Invasive Bladder Carcinoma Research Articles

Percutaneous Ureteral Embolization to Manage Fistulous Bladder Cancer

An 85-year-old male who had an invasive urothelial carcinoma of the urinary bladder complicated by vesicocutaneous fistula, resulting in abscess formation. The patient was managed by percutaneous abscess drainage and ureteral embolization with permanent bilateral nephrostomy. Later, the abdominal drain was removed and the patient remained nephrostomy dependent for 5 months until he died.

Upregulation of Twist2 in Non-Muscle Invasive Urothelial Carcinoma of the Bladder Correlate with Response to Treatment and Progression.

BACKGROUND:Twist2 is a transcription factor and an epithelial-to-mesenchymal transition that plays an important role in cell polarity, cell adhesion, and has a role in tumour invasion and metastases.AIM:In this study, we examined the expression of Twist2 in non-muscle invasive bladder carcinoma (NMIBC) and correlated the expression with response to treatment and tumour progression.METHODS:Data of 305 patients with NMIBC of Ta, T1 were retrieved from hospitals archives. Twist2 expression was examined in tissue samples by immunohistochemistry at initial diagnosis and final follow-up, normal control was 10 normal urothelium, 10 patients with muscle-invasive bladder cancer (MIBC) were a positive control. Treatment of NMIBC was implemented according to the European Association of Urology guidelines on NMIBC. The descriptive statistical analysis included means, standard deviation, p-value; Univariate and multivariate Cox regression analyses.RESULTS:Twist2 expression score was identified as negative, low (1-15%); medium (15-40%); and high (40-100%). Patients who had low or low medium scores at the initial diagnosis had a good response and a favourable prognosis. Expression of a high score of Twist2 in patients having high-grade T1 tumours showed non-responsiveness to repeated courses of intravesical bacillus Calmette Guerin (BCG) therapy and was upstaged to MIBC.CONCLUSION:Twist2 expression in tissue samples of NMIBC would indicate the tumour response to therapy, upgrading and upstaging in the follow up after intravesical BCG therapy.

Diagnostic Value of Pre treatment Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Lymphocyte-to-Monocyte Ratio for Invasive Bladder Carcinoma

Diagnostic Value of Pre treatment Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Lymphocyte-to-Monocyte Ratio for Invasive Bladder Carcinoma

The Role of Vitamin D Receptor Polymorphisms in Predicting the Response to Therapy for Nonmuscle Invasive Bladder Carcinoma

Clinical and pathological predictors of bladder carcinoma recurrence and progression are relatively well defined. However, there is a paucity of genetic data specifically on the association of single nucleotide polymorphisms in specific genes for predicting recurrence and progression following immunotherapy. The VDR gene was found to regulate the immunomodulatory effects of vitamin D and it enhances the innate immunity system. We evaluated 3 VDR single nucleotide polymorphisms and their predictive role on the response to immunotherapy. Patients with bladder cancer at intermediate-high risk who underwent post-transurethral resection intravesical bacillus Calmette-Guérin in Singapore and Hong Kong from 1995 to 2014 were recruited for analysis. We evaluated 3 VDR single nucleotide polymorphisms using polymerase chain reaction. Kaplan-Meier survival curves and relationships with outcomes were analyzed by multivariable Cox regression. A total of 338 predominantly Chinese patients were included in study. Individuals carrying the VDR genotype Bsm A/G were significantly associated with lower time to recurrence after bacillus Calmette-Guérin therapy (p <0.001). On multivariable analysis the HR of recurrence in patients with the Bsm A allele was 3.95 times that in patients without the allele (p = 0.037). Patients with the VDR GATC subhaplotype were 3.05 times more likely than patients with other subhaplotypes to experience recurrences (p = 0.003). Study limitations include the small sample size and the lack of information on previous bacillus Calmette-Guérin vaccine exposure and on vitamin D levels. Our findings in this study suggest that various VDR singlenucleotide polymorphisms are associated with recurrences after bacillus Calmette-Guérin immunotherapy. Further functional studies should be performed to elucidate the significance of the VDR gene in the management of bladder cancer and the potential therapy implications.

A glance at imaging bladder cancer.

