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Differences in the Central Energy Metabolism of Cancer Cells between Conventional 2D and Novel 3D Culture Systems.
Ikari, R, Mukaisho, KI, Kageyama, S, Nagasawa, M, Kubota, S, Nakayama, T, Murakami, S, Taniura, N, Tanaka, H, Kushima, RP, et al
International journal of molecular sciences. 2021;(4)
Abstract
The conventional two-dimensional (2D) culture is available as an in vitro experimental model. However, the culture system reportedly does not recapitulate the in vivo cancer microenvironment. We recently developed a tissueoid cell culture system using Cellbed, which resembles the loose connective tissue in living organisms. The present study performed 2D and three-dimensional (3D) culture using prostate and bladder cancer cell lines and a comprehensive metabolome analysis. Compared to 3D, the 2D culture had significantly lower levels of most metabolites. The 3D culture system did not impair mitochondrial function in the cancer cells and produce energy through the mitochondria simultaneously with aerobic glycolysis. Conversely, ATP production, biomass (nucleotides, amino acids, lipids and NADPH) synthesis and redox balance maintenance were conducted in 3D culture. In contrast, in 2D culture, biomass production was delayed due to the suppression of metabolic activity. The 3D metabolome analysis using the tissueoid cell culture system capable of in vivo cancer cell culture yielded results consistent with previously reported cancer metabolism theories. This system is expected to be an essential experimental tool in a wide range of cancer research fields, especially in preclinical stages while transitioning from in vitro to in vivo.
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Systematic review and meta-analysis of radiation therapy for high-risk non-muscle invasive bladder cancer.
Rodrigues Pessoa, R, Mueller, AC, Boxley, P, Flaig, TW, Piper, C, Konety, B, Yu, JB, Gershman, B, Kukreja, J, Kim, SP
Urologic oncology. 2021;(11):786.e1-786.e8
Abstract
INTRODUCTION Radiation therapy (XRT) has been investigated as a possible treatment for high-risk non-muscle invasive bladder cancer (NMIBC) with the goal of bladder preservation, especially with the ongoing Bacillus Calmette-Guerin (BCG) shortage. Yet, little is known about the clinical efficacy and the quality of evidence supporting XRT for NMIBC. Herein, we performed a systematic review and meta-analysis to evaluate XRT in the treatment of patients with high-risk NMIBC. METHODS Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were searched for high-risk NMIBC (high grade T1, T1/Ta with associated risk features: carcinoma in-situ (CIS), multifocality, > 5cm in diameter, and/or multiple recurrences) treated with primary XRT. Outcomes evaluated were recurrence-free survival (RFS), cancer-specific-survival (CSS), overall survival (OS), and salvage cystectomy and progression to metastatic disease rates. A meta-analysis was performed to assess outcomes for XRT in NMIBC. RESULTS Overall,13 studies including 746 patients met the search criteria. The 5-year rates of RFS, CSS and OS were 54% (95% CI = 38% - 70%), 86% (95% CI = 80% - 92%), and 72% (95% CI = 64% - 79%). Notably, 13% of patients proceeded to salvage radical cystectomy and 9% developed metastatic disease. All studies were of poor quality, comprising single institution and retrospective studies with only one clinical trial. CONCLUSION XRT for high-risk NMIBC provides some degree of oncologic control, although distant progression was noted. In the setting of the low-quality evidence, a prospective clinical trial is needed to clearly define the risks and benefits of this approach.
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Glycoproteomics identifies HOMER3 as a potentially targetable biomarker triggered by hypoxia and glucose deprivation in bladder cancer.
