Shoji Kimura

Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients

BackgroundPreoperative blood-based inflammatory biomarkers have been suggested to improve staging and prognostication in patients with upper-tract urothelial carcinoma (UTUC). Neutrophil-to-lymphocyte ratio (NLR) is the most studied blood-based biomarker. NLR is an indicator of systemic inflammation and has been shown to be associated with a poor prognosis in various malignancies. The aim of this study was to analyze the current evidence regarding the prognostic significance of preoperative NLR in patients undergoing radical nephroureterectomy (RNU) for UTUC to assess its prognostic potential.Materials and methodsA systematic search of Web of Science, Medline/PubMed and Cochrane library was performed on the 1st of October, 2017. Studies were deemed eligible if they compared patients with high NLR before surgical treatment for UTUC to patients with low NLR to determine its predictive value for survival using multivariable logistic regression analysis. We performed a formal meta-analysis for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS).ResultsNine studies including a total of 4385 patients assessing the importance of NLR were included in this meta-analysis. The cut-off NLR varied in the eligible studies ranging from 2 to 3. Increased pretreatment NLR predicted OS (pooled HR 1.64 95% CI; 1.23–2.17), RFS (pooled HR 1.60 95% CI; 1.16–2.20) and CSS (pooled HR 1.73 95% CI; 1.23–2.44) in multivariable analyses.ConclusionIn this meta-analysis, preoperative blood-based NLR is associated with worse prognosis in patients who underwent RNU for UTUC. NLR could be used to improve clinical decision making regarding RNU vs. kidney-sparing surgery, extent of lymphadenectomy, perioperative systemic therapy and follow-up schedule.

Prognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non–muscle-invasive bladder cancer (NMIBC): A systematic review and meta-analysis

OBJECTIVEnThe aim of this study was to summarize and analyze the current evidence regarding the prognostic and predictive value of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients undergoing transurethral resection of bladder tumors (TURBT) for non-muscle-invasive bladder cancer (NMIBC).nnnMATERIAL AND METHODSnA systematic search of Web of Science, Medline/PubMed, Google Scholar, and Cochrane library was performed on the 1st of March, 2018. Studies were deemed eligible if they compared NMIBC patients with high vs. low NLR before TURBT to determine its value for prognosticating disease recurrence and progression using multivariable analysis. We performed a formal meta-analysis for both recurrence-free (RFS) and progression-free survival (PFS).nnnRESULTSnSix studies encompassing 2,298 patients (477 [20.7%] females) assessed the prognostic value of NLR in NMIBC patients treated with TURBT. NLR predicted worse RFS (pooled HR = 1.78; 95% CI: 1.32-2.4, P<0.001) and PFS (pooled HR = 2.14; 95% CI: 1.59-2.87, P<0.001). In 4 studies encompassing 599 patients, high pretreatment NLR was associated with decreased RFS (pooled HR = 2.31; 95% CI: 1.27-4.22, P = 0.006) and in 3 of them high pretreatment NLR was associated with decreased PFS (pooled HR = 2.54; 95% CI: 1.36-4.71, P = 0.003) in high-risk NMIBC patients treated with BCG.nnnCONCLUSIONnIn this meta-analysis, peripheral blood levels of NLR were associated with an increased risk of disease recurrence and progression in patients who underwent TURBT for NMIBC. Furthermore, NLR was an independent predictor of disease recurrence and progression in NMIBC treated with BCG patients. NLR could be used to improve clinical decision-making regarding treatment and follow-up scheduling.

Association of Smoking Status With Recurrence, Metastasis, and Mortality Among Patients With Localized Prostate Cancer Undergoing Prostatectomy or Radiotherapy: A Systematic Review and Meta-analysis