Early and accurate diagnosis of Bladder cancer (BCa) will contribute extensively to the management of the disease. The purpose of this review was to briefly describe the conventional imaging methods and other novel imaging modalities used for early detection of BCa and outline their pros and cons. Literature search was performed on Pubmed, PMC, and Google scholar for the period of January 2014 to February 2018 and using such words as "bladder cancer, bladder tumor, bladder cancer detection, diagnosis and imaging". A total of 81 published papers were retrieved and are included in the review. For patients with hematuria and suspected of BCa, cystoscopy and CT are most commonly recommended. Ultrasonography, MRI, PET/CT using 18F-FDG or 11C-choline and recently PET/MRI using 18F-FDG also play a prominent role in detection of BCa. For initial diagnosis of BCa, cystoscopy is generally performed. However, cystoscopy can not accurately detect carcinoma insitu (CIS) and can not distinguish benign masses from malignant lesions. CT is used in two modes, CT and computed tomographic urography (CTU), both for dignosis and staging of BCa. However, they cannot differentiate T1 and T2 BCa. MRI is performed to diagnose invasive BCa and can differentiate muscle invasive bladder carcinoma (MIBC) from non-muscle invasive bladder carcinoma (NMIBC). However, CT and MRI have low sensitivity for nodal staging. For nodal staging PET/CT is preferred. PET/MRI provides better differentiation of normal and pathologic structures as compared with PET/CT. Nonetheless none of the approaches can address all issues related for the management of BCa. Novel imaging methods that target specific biomarkers, image BCa early and accurately, and stage the disease are warranted.

Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq

BackgroundInvasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC.MethodsTotal RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks.ResultsDifferential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E2 receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property.ConclusionsOur data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC.

Monopolar vs. bipolar transurethral resection for non–muscle invasive bladder carcinoma: A post-hoc analysis from a randomized controlled trial

PurposeTraditionally, transurethral resection of bladder tumors (TURB) is performed using monopolar technique. Bipolar resection has been postulated to reduce complications. In this study we compare safety and efficacy between monopolar TURB (mTURB) and bipolar TURB (bTURB) for patients with primary non-muscle invasive bladder cancer (NMIBC). Materials and methodsData were obtained from an international multicenter randomized clinical trial that compared the use of white light cystoscopy with narrow band imaging-assisted TURB using the Olympus system between 2010 and 2014. Main outcomes of interest were operative time, perioperative, and postoperative complications, and 12-month recurrence-free survival. ResultsIn total, 716 patients were treated for primary NMIBC with mTURB (310 patients) or bTURB (406 patients). The use of white light cystoscopy or narrow band imaging was equally distributed between the 2 resection techniques. Multilevel logistic and linear regression corrected for possible confounders showed no significant difference between mTURB and bTURB for postoperative complications (OR = 1.76, P = 0.180), postoperative bleeding (OR = 1.27, P = 0.722), and the combination of intra + postoperative bleeding (OR = 1.992, P = 0.108). Additionally, no significant difference was found between mTURB and bTURB concerning operative time (1.05min. longer for bTURB, P = 0.536), intraoperative bleeding requiring intervention (OR:1.38, P=0.809), incidence of obturator reflex (OR = 0.93, P = 0.854), and bladder perforation (OR = 3.05, P = 0.195). In total, 185 patients (25.8%) developed a recurrence (mTURB = 88, bTURB = 97). Recurrence-free survival at 12 months in the mTURB and bTURB group was 70% and 74% (P = 0.410), respectively. ConclusionBased on these results, bTURB is as safe and effective as mTURB in treatment of primary NMIBC. bTURB seems to have no evident advantages over mTURB with respect to operation time, perioperative and postoperative complication rates, and recurrence rates at 12 months.

