Manejo del cáncer de vejiga invasor de músculo con enfoque preservador de órgano: terapia trimodal / Management of muscle-invasive bladder cancer with an organ-sparing approach: trimodal therapy

El cáncer de vejiga es una patología frecuente del tracto genitourinario, cuyo tratamiento acarrea morbilidad y alteración de la calidad de vida y en particular en el subgrupo de pacientes con tumores vesicales clasificados como invasores de músculo. En los últimos años se han venido buscando alternativas terapéuticas para la cistectomía radical + linfadenectomía pélvica extendida, que es en la actualidad el estándar de manejo para los pacientes con carcinoma de vejiga invasor de músculo. Con el advenimiento de perfiles de manejo oncológico menos ablativos pero sin sacrificar resultados oncológicos y con las nuevas técnicas de radioterapia y quimioterapia, las modalidades terapéuticas preservadoras de órgano como la terapia trimodal (resección transuretral de tumor vesical + quimioterapia + radioterapia) se convierte en una alternativa terapéutica viable y con resultados oncológicos satisfactorios a largo plazo. Objetivo y metodología: Con esta revisión se pretende mostrar la actualidad de la terapia trimodal en el manejo de los tumores vesicales con invasión muscular, definir los mejores pacientes a considerar para recibir esta terapia, exponer los resultados oncológicos comparados con el estándar de manejo y los resultados en calidad de vida. También se propone un algoritmo de manejo y se presentar las recomendaciones al respecto en guías de práctica clínica. Conclusiones: La terapia trimodal es una alternativa al estándar de manejo que conduce a resultados oncológicos aceptables y puede considerarse una opción de tratamiento en pacientes bien seleccionados.

Introduction: Bladder cancer is a frequent pathology of the genitourinary tract, whose treatment causes morbidity and impaired quality of life, particularly in the subgroup of patients with bladder tumors classified as muscle invaders. In recent years, therapeutic alternatives have been sought for radical cystectomy + extended pelvic lymphadenectomy, which is currently the standard of care for patients with muscle-invasive bladder carcinoma. With the advent of less ablative oncological management profiles but without sacrificing oncological results and with new radiotherapy and chemotherapy techniques, organ-sparing therapeutic modalities such as trimodal therapy (transurethral resection of bladder tumor + chemotherapy + radiotherapy) becomes a viable therapeutic alternative with satisfactory long-term oncological results. Objective and methodology: This review aims to show the current status of trimodal therapy in the management of muscle-invasive bladder tumors, define the best patients to consider for receiving this therapy, present the oncological results compared with the management standard and the results in quality of life. A management algorithm is also proposed and recommendations in this regard are presented in clinical practice guidelines. Conclusions: Trimodal therapy is an alternative to standard management that leads to acceptable oncological outcomes and can be considered a treatment option in well-selected patients.

Andrographolide Inhibits Proliferation and Promotes Apoptosis in Bladder Cancer Cells by Interfering with NF- κ B and PI3K/AKT Signaling In Vitro and In Vivo / 中国结合医学杂志

OBJECTIVE@#To explore the influences of andrographolide (Andro) on bladder cancer cell lines and a tumor xenograft mouse model bearing 5637 cells.@*METHODS@#For in vitro experiments, T24 cells were stimulated with Andro (0-40 µmol/L) and 5637 cells were stimulated with Andro (0 to 80 µmol/L). Cell growth, migration, and infiltration were assessed using cell counting kit-8, colony formation, wound healing, and transwell assays. Apoptosis rate was examined using flow cytometry. In in vivo study, the antitumor effect of Andro (10 mg/kg) was evaluated by 5637 tumor-bearing mice, and levels of nuclear factor κ B (NF- κ B) and phosphoinositide 3-kinase/AKT related-proteins were determined by immunoblotting.@*RESULTS@#Andro suppressed growth, migration, and infiltraion of bladder cancer cells (P⩽0.05 or P⩽0.01). Additionally, Andro induced intrinsic mitochondria-dependent apoptosis in bladder cancer cell lines. Furthermore, Andro inhibited bladder cancer growth in mice (P⩽0.01). The expression of p65, p-AKT were suppressed by Andro treatment in vitro and in vivo (P⩽0.05 or P⩽0.01).@*CONCLUSIONS@#Andrographolide inhibits proliferation and promotes apoptosis in bladder cancer cells by interfering with NF- κ B and PI3K/AKT signaling in vitro and in vivo.