Importance Studies investigating the association of cigarette smoking with prostate cancer incidence and outcomes have revealed controversial results. Objective To systematically review and analyze the association of smoking status with biochemical recurrence, metastasis, and cancer-specific mortality among patients with localized prostate cancer undergoing primary radical prostatectomy or radiotherapy. Data Sources A systematic search of original articles published between January 2000 and March 2017 was performed using PubMed, MEDLINE, Embase, and Cochrane Library databases in March 2017. Study Selection Observational studies reporting Cox proportional hazards regression or logistic regression analyses were independently screened. Data Extraction and Synthesis This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. Available multivariable hazard ratios (HRs) and corresponding 95% CIs were included in quantitative analysis. A risk-of-bias assessment was completed for nonrandomized studies. Main Outcomes and Measures Prespecified outcomes of interest were biochemical recurrence, metastasis, and cancer-specific mortality. Results A total of 5157 reports were identified, of which 16 articles were selected for qualitative analysis and 11 articles were selected for quantitative analysis. All included studies were observational and nonrandomized and comprised a total of 22 549 patients. Overall, 4202 patients (18.6%) were current smokers. The overall median follow-up was 72 months. Current smokers had a statistically significantly higher risk of biochemical recurrence (HR, 1.40; 95% CI, 1.18-1.66; Pu2009<u2009.001 [10 studies]), as did former smokers (HR, 1.19; 95% CI, 1.09-1.30; Pu2009<u2009.001 [7 studies]). Current smokers were also at a higher risk of metastasis (HR, 2.51; 95% CI, 1.80-3.51; Pu2009<u2009.001 [3 studies]) and cancer-specific mortality (HR, 1.89; 95% CI, 1.37-2.60; Pu2009<u2009.001 [5 studies]), whereas former smokers were not (metastasis: HR, 1.61; 95% CI, 0.65-3.97; Pu2009=u2009.31 [2 studies]; cancer-specific mortality: HR, 1.05; 95% CI, 0.81-1.37; Pu2009=u2009.70 [4 studies]). Conclusions and Relevance Current smokers at the time of primary curative treatment for localized prostate cancer are at higher risk of experiencing biochemical recurrence, metastasis, and cancer-specific mortality.

Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: A clinical decision-making tool

PURPOSEnTo improve current prognostic models for the selection of patients with T1G3 urothelial bladder cancer who are more likely to fail intravesical therapy and progress to muscle-invasive bladder cancer (MIBC).nnnMATERIALS AND METHODSnWe performed a retrospective analysis of 1,289 patients with pT1G3 urothelial bladder cancer who were treated with transurethral resection of the bladder (TURB) and adjuvant intravesical bacillus-Calmette-Guérin (BCG). Random-split sample data and competing-risk regression were used to identify the independent impact of lymphovascular invasion (LVI) and variant histology (VH) on progression to MIBC. We developed a nomogram for predicting patient-specific probability of disease progression at 2 and 5 years after TURB. Decision curve analysis (DCA) was performed to evaluate the clinical benefit associated with the use of our nomogram.nnnRESULTSnIn the development cohort, within a median follow-up of 51.6 months (IQR: 19.3-92.5), disease progression occurred in 89 patients (13.8%). A total of 84 (13%) patients were found to have VH and 57 (8.8%) with LVI at TURB. Both factors were independently associated with disease progression on multivariable competing-risk analysis (HR: 4.4; 95% CI: 2.8-6.9; P<0.001 and HR: 3.5; 95% CI: 2.1-5.8; P<0.001, respectively). DCA showed superior net benefits for the nomogram within a threshold probability of progression between 5% and 55%. Limitations are inherent to the retrospective design.nnnCONCLUSIONSnWe demonstrated the clinical value of the integration of LVI and VH in a prognostic model for the prediction of MIBC. Indeed, our tool provides superior individualized risk estimation of progression facilitating decision-making regarding early RC.

Genetic determinants for chemo- and radiotherapy resistance in bladder cancer

Bladder cancer (BCa) is burdened by high rates of chemo- and radio-resistance. We reviewed and summarized the current evidence regarding the genetic determinants of resistance in patients treated with chemotherapy and/or radiotherapy (RT) for BCa. Genetic heterogeneity may preexist to treatment arising with tumorigenesis or increasing progressively during the treatment. Several biological pathways seem to be involved in the cellular response to treatment. These pathways comprehend mechanisms leading to modify the intracellular concentration of the drug, mechanisms leading to increase the repair of DNA damage caused by the treatment, mechanisms leading to increase cell survival, despite DNA damage, acting on the signaling pathways affecting apoptosis, mechanisms promoting autophagy. In the present review, we focused on the genetic determinants of resistance affecting the aforementioned mechanisms.

