Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function

Background

Cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care in muscle-invasive bladder cancer. There are limited data regarding chemotherapy tolerability and outcomes for patients with low glomerular filtration rate (GFR) who receive cisplatin-based NAC.

Comparison of Neoadjuvant and Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer

BackgroundWe use observational methods to compare impact of perioperative chemotherapy timing (ie, neoadjuvant and adjuvant) on overall survival (OS) in muscle-invasive bladder cancer because there is no head-to-head randomized trial, and patient factors may influence decision-making.Patients and MethodsUsing Surveillance, Epidemiology, and End Results-Medicare data, we identified patients receiving cystectomy for muscle-invasive bladder cancer diagnosed between 2004 and 2013. Patients were classified as receiving neoadjuvant or adjuvant chemotherapy. Propensity of receiving neoadjuvant chemotherapy was determined using gradient boosted models. Inverse probability of treatment weighted survival curves were adjusted for 13 demographic, socioeconomic, temporal, and oncologic covariates.ResultsWe identified 1342 patients who received neoadjuvant (n = 676) or adjuvant chemotherapy (n = 666) with a median follow-up of 23 months (interquartile range, 9-55 months). Inverse probability of treatment weighted adjustment allows comparison of the groups head-to-head as well as counterfactual scenarios (eg, effect if those getting one treatment were to receive the other). The average treatment effect (ie, “head-to-head” comparison) of adjuvant compared with neoadjuvant on OS was not significant (hazard ratio, 1.14; 95% confidence interval, 0.99-1.31). However, the average treatment effect of the treated (ie, the effect if the neoadjuvant patients were to receive adjuvant instead) was associated with a 33% increase in risk of mortality if they were given adjuvant therapy instead (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57).ConclusionSignificant treatment selection bias was noted in peri-cystectomy timing, which limits the ability to discriminate differential efficacy of these 2 approaches with observational data. However, patients with higher propensity to receive neoadjuvant therapy were predicted to have increased OS with approach, in keeping with existing paradigms from trial data.     

Predictors of Pathological Complete Response to Neoadjuvant Chemotherapy in Iranian Breast Cancer Patients

Background: Achievement of pathologic complete response (pCR) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is associated with both overall survival and disease-free survival. The aim of present study was to identify clinical and pathological factors associated with achieving pCR in Iranian breast cancer patients receiving NAC. Methods: A retrospective review of all breast cancer patients treated with neoadjuvant chemotherapy between April 2012 and September 2016 at our institution was performed; 207 cases were evaluable for analysis. pCR was defined as having no residual invasive tumor in the breast surgical specimen removed following neoadjuvant therapy. Results: In univariate analysis, factors associated with pCR were age less than 35 years (p = 0.03), absence of Lymphovascular invasion (LVI) (p = 0.002) and negative hormone receptor status (p = 0.003). Hormone receptor status (P = 0.01; OR, 2.45; CI, 1.20 - 4.99) and LVI (P = 0.001; OR, 0.22; CI, 0.10 - 0.46) remained predictive variables in multivariate analysis after correction for the other variables. Conclusions: In conclusion, the results of this study suggests that presence of Lymphovascular invasion and positive hormone receptor status are associated with poorer response to neoadjuvant chemotherapy in breast cancer patients.     

Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer

Background

Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle-invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin-eligible patients who opt for bladder preservation warrants further evaluation.

Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance,Epidemiology, and End Results (SEER) Program

BackgroundMicropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare.Patients and MethodsWe retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS.ResultsOur institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group.ConclusionPathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.     

Neoadjuvant Gemcitabine-Cisplatin Plus Radical Cystectomy-Pelvic Lymph Node Dissection for Muscle-invasive Bladder Cancer: A 12-year Experience

IntroductionThe aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND).Patients and MethodsChemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression).ResultsClinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval [CI], 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for < pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P < .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P < .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P < .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056).ConclusionsNeoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival.     

Role of 18F-PET/CT in Predicting Prognosis of Patients With Breast Cancer After Neoadjuvant Chemotherapy

Background

Breast cancer can be assessed preoperatively and postoperatively using ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). We prospectively analyzed the maximum baseline standardized uptake value (SUVmax) derived from FDG PET/CT to predict the outcomes after neoadjuvant chemotherapy (NAC) for breast cancer.

Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy

IntroductionMajor pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome.MethodsA total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients’ treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model.ResultsLN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001).ConclusionsLN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.     

