BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer.

Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.

Thiolated Mesoporous Silica Nanoparticles as an Immunoadjuvant to Enhance Efficacy of Intravesical Chemotherapy for Bladder Cancer.

The characteristics of global prevalence and high recurrence of bladder cancer has led numerous efforts to develop new treatments. The spontaneous voiding and degradation of the chemodrug hamper the efficacy and effectiveness of intravesical chemotherapy following tumor resection. Herein, the externally thiolated hollow mesoporous silica nanoparticles (MSN-SH(E)) is fabricated to serve as a platform for improved bladder intravesical therapy. Enhanced mucoadhesive effect of the thiolated nanovector is confirmed with porcine bladder. The permeation-enhancing effect is also verified, and a fragmented distribution pattern of a tight junction protein, claudin-4, indicates the opening of tight junction. Moreover, MSN-SH(E)-associated reprogramming of M2 macrophages to M1-like phenotype is observed in vitro. The antitumor activity of the mitomycin C (MMC)-loaded nanovector (MMC@MSN-SH(E)) is more effective than that of MMC alone in both in vitro and in vivo. In addition, IHC staining is used to analyze IFN-γ, TGF-ß1, and TNF-α. These observations substantiated the significance of MMC@MSN-SH(E) in promoting anticancer activity, holding the great potential for being used in intravesical therapy for non-muscle invasive bladder cancer (NMIBC) due to its mucoadhesivity, enhanced permeation, immunomodulation, and prolonged and very efficient drug exposure.

Supportive Care Needs of Patients on Surveillance and Treatment for Non-Muscle-Invasive Bladder Cancer.

OBJECTIVE: This literature review provides an overview of non-muscle-invasive bladder cancer diagnosis (NMIBC), treatment, and surveillance. Existing evidence is reviewed to identify the NMIBC patient pathway, highlight its effect on quality of life, and identify supportive care needs of this patient group. A framework to guide nurses in the care of this underserved population is proposed. DATA SOURCES: Electronic databases including CINAHL, Medline, PsychInfo, Cochrane, and Google Scholar were searched. CONCLUSION: NMIBC is a chronic disease with high recurrence and progression rates with most patients requiring invasive treatment and burdensome surveillance schedules with frequent hospital visits. Treatment-related side effects may interrupt therapy and possibly result in its discontinuation. Patients' quality of life can be negatively affected at various stages of the cancer trajectory. Specialist nurses provide holistic care throughout all stages of the patient journey to optimize supportive care, information provision, and delivery of appropriate treatment and surveillance protocols. NMIBC research is historically underfunded with a paucity of evidence identifying the supportive care needs of this population. Further research is urgently required to fill the gaps identified. IMPLICATIONS FOR NURSING PRACTICE: This timely paper raises the profile of unmet supportive care needs in an underserved research cancer population. Suggestions are proposed to improve the quality of nursing care through standardized practices and the development and integration of patient pathways. Evidence of the effect of NMIBC on family members or carers is absent from the literature. Future research implications and directions are proposed.

Intravesical In Situ Immunostimulatory Gel for Triple Therapy of Bladder Cancer.

Bladder cancer displays multiple biological features aided in drug resistance; therefore, single therapy fails to induce complete tumor regression. To address this issue, various kinds of cell death of cancer cells as well as restoring tumor immune microenvironment need to be taken into consideration. Here, we introduce a gel system termed AuNRs&IONs@Gel, which target-delivers a combination of photothermal, ferroptotic, and immune therapy through intravesical instillation. AuNRs&IONs@Gel consists of a gel delivery platform, embedded gold nanorods (AuNRs), and iron oxide nanoparticles (IONs). The targeted delivery gel platform provides dextran aldehyde-selective adhesion with cancer collagen. In this condition, photothermal therapy can be performed by gold nanorods (AuNRs) under imaging-guided near-infrared radiation. Local high concentrations of IONs can be absorbed by cancer cell to induce ferroptosis. Moreover, tumor-associated macrophages which often display an immune-suppressive M2-like phenotype will be repolarized by IONs into the antitumor M1-like phenotype, exerting a direct antitumor effect and professional antigen presentation of dead cancer cells. This process triggers a potent immune response of innate and adapt immunities to protect tumor rechallenge in long terms. Our triple-therapy strategy employs FDA-approved nanoparticles to inhibit bladder cancer which may possess great potential for clinical translation.

An evaluation of the pharmacotherapy for interstitial cystitis.

INTRODUCTION: Interstitial cystitis (IC) and bladder pain syndrome (BPS) are chronic conditions that can be debilitating for patients. There is no consensus as to their etiology, and there are many proposed treatment algorithms. Oftentimes multimodal therapy, such as combining behavioral modification and physical therapy alongside pharmacotherapies, will be utilized. With the various treatment options available to patients and providers, there is an ever-growing need to implement evidence-based therapies. AREAS COVERED: The authors explore the different pharmacotherapies as commonly recommended in the American Urological Association (AUA) and European Association of Urology (EAU) multitiered guidelines for IC/BPS treatment as well as other investigational therapies. Pharmacotherapies targeting bladder, pelvic, and/or systemic factors in the overall treatment of IC/BPS are discussed with a particular focus on evidence-based guideline therapies. This article also looks at emerging therapies of interest. EXPERT OPINION: IC/BPS is a syndrome that requires a multimodal approach, including clinical phenotyping and directed therapy based on the patient's symptoms. The AUA and EAU provide guidelines for practitioners to follow, but adequate treatment requires the therapy to be targeted toward the patient's phenotypic domain.

