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Urologic Oncology Sep 2024Guidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing...
BACKGROUND
Guidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce.
METHODS
A secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method.
RESULTS
Median follow-up (f/u) for all patients was 23 months (IQR 13-34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months).
CONCLUSIONS
Gem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results.
Topics: Humans; Urinary Bladder Neoplasms; Docetaxel; Gemcitabine; Deoxycytidine; Male; Female; Aged; Administration, Intravesical; Neoplasm Invasiveness; Middle Aged; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Non-Muscle Invasive Bladder Neoplasms
PubMed: 38796357
DOI: 10.1016/j.urolonc.2024.05.006 -
Cell Death & Disease May 2024We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily...
We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34 hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.
Topics: Animals; Humans; Liposomes; Mice; Xenograft Model Antitumor Assays; Cell Death; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Cell Line, Tumor; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38734740
DOI: 10.1038/s41419-024-06715-5 -
Archivio Italiano Di Urologia,... Mar 2024To understand the treatment plans suggested for BCG-unresponsive non-muscle invasive disease (NMIBC) patients in the Arab countries and therapeutic decisions applied for...
PURPOSE
To understand the treatment plans suggested for BCG-unresponsive non-muscle invasive disease (NMIBC) patients in the Arab countries and therapeutic decisions applied for BCG-naive patients during BCG shortage time.
METHODS
A 10-minute online survey was distributed through the Arab Association of Urology (AAU) office to urologists in the Arab countries who treat patients with NMIBC.
RESULTS
One hundred six urologists responded to the survey. The majority of urologists had treated, in the past 6 months, > 10 patients with NMIBC who were considered BCG-unresponsive (55% of respondents). Radical cystectomy (RC) was the most popular treatment option (recommended by 50%) for these patients. This was followed by intravesical chemotherapy (30%), repeat BCG therapy (12%), resection with ongoing surveillance (8%). Clinical trials and intravenous checkpoint inhibitors were never selected. The most preferred intravesical chemotherapy was by ranking: 60% gemcitabine, 19% mitomycin C, 8% docetaxel, 8% gemcitabine/docetaxel, 4% sequential gemcitabine/mitomycin C, and 1% valrubicin. The use of intravesical chemotherapy appears limited by Arab urologists due to concerns regarding clinical efficacy (fear of progression) and the lack of clear recommendations by urology societies. Given the BCG shortage, which may vary per Arab country, Arab urologists have adjusted by prioritizing BCG for T1 and carcinoma in situ (CIS) patients over Ta, adapting intravesical chemotherapy, and reducing the dose/strength of BCG administered. Most physicians report an eagerness to utilize novel therapies to address the BCG deficit, especially to try intravesical chemotherapy.
CONCLUSIONS
Even though Arab urologists are in the majority of cases selecting RC for BCG-unresponsive cases, one-third of them are most recently initiating intravesical chemotherapy as an alternative option. To further assist Arab urologists in the appropriate selection of BCG unresponsive high risk NMIBC patient treatments, enhanced education and pathway protocols are needed.
Topics: Humans; Mitomycin; Gemcitabine; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Urologists; Docetaxel; Arabs; Urinary Bladder Neoplasms; Neoplasm Invasiveness; Adjuvants, Immunologic; Neoplasm Recurrence, Local
PubMed: 38502039
DOI: 10.4081/aiua.2024.12244 -
Journal of Pharmaceutical Sciences Jul 2024Small interfering RNAs (siRNAs) have the ability to induce selective gene silencing, although siRNAs are vulnerable to degradation in vivo. Various active pharmaceutical...
Small interfering RNAs (siRNAs) have the ability to induce selective gene silencing, although siRNAs are vulnerable to degradation in vivo. Various active pharmaceutical ingredients (APIs) are currently used as effective therapeutics in the treatment of cancer. However, routes of administration are limited due to their physicochemical and biopharmaceutical properties. This research aimed to develop oral pharmaceutical formulations based on self-nanoemulsifying drug delivery systems (SNEDDS) for optimal transport and co-delivery of siRNAs related to cancer and APIs. Formulations were developed using optimal mixing design (Design-Expert 11 software) for SNEDDS loading with siRNA (water/oil emulsion), API (oil/water emulsion), and siRNA-API (multiphase water/oil/water emulsion). The final formulations were characterized physicochemically and biologically. The nanosystems less than 50 nm in size had a drug loading above 48 %. The highest drug release occurred at intestinal pH, allowing drug protection in physiological fluids. SNEDDS-siRNA-APIs showed a twofold toxicity effect than APIs in solution and higher transfection and internalization of siRNA in cancer cells with respect to free siRNAs. In the duodenum, higher permeability was observed with SNEDDS-API than with the API solution, as determined by ex-vivo fluorescence microscopy. The multifunctional formulation based on SNEDDS was successfully prepared, siRNA, hydrophobic chemotherapeutics (doxorubicin, valrubicin and methotrexate) and photosensitizers (rhodamine b and protoporphyrin IX) agents were loaded, using a chitosan-RNA core, and Labrafil® M 1944 CS, Cremophor® RH40, phosphatidylcholine shell, forming stable hybrid SNEDDS as multiphasic emulsion, suitable as co-delivery system with a potent anticancer activity.