A systematic review and meta-analysis of lymphovascular invasion in patients treated with radical cystectomy for bladder cancer

PURPOSEnLymphovascular invasion (LVI) is an important step in bladder cancer cell dissemination. We aimed to perform a systematic review and meta-analysis of the literature to assess the prognostic value of LVI in radical cystectomy (RC) specimens.nnnPATIENTS AND METHODSnA systematic review and meta-analysis of the last 10 years was performed using the MEDLINE, EMBASE, and the Cochrane libraries in July 2017. The analyses were performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement.nnnRESULTSnWe retrieved 65 studies (including 78,107 patients) evaluating the effect of LVI on oncologic outcomes in patients treated with RC. LVI was reported in 35.4% of patients. LVI was associated with disease recurrence (pooled hazard ratio [HR] = 1.57; 95% CI: 1.45-1.70) and cancer-specific mortality (CSM) (pooled HR = 1.59; 95% CI: 1.48-1.73) in all studies regardless of tumor stage and node status (pT1-4 pN0-2). LVI was associated with recurrence and CSM in patients with node-negative bladder cancer (BC). In patients with node-negative BC, LVI rate increased and was associated with worse oncologic outcome. LVI had a lower but still significant association with disease recurrence and CSM in node-positive BC.nnnCONCLUSIONSnLVI is a strong prognostic factor of worse prognosis in patients treated with RC for bladder cancer. This association is strongest in node-negative BC, but it is also in node-positive BC. LVI should be part of all pathological reporting and could provide additional information for treatment-decision making regarding adjuvant therapy after RC.

Prognostic value of concomitant carcinoma in situ in the radical cystectomy specimen: A systematic review and meta-analysis

Purpose: We investigated the prognostic impact of concomitant carcinoma in situ in radical cystectomy specimens. Materials and Methods: We performed a systematic review and meta-analysis using MEDLINE®, Scopus®, Web of Science™ and The Cochrane Library to identify eligible studies published until October 2017. Studies were eligible for analysis if they compared patients with concomitant carcinoma in situ in radical cystectomy specimens for bladder cancer to patients without concomitant carcinoma in situ to determine its value to prognosticate overall mortality, recurrence-free survival, cancer specific mortality and ureteral involvement using multivariable analysis. The protocol for this systematic review was registered in PROSPERO (Prospective Register of Systematic Reviews, CRD42018086539) and is available in full on the University of York website. Results: Overall 23 studies published between 2006 and 2017 including a total of 20,647 patients were selected for the systematic review and meta-analysis. Concomitant carcinoma in situ was reported in 39.4% of radical cystectomy specimens. In studies analyzing all patients the presence of concomitant carcinoma in situ was not associated with overall mortality (pooled HR 0.92, 0.77–1.10), recurrence-free survival (pooled HR 1.06, 0.99–1.13) or cancer specific mortality (pooled HR 1.00, 0.93–1.07). It was associated with ureteral involvement (pooled OR 4.51, 2.59–7.84). On subanalysis of studies restricted to patients with organ confined bladder cancer at radical cystectomy concomitant carcinoma in situ was associated with worse recurrence-free survival (pooled HR 1.57, 1.12–2.21) and cancer specific mortality (pooled HR 1.51, 1.001–2.280). Conclusions: Concomitant carcinoma in situ is significantly associated with ureteral involvement in patients treated with radical cystectomy. In patients with organ confined disease concomitant carcinoma in situ in the radical cystectomy specimen is a prognosticator of recurrence-free survival and cancer specific mortality.

Systematic Review of the Impact of Testosterone Replacement Therapy on Depression in Patients with Late-onset Testosterone Deficiency

CONTEXTnClinical guidelines recommend testosterone replacement therapy (TRT) for adult men with late-onset testosterone deficiency (TD), with the goal of improving symptoms and elevating testosterone levels into the normal reference range.nnnOBJECTIVEnTo investigate and critically analyze the current evidence regarding the impact of TRT on depression and depressive symptoms in adult men with late-onset TD compared with placebo.nnnEVIDENCE ACQUISITIONnA systematic search of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials databases, and clinicaltrials.gov was performed on April 1, 2018 using any combination of the terms Testosterone (EXP) OR Testosterone replacement therapy (EXP) AND Depression (EXP) OR Depressive symptoms (EXP). Studies were considered eligible if they included adult men with late-onset TD (total testosterone <350ng/ml and age >30yr.) treated with TRT, used placebo groups comparison arm, were randomized clinical trials (RCTs), included at least 10 individuals per treatment arm, and assessed the impact of TRT on depression compared with that of placebo.nnnEVIDENCE SYNTHESISnFifteen studies encompassing 1586 individuals were included. Six RCTs investigated the impact of TRT on patients with late-onset TD compared with placebo in patients with clinically significant levels of depression, and nine RCTs investigated the impact of TRT on patients with late-onset TD compared with placebo in patients with no clinically significant depression.nnnCONCLUSIONSnTRT reduces depressive symptoms, according to data coming from small-sized, placebo-controlled RCTs of patients with pretreatment clinical mild depression. This impact was not noticed in men with major depressive disorders. In patients without pretreatment depression, TRT leads to a reduction of scores for depressive symptoms; however, clinical value of this is difficult to measure.nnnPATIENT SUMMARYnWe investigated the effect of testosterone replacement therapy (TRT) on depressive symptoms in patients with late-onset testosterone deficiency. TRT improves depressive symptoms in most trials, except in patients with major depressive disorder.

