Survival In Muscle-invasive Bladder Cancer Research Articles

Utilization of neoadjuvant chemotherapy for muscle-invasive bladder cancer in elderly patients: a retrospective cohort study.

Neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). Older patients often do not receive NAC due to its potential toxicities. We examined treatment patterns of elderly MIBC patients as well as impact of NAC on survival in this population. The National Cancer Database was queried from 2006 to 2019 for stage T2-T4a MIBC patients ≥ 80years old. Treatment exposures (extirpative surgery; chemotherapy; radiation) were ascertained. Kaplan-Meier survival curves were generated based on treatment modalities (no treatment; radiation only; chemotherapy only; chemoradiation; surgery only; NAC with surgery). Multivariable Cox proportional hazards regression assessed associations with overall survival (OS). The cohort included 16,391 patients (mean age 86years); 51% received treatment. MIBC treatment was less common with advancing age; patients receiving NAC then surgery were younger and had lower comorbidity scores. From 2006 to 2019, more patients received chemoradiation, while rates of NAC rose modestly. Median OS for the NAC with surgery group was 48months versus 9months for the no treatment group. Log-rank tests showed significantly improved survival in the NAC with surgery group compared to the surgery only group, while Cox proportional hazards regression analysis showed highest survival benefit in the NAC with surgery group. Only half of elderly MIBC patients received treatment, with fewer undergoing curative intent. NAC with surgery was associated with the greatest survival benefit. While our findings should be taken in the context of potential selection bias and patient preferences, they support NAC as part of shared-decision making regardless of age.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer

BackgroundLuminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC.MethodsThis study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC.ResultsAmong patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy.ConclusionsWe emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Comparison of trimodality therapy and neoadjuvant chemotherapy combined with radical cystectomy for the survival of muscle-invasive bladder cancer: a population-based analysis

BackgroundTrimodality therapy (TMT) is a mature alternative to radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC) who seek to preserve their primary bladder or are inoperable due to comorbidities. To date, there has been increasing evidence of the effectiveness of TMT as an alternative to RC. In contrast, no literature has stated the effectiveness of neoadjuvant chemotherapy combined with RC (NAC + RC) compared with TMT.ObjectiveWe aimed to compare the prognosis between patients receiving TMT and NAC + RC.MethodsThe clinicopathological characteristics of patients with T2-4aN0M0 MIBC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazards regression models and Kaplan‒Meier survival curves were used for the survival analysis. Propensity-score matching (PSM) was applied to determine the differences between the two groups. The primary outcome was cancer-specific survival (CSS), and the secondary outcome was overall survival (OS).ResultsIn total, 1,175 patients with MIBC who underwent TMT (n = 822) or NAC + RC (n = 353) were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. After 1:1 PSM, the final patient sample included 303 pairs. The prognosis of patients receiving NAC + RC was significantly better than that of patients receiving TMT in both unmatched and matched cohorts (5-year CSS: before PSM, 75.4% vs. 50.6%, P < 0.0001; after PSM, 76.3% vs. 49.5%, P < 0.0001; 5-year OS: before PSM, 71.7% vs. 37.4%, P < 0.0001; after PSM, 71.7% vs. 31.4%, P < 0.0001). The survival advantages of NAC + RC remained remarkable in the stratified analysis of most factors after PSM. Multivariate Cox regression analysis showed that being older than 68 years old, unmarried, grade III/IV, T3-4a stage, and undergoing TMT independently correlated with poor OS.ConclusionThus, in this study, patients with MIBC receiving NAC + RC presented with a better prognosis than those receiving TMT.

Neural network analysis of tumor and germline profiling to predict survival of muscle-invasive bladder cancer following radical cystectomy: An analysis of the Cancer Genome Atlas (TCGA).