Beyond diabetes mellitus: role of metformin in non-muscle-invasive bladder cancer

INTRODUCTION@#Usage of metformin is associated with improved survival in lung, breast and prostate cancer, and metformin has been shown to inhibit cancer cell growth and proliferation in in vitro studies. Given the lack of clinical data on metformin use in patients with bladder cancer, we aimed to evaluate the role of metformin in their oncological outcomes.@*METHODS@#Medication use data from a prospectively maintained database of 122 patients with non-muscle-invasive bladder cancer treated with intravesical Bacille Calmette-Guerin (BCG), who were recruited under a randomised, double-blinded, controlled clinical trial, was collected and analysed. Kaplan-Meier curves were used to assess overall survival (OS) and disease-specific survival (DSS).@*RESULTS@#At a median follow-up duration of 102 (range 3-357) months, 53 (43.4%) patients experienced disease recurrence and 21 (17.2%) experienced disease progression. There was no significant difference in mortality between patients with and without diabetes mellitus. There was significant difference in OS between patients without diabetes mellitus, patients with diabetes mellitus on metformin and patients with diabetes mellitus but not on metformin (p = 0.033); patients with diabetes mellitus on metformin had the best prognosis. Metformin use was associated with significantly lower DSS (p = 0.042). Other oral hypoglycaemic agents, insulin or statins were not associated with disease recurrence or progression.@*CONCLUSION@#Metformin use was associated with improved oncological outcomes in patients with non-muscle-invasive bladder cancer treated with intravesical BCG. Prospective studies with larger patient populations are needed to validate the role of metformin as potential therapy for bladder cancer.

Factors associated with utilization of neoadjuvant chemotherapy in charlson comorbidity zero non-metastatic muscle-invasive bladder cancer patients

ABSTRACT Background: Guideline-based best practice treatment for muscle invasive bladder cancer (MIBC) involves neoadjuvant chemotherapy followed by radical cystectomy (NACRC). Prior studies have shown that a minority of patients receive NACRC and older age and renal function are drivers of non-receipt of NACRC. This study investigates treatment rates and factors associated with not receiving NACRC in MIBC patients with lower comorbidity status most likely to be candidates for NACRC. Materials and Methods: Retrospective United States National Cancer Database analysis from 2006 to 2015 of MIBC patients with Charlson comorbidity index (CCI) of zero. Analysis of NACRC treatment trends in higher CCI patients was also performed. Results: 15.561 MIBC patients met inclusion criteria. 1.507 (9.7%) received NACRC within 9 months of diagnosis. NACRC increased over time (15.0% in 2015 compared to 3.6% in 2006). Higher NACRC was noted in females, cT3 or cT4 cancer, later year of diagnosis, and academic facility treatment. Lower utilization was noted for blacks and NACRC decreased with increasing age and CCI. Only 16.9% of patients aged 23-62 in the lowest age quartile with muscle invasive bladder cancer and CCI of 0 received NACRC. Conclusions: Although utilization is increasing, receipt of NACRC remains low even in populations most likely to be candidates. Further study should continue to elucidate barriers to utilization of NACRC.