Tumor inhibitory effects of intravesical Ganoderma lucidum instillation in the syngeneic orthotopic MB49/C57 bladder cancer mice model.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (GL) has been traditionally used in oriental medicine as superior health tonic, and there are numerous scientific evidences of its antitumorigenic activities. AIM OF THE STUDY: To evaluate the intravesical chemopreventive effects of ethanol extract of GL (GLe) on bladder cancer. MATERIALS AND METHODS: Intravesical therapy is defined as the direct instillation of a liquid drug into bladder through a catheter. Bacille Calmette-Guerin(BCG) solution is applied intravesically as a conventional immunotherapy for preventing recurrence of bladder cancer. By adopting the MB49/C57 bladder cancer mice model, an overall 60 MB49-implanted mice were randomized into 3 groups and treated according to 3 treatment arms, including GLe, BCG and PBS. Additionally, wild-type mice without MB49 cell inoculation and treated with PBS were used as the negative control group. Testing agents were instilled intravesically for 2 h and repeated after one week for evaluating the effects on preventing the tumor formation and growth. The treated-mice were closely monitored for major adverse effects. RESULTS: GLe demonstrated more potent cytotoxic effects than BCG on MB49 cells, although both in dose-dependent manner. In the MB49-implanted mice, 80 µg/ml GLe was shown to delay the tumor formation by one week, whereas the averaged tumor volume measured at endpoint was 3.6-fold and 4.6-fold smaller than that of the BCG or PBS, respectively. However, no significant effects were observed on body weight and hematuria. CONCLUSION: Current findings in mice suggested intravesical GLe therapy as an effective and safe chemopreventive strategy for inhibiting bladder tumor formation.

Advances in intravesical therapy for bladder pain syndrome (BPS)/interstitial cystitis (IC).

Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic symptom complex that may cause bothersome storage symptoms and pain or discomfort of the bladder, adversely affecting a patient's quality of life. The etiology of IC/BPS remains unclear, and its cause may be multifactorial. Diagnosis of IC/BPS is based on clinical features, and the possibility of other conditions must be ruled out first. Although no definitive treatment is currently available for IC/BPS, various intravesical therapies are used for IC/BPS, including heparin, hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dimethylsulfoxide, liposomes, and botulinum onabotulinumtoxinA (BoNT-A). This review summarizes the intravesical therapy for IC/BPS and discusses recent advances in the instillation of liposomal-mediated BoNT-A and other newly developed intravesical therapies.

Poly - (l) - glutamic acid drug delivery system for the intravesical therapy of bladder cancer using WGA as targeting moiety.

In the management of bladder cancer, surgical resection of the tumour is usually followed by intravesical instillation of immunomodulatives and/or chemotherapeutics. The purpose of this local intravesical therapy is to eliminate residual malignant cells after surgical intervention. The main limitation of a localised adjuvant therapy is the insufficient concentration of the active pharmaceutical ingredient (API) in malignant cells due to the unique structure of the human urothelium making it an exclusively hard to overcome barrier in the human body. Different strategies such as electromotive drug administration or local hyperthermia are employed to ameliorate intravesical drug uptake. Previous studies on biorecognitive targeting showed promising results for lectin-, especially wheat germ agglutinin (WGA), mediated drug delivery. Here, we present a targeted conjugate that provides enough binding sites for a possible API as well as high cytoadhesive and cytoinvasive potential. The conjugate should comprise the following components: First WGA, as the targeting moiety, second poly-l-glutamic acid (PGA) as a polymeric backbone providing more than 300 possible binding sites for an API and third fluorescein cadaverine (Fc), a fluorescent dye we coupled to PGA rendering the conjugate traceable. After purification via size exclusion chromatography (SEC) the WGA containing and therefore binding conjugate was isolated from the reaction mix. In flow-cytometric and fluorimetric experiments with single cells and cell monolayers, respectively, binding and internalisation of the conjugate representing a high molecular weight (>100kDa) could be demonstrated. Fluorescent PGA without the WGA component showed neither binding nor internalisation potential. Microscopic colocalization studies with cell monolayers and single cells confirmed the cytoadhesive and cytoinvasive potential of the WGA containing conjugate. In accordance with the results of specificity studies the interaction between the conjugate and the cell surface depended solely on the WGA component of the conjugate. With the help of this targeted drug delivery system limiting factors of intravesical adjuvant therapy could eventually be overcome and thereby treatment efficacy of instillative chemotherapy could be improved. In addition, traceable drug conjugates might bear interesting advantages for theranostic purposes in the treatment of bladder cancer.