Peixoto, A, Ferreira, D, Azevedo, R, Freitas, R, Fernandes, E, Relvas-Santos, M, Gaiteiro, C, Soares, J, Cotton, S, Teixeira, B, et al
Journal of experimental & clinical cancer research : CR. 2021;(1):191
Abstract
BACKGROUND Muscle invasive bladder cancer (MIBC) remains amongst the deadliest genitourinary malignancies due to treatment failure and extensive molecular heterogeneity, delaying effective targeted therapeutics. Hypoxia and nutrient deprivation, oversialylation and O-glycans shortening are salient features of aggressive tumours, creating cell surface glycoproteome fingerprints with theranostics potential. METHODS A glycomics guided glycoproteomics workflow was employed to identify potentially targetable biomarkers using invasive bladder cancer cell models. The 5637 and T24 cells O-glycome was characterized by mass spectrometry (MS), and the obtained information was used to guide glycoproteomics experiments, combining sialidase, lectin affinity and bottom-up protein identification by nanoLC-ESI-MS/MS. Data was curated by a bioinformatics approach developed in-house, sorting clinically relevant molecular signatures based on Human Protein Atlas insights. Top-ranked targets and glycoforms were validated in cell models, bladder tumours and metastases by MS and immunoassays. Cells grown under hypoxia and glucose deprivation disclosed the contribution of tumour microenvironment to the expression of relevant biomarkers. Cancer-specificity was validated in healthy tissues by immunohistochemistry and MS in 20 types of tissues/cells of different individuals. RESULTS Sialylated T (ST) antigens were found to be the most abundant glycans in cell lines and over 900 glycoproteins were identified potentially carrying these glycans. HOMER3, typically a cytosolic protein, emerged as a top-ranked targetable glycoprotein at the cell surface carrying short-chain O-glycans. Plasma membrane HOMER3 was observed in more aggressive primary tumours and distant metastases, being an independent predictor of worst prognosis. This phenotype was triggered by nutrient deprivation and concomitant to increased cellular invasion. T24 HOMER3 knockdown significantly decreased proliferation and, to some extent, invasion in normoxia and hypoxia; whereas HOMER3 knock-in increased its membrane expression, which was more pronounced under glucose deprivation. HOMER3 overexpression was associated with increased cell proliferation in normoxia and potentiated invasion under hypoxia. Finally, the mapping of HOMER3-glycosites by EThcD-MS/MS in bladder tumours revealed potentially targetable domains not detected in healthy tissues. CONCLUSION HOMER3-glycoforms allow the identification of patients' subsets facing worst prognosis, holding potential to address more aggressive hypoxic cells with limited off-target effects. The molecular rationale for identifying novel bladder cancer molecular targets has been established.
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The impact of preoperative nutritional status on post-surgical complication and mortality rates in patients undergoing radical cystectomy for bladder cancer: a systematic review of the literature.
Ornaghi, PI, Afferi, L, Antonelli, A, Cerruto, MA, Odorizzi, K, Gozzo, A, Mordasini, L, Mattei, A, Baumeister, P, Cornelius, J, et al
World journal of urology. 2021;(4):1045-1081
Abstract
PURPOSE To investigate the impact of preoperative nutritional factors [body mass index (BMI)], hypoalbuminemia (< 3.5 g/dL, sarcopenia) on complication and mortality rates after radical cystectomy (RC) for bladder cancer. METHODS The PubMed database was systematically searched for studies investigating the effect of nutritional status on postoperative outcomes after RC. English-language articles published between March 2010 and March 2020 were reviewed. For statistical analyses odds ratios (ORs) and hazard ratios (HRs) weighted mean was applied. RESULTS Overall, 81 studies were included. Twenty-nine studies were enrolled in the final analyses. Patients with a 25-29.9 kg/m2 BMI (OR 1.55, 95% confidence interval [CI] 1.14-2.07) and those with a BMI ≥ 30 kg/m2 (OR 1.73, 95% CI 1.29-2.40) had a significantly increased risk of 30 day complications after RC. Preoperative hypoalbuminemia increased the risk of 30 day complications (OR 1.56, 95% CI 1.07-2.35); it was a predictor of worse 3 year overall survival (OS) (HR 1.86, 95% CI 1.32-2.66). Sarcopenic patients had a higher risk of 90 day complications than non-sarcopenic ones (OR 2.49, 95% CI 1.22-5.04). Sarcopenia was significantly associated with unfavorable 5 year cancer-specific survival (CSS) (HR 1.73, 95% CI 1.07-2.80), and OS (HR 1.60, 95% CI 1.13-2.25). CONCLUSION High BMI, hypoalbuminemia, and sarcopenia significantly increased the complication rate after RC. Hypoalbuminemia predicted worse 3 year OS and sarcopenia predicted unfavorable 5 year CSS and OS. Preoperative assessment of RC patients' nutritional status is a useful tool to predict perioperative and survival outcomes.
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Multimodal Prehabilitation to Enhance Functional Capacity Following Radical Cystectomy: A Randomized Controlled Trial.