Suppressive effect of platycodin D on bladder cancer through microRNA-129-5p-mediated PABPC1/PI3K/AKT axis inactivation

Platycodin D (PD) is a major constituent of Platycodon grandiflorum and has multiple functions in disease control. This study focused on the function of PD in bladder cancer cell behaviors and the molecules involved. First, we administered PD to the bladder cancer cell lines T24 and 5637 and the human uroepithelial cell line SV-HUC-1. Cell viability and growth were evaluated using MTT, EdU, and colony formation assays, and cell apoptosis was determined using Hoechst 33342 staining and flow cytometry. The microRNAs (miRNAs) showing differential expression in cells before and after PD treatment were screened. Moreover, we altered the expression of miR-129-5p and PABPC1 to identify their functions in bladder cancer progression. We found that PD specifically inhibited the proliferation and promoted the apoptosis of bladder cancer cells; miR-129-5p was found to be partially responsible for the cancer-inhibiting properties of PD. PABPC1, a direct target of miR-129-5p, was abundantly expressed in T24 and 5637 cell lines and promoted cell proliferation and suppressed cell apoptosis. In addition, PABPC1 promoted the phosphorylation of PI3K and AKT in bladder cancer cells. Altogether, PD had a concentration-dependent suppressive effect on bladder cancer cell growth and was involved in the upregulation of miR-129-5p and the subsequent inhibition of PABPC1 and inactivation of PI3K/AKT signaling.

Expert consensus on intravesical therapy for non-muscle invasive bladder cancer (2021 edition) / 中华肿瘤杂志

Bladder cancer is one of the common malignant tumors in China, with 75% of bladder cancer being non-muscle invasion with a high recurrence rate after surgery. Intravesical therapy is an useful methods to either directly kill tumor cells by infusing cytotoxic drugs into the bladder or directly or indirectly induce local immune responses of the body through infusing immune agents, such as bacillus calmette guerin, and thus reduce the risk of tumor recurrence and progression. In 2019, the Urological Chinese Oncology Group issued the "Expert consensus on intravesical therapy on non-muscle invasive bladder cancer" . Recently, great progress in the clinical diagnosis and treatment of non-muscle invasive bladder cancer has been achieved domestically and abroad, including the risk assessment of non-muscle invasive bladder cancer, the therapeutic choice of intravesical drugs, the adverse reactions and treatment experience of intravesical therapy, and clinical research on new types of intravesical drugs. This consensus is made according to domestic and overseas evidence-based medicine in combination with current clinical practice and experience of intravesical therapy for non-muscle invasive bladder cancer in China. It is an update of the 2019 expert consensus, with the wish to provide a guidance for domestic clinical standardized intravesical therapy for non-muscle invasive bladder cancer.

Can Neutrophil-to-Lymphocyte ratio predict the response to BCG in high-risk non muscle invasive bladder cancer?

ABSTRACT Objectives: To evaluate the neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor for response of high risk non muscle invasive bladder cancer (HRNMIBC) treated with BCG therapy. Materials and Methods: Between March 2010 and February 2014 in a tertiary center 100 consecutive patients with newly diagnosed HRNMIBC were retrospectively analyzed. Patients were divided according to NLR value: 46 patients with NLR value less than 3 (NLR < 3 group), and 54 patients with NLR value more than 3 (NLR ≥ 3 group). At the end of follow-up 52 patients were high grade disease free (BCG-responder group) and 48 patients underwent radical cystectomy for high grade recurrence or progression to muscle invasive disease (BCG non-responder group). The average follow-up was 60 months. Intervention: analysis and correlation of preoperative NLR value with response to BCG in terms of recurrence and progression. Results: The optimal cut-off for NLR was ≥ 3 according to the receiver operating characteristics analysis (AUC 0.760, 95% CI, 0.669-0.850). Mean NLR value was 3.65 ± 1.16 in BCG non-responder group and 2.61 ± 0.77 in BCG responder group (p = 0.01). NLR correlated with recurrence (r = 0.55, p = 0.01) and progression risk scores (r = 0.49, p = 0.01). In multivariate analysis, NLR (p = 0.02) and EORTC recurrence risk groups (p = 0.01) were associated to the primary endpoint. The log-rank test showed statistically significant difference between NLR < 3 and NLR ≥ 3 curves (p < 0.05). Conclusions: NLR value preoperatively evaluated could be a useful tool to predict BCG response of HRNMIBC. These results could lead to the development of prospective studies to assess the real prognostic value of NLR in HRNMIBC.

