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NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype.
Bocci, F, Tripathi, SC, Vilchez Mercedes, SA, George, JT, Casabar, JP, Wong, PK, Hanash, SM, Levine, H, Onuchic, JN, Jolly, MK
Integrative biology : quantitative biosciences from nano to macro. 2019;(6):251-263
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Abstract
The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the 'metastatic sweet spot'.
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Impact of enhanced recovery after surgery protocols versus standard of care on perioperative outcomes of radical cystectomy: a systematic review and meta-analysis of comparative studies.
Giannarini, G, Crestani, A, Inferrera, A, Rossanese, M, Subba, E, Novara, G, Ficarra, V
Minerva urologica e nefrologica = The Italian journal of urology and nephrology. 2019;(4):309-323
Abstract
INTRODUCTION Among the measures taken in the recent years to reduce the morbidity and improve functional recovery after radical cystectomy (RC), the optimization of perioperative care pathways is gaining a prominent role. The aim of this systematic review of the literature with meta-analysis is to assess the impact of enhanced recovery after surgery (ERAS) protocols vs. standard of care on perioperative outcomes of patients undergoing RC. EVIDENCE ACQUISITION A systematic review with meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. MEDLINE, SCOPUS and Web of Science databases were searched. Only comparative studies evaluating the impact of ERAS protocols vs. standard of care on intraoperative and postoperative outcomes of patients undergoing RC were included. Cumulative analysis was conducted using Review Manager v.5.3 software. Statistical heterogeneity was tested using the χ2 Test, and a P value <0.10 was used to indicate heterogeneity. Random-effects and fixed-effects models were used as appropriate depending on heterogeneity status. EVIDENCE SYNTHESIS A total of 27 studies were included, namely 3 randomized and 24 non-randomized controlled studies, resulting in 4712 patients, 2690 (57%) participants to some ERAS protocol and 2022 (43%) controls receiving standard of care. A number of primary and secondary outcome measures were assessed in the original studies. Pooled data showed that ERAS protocols were associated with significantly faster recovery of bowel function, faster return to regular diet and shorter hospital stay with no increase in 30-day and 90-day major complication, mortality or readmission rates compared to standard of care. The magnitude of benefit of the various ERAS protocols tested had, however, a non-negligible inter-study variability. CONCLUSIONS This systematic review with meta-analysis of comparative studies showed that ERAS protocols applied to patients undergoing RC enabled a faster recovery of bowel function, a faster return to regular diet and a shorter hospital stay with no increase in major complication or readmission rate compared to standard perioperative care. RC with ERAS protocols should be considered the new standard of care.
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Dietary fat intake and risk of bladder cancer: Evidence from a meta-analysis of observational studies.
Wang, J, Wang, C
Cellular and molecular biology (Noisy-le-Grand, France). 2019;(7):5-9
Abstract
The association between dietary fat intake and bladder cancer had been inconsistent in the previous epidemiological studies. The aim of this study was to investigate the difference between fat intake and bladder cancer risk. Databases of PubMed, Embase, and Web of Science were systematically searched for suitable studies from inception to June 2018. A meta-analysis was performed to analyze the efficacy of dietary fat intake on bladder cancer risk. A Forest plot was prepared to indicate the relationship. Ten citations were used in this study. The Funnel plot suggested highest category of dietary fat intake could increase the risk of bladder cancer (summarized relative risk (RR)= 1.279, 95% confidence interval (CI)= 1.036-1.577, I2= 53.2%, P for heterogeneity = 0.019). A positive association was found among European populations (summarized RR= 1.359, 95%CI= 1.027-1.798), but not in North American populations. The association was not significant in the subgroup analysis by fat type on bladder cancer risk. Egger test (P= 0.239) and Funnel plot showed there was no significant publication bias in the included publications. In conclusions, compared with the lowest category of dietary fat intake, the highest category could significantly increase the bladder cancer risk, especially among European populations. As some limitations existed in our analysis, large scale studies with detailed amount of dietary fat intake are needed to verify our results.