Topics: RNA, Small Interfering; Emulsions; Humans; Antineoplastic Agents; Drug Delivery Systems; Nanoparticles; Animals; Cell Line, Tumor; Drug Liberation
PubMed: 38369021
DOI: 10.1016/j.xphs.2024.02.017 -
Cancer Medicine Dec 2023High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical... (Review)
Review
BACKGROUND
High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive bladder cancer (MIBC). Patients who are BCG-unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.
METHODS
To address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR-NMIBC treated with immune-related agents were retrieved from clinicaltrials.gov.
FINDINGS AND FUTURE PERSPECTIVES
Exploratory treatments for BCG-Unresponsive HR-NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long-term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.
Topics: Humans; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Quality of Life; Urinary Bladder Neoplasms; Immunotherapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local
PubMed: 38037752
DOI: 10.1002/cam4.6768 -
Biosensors Oct 2023A novel electrochemical DNA sensor was developed for the detection of the anthracycline drug, valrubicin, on the base of poly(Azure C) electropolymerized from the deep...
A novel electrochemical DNA sensor was developed for the detection of the anthracycline drug, valrubicin, on the base of poly(Azure C) electropolymerized from the deep eutectic solvent reline and covered with adsorbed DNA from calf thymus. Biosensor assembling was performed by multiple scanning of the potential in one drop (100 µL) of the dye dissolved in reline and placed on the surface of a screen-printed carbon electrode. Stabilization of the coating was achieved by its polarization in the phosphate buffer. The electrochemical characteristics of the electron transfer were determined and compared with a similar coating obtained from phosphate buffer. The use of deep eutectic solvent made it possible to increase the monomer concentration and avoid using organic solvents on the stage of electrode modification. After the contact of the DNA sensor with valrubicin, two signals related to the intrinsic redox activity of the coating and the drug redox conversion were found on voltammogram. Their synchronous changes with the analyte concentration increased the reliability of the detection. In the square-wave mode, the DNA sensor made it possible to determine from 3 µM to 1 mM (limit of detection, 1 µM) in optimal conditions. The DNA sensor was successfully tested in the voltammetric determination of valrubicin in spiked artificial urine, Ringer-Locke solution mimicking plasma electrolytes and biological samples (urine and saliva) with a recovery of 90-110%. After further testing on clinical samples, it can find application in the pharmacokinetics studies and screening of new drugs' interaction with DNA.
Topics: Deep Eutectic Solvents; Solvents; Reproducibility of Results; Electrodes; DNA; Phosphates; Electrochemical Techniques
PubMed: 37887124
DOI: 10.3390/bios13100931 -
Cureus Apr 2023A 75-year-old male was diagnosed with carcinoma in-situ of the bladder. He failed standard therapy and was started on pembrolizumab to prevent the need for cystectomy....
A 75-year-old male was diagnosed with carcinoma in-situ of the bladder. He failed standard therapy and was started on pembrolizumab to prevent the need for cystectomy. His malignancy recurred, and he was treated with intravesical valrubicin and gemcitabine/docetaxel. Three years after starting pembrolizumab, he developed severe neutropenia and thrombocytopenia. He was treated for suspected auto-immune cytopenias but was later found to have acute promyelocytic leukemia on peripheral blood smear and cytometry. He was hospitalized, treated with all-trans retinoic acid and arsenic trioxide, and is currently in molecular remission. This case describes therapy-related acute promyelocytic leukemia (t-APL) diagnosed while on pembrolizumab. Pembrolizumab is an immune checkpoint inhibitor that exhibits anti-tumor effects. Development of hematologic malignancies after immune checkpoint inhibitor therapy is rare. The definitive etiology of our patient's t-APL is uncertain; however, it is more likely that he developed de novo acute promyelocytic leukemia (APL), which was suppressed by pembrolizumab and later revealed when pembrolizumab was discontinued.