Chorioallantoic urothelial tumor avatar. A clinical tool for phenotype-based therapy

Abstract In the muscle invasive bladder cancer (MIBC) standard of care treatment only patients presenting a major pathological tumor response are more likely to show the established modest 5% absolute survival benefit at 5 years after cisplatin-based neoadjuvant chemotherapy (NAC). To overcome the drawbacks of a blind NAC (i.e. late cystectomy with unnecessary NAC adverse events) with potential to survival improvements, preclinical models of urothelial carcinoma have arisen in this generation as a way to pre-determine drug resistance even before therapy is targeted. The implantation of tumor specimens in the chorioallantoic membrane (MCA) of the chicken embryo results in a high-efficiency graft, thus allowing large-scale studies of patient-derived "tumor avatar". This article discusses a novel approach that exploits cancer multidrug resistance to provide personalized phenotype-based therapy utilizing the MIBC NAC dilemma.

Interleukin-27 augments the inhibitory effects of sorafenib on bladder cancer cells

Both sorafenib and interleukin-27 (IL-27) are antineoplastic drugs. This study aimed to investigate the synergistic effect of these two drugs on bladder cancer cells. HTB-9 and T24 cells were stimulated with IL-27 (50 ng/mL), sorafenib (2 μM) or the synergistic action of these two drugs. The cells without treatment acted as control. Cell proliferation, apoptosis and invasion were measured by bromodeoxyuridine assay, flow cytometry and modified Boyden chamber, respectively. Simultaneously, both modified Boyden chamber and scratch assay were used to assess cell migration. Finally, the phosphorylation levels of key kinases in the Akt/mechanistic target of rapamycin (mTOR)/mitogen-activated protein kinase (MAPK) pathway, and expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were detected by western blot analysis. Stimulation with IL-27 or sorafenib repressed proliferation, migration and invasion but promoted apoptosis, and the effects were all enhanced by the combination of these two drugs in HTB-9 cells. The effect of the combined treatment on bladder cancer cells was verified in T24 cells. Additionally, the phosphorylation levels of AKT, mTOR and MAPK as well as the expression levels of MMP-2 and MMP-9 were all decreased by a single treatment of IL-27 or sorafenib, and further decreased by the combined treatment of these two drugs. The combination of IL-27 and sorafenib inhibited proliferation, migration and invasion and promoted apoptosis of bladder cancer cells compared with mono-drug treatment. Additionally, the AKT/mTOR/MAPK pathway might be implicated in the functional effects by down-regulations of MMP-2 and MMP-9.

Agregação familiar da doença renal crônica secundária à hipertensão arterial ou diabetes mellitus: estudo caso-controle / Family clustering of secondary chronic kidney disease with hypertension or diabetes mellitus. A case-control study

No Brasil, a hipertensão e o diabetes mellitus tipo 2 são responsáveis por 60% dos casos de doença renal crônica terminal em terapia renal substitutiva. Estudos americanos identificaram agregação familiar da doença renal crônica, predominante em afrodescendentes. Um único estudo brasileiro observou agregação familiar entre portadores de doença renal crônica quando comparados a indivíduos internados com função renal normal. O objetivo deste artigo é avaliar se existe agregação familiar da doença renal crônica em familiares de indivíduos em terapia renal substitutiva causada por hipertensão e/ou diabetes mellitus. Estudo caso-controle tendo como casos 336 pacientes em terapia renal substitutiva portadores de diabetes mellitus ou hipertensão há pelo menos 5 anos e controles amostra pareada de indivíduos com hipertensão ou diabetes mellitus e função renal normal (n = 389). Os indivíduos em terapia renal substitutiva (casos) apresentaram razão de chance de 2,35 (IC95% 1,42-3,89; p < 0,001) versus controles de terem familiares com doença renal crônica terminal, independente da raça ou doença de base. Existe agregação familiar da doença renal crônica na amostra estudada e esta predisposição independe da raça e da doença de base (hipertensão ou diabetes mellitus).