Minnella, EM, Awasthi, R, Bousquet-Dion, G, Ferreira, V, Austin, B, Audi, C, Tanguay, S, Aprikian, A, Carli, F, Kassouf, W
European urology focus. 2021;(1):132-138
Abstract
BACKGROUND In patients with bladder cancer, poor functional status has remarkable deleterious effects on postoperative outcome and prognosis. Conditioning intervention initiated before surgery has the potential to reduce functional decline attributable to surgery. Nonetheless, evidence is lacking in patients undergoing radical cystectomy. OBJECTIVE To determine whether a preoperative multimodal intervention (prehabilitation) is feasible and effective in radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS This study, conducted at an academic tertiary health care institution, enrolled adult patients scheduled for radical cystectomy. From August 2013 to October 2017, 70 patients were randomized: 35 to multimodal prehabilitation (prehab group) and 35 to standard care (control group). INTERVENTION Multimodal prehabilitation was a preoperative conditioning intervention including aerobic and resistance exercise, diet therapy, and relaxation techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome was perioperative change in functional capacity, measured with the distance covered during a 6-min walk test (6MWD), assessed at baseline, before surgery, and at 4 and 8 wk after surgery. Data were compared using robust mixed linear models for repeated measures. RESULTS AND LIMITATIONS Preoperative change in 6MWD compared with baseline was not significantly different between groups (prehab group 40.8 [114.0] m vs control group 9.7 (108.4) m, p=0.250). However, at 4 wk after surgery, a significant difference in functional capacity was detected (6MWD, prehab group -15.4 [142.5] m vs control group -97.9 [123.8] m, p=0.014). No intervention-related adverse effects were reported. CONCLUSIONS Data suggested that multimodal prehabilitation resulted in faster functional recovery after radical cystectomy. PATIENT SUMMARY After major cancer surgery, people usually feel week and tired, and have less energy to perform activities of daily living. In this study, we showed that using the time before surgery to promote exercise and good nutrition could fasten recovery after the surgical removal of the bladder.
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The role of Protopine associated with Nuciferine in controlling adverse events during hyperthermic intravesical chemotherapy instillations. A nutraceutical approach to control adverse event during intravesical instillations.
Chiancone, F, Carrino, M, Fedelini, M, Fabiano, M, Persico, F, Meccariello, C, Fedelini, P
Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2020;(3)
Abstract
OBJECTIVES The aim of this study was to analyse the role of two alkaloid, Protopine and Nuciferine, in the prevention and the treatment of the low and mild grade adverse events related to the use of HIVEC® (Hyperthermic IntraVEsical Chemotherapy) instillations. MATERIALS AND METHODS From September 2017 to September 2019, 100 patients were prospectively randomized into two groups: Group A = Protopine and Nuciferine syrup, 10 ml, once a day, for 8 weeks; Group B = placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks. The primary endpoint was the evaluation of the efficacy of the therapy with Protopine and Nuciferine in controlling of the irritative symptoms. The secondary endpoint was the evaluation of the influences of the treatment on the uroflowmetric parameters. RESULTS The patients of Group A showed a better International Prostatic Symptoms Score (IPSS) score, a better control of urgency symptoms (PPIUS) and tolerate well the pain (VAS score). The treatment doesn't modify Uroflow-Qmax and seems to improve the Uroflow-Voided Volume (ml) without influencing the Uroflow-Post Void Residual volume (PVR). Moreover, the treatment with Protopine and Nuciferine has been proven to be effective in the treatment of overactive bladder (OAB) symptoms. Patients' evaluation of the two different treatments assessed with Patient Global Impression of Improvement questionnaire (PGI-I), demonstrated improvements in the Group A, while the Group B showed a lower satisfaction. CONCLUSIONS Protopine and Nuciferine can be interesting nutraceutical compounds useful to control irritative and pain related symptoms of intravesical chemo/immunotherapy.
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Coffee consumption and risk of bladder cancer: a pooled analysis of 501,604 participants from 12 cohort studies in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.
Yu, EYW, Dai, Y, Wesselius, A, van Osch, F, Brinkman, M, van den Brandt, P, Grant, EJ, White, E, Weiderpass, E, Gunter, M, et al
European journal of epidemiology. 2020;(6):523-535
Abstract
Recent epidemiological studies have shown varying associations between coffee consumption and bladder cancer (BC). This research aims to elucidate the association between coffee consumption and BC risk by bringing together worldwide cohort studies on this topic. Coffee consumption in relation to BC risk was examined by pooling individual data from 12 cohort studies, comprising of 2601 cases out of 501,604 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel Weibull regression models. Furthermore, dose-response relationships were examined using generalized least squares regression models. The association between coffee consumption and BC risk showed interaction with sex (P-interaction < 0.001) and smoking (P-interaction = 0.001). Therefore, analyses were stratified by sex and smoking. After adjustment for potential confounders, an increased BC risk was shown for high (> 500 ml/day, equivalent to > 4 cups/day) coffee consumption compared to never consumers among male smokers (current smokers: HR = 1.75, 95% CI 1.27-2.42, P-trend = 0.002; former smokers: HR = 1.44, 95% CI 1.12-1.85, P-trend = 0.001). In addition, dose-response analyses, in male smokers also showed an increased BC risk for coffee consumption of more than 500 ml/day (4 cups/day), with the risk of one cup (125 ml) increment as 1.07 (95% CI 1.06-1.08). This research suggests that positive associations between coffee consumption and BC among male smokers but not never smokers and females. The inconsistent results between sexes and the absence of an association in never smokers indicate that the associations found among male smokers is unlikely to be causal and is possibly caused by residual confounding of smoking.
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Bayesian network analysis of open, laparoscopic, and robot-assisted radical cystectomy for bladder cancer.