546 Background: Following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), recurrence is suboptimally associated with pathologic stage. A prognostic model that incorporates information from comprehensive genomic and transcriptomic data from germline and tumor tissues will improve the selection of high-risk patients (pts) for adjuvant therapy and tailored surveillance. Methods: Pts with MIBC in TCGA who underwent RC (without neoadjuvant chemotherapy) and with whole exome sequencing (WES) of tumor + normal, and tumor RNA-Seq were eligible. Germline variants were called and annotated using GATK4 and Variant Effect Predictor (VEP). Only high and moderate VEP-Impact variants contributed to burdens. Given that recurrence is associated with 5-year survival, pts were required to have data for survival at a landmark of 5 years post-RC or may have died within 5 years of RC. Patients who died &lt;4 months of diagnosis were excluded since they may have died from post-operative complications. Dead patients were propensity-matched against alive patients by pathologic stage, adjuvant chemotherapy, gender, race, age and smoking. A linear artificial neural network was trained to predict 5-year survival using Artificial Intelligence Quality Control (AIQC)-a deep learning experience tracker. The samples were divided into 3 equally distributed subsets of alive and dead pts. The algorithm was trained on 50% of the dataset, evaluated on 40% and tested on 10%. The remaining 39 dead pts were used for additional holdout validation. The accuracy (percentage of correct prediction of death or survival) was reported. Results: A cohort of 117 pts were evaluable for 5 year survival. The cohort included 39 survivors that satisfied inclusion criteria, and 78 dead pts that were propensity matched against them (one set of 39 dead pts for training &amp; evaluation, and a second set of 39 dead pts as an additional holdout). The binary classification neural network was trained on 38 samples to predict survival based on their most differentiated: germline alteration burdens + tumor alteration burdens + tumor gene expression. The differentially mutated genes most important to the algorithm were: PTPRN(n-m), TECTA(t-m), BPIFB1(n-m), SORL1(n-m), SLC39A5(n-m), and RBBP6(n-h) [t=tumor/ n=normal tissue origin | m=moderate/ h=high VEP impact]. The algorithm was 97% accurate on the 38 training samples, and 94% accurate across the 79 evaluation (validation, test and holdout) samples. Conclusions: Neural network analysis of germline and tumor profiling was validated to optimally differentiate between dead and surviving pts at 5 years following RC for MIBC. Further validation and application of this promising algorithm may advance precision medicine by permitting the selection of the most appropriate pts with high-risk MIBC for adjuvant therapy.

Quantitative Assessment of Tumor-Infiltrating Lymphocytes Using Machine Learning Predicts Survival in Muscle-Invasive Bladder Cancer.

(1) Purpose: Although assessment of tumor-infiltrating lymphocytes (TILs) has been acknowledged to have important predictive prognostic value in muscle-invasive bladder cancer (MIBC), it is limited by inter- and intra-observer variability, hampering widespread clinical application. We aimed to evaluate the prognostic value of quantitative TILs score based on a machine learning (ML) algorithm to identify MIBC patients who might benefit from immunotherapy or the de-escalation of therapy. (2) Methods: We constructed an artificial neural network classifier for tumor cells, lymphocytes, stromal cells, and "ignore" cells from hematoxylin-and-eosin-stained slide images using the QuPath open source software. We defined four unique TILs variables based on ML to analyze TILs measurements. Pathological slide images from 133 MIBC patients were retrospectively collected as the discovery set to determine the optimal association of ML-read TILs variables with patient survival outcomes. For validation, we evaluated an independent external validation set consisting of 247 MIBC patients. (3) Results: We found that all four TILs variables had significant prognostic associations with survival outcomes in MIBC patients (p &lt; 0.001 for all comparisons), with higher TILs score being associated with better prognosis. Univariate and multivariate Cox regression analyses demonstrated that electronic TILs (eTILs) variables were independently associated with overall survival after adjustment for clinicopathological factors including age, sex, and pathological stage (p &lt; 0.001 for all analyses). Results analyzed in different subgroups showed that the eTILs variable was a strong prognostic factor that was not redundant with pre-existing clinicopathological features (p &lt; 0.05 for all analyses). (4) Conclusion: ML-driven cell classifier-defined TILs variables were robust and independent prognostic factors in two independent cohorts of MIBC patients. eTILs have the potential to identify a subset of high-risk stage II or stage III-IV MIBC patients who might benefit from adjuvant immunotherapy.

EP029 - Ki67 and FOXC1-based complementary diagnostic for neoadjuvant cisplatin-based chemotherapy predicts response and improved survival in muscle-invasive bladder cancer

EP029 - Ki67 and FOXC1-based complementary diagnostic for neoadjuvant cisplatin-based chemotherapy predicts response and improved survival in muscle-invasive bladder cancer

Bladder-Sparing Chemoradiotherapy Combined with Immune Checkpoint Inhibition for Locally Advanced Urothelial Bladder Cancer-A Review.