Bladder cancer survival: Women better off in the long run

AimMortality among patients with bladder cancer is usually reported to be higher for women than men, but how the risk differs and why remain largely unexplained. We also described gender-specific differences in survival for patients with bladder cancer and estimated to what extent they can be explained by differences in T-stage distribution at the first diagnosis. MethodsThe present study comprised all 15,129 new cases of histologically verified invasive and non-invasive urothelial carcinoma of the urinary bladder diagnosed between 1997 and 2011 as registered in the Cancer Registry of Norway. Gender-specific excess mortality risk rates and risk ratios were calculated based on a flexible parametric relative survival model adjusting for T-stage and age, allowing the effect of gender to vary over time. We also present gender-specific relative survival curves for different T-stage patterns adjusted for age. ResultsRisk rates were significantly higher for women than men up to 2 years after bladder cancer diagnosis, particularly for muscle-invasive cancers. Thereafter, risk rates appeared to be higher in men. Adverse T-Stage distribution in women explained half of the unfavourable survival difference in female patients 2 years after diagnosis. ConclusionThe common view of worse bladder cancer prognosis in women than in men needs to be revised. Norwegian women have a less favourable prognosis solely within the first 2 years after diagnosis, particularly when diagnosed with a muscle-invasive tumour; parts of this discrepancy can be attributed to more severe initial diagnoses in women.

PD66-10 IDENTIFYING POLYMORPHISMS THAT MODULATE RESPONSE TO BACILLUS CALMETTE-GUERIN THERAPY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CARCINOMA

You have accessJournal of UrologyBladder Cancer: Non-invasive III1 Apr 2018PD66-10 IDENTIFYING POLYMORPHISMS THAT MODULATE RESPONSE TO BACILLUS CALMETTE-GUERIN THERAPY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CARCINOMA Ziting Wang, Jen-Hwei Sng, Yew Koon Lim, Esuvaranathan Kesavan, Ratha Mahendran, Lata Raman Nee Mani, Yiong Huak Chan, Jeremy Yuen Chun Yeoh, Chi Fai Ng, Shu Yin Eddie Chan, and Edmund Chiong Ziting WangZiting Wang More articles by this author , Jen-Hwei SngJen-Hwei Sng More articles by this author , Yew Koon LimYew Koon Lim More articles by this author , Esuvaranathan KesavanEsuvaranathan Kesavan More articles by this author , Ratha MahendranRatha Mahendran More articles by this author , Lata Raman Nee ManiLata Raman Nee Mani More articles by this author , Yiong Huak ChanYiong Huak Chan More articles by this author , Jeremy Yuen Chun YeohJeremy Yuen Chun Yeoh More articles by this author , Chi Fai NgChi Fai Ng More articles by this author , Shu Yin Eddie ChanShu Yin Eddie Chan More articles by this author , and Edmund ChiongEdmund Chiong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.3006AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bacillus Calmette-Guerin (BCG) immunotherapy has a considerable failure rate. Various centres have found associations between polymorphisms in genes involved in the immune inflammatory pathways and treatment outcomes. We evaluated a panel of polymorphisms in a prospectively maintained cohort of Asian non-muscle invasive bladder carcinoma (NMIBC) patients. MicroArray analysis was also performed to assess candidate variants and their association with BCG immunotherapy response. METHODS 218 NMIBC patients that had received BCG therapy and 200 normal controls from the Chinese University of Hong Kong and National University Hospital of Singapore were recruited for the study. Single Nucleotide Polymorphisms (SNP) were classified by High Resolution Melting analysis and Sequence analysis. 18 SNPs from the Natural Resistance-Associated Macrophage Protein1 (NRAMP1)gene and 8 SNPs from the immune response gene family were evaluated. Kaplan-Meier together with Log-Rank test and Cox regression methods were used to analyse the data. Illumina Infinium OncoArray-500K BeadChip MicroArray were then used to interrogate 12 BCG responders and 12 non-responders (6 recurrences and 6 progressions). RESULTS Polymorphism genotype distributions were similar between controls and patients, in accordance to the Hardy-Weinberg equilibrium. NRAMP1 rs34448891 Allele 3/3 were associated with increased incidence of cancer progression (p=0.014) compared to Allele 3/2. Patients carrying the Interleukin 17A rs2275913 G/A and G/G genotype were also found to have shorter time to recurrence (p=0.004). The Interleukin 18 receptor 1 rs3771171 A/A genotype was associated with shorter time to recurrence (p=0.04) and time to progression (p=0.043). The MicroArray Analysis revealed that rs8125878 (GA) of chromosome 20 and rs6569926 (AG) of chromosome 6 both carried prognostication value, with all responders having a homozygous genotype and all non-responders having a heterozygous genotype. CONCLUSIONS Our findings show that specific polymorphisms in NRAMP1, IL17A and IL18R1 correlate with response to BCG therapy in Asian NMIBC patients. Further functional studies should be performed to elucidate the significance of these genes in the management of bladder cancer and potential therapy implications. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1234 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Ziting Wang More articles by this author Jen-Hwei Sng More articles by this author Yew Koon Lim More articles by this author Esuvaranathan Kesavan More articles by this author Ratha Mahendran More articles by this author Lata Raman Nee Mani More articles by this author Yiong Huak Chan More articles by this author Jeremy Yuen Chun Yeoh More articles by this author Chi Fai Ng More articles by this author Shu Yin Eddie Chan More articles by this author Edmund Chiong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Snail immunohistochemical overexpression correlates to recurrence risk in non-muscle invasive bladder cancer: results from a longitudinal cohort study.