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Re: Perioperative Oral Nutrition Supplementation Reduces Prevalence of Sarcopenia following Radical Cystectomy: Results of a Prospective Randomized Controlled Trial.
Sefik, E, Bozkurt, IH, Basmaci, I, Celik, S
The Journal of urology. 2019;(4):819
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Re: Perioperative Oral Nutrition Supplementation Reduces Prevalence of Sarcopenia following Radical Cystectomy: Results of a Prospective Randomized Controlled Trial.
Luo, Y, Wang, X, Xiao, Y
The Journal of urology. 2019;(4):819-820
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Does the Use of a Robot Decrease the Complication Rate Adherent to Radical Cystectomy? A Systematic Review and Meta-Analysis of Studies Comparing Open with Robotic Counterparts.
Tzelves, L, Skolarikos, A, Mourmouris, P, Lazarou, L, Kostakopoulos, N, Manatakis, DK, Kural, AR
Journal of endourology. 2019;(12):971-984
Abstract
Introduction: Radical cystectomy (RC) is the mainstay of treatment for muscle-invasive bladder cancer. In 2003, the first robot-assisted radical cystectomy (RARC) was performed and since then many studies, mainly observational, were conducted to compare robotic and open methods. This study aims to assess perioperative outcomes between the two methods based on pooled data from existing literature. Methods: A literature search of articles in English and French languages was performed in three databases (Medline, Embase, and Cochrane) until 30th of June 2018, as well as in urology conference programs and reference lists of included studies. The study protocol was registered at PROSPERO (CRD42018103063). Terms such as "robotic," "open," and "radical cystectomy" and synonyms were used for the searching algorithm. The primary outcome was the number of minor and major postoperative complications (Clavien grading system). Risk of bias was assessed with the Cochrane tool and Newcastle-Ottawa scale. Comparison of continuous outcomes was performed with weighted mean differences, while for dichotomous outcomes, odds ratios (ORs) were used. Review Manager 5.3 was used. Results: Fifty-four studies (5 randomized trials and 49 observational) were eligible, including 29,697 patients (6500 in the RARC group and 23,197 in the open radical cystectomy group). Minor complications (grade 1-2) in pooled data of 29 studies were fewer in the RARC group (OR = 0.54, 95% confidence interval [CI]: 0.38-0.76, p < 0.001), a difference persisting after sensitivity analysis for 30 and 90 days. Major complications (grade 3-5) in 31 studies were fewer in the RARC group (OR = 0.78, 95% CI: 0.65-0.94, p = 0.009), but this difference disappeared in the 30-day subanalysis. RARC was associated with lower blood transfusion rates (p < 0.001), lower length of stay (p < 0.001), faster return to regular diet (p < 0.001), and lower postoperative mortality rates (p < 0.001), but longer operating time. Conclusions: RARC appears to be associated with fewer complications and favoring perioperative outcomes in comparison with the open method. Due to the observational nature of most studies, larger randomized trials are needed to confirm these findings.
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Perioperative nutrition for the treatment of bladder cancer by radical cystectomy.