肌层浸润性膀胱癌的新辅助化疗研究进展

肌层浸润性膀胱癌（muscle-invasive bladder cancer , MIBC)是指临床分期为cT2-cT4的膀胱癌。根治性膀胱全切术是肌层浸润性膀胱癌的标准治疗,但是根治术后MIBC患者5年生存率差异巨大。新辅助化疗则可以提高 MIBC患者的5年生存率。本文将对新辅助化疗的最佳化疗方案、现状以及研究方向等方面进行综述。     

PD-L1 Acts as a Promising Immune Marker to Predict the Response to Neoadjuvant Chemotherapy in Breast Cancer Patients

BackgroundProgrammed death ligand 1 (PD-L1) is a negative immune stimulatory molecule that plays a key role in tumor immune escape. We analyzed the clinical value of PD-L1–positive expression in predicting the outcome of breast cancer patients and to establish its role as new biomarker to guide precise treatment.Patients and MethodsPubMed and Embase were searched for all original English-language articles published before January 30, 2019; all articles reported the predictive and prognostic implications of PD-L1⁺ in breast cancer. Data were analyzed by Stata SE 12 software.ResultsThe PD-L1⁺ rate varied from 19.7% to 77.6% in breast cancer patients. Specifically, patients with estrogen receptor–positive, progesterone receptor–positive, luminal A, luminal B, and HER2⁺ disease subtypes had lower PD-L1 expression, while the PD-L1⁺ percentages did not follow any trend in patients with Ki-67⁺, normal-like, HER2 overexpression, and basal-like subtype. In addition, PD-L1⁺ was observed to be associated with significantly improved pathologic complete response to neoadjuvant chemotherapy (odds ratio = 2.01; 95% confidence interval, 1.35-3.01; P < .05). Using PD-L1⁺ to predict pathologic response showed obvious accuracy. However, PD-L1⁺ did not show significant association with risk of higher recurrence or metastasis, or higher death risk (hazard ratio = 0.91, P = .655; hazard ratio = 1.00, P = .995).ConclusionPD-L1⁺ is a promising immune parameter with the potential to predict response to neoadjuvant chemotherapy, but it cannot indicate a higher risk of death, recurrence, or metastasis.     

Sarcopenia and Response to Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

IntroductionThe objective of the study was to determine whether sarcopenia is associated with pathologic and survival outcomes for patients with muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC).Patients and MethodsWe identified MIBC patients treated with cisplatin-based NAC in our cystectomy registry from 2000 to 2016. Pre- and post-NAC computed tomography images were analyzed with BodyCompSlicer, a validated body composition assessment tool. Sarcopenia was defined as a skeletal muscle index (SMI) below sex-specific international consensus values. Associations of clinical features with pathologic downstaging (<ypT2), major (Clavien III-V) complications, and cancer-specific mortality (CSM) were modeled using multivariable logistic and Cox proportional hazard regression models.ResultsA total of 183 patients were identified. Median follow-up was 3.0 years (interquartile range, 1.8-5.0), during which time 79 patients died, including 62 of bladder cancer. SMI declined by a median of 8.4% during NAC treatment. In multivariable logistic regression, neither pretreatment sarcopenia nor the amount of muscle mass loss during NAC was associated with downstaging to <ypT2 disease (P > .05). Meanwhile, only post-NAC sarcopenia (hazard ratio, 1.90; 95% confidence interval, 1.02-3.56; P = .04) was independently associated with an increased risk of CSM.ConclusionSarcopenia after NAC and before RC appeared to be prognostic. Although skeletal muscle mass declined significantly during NAC, neither the degree of muscle loss nor pretreatment SMI were significantly associated with downstaging after NAC and RC. These data do not support the use of sarcopenia as a risk stratification tool for selection of patients for or monitoring response to NAC.     

Assessing the Impact of Neoadjuvant Chemotherapy on the Management of the Breast and Axilla in Breast Cancer

BackgroundNodal status is a sensitive prognostic indicator in breast cancer. Axillary metastases may be an indication for neoadjuvant systemic therapy. The aims of this study were to compare pathologic response rates to neoadjuvant chemotherapy (NAC) in the breast and axilla across different molecular subtypes of breast cancer and to compare the predictive value of axillary assessment before and after chemotherapy in determining final nodal status in this cohort of patients.Patients and MethodsThe cohort comprised patients undergoing NAC from 2003 to November 2012. Data regarding patient and tumor characteristics, management, and outcomes were obtained from a prospectively maintained database and analyzed using PASW Statistics, version 18 (SPSS Inc, Chicago, IL).ResultsTwo hundred two cancers were identified in 196 patients. One hundred thirty-one (65%) diagnostic axillary procedures were performed, 105 (80%) before NAC, of which 93 (89%) were positive. In 28 (30%), downstaging was noted before NAC. Human epidermal growth factor receptor 2 (HER2) subtypes had the highest rate of complete pathologic response (n = 11 [61%]) and negative axillary clearance (AXCn) (n = 11 [69%]). Of 177 AXCns, 68 (38%) were negative before NAC.ConclusionAXCn in patients undergoing NAC remains controversial. HER2 subtypes are less likely to have axillary involvement after NAC and may demand different management.     