The current WHO/ISUP classification and grading system subdivides urothelial tumours into prognostically distinct categories. Understanding the molecular pathways involved in bladder cancer development can improve patient stratification and management. This study aims to investigate the relationship between Snail, Slug and E-cadherin expressions and clinico-pathological features of non-muscle invasive bladder carcinoma (NMIBC). All patients attending the same urological centre from January to May 2002, who were pathologically diagnosed with NMIBC, were enrolled in this longitudinal cohort study. E-cadherin, Snail and Slug protein expressions were assessed by immunohistochemical analysis and compared with follow-up data. The main outcome measures were recurrence and progression rates. The cohort under investigation included 43 patients (38 men and 5 women, mean age 67.7 ± 10.6years). High-grade (HG) carcinomas were 20/43, with 10 invasive cases (pT1). Low-grade (LG) carcinomas were 23/43, with no invasive cases (pTa). Among the eight HGpTa cases with recurrence, strong Snail expression was detected in six (75%). Out of the 17 LGpTa patients who experienced recurrence, 12 (70.6%) showed strong positivity for Snail. Among the 10 HGpT1 cases, recurrence was observed in 4, of which, 3 (75%) stained intensely for Snail. The Kaplan-Meier curves showed significantly different recurrence rates for patients with strong or weak Snail reactivity (p = 0.027). E-cadherin and Slug expression did not correlate with any of the parameters considered. On multivariate analysis, Snail expression was recognised as an independent prognostic factor for tumour recurrence (p = 0.003). In our study population, Snail immunohistochemical overexpression proved to be related to tumour recurrence in patients affected by NMIBC.

Evaluation of the relationship between compliance with the follow-up and treatment protocol and health literacy in bladder tumor patients

Objective: To investigate the relationship between the compliance of bladder cancer patients with cystoscopic follow-up and the treatment protocol, and their health literacy.Methods: Patients who underwent transurethral resection surgery for bladder tumor were found to have non-muscular invasive bladder carcinoma on pathology examination and then underwent cystoscopic follow-up for 1 year or more were included in the study. Cystoscopic follow-up was recommended to the low- and high-risk groups in terms of progression and recurrence. The patients were evaluated with the Health Literacy Survey-European Union scale.Results: The mean age of the patients was 67.13 ± 10.77 years. The treatment continuity rate was 80.50% (n = 33) in the adequate health literacy group (n = 41) and significantly higher than the 56.50% (n = 48) rate in the inadequate health literacy group (n = 85) (p = .008). The health literacy results revealed that the health promotion and general index score was higher in the group of patients under the age of 65.Conclusions: Adequate health literacy in bladder cancer patients is associated with better compliance with the treatment protocol. Young patients show better compliance with the follow-up protocol recommended by the physician. Increasing the follow-up protocol compliance of elderly patients with inadequate health literacy is necessary.

Robot-assisted laparoscopic radical cystectomy with extracorporeal urinary diversion: Initial experience and outcomes.