Burden, S, Billson, HA, Lal, S, Owen, KA, Muneer, A
The Cochrane database of systematic reviews. 2019;(5):CD010127
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Abstract
BACKGROUND Radical cystectomy (RC) is the primary surgical treatment for muscle-invasive urothelial carcinoma of the bladder. This major operation is typically associated with an extended hospital stay, a prolonged recovery period and potentially major complications. Nutritional interventions are beneficial in some people with other types of cancer and may be of value in this setting too. OBJECTIVES To assess the effects of perioperative nutrition in people undergoing radical cystectomy for the treatment of bladder cancer. SEARCH METHODS We performed a comprehensive search using multiple databases (Evidence Based Medicine Reviews, MEDLINE, Embase, AMED, CINAHL), trials registries, other sources of grey literature, and conference proceedings published up to 22 February 2019, with no restrictions on the language or status of publication. SELECTION CRITERIA We included parallel-group randomised controlled trials (RCTs) of adults undergoing RC for bladder cancer. The intervention was any perioperative nutrition support. DATA COLLECTION AND ANALYSIS Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias and the quality of evidence using GRADE. Primary outcomes were postoperative complications at 90 days and length of hospital stay. The secondary outcome was mortality up to 90 days after surgery. When 90-day outcome data were not available, we reported 30-day data. MAIN RESULTS The search identified eight trials including 500 participants. Six trials were conducted in the USA and two in Europe.1. Parenteral nutrition (PN) versus oral nutrition: based on one study with 157 participants, PN may increase postoperative complications within 30 days (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.07 to 1.82; low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection, performance and selective reporting bias) and serious imprecision. This corresponds to 198 more complications per 1000 participants (95% CI 35 more to 405 more). Length of hospital stay may be similar (mean difference (MD) 0.5 days higher, CI not reported; low-quality evidence).2. Immuno-enhancing nutrition versus standard nutrition: based on one study including 29 participants, immuno-enhancing nutrition may reduce 90-day postoperative complications (RR 0.31, 95% CI 0.08 to 1.23; low-quality evidence). These findings correspond to 322 fewer complications per 1000 participants (95% CI 429 fewer to 107 more). Length of hospital stay may be similar (MD 0.20 days, 95% CI 1.69 lower to 2.09 higher; low-quality evidence). We downgraded the quality of evidence of both outcomes for very serious imprecision.3. Preoperative oral nutritional support versus normal diet: based on one study including 28 participants, we are very uncertain if preoperative oral supplements reduces postoperative complications. We downgraded quality for serious study limitations (unclear risk of selection, performance, attrition and selective reporting bias) and very serious imprecision. The study did not report on length of hospital stay.4. Early postoperative feeding versus standard postoperative management: based on one study with 102 participants, early postoperative feeding may increase postoperative complications (very low-quality evidence) but we are very uncertain of this finding. We downgraded the quality of evidence for serious study limitations (unclear risk of selection and performance bias) and very serious imprecision. Length of hospital stay may be similar (MD 0.95 days less, CI not reported; low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection and performance bias) and serious imprecision.5. Amino acid with dextrose versus dextrose: based on two studies with 104 participants, we are very uncertain whether amino acids reduce postoperative complications (very low-quality evidence). We are also very uncertain whether length of hospital stay is similar (very low-quality evidence). We downgraded the quality of evidence for both outcomes for serious study limitations (unclear and high risk of selection bias; unclear risk of performance, detection and selective reporting bias), serious indirectness related to the patient population and very serious imprecision.6. Branch chain amino acids versus dextrose only: based on one study including 19 participants, we are very uncertain whether complication rates are similar (very low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection, performance, detection, attrition and selective reporting bias), serious indirectness related to the patient population and very serious imprecision. The study did not report on length of hospital stay.7. Perioperative oral nutritional supplements versus oral multivitamin and mineral supplement: based on one study with 61 participants, oral supplements compared to a multivitamin and mineral supplement may slightly decrease postoperative complications (low-quality evidence). These findings correspond to 135 fewer occurrences per 1000 participants (95% CI 256 fewer to 65 more). Length of hospital stay may be similar (low-quality evidence). We downgraded the quality of evidence of both outcomes for study limitations and imprecision. AUTHORS' CONCLUSIONS Based on few, small and dated studies, with serious methodological limitations, we found limited evidence for a benefit of perioperative nutrition interventions. We rated the quality of evidence as low or very low, which underscores the urgent need for high-quality research studies to better inform nutritional support interventions for people undergoing surgery for bladder cancer.
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Minimally invasive versus open radical cystectomy for bladder cancer: A systematic review and meta-analysis.