High-Risk Non-Muscle-Invasive Bladder Cancer-Therapy Options During Intravesical BCG Shortage.

Bladder cancer is the second commonest urinary tract malignancy with 70-80 % being non-muscle invasive (NMIBC) at diagnosis. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression. Intravesical Bacilli Calmette-Guerin (BCG) is commonly used as first line therapy in this patient group but there is a current worldwide shortage. BCG has been shown to reduce recurrence in high-risk NMIBC and is more effective that other intravesical agents including mitomycin C, epirubicin, interferon-alpha and gemcitabine. Primary cystectomy offers a high change of cure in this cohort (80-90 %) and is a more radical treatment option which patients need to be counselled carefully about. Bladder thermotherapy and electromotive drug administration with mitomycin C are alternative therapies with promising short-term results although long-term follow-up data are lacking.

Anti-tumor effect of Radix Paeoniae Rubra extract on mice bladder tumors using intravesical therapy.

Radix Paeoniae Rubra (RPR) is the dried root of Paeonia lactiflora Pallas and Paeonia veitchii Lynch, and is a herbal medicine that is widely used in traditional Chinese medicine for the treatment of blood-heat and blood-stasis syndrome, similarly to Cortex Moutan. The present study identified the same three components in RPR and Cortex Moutan extracts. In addition, it has been reported that RPR has an anti-cancer effect. Bladder cancer is the seventh most common type of cancer worldwide. Due to the high recurrence rate, identifying novel drugs for bladder cancer therapy is essential. In the present study, RPR extract was evaluated as a bladder cancer therapy in vitro and in vivo. The present results revealed that RPR extract reduced the cell viability of bladder cancer cells with a half maximal inhibitory concentration of 1-3 mg/ml, and had an extremely low cytotoxic effect on normal urothelial cells. Additionally, RPR decreased certain cell cycle populations, predominantly cells in the G1 phase, and caused a clear sub-G increase. In a mouse orthotopic bladder tumor model, intravesical application of RPR extract decreased the bladder tumor size without altering the blood biochemical parameters of the mice. In summary, the present results demonstrate the anti-proliferative properties of RPR extract on bladder cancer cells, and its anti-bladder tumor effect in vivo. Compared to Cortex Moutan extract, RPR extract may provide a more effective alternative therapeutic strategy for the intravesical therapy of superficial bladder cancer.

Minimizing Staff Exposure to Antineoplastic Agents During Intravesical Therapy.

Exposure to chemotherapy is a daily risk for nurses in oncology infusion centers. Although significant advances have been made in developing systems to make IV administration of antineoplastic agents safer, less attention has been given to developing systems to minimize exposure risk during instillation of intravesical chemotherapy. This article describes the use of a closed system developed at a comprehensive cancer center and compares it to two closed systems reported in the literature. At a Glance • Safe handling of biohazard medications is important for all healthcare workers involved in the administration of antineoplastic agents. • Nurses need to advocate for use of chemotherapy administration systems that minimize exposure to staff and patients. • Infrequently performed procedures need to be supported by clearly specified procedural steps that are readily accessible to the nurse.

Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer.

OBJECTIVES: In this article, we review the various options for and the potential role of interferon alfa (IFN-α) in the treatment of non-muscle-invasive bladder cancer (NMIBC). METHODS: PubMed was searched for journal articles on IFN-α use in treating bladder cancer. The references listed in the National Comprehensive Cancer Network guidelines were used as a guide to identify relevant publications on treatments for NMIBC. RESULTS: Transurethral resection with adjuvant intravesical chemotherapy or immunotherapy is the standard treatment option for NMIBC. Adjuvant IFN-α therapy has limited efficacy in preventing recurrences in intermediate-risk and high-risk patients; bacillus Calmette-Guérin (BCG) monotherapy is the recommended first-line treatment in these patients. Unfortunately, cancer progression or recurrence is a common outcome; radical cystectomy, which is often the lifesaving approach in such a scenario, is associated with significant morbidity, mortality, and decreased quality of life. Current alternatives to cystectomy include repeat intravesical immunotherapy, conventional instillation chemotherapy, and device-assisted intravesical chemotherapy. The efficacy of any chemotherapy after BCG failure, either conventional or device assisted, has not been established. BCG and IFN-α combination intravesical therapy has not been investigated thoroughly; based on available data, combination therapy appears to be most effective in patients with carcinoma in situ and may be preferentially considered as an alternative to radical cystectomy for patients with intermediate-risk or high-risk NMIBC who do not tolerate the standard BCG dose or experience BCG failure after 1 year of therapy. However, this approach requires close follow-up and should only be chosen after careful consideration of all risk factors. CONCLUSIONS: There is a lack of efficacious treatment options for patients with NMIBC recurrence or progression after initial BCG treatment. There is a need for well-designed clinical trials investigating the safety and efficacy of available therapies, including BCG and IFN-α2b combination therapy.