Simple SummaryImmunotherapy with immune checkpoint inhibition (ICI) has provided durable treatment responses in advanced, metastatic, bladder cancer patients. The first trials using checkpoint inhibitors before surgery, when the cancer is still confined to the pelvis, without signs of metastasis, have reported promising results. We reviewed the literature to identify clinical trials combining ICI with bladder-sparing chemoradiotherapy (CRT). Radiotherapy stimulates the immune system, thereby possibly inducing an additive effect in combination with checkpoint inhibition. Currently, twelve trials are treating patients with this immunochemoradiotherapy (iCRT) combination treatment. Several combinations with different chemotherapeutics and ICI added to CRT appear safe and feasible. Further research and comparative trials are needed to prove whether iCRT has additional clinical value for bladder cancer patients.Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer.

Role of immunotherapy in localized muscle invasive urothelial cancer.

The standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy with chemoradiation in select patients. Pathologic complete response (pCR) to neoadjuvant chemotherapy is a reliable predictor of overall and disease-specific survival in MIBC. A pCR rate of 35–40% is attained with neoadjuvant cisplatin-based chemotherapy. With the approval of immune checkpoint inhibitors (ICIs) for the treatment of metastatic urothelial cancer, these agents are now being studied in the neoadjuvant setting for MIBC. We describe the results from clinical trials using single agent ICI, ICI/ICI and ICI/chemotherapy combination therapies in the neoadjuvant setting for MIBC. These single-arm clinical trials have demonstrated safety and pCR comparable to cisplatin-based chemotherapy. Neoadjuvant ICI is a promising approach for cisplatin-ineligible patients, and the role of adding ICIs to cisplatin-based chemotherapy is also being investigated in randomized phase III clinical trials. Ongoing biomarker research to suggest a response to neoadjuvant ICIs will also guide appropriate treatment selection. We also describe the studies using ICIs for adjuvant therapy and in combination with chemoradiation.

703P Camrelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer

Chemotherapy combined with immunotherapy before radical cystectomy (RC) is anticipated to improve survival of muscle-invasive bladder cancer (MIBC) patients(pts). We investigated the efficacy and safety of camrelizumab in combination with gemcitabine plus cisplatin (GC) as neoadjuvant therapy in MIBC pts.

Neuropilin-2 and Its Transcript Variants Correlate with Clinical Outcome in Bladder Cancer.

Urothelial bladder cancer ranks among the 10 most frequently diagnosed cancers worldwide. In our previous study, the transmembrane protein neuropilin-2 (NRP2) emerged as a predictive marker in patients with bladder cancer. NRP2 consists of several splice variants; the most abundant of these, NRP2a and NRP2b, are reported to have different biological functions in lung cancer progression. For other cancer types, there are no published data on the role of these transcript variants in cancer progression and the clinical outcome. Here, we correlate NRP2 and its two most abundant transcript variants, NRP2A and NRP2B, with the clinical outcome using available genomic data with subsequent validation in our own cohort of patients with muscle-invasive bladder cancer. In addition to NRP2, NRP1 and the NRP ligands PDGFC and PDGFD were studied. Only NRP2A emerged as an independent prognostic marker for shorter cancer-specific survival in muscle-invasive bladder cancer in our cohort of 102 patients who underwent radical cystectomy between 2008 and 2014 with a median follow-up time of 82 months. Additionally, we demonstrate that high messenger expression of NRP2, NRP1, PDGFC and PDGFD associates with a more aggressive disease (i.e., a high T stage, positive lymph node status and reduced survival).

Meta-analysis of neoadjuvant chemotherapy compared to radical cystectomy alone in improving overall survival of muscle-invasive bladder cancer patients

BackgroundMost patients with muscle-invasive bladder cancer (MIBC) developed metastasis within 2 years, even after radical cystectomy (RC). The recurrence rate of MIBC was more than 50% of the cases. A meta-analysis conducted by Yin et al. showed that neoadjuvant chemotherapy (NAC) + RC improves overall survival in MIBC compared with RC only. However, a new meta-analysis by Li et al. concluded that NAC + RC was not superior to RC only in improving overall survival. The inconsistencies of these studies required further comprehensive analysis to recommend NAC use in bladder cancer treatment. Therefore, this meta-analysis aims to analyze previous studies that compare the efficacy of NAC + RC versus RC only to improve overall survival of MIBC.MethodsThe articles were searched using Pubmed with keywords “muscle-invasive bladder cancer”, “neoadjuvant chemotherapy”, “cystectomy”, and “overall survival”. The articles that were published until June 2020 were screened. The overall survival outcome was analyzed as hazard ratio (HR) and presented in a forest plot.ResultSeventeen studies were included in meta-analysis with a total sample of 13,391 patients, consist of 2890 received NAC followed by RC and 10,418 underwent RC only. Two studies used methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), two studies used gemcitabine/cisplatin (GC), one study used Cisplatin-based regimen, one study used MVAC or GC, one study used gemcitabine/carboplatin (GCarbo) or GC or MVAC, one study used Cisplatin/Gemcitabine or MVAC, one study used Cisplatin only, one study used Cisplatin-based (GC, MVAC) or non-Cisplatin-based (combined paclitaxel/gemcitabine/carboplatin), one study used GC, MVAC, Carboplatin, or Gemcitabine/Nedaplatin (GN), and five studies did not mention the regimen The overall survival in the NAC + RC only group was significantly better than the RC only group (HR 0.82 [0.71–0.95], p = 0.009).ConclusionNAC + RC is recommended to improve overall survival in MIBC patients. A further study assessing side effects and quality of life regarding NAC + RC is needed to establish a strong recommendation regarding this therapy.

