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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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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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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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Minimally invasive vs open radical cystectomy in patients with bladder cancer: A systematic review and meta-analysis of randomized controlled trials.
Hu, X, Xiong, SC, Dou, WC, Shao, YX, Yang, WX, Liu, JB, Li, X
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2020;(1):44-52
Abstract
OBJECTIVE Minimally invasive surgical (MIS) approaches to radical cystectomy (RC) develop well in the past decades. We performed the present study to compare the perioperative outcomes, pathological outcomes, and oncologic outcomes between MIS approaches and open radical cystectomy (ORC) for bladder cancer. METHOD We conducted a comprehensive study search up to March 2019, searching the online database Embase, PubMed and Cochrane Library. RESULTS A total of 8 randomized controlled trials comprising 805 patients were included. We observed that MIS approaches were significantly associated with lower estimated blood loss (WMD = -343.21; 95%CI -431.34 to -255.08; P < 0.001), shorter length of stay (WMD = -0.76; 95%CI -1.28 to -0.24; P = 0.004), shorter time to flatus and diet (WMD = -0.46; 95%CI -0.64 to -0.27; P < 0.001; WMD = -0.92; 95%CI -1.58 to -0.28; P = 0.005; respectively), longer operation time (WMD = 61.38; 95%CI 34.89 to 87.88; P < 0.001), fewer 30-day overall complication (OR = 0.36; 95%CI 0.17 to 0.75; P = 0.007). And we did not detect significant difference in terms of 30-day (P = 0.278) and 90-day major complication (P = 0.899), positive surgical margins (P = 0.986), lymph node yield (P = 0.711), OS (P = 0.473), CSS (P = 0.778), RFS (P = 0.880), PFS (P = 0.324) between MIS approaches and ORC. CONCLUSION In the present studies, we demonstrated that MIS approaches improved perioperative outcomes and had similar pathological and oncological outcomes compared with ORC. Stratified by type of MIS approaches, the results are similar. In conclusion, MIS approaches could serve as an alternative choice in patients with bladder cancer. However, long-term clinical outcomes highlight the need for future studies.
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Management of cisplatin-associated toxicities in bladder cancer patients.
Desilets, A, Adam, JP, Soulières, D
Current opinion in supportive and palliative care. 2020;(3):286-292
Abstract
PURPOSE OF REVIEW Cisplatin remains the treatment cornerstone for bladder cancer, either in neoadjuvant or in metastatic (cisplatin-gemcitabine or dose-dense methotrexate, vinblastine, and doxorubicin). Timely and adequate management of cisplatin's adverse events is important in order to avoid dose reductions, treatment delays, or cessation. Over the last years, several randomized studies and updated guidelines have been published on this subject. RECENT FINDINGS The incidence, physiopathology, risk factors, preventive treatment, and optimal management of such complications will be presented, with special focus on cisplatin-associated nausea and vomiting, acute kidney injury (AKI), hypomagnesemia, neurotoxicity, and ototoxicity. SUMMARY Optimal prevention of cisplatin-associated nausea and vomiting requires an aggressive approach with the use of a four-drug prophylactic regimen (NK1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone, olanzapine). The use of intensive hydration before and after cisplatin infusion has been the mainstay of AKI prevention. The management of hypomagnesemia and neurotoxicity remains largely symptomatic. In an adult population, no therapy has yet demonstrated benefits in the prevention or treatment of platinum-related ototoxicity.
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Urothelial carcinoma of the bladder with abundant myxoid stroma: A case report and literature review.
Tao, TT, Chen, J, Hu, Q, Huang, XJ, Fu, J, Lv, BD, Duan, Y
Medicine. 2020;(28):e21204
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Abstract
INTRODUCTION Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We summarized the clinicopathological features, immunophenotype, diagnosis, and differential diagnosis of this type of bladder cancer, in order to improve the understanding of surgeons and pathologists. PATIENT CONCERNS An 83-year-old female presented with hematuria and frequent micturition, without odynuria, hypogastralgia, or fever. DIAGNOSIS The computed tomography scan demonstrated extensive tumors in the anterior wall of the bladder and a soft tissue shadow anterior to the sacrum. Cystoscopy showed massive wide-based tumors located on the anterior and lateral walls of the bladder, with no tumor involving the bladder neck. Multiple punch biopsies were performed, the histologic evaluation of which revealed a poorly differentiated invasive UCs with myxoid stroma. INTERVENTIONS The patient underwent a laparoscopic radical cystectomy and cutaneous ureterostomy. OUTCOMES The patient discharged without any complications. Histologic evaluation revealed an invasive UC; the most prominent feature was an abundant myxoid stroma that covered approximately 80% of the lesion and the tumor cells were arranged in cords, small nests, or a sheet-like structure. Immunohistochemically, the tumor cells were positive for CK19, CK20, VEGF, EGFR, p63, 34βE12, MUC1, GATA3, uroplakin3, and TopII (rate = 15%), while the Ki-67 proliferation index was 10%. The myxoid stroma in the mesenchyme stained positively with AB-PAS and colloidal iron, and some tumor cells stained positive for colloidal iron. Considering the histologic, histochemical, and immunohistochemical findings, a diagnosis of UC with abundant myxoid stroma was made. After surgery, the regular follow-up was continued in clinic, and there was no recurrence for 2 years. CONCLUSION Morbidity associated with UC with abundant myxoid stroma is very low. The diagnosis mainly depends on histopathological and immunohistochemical findings.
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Assessments of frailty in bladder cancer.
Grimberg, DC, Shah, A, Molinger, J, Whittle, J, Gupta, RT, Wischmeyer, PE, McDonald, SR, Inman, BA
Urologic oncology. 2020;(9):698-705
Abstract
BACKGROUND AND AIMS The incidence of frailty is increasing as the population ages, which has important clinical implications given the associations between frailty and poor outcomes in the bladder cancer population. Due to a multi-organ system decline and decreased physiologic reserve, frail patients are vulnerable to stressors of disease and have poorer mortality and morbidity rates than their nonfrail peers. The association between frailty and poor outcomes has been documented across multiple populations, including radical cystectomy, creating a need for frailty assessments to be used preoperatively for risk stratification. We aim to provide a review of the common frailty assessments and their relevance to radical cystectomy patients. FINDINGS A variety of assessments for frailty exist, from short screening items to comprehensive geriatric assessments. The syndrome spans multiple organ systems, as do the potential diagnostic instruments. Some instruments are less practical for use in clinical practice by urologists, such as the Canadian Study of Health and Aging Frailty Index and Comprehensive Geriatric Assessment. The tool most studied in radical cystectomy is the modified Frailty Index, associated with high grade complications and 30-days mortality. Frailty often coexists with malnutrition and sarcopenia, stressing the importance of screening for and addressing these syndromes to improve patient's perioperative outcomes. CONCLUSIONS There is no universally agreed upon frailty assessment, but the most studied in radical cystectomy is the modified Frailty Index, providing valuable data with which to counsel patients preoperatively. Alterations in immune phenotypes provide potential future diagnostic biomarkers for frailty.
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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.