PubMed: 37220434
DOI: 10.7759/cureus.37919 -
Journal of Molecular Graphics &... May 2023Roxadustat, a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase domain 2 (HIF-PHD2) has been recently overruled by the American Food and Drug... (Comparative Study)
Comparative Study
Roxadustat, a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase domain 2 (HIF-PHD2) has been recently overruled by the American Food and Drug Administration (FDA) in Phase 3 clinical trials. This study provides insights into the dynamics of Roxadustat with PHD2 and proposes two FDA-approved drugs; Pemetrexed and Valrubicin to treat chronic kidney disease (CKD). Role of chemical scaffolds such as synthetic pyrimidine-based antifolate is found critical for PHD2 inhibitory activity, which is concurrent with the experimental findings for stimulating Endogenous erythropoietin (EPO) gene expression. Furthermore, Fe and Mn in solution are essential for imparting structural stability to the screened carboxylic and non-carboxylic acid drugs. Comparative analysis of FDA-approved drugs namely, Roxadustat, two-hit carboxylic, and non-carboxylic-acid type compounds (Pemetrexed and Valrubicin), as well as the control ligands (KU1 and 4JR), unveil structural dynamics of Roxadustat and its failure. However, the proposed FDA compounds, Pemetrexed and Valrubicin, used to treat mesothelioma, non-small cell lung cancer, and bladder cancer should be subjected to in vitro analysis for renal anemia.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Glycine; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Lung Neoplasms; Pemetrexed
PubMed: 36708643
DOI: 10.1016/j.jmgm.2023.108422 -
Frontiers in Immunology 2022Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC).... (Review)
Review
Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8 T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.
Topics: United States; Humans; Urinary Bladder Neoplasms; CD8-Positive T-Lymphocytes; BCG Vaccine; Neoplasm Recurrence, Local; Mycobacterium bovis
PubMed: 36439125
DOI: 10.3389/fimmu.2022.1040669 -
The Journal of Urology Nov 2022Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue...
PURPOSE
Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue therapies are needed for subsequent recurrences or intolerance, particularly when cystectomy is refused or precluded. Valrubicin is a U.S. Food and Drug Administration-approved agent for bacillus Calmette-Guérin unresponsive disease, yet as monotherapy has demonstrated poor efficacy. We report our experience with sequential intravesical valrubicin and docetaxel as a rescue therapy for non-muscle-invasive bladder cancer.
MATERIALS AND METHODS
We retrospectively identified all patients with recurrent non-muscle-invasive bladder cancer treated with valrubicin and docetaxel between April 2013 and June 2021. Patients received weekly sequential intravesical instillations of 800 mg valrubicin and 37.5 mg docetaxel for 6 weeks. If disease-free at first follow-up, monthly maintenance of 2 years was initiated. The primary outcome was recurrence-free survival, assessed using the Kaplan-Meier method.
RESULTS
The analysis included 75 patients with median follow-up of 21 months (IQR: 13-37). Twelve patients with low-grade disease had a 73% recurrence-free survival at 2 years. Sixty-three patients with recurrent high-grade disease had a 38% 2-year high-grade recurrence-free survival. Forty-two (56%) patients had carcinoma in situ present; recurrence-free survival was similar for those with and without carcinoma in situ ( = .63). Two patients died of metastatic bladder cancer while 10 underwent cystectomy. Among patients with high-grade disease, overall, cancer-specific, and cystectomy-free survivals were 87%, 96%, and 84% at 2 years, respectively. Adverse events included bladder spasms (n = 18), urinary frequency (n = 10), and dysuria (n = 8). Two patients could not tolerate valrubicin and docetaxel induction.
CONCLUSIONS
In a heavily pretreated population, our results suggest valrubicin and docetaxel is an effective rescue treatment for patients with recurrent non-muscle-invasive bladder cancer. Further prospective evaluation is needed.
Topics: Adjuvants, Immunologic; Administration, Intravesical; BCG Vaccine; Carcinoma in Situ; Docetaxel; Doxorubicin; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Retrospective Studies; Salvage Therapy; Urinary Bladder Neoplasms
PubMed: 35830552
DOI: 10.1097/JU.0000000000002848