In Brazil hypertension and type 2 diabetes mellitus are responsible for 60% of cases of end-stage renal disease in renal replacement therapy. In the United States studies have identified family clustering of chronic kidney disease, predominantly in African-Americans. A single Brazilian study observed family clustering among patients with chronic kidney disease when compared with hospitalized patients with normal renal function. This article aims to assess whether there is family clustering of chronic kidney disease in relatives of individuals in renal replacement therapy caused by hypertension and/or diabetes mellitus. A case-control study with 336 patients in renal replacement therapy with diabetes mellitus or hypertension for at least 5 years (cases) and a control matched sample group of individuals with hypertension or diabetes mellitus and normal renal function (n = 389). Individuals in renal replacement therapy (cases) had a ratio of 2.35 (95% CI 1.42-3.89, p < 0.001) versus the control group in having relatives with chronic renal disease, irrespective of race or causative illness. There is family clustering of chronic kidney disease in the sample studied, and this predisposition is irrespective of race and underlying disease (hypertension or diabetes mellitus).

Predictors of fluid intravasation during operative hysteroscopy: a preplanned prospective observational study with 200 cases / Preditores de intravasamento durante histeroscopia cirúrgica: um estudo observacional prospectivo com 200 casos

PURPOSE: To verify the predictors of intravasation rate during hysteroscopy. METHODS: Prospective observational study (Canadian Task Force classification II-1). All cases (n=200 women; 22 to 86 years old) were treated in an operating room setting. Considering respective bag overfill to calculate water balance, we tested two multiple linear regression models: one for total intravasation (mL) and the other for absorption rate (mL.min-1). The predictors tested (independent variables) were energy (mono/bipolar), tube patency (with/without tubal ligation), hysterometry (cm), age≤50 years, body surface area (m2), surgical complexity (with/without myomectomy) and duration (min). RESULTS: Mean intravasation was significantly higher when myomectomy was performed (442±616 versus 223±332 mL; p<0.01). In the proposed multiple linear regression models for total intravasation (adjusted R2=0.44; p<0.01), the only significant predictors were myomectomy and duration (p<0.01).In the proposed model for intravasation rate (R2=0.39; p<0.01), only myomectomy and hysterometry were significant predictors (p=0.02 and p<0.01, respectively). CONCLUSIONS: Not only myomectomy but also hysterometry were significant predictors of intravasation rate during operative hysteroscopy. .

OBJETIVO: Testar preditores do ritmo de intravasamento durante histeroscopia cirúrgica. MÉTODOS: Estudo prospectivo observacional (classificação: Canadian Task Force II-1) incluindo casos conduzidos em centro cirúrgico (n=200 mulheres; 22 a 86 anos de idade). Considerando os erros de aferição nas embalagens de solução de irrigação para calcular o balanço hídrico, nós testamos dois modelos de regressão linear múltipla: um para intravasamento total (mL) e outro para ritmo de intravasamento (mL.min-1). Os preditores testados (variáveis independentes) foram energia (mono/bipolar), permeabilidade tubária (com/sem ligadura tubária), histerometria (cm), status ovariano (idade≤50 anos), área de superfície corporal (m2), complexidade de cirurgia (com/sem miomectomia) e tempo de ressecção (min). RESULTADOS: O intravasamento médio foi significativamente maior quando miomectomia foi realizada (442±616 versus 223±332 mL, p<0,01). No modelo proposto para intravasamento total (R2 ajustado=0,44; p<0,01), os únicos preditores significativos foram miomectomia e tempo de duração (p<0,01). No modelo proposto para a taxa de intravasamento (R2=0,39; p<0,01), somente miomectomia e histerometria foram preditores significativos (p=0,02 e p<0,01, respectivamente). CONCLUSÕES: Não só a miomectomia mas também a histerometria são preditores significativo da taxa de intravasamento durante histeroscopia cirúrgica. .