Optimization of Patient Selection for Neoadjuvant Chemotherapy in Muscle-invasive Urothelial Carcinoma of the Bladder

Background

Radical cystectomy (RC) is delayed in a subset of patients who respond poorly to neoadjuvant chemotherapy (NAC). The present study investigated the clinicopathologic characteristics predicting extravesical disease at RC and the factors associated with NAC tolerability to improve patient selection and the sequence of definitive therapy.

Induction Chemotherapy Followed by Surgery Versus Upfront Radical Cystectomy in Patients With Clinically Node-positive Muscle-invasive Bladder Cancer

BackgroundThe aim of this study was to compare survival outcomes in patients with clinically node-positive muscle-invasive bladder cancer receiving induction chemotherapy (IC) followed by surgery and those who underwent upfront radical cystectomy (RC).Patients and MethodsOutcomes were reviewed in patients with cT2-4N1-3M0 bladder cancer treated with IC followed by surgery or upfront RC between January 1995 and June 2017. Survival outcomes were analyzed using a propensity score matched cohort analysis.ResultsOf the 340 eligible patients, 106 received IC and 234 underwent upfront RC. The overall 3-year metastasis-free survival rate and 5-year cancer-specific survival rate of patients in the IC and RC groups were similar (49.4% vs. 46.0% and 49.6% vs. 49.8%, respectively). The 5-year cancer-specific survival rate of cN1-2 patients was higher in the IC group than the RC group (68.1% vs. 52.9%; P = .035). However, the 5-year cancer-specific survival rate of patients with cN3 cancers was significantly lower in the IC group than the RC group (19.2% vs. 44.5%; P = .015).ConclusionsIn this study, IC was seen to improve cancer-specific survival in patients with cN1-2 muscle-invasive bladder cancers but was associated with poorer survival outcomes than upfront RC in patients with cN3 cancers. Further investigation in prospective, randomized studies is warranted.     

Impact of Neoadjuvant Chemotherapy on Pathologic Response in Patients With Upper Tract Urothelial Carcinoma Undergoing Extirpative Surgery

Background

Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.

The Neutrophil to Lymphocyte Ratio has a High Negative Predictive Value for Pathologic Complete Response in Locally Advanced Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Background: The neutrophil-to-lymphocyte ratio (NLR) is a strong predictor of mortality in patients withpancreatic, colorectal, lung, gastric cancer and renal cell carcinoma. The aim of this study was to determine therelationship between pathological complete response (pCR) and pretreatment NLR values in locally advancedbreast cancer (BC) patients receiving neoadjuvant chemotherapy (NACT). Materials and Methods: Datawerecollected retrospectively from the Akdeniz University School of Medicine Database for locally advanced BCpatients treated with NACT between January 2000- December 2013. Results: A total of 78 patients were analyzed.Sixteen (20%) patients achieved pCR. Estrogen receptor (ER) positivity was lower in pCR+ than pCR- cases(p=0.011). The median NLR values were similar in both arms. The optimum NLR cut-off point for BC patientswith PCR+ was 2.33 (AUC:0.544, 95%CI [0.401- 0.688], p=0.586) with sensitivity, specificity, positive predictivevalue and negative predictive value (NPV) of 50%, 51,6%, 21,1%, and 80%, respectively. Conclusions: This studyshowed no relationship between the pCR and pretreatment NLR values. Because of a considerable high NPV,in the patients with higher NLR who had luminal type BC in which pCR is lower after NACT, such treatmentmay not be recommended.     

Nonresponse to Neoadjuvant Chemotherapy for Muscle-Invasive Urothelial Cell Carcinoma of the Bladder