Shi, H, Li, J, Li, K, Yang, X, Zhu, Z, Tian, D
The Journal of international medical research. 2019;(10):4604-4618
Abstract
BACKGROUND We performed a systematic review and meta-analysis to evaluate the efficacy and safety of minimally invasive radical cystectomy (MIRC) versus open radical cystectomy (ORC) for bladder cancer. METHODS We searched the EMBASE and MEDLINE databases to identify randomized controlled trials (RCTs) of MIRC versus ORC in the treatment of bladder cancer. RESULTS Eight articles describing nine RCTs (803 patients) were analyzed. No significant differences were found between MIRC and ORC in two oncologic outcomes: the recurrence rate and mortality. Additionally, no significant differences were found in three pathologic outcomes: lymph node yield, positive lymph nodes, and positive surgical margins. With respect to perioperative outcomes, however, MIRC showed a significantly longer operating time, less estimated blood loss, lower blood transfusion rate, shorter time to regular diet, and shorter length of hospital stay than ORC. The incidence of complications was similar between the two techniques. We found no statistically significant differences in the above outcomes between robot-assisted radical cystectomy and ORC or between laparoscopic radical cystectomy and ORC with the exception of the complication rate. CONCLUSIONS MIRC is an effective and safe surgical approach in the treatment of bladder cancer. However, a large-scale multicenter RCT is needed to confirm these findings.
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Supportive interventions to improve physiological and psychological health outcomes among patients undergoing cystectomy: a systematic review.
Quirk, H, Rosario, DJ, Bourke, L
BMC urology. 2018;(1):71
Abstract
BACKGROUND Our understanding of effective perioperative supportive interventions for patients undergoing cystectomy procedures and how these may affect short and long-term health outcomes is limited. METHODS Randomised controlled trials involving any non-surgical, perioperative interventions designed to support or improve the patient experience for patients undergoing cystectomy procedures were reviewed. Comparison groups included those exposed to usual clinical care or standard procedure. Studies were excluded if they involved surgical procedure only, involved bowel preparation only or involved an alternative therapy such as aromatherapy. Any short and long-term outcomes reflecting the patient experience or related urological health outcomes were considered. RESULTS Nineteen articles (representing 15 individual studies) were included for review. Heterogeneity in interventions and outcomes across studies meant meta-analyses were not possible. Participants were all patients with bladder cancer and interventions were delivered over different stages of the perioperative period. The overall quality of evidence and reporting was low and outcomes were predominantly measured in the short-term. However, the findings show potential for exercise therapy, pharmaceuticals, ERAS protocols, psychological/educational programmes, chewing gum and nutrition to benefit a broad range of physiological and psychological health outcomes. CONCLUSIONS Supportive interventions to date have taken many different forms with a range of potentially meaningful physiological and psychological health outcomes for cystectomy patients. Questions remain as to what magnitude of short-term health improvements would lead to clinically relevant changes in the overall patient experience of surgery and long-term recovery.
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Impact of Sarcopenia as a Prognostic Biomarker of Bladder Cancer.
Fukushima, H, Takemura, K, Suzuki, H, Koga, F
International journal of molecular sciences. 2018;(10)
Abstract
Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, indicates patient frailty and impaired physical function. Sarcopenia can be caused by multiple factors, including advanced age, lack of exercise, poor nutritional status, inflammatory diseases, endocrine diseases, and malignancies. In patients with cancer cachexia, anorexia, poor nutrition and systemic inflammation make the metabolic state more catabolic, resulting in sarcopenia. Thus, sarcopenia is considered as one of manifestations of cancer cachexia. Recently, growing evidence has indicated the importance of sarcopenia in the management of patients with various cancers. Sarcopenia is associated with not only higher rates of treatment-related complications but also worse prognosis in cancer-bearing patients. In this article, we summarized metabolic backgrounds of cancer cachexia and sarcopenia and definitions of sarcopenia based on computed tomography (CT) images. We conducted a systematic literature review regarding the significance of sarcopenia as a prognostic biomarker of bladder cancer. We also reviewed recent studies focusing on the prognostic role of changes in skeletal muscle mass during the course of treatment in bladder cancer patients. Lastly, we discussed the impact of nutritional support, medication, and exercise on sarcopenia in cancer-bearing patients.