Prognostic Value of Serum Cholinesterase in Non–muscle-invasive Bladder Cancer

Background: Serum cholinesterase (ChE) has been reported to be a prognostic factor in several cancers, but its relationship with oncologic outcomes of non–muscle‐invasive bladder cancer (NMIBC) has not yet been well‐studied. Materials and Methods: We retrospectively assessed 1117 patients with NMIBC undergoing transurethral resection of the bladder. Cox regression analyses were performed to elucidate the association between preoperative ChE and oncologic outcomes such as recurrence‐free survival (RFS) and progression‐free survival. Results: The median preoperative ChE level was 5.51 kU/L (interquartile range, 4.95‐7.01), and the optimal cut‐off value of ChE obtained from receiver operator characteristic analysis was 5.55 kU/L. The 5‐year RFS in patients with low and normal ChE levels were 41.1% and 70.0%, respectively (P < .001). The 5‐year progression‐free survival in patients with low and normal ChE levels were 93.2% and 91.4%, respectively (P = .053). On multivariable analysis, ChE was significantly associated with shorter RFS (P < .001). ChE as a continuous variable and low ChE levels improved the C‐index for prediction of disease recurrence by 4.0% and 2.7% to 72.4% and 71.1%, respectively. In patients stratified into the European Association of Urology high‐risk category, serum ChE was also a strong predictor of disease recurrence (hazard ratio, 4.14; 95% confidence interval, 2.90‐5.89). Moreover, in the European Association of Urology high‐risk patients treated with bacillus Calmette‐Guérin immunotherapy, serum ChE was still strongly correlated with worse RFS (hazard ratio, 5.46; 95% confidence interval, 2.91‐10.2). Conclusions: Decreased ChE is associated with shorter RFS in patients with NMIBC undergoing transurethral resection of the bladder. Preoperative ChE could improve patients risk stratification and selection for adjuvant therapy. The mechanisms underlying this association needs further elucidation to design potential targets for intervention.

A systematic review and meta-analysis of the impact of lymphovascular invasion in bladder cancer transurethral resection specimens

The aim of the present review was to assess the prognostic impact of lymphovascular invasion (LVI) in transurethral resection (TUR) of bladder cancer (BCa) specimens on clinical outcomes. A systematic review and meta‐analysis of the available literature from the past 10 years was performed using MEDLINE, EMBASE and Cochrane library in August 2017. The protocol for this systematic review was registered on PROSPERO (Central Registration Depository: CRD42018084876) and is available in full on the University of York website. Overall, 33 studies (including 6194 patients) evaluating the presence of LVI at TUR were retrieved. LVI was detected in 17.3% of TUR specimens. In 19 studies, including 2941 patients with ≤cT1 stage only, LVI was detected in 15% of specimens. In patients with ≤cT1 stage, LVI at TUR of the bladder tumour (TURBT) was a significant prognostic factor for disease recurrence (pooled hazard ratio [HR] 1.97, 95% CI: 1.47–2.62) and progression (pooled HR 2.95, 95% CI: 2.11–4.13), without heterogeneity (I2 = 0.0%, P = 0.84 and I2 = 0.0%, P = 0.93, respectively). For patients with cT1–2 disease, LVI was significantly associated with upstaging at time of radical cystectomy (pooled odds ratio 2.39, 95% CI: 1.45–3.96), with heterogeneity among studies (I2 = 53.6%, P = 0.044). LVI at TURBT is a robust prognostic factor of disease recurrence and progression in non‐muscle invasive BCa. Furthermore, LVI has a strong impact on upstaging in patients with organ‐confined disease. The assessment of LVI should be standardized, reported, and considered for inclusion in the TNM classification system, helping clinicians in decision‐making and patient counselling.