BackgroundCisplatin-based neoadjuvant chemotherapy (NC) is commonly used in the treatment of muscle-invasive urothelial cell carcinoma of the bladder (UC) and has been shown to improve survival. However, not all patients respond to NC, thus delaying the interval to potentially curative surgical therapy, risking disease progression and subjecting patients to potential morbidity from NC. In this study, we perform a retrospective analysis of patients who received NC prior to cystectomy to identify factors associated with nonresponse.Patients and MethodsWe identified 80 patients with clinical T2 to T4, N0 to N1 UC of the bladder who received NC and underwent radical cystectomy. Nonresponse was defined as patients with higher pathologic T stage than clinical stage or patients with nodal involvement identified on final pathology.ResultsOverall, 20% of patients were considered nonresponders. In multivariate analysis, age was predictive of nonresponse (P_trend < .05). Compared with those < 60 years of age, those aged 60 to 69 years (odds ratio [OR], 2.9; 95% CI, 0.7-12) and those aged ≥ 70 (OR, 5.0; 95% CI, 0.9-28) had higher odds of nonresponse. Patients who received gemcitabine-carboplatin had higher odds of nonresponse compared with those who received gemcitabine-cisplatin (OR, 4.4; 95% CI, 0.8-21).ConclusionA subset of patients receiving NC prior to cystectomy will experience disease progression. Future study will need to better identify methods to distinguish individuals more likely to benefit from NC and those that should receive upfront cystectomy.     

Evaluation of the Tumor Response After Neoadjuvant Chemotherapy in Breast Cancer Patients: Correlation Between Dynamic Contrast-enhanced Magnetic Resonance Imaging and Pathologic Tumor Cellularity

Background

We evaluated the tumor response after neoadjuvant chemotherapy (NAC) in breast cancer patients using dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging parameters assessed using a commercially available computer-aided system. We also analyzed their correlation with pathologic tumor cellularity.

Ki-67 as a Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer Patients

Purpose

The objectives of this study were to assess the potential value of Ki-67 in predicting response to neoadjuvant chemotherapy in breast cancer patients and to suggest a reasonable cutoff value for classifying Ki-67 expression.

Methods

This study included 74 breast cancer patients who underwent surgery after anthracycline-based neoadjuvant chemotherapy between 2007 and 2012. We analyzed the clinical and immunohistochemical characteristics using core biopsy specimens obtained before neoadjuvant chemotherapy to determine their correlations with the response to chemotherapy.

Results

A clinical complete response was observed in 6 patients (8.1%); a clinical partial response, in 44 patients (59.5%); and clinical stable disease, in 24 patients (32.4%). A pathologic complete response (pCR) was observed in 10 patients (13.5%). In univariate analysis, estrogen receptor (ER) negativity (p=0.031), human epidermal growth factor receptor 2 (HER2) positivity (p=0.040), and high Ki-67 expression (p=0.036) were predictive factors for a pCR. In multivariate analysis, Ki-67 was the only independent predictor of a pCR (p=0.049). The analysis of Ki-67 values revealed that 25% was a reasonable cutoff value for predicting the response to chemotherapy. In subgroup analysis, a higher Ki-67 value (≥25%) was a significant predictive factor for the response to neoadjuvant chemotherapy, especially in ER-negative and HER2-positive breast cancer patients.

Conclusion

Ki-67 expression in breast cancer tissue may be an effective factor for predicting the response to neoadjuvant chemotherapy. We suggest that a 25% level of Ki-67 expression is a reasonable cutoff value for predicting a response to chemotherapy. Moreover, Ki-67 is a useful predictive factor for pCR, especially in patients with ER-negative and HER2-positive breast cancer.     

TERT Promoter Mutations and TERT mRNA but Not FGFR3 Mutations Are Urinary Biomarkers in Han Chinese Patients With Urothelial Bladder Cancer

The TERT promoter and FGFR3 gene mutations are two of the most common genetic events in urothelial bladder cancer (UBC), and these mutation assays in patient urine have been shown to be promising biomarkers for UBC diagnosis and surveillance. These results were obtained mainly from studies of patients with UBC in Western countries, and little is known about such information in Han Chinese patients with UBC. In the present study, we addressed this issue by analyzing tumors from 182 Han Chinese patients with UBC and urine samples from 102 patients for mutations in the TERT promoter and FGFR3 and TERT mRNA expression in tumors and/or urine. TERT promoter and FGFR3 mutations were identified in 87 of 182 (47.8%) and 7 of 102 (6.7%) UBC cases, respectively. In 46 urine samples from patients with TERT promoter mutation‐carrying tumors, the mutant promoter was detected in 24 (52%) prior to operation and disappeared in most examined urine samples (80%) taken 1 week after operation. TERT mRNA was detected in urine derived from 46 of 49 patients (94%) that was analyzed before operation independently of the presence of TERT promoter mutations. Collectively, FGFR3 mutations occur at a very low rate in Han Chinese UBC and cannot serve as diagnostic markers for Chinese patients. Han Chinese patients with UBC have relatively low TERT promoter mutation frequency compared with patients in Western countries, and simultaneous detection of both mutant TERT promoter and TERT mRNA improves sensitivity and specificity of urine‐based diagnosis.