Is Intravesical Bacillus Calmette-Guerin Therapy Superior to Chemotherapy for Intermediate-risk Non-muscle-invasive Bladder Cancer?: An Ongoing Debate

The objective of this study was to evaluate the risk of recurrence in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) after intravesical instillation with chemotherapeutic agents or Bacillus Calmette-Guerin (BCG) therapy. A cohort of 746 patients with intermediate-risk NMIBC comprised the study group. The primary outcome was time to first recurrence. The recurrence rates of the transurethral resection (TUR) alone, chemotherapy, and BCG groups were determined using Kaplan-Meier analysis. Risk factors for recurrence were identified using Cox regression analysis. In total, 507 patients (68.1%), 78 patients (10.5%), and 160 (21.4%) underwent TUR, TUR+BCG, or TUR+chemotherapy, respectively. After a median follow-up period of 51.7 months (interquartile range=33.1-77.8 months), 286 patients (38.5%) developed tumor recurrence. The 5-yr recurrence rates for the TUR, chemotherapy, and BCG groups were 53.6%+/-2.7%, 30.8%+/-5.7%, and 33.6%+/-4.7%, respectively (P<0.001). Chemotherapy and BCG treatment were found to be predictors of reduced recurrence. Cox-regression analysis showed that TUR+BCG did not differ from TUR+chemotherapy in terms of recurrence risk. Adjuvant intravesical instillation is an effective prophylactic that prevents tumor recurrence in intermediate-risk NMIBC patients following TUR. In addition, both chemotherapeutic agents and BCG demonstrate comparable efficacies for preventing recurrence.

Multiphase Contrast-Enhanced Magnetic Resonance Imaging Features of Bacillus Calmette-Guerin-Induced Granulomatous Prostatitis in Five Patients

OBJECTIVE: To evaluate the multiphase contrast-enhanced magnetic resonance (MR) imaging features of Bacillus Calmette-Guerin (BCG)-induced granulomatous prostatitis (GP). MATERIALS AND METHODS: Magnetic resonance images obtained from five patients with histopathologically proven BCG-induced GP were retrospectively analyzed for tumor location, size, signal intensity on T2-weighted images (T2WI) and diffusion-weighted images (DWI), apparent diffusion coefficient (ADC) value, and appearance on gadolinium-enhanced multiphase images. MR imaging findings were compared with histopathological findings. RESULTS: Bacillus Calmette-Guerin-induced GP (size range, 9-40 mm; mean, 21.2 mm) were identified in the peripheral zone in all patients. The T2WI showed lower signal intensity compared with the normal peripheral zone. The DWIs demonstrated high signal intensity and low ADC values (range, 0.44-0.68 x 10(-3) mm2/sec; mean, 0.56 x 10(-3) mm2/sec), which corresponded to GP. Gadolinium-enhanced multiphase MR imaging performed in five patients showed early and prolonged ring enhancement in all cases of GP. Granulomatous tissues with central caseation necrosis were identified histologically, which corresponded to ring enhancement and a central low intensity area on gadolinium-enhanced MR imaging. The findings on T2WI, DWI, and gadolinium-enhanced images became gradually obscured with time. CONCLUSION: Bacillus Calmette-Guerin-induced GP demonstrates early and prolonged ring enhancement on gadolinium-enhanced MR imaging which might be a key finding to differentiate it from prostate cancer.