Association between surgical case volume and survival in T1 bladder cancer: A plea for regionalization of care?

Introduction: Prior research demonstrated an association between surgical case volume and survival in muscle-invasive bladder cancer (BC). This relationship, however, has not been investigated in the setting of T1 BC so far. Therefore, we investigated whether a higher surgical case volume of T1 BC translates into improved survival outcomes.&#x0D; Methods: Province-wide pathology reports (January 2002 to December 2015) were linked with health administrative data to identify patients diagnosed with T1 BC. For each patient, we determined the T1 case volume of the involved surgeon by benchmarking (percentile) her/him against his/her colleagues during a lookback period of one year. The volume-outcome (overall survival) relationship was then investigated by Cox proportional hazards regression (unadjusted and adjusted for a wide range of assumed confounders) that incorporated volume in three different ways (80th percentile and higher vs. below, median and higher vs. below, continuous [quintiles]). Effect sizes were presented as hazard ratios (95% confidence interval).&#x0D; Results: We identified 7426 patients who were diagnosed with T1 BC and followed for 4.8 years. A third of all patients (n=1895, 25.5%) received surgery by a high-volume surgeon (80th percentile and higher). Higher T1 case volume was associated with improved survival both in unadjusted (80th percentile: 0.93 [0.86–0.99]; median: 0.93 [0.87–0.99]; continuous: 0.97 [0.94–0.99]) and adjusted analysis (80th percentile: 0.94 [0.88–1.01]; median: 0.93 [0.87–0.99]; continuous: 0.97 [0.95–0.99]).&#x0D; Conclusions: This province-wide cohort study could demonstrate a volume-outcome relationship in T1 BC and raises questions regarding the regionalization of care in high-risk non-muscle-invasive BC. The generalizability of our findings, however, is limited by the fact that the performance of the initial resection by a high-volume surgeon does not necessarily translate into downstream care by the same surgeon.

Serum LUCAT1 implicates the pathogenesis of muscle-invasive bladder cancer via targeting miR-199a-5p and miR-199b-5p.

Muscle-invasive bladder cancer (MIBC) is a common malignancy of urinary system cancers, accounting for about 1/3 of all newly diagnosed bladder cancer cases. Due to its strong metastasis, the 5-year survival of MIBC is less than 50%, and in serious cases, the overall survival of metastatic bladder cancer patients is about 1.3years. LncRNAs, a type of non-coding RNAs defined as the transcripts exceeding 200 nucleotides in length, are frequently aberrant in multiple cancers including cervical, ovarian, breast and bladder cancers. Recently, LUCAT1 (short for lung cancer-associated transcript 1), a lncRNA first reported to be involved in smoking-related lung cancer, has been observed to exhibit crucial roles in the epithelial-to-mesenchymal transition (EMT), migration and invasion processes of clear cell renal cell carcinoma (ccRCC) and colorectal cancer. However, whether it involves in the pathogenesis of MIBC remains underexplored. In the present study, LUCAT1 was up-regulated in the serum samples of MIBC patients and bladder cancer cell lines, as assessed using real-time PCR. Our in vitro data (including wound healing and trans-well assays) showed that LUCAT1 was required for the proliferation, EMT, migration and invasion processes of T24 cells. Moreover, LUCAT1 directly targeted miR-199a-5p and miR-199b-5p, as affirmed using the luciferase reporter assay, and manipulation of LUCAT1 significantly suppressed miR-199a-5p and miR-199b-5p. Collectively, our findings highlight an axis of LUCAT1/miR-199a/b-5p in MIBC pathogenesis. Therefore, LUCAT1 may possibly be a promising candidate for diagnostic biomarker and therapeutic target of MIBC.