Introduction:Open radical cystectomy (ORC) is the most common surgical approach for invasive carcinoma of the urinary bladder, but robot-assisted radical cystectomy (RARC) has recently gained popularity. There is limited data from the Indian subcontinent on RARC. The aim of this study was to assess the perioperative, pathological, and oncological outcomes of RARC and follow-up in our initial 63 cases.Materials and Methods:A retrospective analysis of prospectively maintained data of 63 RARC procedures performed in our tertiary care institute from July 2006 to January 2016 was done. All patients underwent RARC with extracorporeal urinary diversion. We analyzed perioperative parameters, length of hospital stay, pathological and oncological outcomes, and rate of complications. Follow-up data were analyzed for disease recurrence and survival.Results:The mean age of the patients was 58 years. The mean American Society of Anesthesiologists (ASA) score was 1.66. Mean operative time was 348.6 min and mean blood loss was 868.2 ml. Mean hospital stay was 10.4 days (±5.4 days). 42.8% patients had pT2 disease, 49.2% pT3, 1.58% pT1, and 6.34% had pT4 disease. Mean lymph node yield was 12.4 (3-25). One patient had positive surgical margins. Twenty-four patients had postoperative complications of which four were major complications (Clavien-Dindo 3 or higher). At a median follow-up of 60 months (range: 3–108 months), 11 patients were lost to follow-up 10 patients developed metastasis, out of which 4 died. Four had recurrence, two died and two are receiving chemotherapy.Conclusion:This study shows the feasibility and safety of RARC. The operative time, blood loss, return of bowel activity and hospital stay were higher than those reported in the literature but may reflect the learning curve.

The Endless Debate Concerning the Timing of Chemotherapy in Muscle Invasive Bladder Carcinoma: Before or After the Radical Cystectomy?

The Endless Debate Concerning the Timing of Chemotherapy in Muscle Invasive Bladder Carcinoma: Before or After the Radical Cystectomy?

94P - The role of vitamin D receptor polymorphisms in predicting response to therapy in non-muscle invasive bladder carcinoma

94P - The role of vitamin D receptor polymorphisms in predicting response to therapy in non-muscle invasive bladder carcinoma

Impact of squamous and/or glandular differentiation on recurrence and progression following transurethral resection for non-muscle invasive urothelial carcinoma of bladder.

The aim of the present study was to investigate the impact of squamous and/or glandular differentiation on the recurrence and progression in patients with nonmuscle invasive urothelial carcinoma of bladder (NMIUCB) following transurethral resection (TURBT). A total of 869 patients with NMIUCB who had been treated with TURBT at The Second Hospital of Tianjin Medical University (Tianjin, China) between January 2006 and January 2011 were retrospectively selected for the present analysis. Associations among squamous and/or glandular differentiation with other clinical and pathological features were assessed by the χ2 test. Recurrence-free survival (RFS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed through a Cox's proportional hazards regression model. Among the 869 patients, 232 (26.7%) patients had squamous and/or glandular differentiation. High grade tumors were more common in patients with squamous and/or glandular differentiation compared with those with pure urothelial carcinoma of bladder (P<0.001). Associations between age (P=0.115), sex (P=0.184), tumor size (P=0.223), tumor multiplicity (P=0.108), pathological tumor stage (P=0.909) and squamous and/or glandular differentiation were not observed to be statistically significant. There was a significant tendency towards higher recurrence rate and shorter RFS time in patients with squamous and/or glandular differentiation. However, no statistically significant differences were observed in progression rate and PFS between the two groups. The multivariate Cox regression analysis, identified squamous and/or glandular differentiation as an independent prognostic predictor of recurrence (hazard ratio =1.46, 95% confidence interval=1.10–1.92, P=0.008). In the present study, the presence of squamous and/or glandular differentiation was associated with a higher recurrence rate and shorter RFS time in patients with NMIUCB. Squamous and/or glandular differentiation is therefore an independent prognostic predictor of recurrence.

Factors Impacting the Overall Survival of Patients Irradiated for Invasive Carcinoma of the Urinary Bladder.

To contribute to personalisation of treatment for patients with carcinoma of the urinary bladder, 11 factors were analyzed for survival. Data from 61 patients receiving definitive irradiation for carcinoma of the urinary bladder were retrospectively evaluated, namely gender, age, T-stage, N-stage, grading, pack years, smoking during irradiation, upfront transurethral resection of the bladder tumour (TURBT), equivalent dose in 2-Gy fractions (EQD2), chemotherapy and Karnofsky performance score (KPS). On univariate analysis, female gender (p=0.007), <40 pack years (p=0.029), not smoking during irradiation (p=0.037), TURBT (p=0.007) and KPS >70 (p<0.001) led to improved survival; EQD2 >55 Gy showed a trend (p=0.065) for such association. On Cox regression, gender [risk ratio (RR)=2.81; p=0.039], TURBT (RR=4.44; p=0.033) and KPS (RR=3.45; p=0.018) remained significant. This study identified independent predictors of survival in patients irradiated for carcinoma of the urinary bladder and contributes to creation of personalised treatment programs.

