a major preventive effect on the occurrence of cancer on a worldwide basis. With bladder cancer, a significant protective effect is conferred by a combination of high doses of vitamins A, B6, C and E plus zinc. For prostate cancer, reduced fat intake has a protective effect. A lesser benefit is also suggested with intake of vitamins D and C. Evidence for chemoprevention against renal cell cancer is supported mainly by epidemiologic studies with animal studies indicating possible benefit of vitamin D supplementation. Further research is needed before vitamins and other nutritional supplements can be advocated as standard therapy. Current data support increased intake of vitamins A, B6, C, D and E, reduction of animal fat and increased intake of fruits and vegetables.

Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for bladder cancer.

OBJECTIVES: Despite complete transurethral resection of superficial bladder tumors, the recurrence rate averages 88% at 15 years. Intravesical chemotherapy decreases the recurrence rate, particularly if given immediately after tumor resection. Anticancer drugs such as doxorubicin target topoisomerase II as do the quinolone antibiotics. We evaluated two fluoroquinolones independently and in combination with doxorubicin for cytotoxic effects against bladder cancer cells in vitro. METHODS: Three human transitional carcinoma cell lines, T24 (grade I), HTB9 (grade II), and TccSup (grade IV), were exposed to either ciprofloxacin or ofloxacin in concentrations ranging from 0 (control) to 1000 microg/mL for 24, 48, and 96 hours. In a separate experiment, a 30% cytotoxic dose (IC30) of doxorubicin was applied to the cell cultures for 1 hour and washed off, followed by exposure to ciprofloxacin or ofloxacin for 48 and 96 hours. Cytotoxicity was evaluated using the MTT colorimetric assay. RESULTS: At 96 hours, significant cytotoxicity (P <0.05) for ciprofloxacin was seen starting at 12.5 microg/mL (HTB9, TccSup) and 50 microg/mL (T24) and for ofloxacin at 12.5 microg/mL (HTB9) and 50 microg/mL (TccSup, T24). Maximum cytotoxicity with ciprofloxacin was 95.4+/-0.4% (HTB9, 400 microg/mL) and with ofloxacin was 95.2+/-0.3% (HTB9, 800 microg/mL). Exposure to doxorubicin (IC30, 1 hour) resulted in cell kill rates of 30.9+/-5.2% (T24), 50.7+/-2.7% (HTB9), and 25.4+/-10.6% (TccSup). The addition of as little as 25 microg/mL of ciprofloxacin increased kill rates to 78.5+/-1.2% (T24), 61.2+/-1.6% (HTB9), and 74.2+/-2.4% (TccSup); P < 0.05 relative to doxorubicin alone. Similarly, 50 microg/mL of ofloxacin significantly increased kill rates to 81.8+/-1.6% (T24), 63.3+/-2.5% (HTB9), and 67.8+/-2.0% (TccSup). Both drugs showed even greater synergism at higher concentrations. CONCLUSIONS: Ciprofloxacin and ofloxacin exhibit significant time- and dose-dependent cytotoxicity against transitional carcinoma cells and significantly enhance the cytotoxicity of doxorubicin. These effects occur at concentrations achievable in the urine of patients after oral administration. This suggests that quinolone antibiotics might be useful as an adjunct to intravesical chemotherapy and might reduce seeding of cancer cells after transurethral resection of bladder tumors.

Chemoprevention of urological cancer.

PURPOSE: Cancer is a major cause of mortality and morbidity throughout the world, and ranks as the second leading cause of death in the United States. Most cancers have a latent period of 10 to 20 years, which provides ample time for preventive measures. Transitional cell carcinoma of the bladder and adenocarcinoma of the prostate have protracted courses and may be ideal for chemopreventive strategies. We review the biochemistry and epidemiology of chemopreventive agents, and the laboratory and clinical studies of their role in urological cancer. MATERIALS AND METHODS: We performed a computerized MEDLINE search and manual bibliographical review of relevant peer reviewed studies and reports from 1966 to 1998. These reports were analyzed and scrutinized, and the important findings are summarized. RESULTS: Neoplastic lesions of the bladder and prostate are uniquely suited to the development and evaluation of chemopreventive agents. Epidemiological reports provide the strongest evidence of a protective role for dietary agents in cancer of the bladder, prostate and kidney. Observational and recent experimental trials support these findings in cases of adenocarcinoma of the prostate and transitional cell carcinoma of the bladder. There is strong evidence for a protective effect of vitamin A in bladder cancer. Superior protection has been reported with a combination of high doses of vitamins A, B6, C and E plus zinc. For prostate cancer strong evidence exists for a preventive effect of reduced fat intake, vitamin E, selenium and soy proteins. A lesser benefit is also suggested with intake of vitamins D and C. Evidence of chemoprevention against renal cell cancer is supported mainly by epidemiological studies, and animal studies indicate possible benefit of vitamin D supplementation. CONCLUSIONS: Although there is no incontrovertible proof, numerous studies implicate dietary and nutritional factors in the onset and progression of cancer of the bladder, prostate and kidney. It is possible that the preventive effect of dietary constituents may be in part from consumption with other nutrients and bioactive compounds in whole foods. Further research is needed before vitamins and other nutritional supplements can be advocated as standard therapy but the preponderance of evidence supports increased intake of vitamins A, B6, C, D and E, reduction of animal fat, and increased consumption of fruits and vegetables.

Imperforate anus: an unusual presentation of a common disease.

Imperforate anus is a common problem facing the pediatric surgeon. Most cases of imperforate anus are discovered at birth during the initial physical examination and are corrected early. The pediatric population also accounts for 80% of all cases of ingested foreign bodies. Most of these pass through spontaneously and the treatment is observation. In this article, we present the case of a seven-month-old child in whom failure to pass a swallowed coin led to the diagnosis of imperforate anus. This case illustrates an uncommon presentation of a common disorder and emphasizes the importance of vigilance and careful physical examination in the newborn.