Dong, L, Qin, Y, Ya, L, Liang, C, Tinghui, H, Pinlin, H, Jin, Y, Youliang, W, Shu, C, Tao, W
Medicine. 2020;(52):e23645
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Abstract
BACKGROUND We have performed the direct and network meta-analysis to evaluate the safety and efficacy of robot-assisted (RARC) versus laparoscopic (LRC) versus open radical cystectomy (ORC) for bladder cancer (BCa). METHODS A systematic search of PubMed, Cochrane Library, and Embase was performed up until Dec 20, 2019. Outcome indexes include oncologic outcomes (the recurrence rate, mortality), pathologic outcomes (lymph node yield (LNY), positive lymph node (PLN), positive surgical margins (PSM)), perioperative outcomes (operating time (OP), estimated blood loss (EBL), blood transfusion rate, the length of hospital stay (LOS) and the time to regular diet) and postoperative 90-day complications. RESULTS We have analyzed 6 RCTs, 23 prospective studies, and 25 retrospective studies (54 articles: 6382 patients). On one hand, the direct meta-analysis shows RARC is better than LRC or ORC. On the other hand, the clinical effects of the recurrence rate, Morbidity, PSM, LNY, PLN, and postoperative 90-day complications of RARC, LRC and ORC are all no statistical significance by network meta-analysis. Moreover, the probability rank shows that the comprehensive rank of RARC is better than LRC or ORC. The clinical effects of OP, EBL, LOS, blood transfusion rate and the time to regular diet are all statistical significance by network meta-analysis. There are ORC > LRC > RARC in the EBL ranking. Patients with RARC exhibited a decrease of LOS compared to those with LRC or ORC. Patients with RARC exhibited a decrease in blood transfusion rate and the time to regular diet compared to those with ORC. Patients with ORC exhibited an increase of OP compared to those with RARC or LRC. The heterogeneity tests of most studies are < 50%. Most studies have no publication bias and the quality of the selected studies is good. CONCLUSION The direct meta-analysis and network meta-analysis suggest that RARC is better than LRC or ORC according to comprehensive analysis. However, we need a large sample size and more high-quality studies to verify and improve in the further.
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Impact of body size and body composition on bladder cancer outcomes: Risk stratification and opportunity for novel interventions.
Sanchez, A, Kissel, S, Coletta, A, Scott, J, Furberg, H
Urologic oncology. 2020;(9):713-718
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Body size is emerging as a novel and clinically-relevant patient factor in bladder cancer research. Historically, a patient's body mass index (BMI) has been used as a proxy for obesity but it shows inconsistent associations with risk of developing the disease as well as with most clinical outcomes. More specific body composition features can be derived for patients using a variety of methods. To date, skeletal muscle measurements derived from preoperative computed tomography scans have shown the most consistent associations with clinical outcomes. Importantly, skeletal muscle can potentially be modified through resistance training and/or nutritional interventions. Large scale studies that evaluate the prognostic impact of not only body composition features at baseline but also describe changes in body composition post-treatment are needed to move the field forward to ultimately improve clinical outcomes for bladder cancer patients.
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Enhanced recovery after surgery (ERAS) protocols in patients undergoing radical cystectomy with ileal urinary diversions: A randomized controlled trial.
Vlad, O, Catalin, B, Mihai, H, Adrian, P, Manuela, O, Gener, I, Ioanel, S
Medicine. 2020;(27):e20902
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BACKGROUND Enhanced Recovery After Surgery (ERAS) protocols were introduced in clinical practice to reduce complication rates and hospital stay. We performed a randomized controlled single center study to evaluate perioperative benefits of an adapted ERAS protocol in patients with bladder cancer who underwent radical cystectomy (RC) and ileal urinary diversions (IUD). MATERIALS AND METHODS Forty five from 90 consecutive randomized patients were enrolled in an adapted ERAS protocol. Length of stay, diet issues, return of bowel function, readmission rates and complications were examined. RESULTS Among patients following ERAS protocol, we found a significant reduction in time to first flatus (1 vs 5 days, P < .001), time to first stool (2 vs 5 days, P < .001), time to normal diet (5 vs 6 days, P < .001) and length of stay (16 vs 18 days, P < .001). Also, postoperative ileus at less than 4 days was lower than in non-ERAS patients (15.6% vs 24.4%), but with a marginal trend toward significance (P = .05). Readmission rate was lower in the ERAS group, but the difference did not reach statistical significance. We also found a lower readmission and complication rate in patients with ERAS protocol (6.6% vs 11.1%, P = .23 and 46.6% vs 57.5%, P = .29, respectively). CONCLUSIONS Implementation of ERAS protocol for patients undergoing RC in our center was associated with a significant reduction in the time to the first flatus, time to the first stool, time to a normal diet, length of hospital stay.