Asymptomatic microscopic hematuria as a predictor of neoplasia in the urinary tract

Objective: The Danish hematuria guidelines were revised in January 2016. Before revision, it was recommended that asymptomatic microscopic hematuria in patients more than 40 years old should be routinely urologically investigated. In the revised guidelines, patients with asymptomatic microscopic hematuria are not recommended to be investigated, irrespective of age. The purpose of this study was to investigate whether asymptomatic microscopic hematuria was predictive of neoplasia of the urinary tract in a referred cohort of patients.Methods: All patients older than 40 years referred from primary care to private clinics and public hospitals in the Central Denmark Region for evaluation of asymptomatic microscopic hematuria in a 2 year period from January 2014 to December 2015 were included retrospectively. All patients had been routinely investigated with computed tomography urography and outpatient flexible cystoscopy. Patients’ age and gender were recorded and the final diagnosis after full investigation was retrieved.Results: In total, 1305 patients (492 males and 813 females) were included. Eleven patients (0.8%) were diagnosed with neoplasia in the urinary tract, including non-invasive Ta bladder tumor (n = 6), benign tumors in the kidney (n = 2), invasive bladder cancer (n = 2) and carcinoma in situ in the urinary bladder (n = 1). None of the patients had renal cancer or upper urinary tract tumors as the final diagnosis.Conclusion: A minority of patients with malignancies or non-invasive tumors would have been missed based on the revised Danish hematuria referral pathways.

Effects of Treatment on Angiogenic (Vascular Endothelial Growth Factor-2 and Matrix Metalloproteinase-2) and Antiangiogenic (Endostatin and Thrombospondin-1) Factors in Non-muscle Invasive Bladder Carcinoma

Effects of Treatment on Angiogenic (Vascular Endothelial Growth Factor-2 and Matrix Metalloproteinase-2) and Antiangiogenic (Endostatin and Thrombospondin-1) Factors in Non-muscle Invasive Bladder Carcinoma

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.

Differential Expression of PD-L1 in High Grade T1 vs Muscle Invasive Bladder Carcinoma and its Prognostic Implications

PD-L1 is expressed on tumor cells and tumor immune cell infiltrates. In metastatic bladder cancer increased tumor immune cell infiltrate PD-L1 positivity correlated with better overall survival. However, to our knowledge in highgrade T1 bladder tumors positivity on tumor cells and tumor immune cell infiltrates, and correlation with outcomes or pathological features remain unknown. Formalin fixed, paraffin embedded tumor samples from 140 patients with clinically annotated, high grade T1 bladder tumors were retrieved. All patients were initially diagnosed with high grade T1 bladder tumors by transurethral resection, subsequently received bacillus Calmette-Guérin and had a median followup of 7.4 years. PD-L1 positivity on initial transurethral resection was evaluated by immunohistochemistry using a mouse monoclonal antiPD-L1 antibody (405.9A11). Tumor cell PD-L1 positivity was defined as staining of 5% of the tumor cell membrane. Tumor immune cell infiltrate PD-L1 positivity was scored based on the extent of infiltrate and the percent of positive cells. The Fisher exact test was used to assess associations of PD-L1 positivity with disease outcomes, carcinoma in situ presence and the difference between high grade T1 bladder tumors and muscle invasive bladder cancer. Among 140 patients with high grade T1 bladder tumors tumor cells and tumor immune cell infiltrate PD-L1 positivity was seen in 6 (4%) and 48 (34.3%), respectively. In a subset of 106 patients with adequate followup PD-L1 positivity did not correlate with disease outcomes on tumor cells (p = 0.3) or on tumor immune cell infiltrates (p = 0.47). PD-L1 positivity also did not correlate with the presence of carcinoma in situ. Tumor cell PD-L1 positivity was significantly less in high grade T1 bladder tumors than in muscle invasive bladder cancer (p <0.001). PD-L1 is widely expressed on tumor immune cell infiltrates but not on tumor cells in high grade T1 bladder tumors. We did not find a correlation between PD-L1 positivity and outcomes or carcinoma in situ presence. Tumor cell PD-L1 positivity is significantly lower in high grade T1 bladder tumors than in muscle invasive bladder cancer.