Prognostic Implications of Immunohistochemical Biomarkers in Non-muscle-invasive Blad Cancer and Muscle-invasive Bladder Cancer.

Urothelial carcinoma of the bladder (UCB) is a very heterogeneous disease and divided into invasive and non-invasive disease. In non-muscle-invasive bladder cancer (NMIBC), recurrence after transurethral resection or instillation-therapy, and progression to invasive disease are issues of concern. In muscle-invasive bladder cancer (MIBC), systemic recurrence after radical treatment is a pressing problem, as the available therapies in this setting are of limited efficacy. For both entities there are only few clinicopathological prognostic biomarkers to identify subgroups at risk to aid in decision making to whom to offer early radical cystectomy in case of NMIBC or neoadjuvant/adjuvant chemotherapy in case of MIBC to improve outcomes. Despite advances in surgery and intravesical therapy, up to 30% of NMIBC-patients suffer progression to MIBC. After cystectomy around 50% of MIBC patients suffer local or systemic recurrence and subsequently succumb to the disease. Standard features, like pathological staging and grading, are not sufficient to identify patients at risk beyond doubt. Recent advances in molecular diagnostics in combination with standard pathological features could be used to improve risk stratification of patients, guide treatment plans and ultimately improve outcomes. Immunohistochemical (IHC) analysis can detect altered regulatory pathway-products. Until now a plethora of prognostic IHC-biomarkers has been reported on in UCB, but only few have been validated and no biomarker is in routine use or recommended by guidelines. In this review we discuss the prognostic potential of the most promising IHC-biomarkers in NMIBC and MIBC with a focus on prognostication of recurrence and stage progression in NMIBC as well as recurrence-free, cancer-specific and overall survival in MIBC.

Upregulation of lncRNA plasmacytoma variant translocation 1 predicts poor prognosis in patients with muscle-invasive bladder cancer.

LncRNA plasmacytoma variant translocation 1 (PVT1) has been recognized as an oncogenic lncRNA, which participates in the migration and invasion of many kinds of cancer cells and the development of cancers. In the present study, we explored its clinical significance and prognostic value in muscle invasive bladder cancer (MIBC).A total of 98 MIBC patients’ samples were collected, who had undergone radical cystectomy from the March 2013 to December 2018. The associations between PVT1 expression and clinical data were calculated using the Chi2-test. Overall survival curves were determined by the Kaplan–Meier technique and contrasted via log-rank test. We utilized univariate and multivariate Cox proportional hazard models to examine the HR and 95% CI.The expression levels of PVT1 were significantly higher in MIBC tissues than that in normal bladder tissues (P < .001). PVT1 expression was significantly correlated with tumor grade (P = .009), margin (P = .002), T stage (P = .02), and lymph node metastasis (P < .001). MIBC patients with high PVT1 expression level had shorter overall survival than those with low PVT1 expression level (log-rank test, P = .004). Multivariate Cox regression analysis showed that PVT1 expression level (HR = 2.381, 95% CI: 1.821–7.012, P = .014) was an independent factor in predicting the overall survival of MIBC patients.In summary, increased PVT1 expression in MIBC patients is correlated with a higher MIBC stage and is significantly associated with poor prognosis for MIBC patients, which may provide new insights into new therapeutic strategy and postoperative intervention against bladder cancer.

Impact of preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on overall survival or recurrence free survival in muscle-invasive bladder cancer at cystectomy.

e17050 Background: The role of Neutrophil to Lymphocyte Ratio (NLR) and Platelet to Lymphocyte Ratio (PLR) in prognostication of MIBC is not clearly understood. There is growing evidence that, as markers of inflammation, they may have prognostic utility in MIBC at radical cystectomy (RC). Methods: We performed a retrospective analysis of MIBC patients who underwent RC at the Cleveland Clinic from 2/2015 to 1/2018. 84 patients were identified who were either diagnosed with TaN0M0 treated with Neoadjuvant Chemotherapy (NAC) or T1-T4N0M0 disease treated with or without NAC. For NAC, 27 patients received gemcitabine and cisplatin, 2 patients received gemcitabine and carboplatin, 4 patients received unknown regimen, and 3 patients received MVAC. Of the patients, there were 1 with Ta, 34 with T1, 44 with T2, 1 with T3 and 4 with T4 disease. Complete Blood Count with Differential closest to or on the day of resection was used. NLR and PLR were calculated by dividing Absolute Neutrophil Count and Platelet Count by the Absolute Lymphocyte Count, respectively. PLR and NLR were dichotomized at the median. Outcomes were analyzed via Kruskal-Wallis test. Results: Median follow up of patients was 28.8 months. Median NLR and PLR were 15.7 and 263, respectively. Mean NLR and PLR were 18.9 and 310, respectively. NLR and PLR did not correlate with overall survival, recurrence free survival, T or N stage post resection, or pathological response. Females were found to have a higher NLR than males. Conclusions: Contrary to previous reports, our study did not find any prognostic value of NLR and PLR in MIBC patients at RC. Further evaluation of PLR and NLR in MIBC and correlation with molecular features may help understand its potential prognostic role in patients undergoing surgical resection.

Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma

ABSTRACT Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1–17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

Etiology of Treatment Delays in Patients Receiving Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

BACKGROUND: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) improves overall survival in muscle-invasive bladder cancer (MIBC), but successful completion rates of NAC are low. A retrospective analysis was undertaken to determine the etiology of deviations of NAC administration for MIBC. METHODS: We performed a retrospective review of MIBC patients in an institutional database who received NAC followed by RC from 2008 to 2016. Patients were characterized as having completed NAC without deviation (“No Deviation”) or with deviation (“Deviation”). Factors associated with “Deviation” were assessed with logistic regression models. RESULTS: 172 MIBC patients received NAC followed by RC; 49 were excluded due to incomplete NAC data. Of the remaining 123 patients, 80 (65%) received Gemcitabine and Cisplatin (GC) and 25 (20%) received dose-dense MVAC (ddMVAC). In all, 85 (69%) patients had “Deviation” in planned NAC administration, while the remaining 38 (31%) patients had “No Deviation.” Twenty-six (33%) of GC patients experienced delays (mean = 21.5±17.0 days) and 6 (24%) ddMVAC patients experienced delays (mean = 10.5±9.5 days). Receipt of GC was associated with higher likelihood of “Deviation” in comparison to ddMVAC (OR = 15.4; 95% CI 4.43–53.72, p &lt; 0.01), and administration of NAC at our institution was associated with lower likelihood of “Deviation” in comparison to receipt in the community (OR = 0.25; 95% CI 0.25–0.72, p = 0.01). CONCLUSIONS: Deviations in administration of NAC were common in our cohort (69%) and were associated with receipt of GC and administration of NAC at an outside institution.

Amplification of 7p12 Is Associated with Pathologic Nonresponse to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P<0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P=0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3+ T cells/mm2 tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings.

Development and External Validation of a Novel 12-Gene Signature for Prediction of Overall Survival in Muscle-Invasive Bladder Cancer.

Purpose: We aimed to develop and validate a novel gene signature from published data and improve the prediction of survival in muscle-invasive bladder cancer (MIBC).Methods: We searched the published gene signatures associated with the overall survival (OS) of MIBC and compiled all 274 genes to develop a novel gene signature. RNAseq data of TCGA (the Cancer Genome Atlas) bladder cohort were downloaded. All genes were included in a univariate Cox hazard ratio model. We then used a reduced multivariate Cox regression model, which included only genes achieving P < 0.05 in the univariate model. A total of 172 patients at Fudan University Shanghai Cancer Center (FUSCC) and 61 patients from GEO datasets were used as an external validation set.Results: A total of 327 patients in the TCGA cohort were enrolled. We identified 274 genes from eight published papers on the OS of MIBC. Using the TCGA database, we identified 12 genes that correlated with OS (P < 0.05 in both univariate and multivariate analyses). By integrating these genes with the RT-qPCR data in our validation dataset and GEO datasets, we confirmed that the power for predicting OS of the 12-gene panel (AUC of 0.741 and 0.727, respectively) was higher than just clinical data (including gender, age, T stage, grade, and N stage) alone in the TCGA and FUSCC cohort (AUC of 0.667 and 0.631, respectively). Additionally, upon combining the clinical data and 12-gene panel together, the AUC increased to 0.768, 0.757, and 0.88 in the TCGA, FUSCC and GSE13507 cohorts, respectively.Conclusions: Applying published gene signatures and TCGA data, we successfully built and externally validated a novel 12-gene signature for the survival of MIBC.Brief ExplanationWe systemically reviewed all published prognostic gene signatures of muscle-invasive bladder cancer (MIBC) and integrated the genes in the TCGA MIBC cohort. This new gene panel was validated in a newly established MIBC cohort in GEO and FUSCC. This method can help update the previous established panels in a new way.