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Fulltext Reiter's syndrome postintravesical Bacillus Calmette-Guérin instillations

Ng KL, Chua CB

Asian J Surg, 2017 Apr;40(2):163-165.
PMID: 25183290 DOI: 10.1016/j.asjsur.2014.01.016

Intravesical Bacillus Calmette-Guérin (BCG) has been a proven and effective immunotherapy treatment for superficial transitional cell carcinoma (TCC) of the bladder, especially for high-grade tumors and carcinoma in situ. Nevertheless, significant side effects are associated with BCG instillations, including fever, myalgia, malaise, dysuria, hematuria, and irritable lower urinary tract symptoms. We herein report the case of a patient who developed Reiter's syndrome following intravesical BCG instillations. A 39-year-old Chinese man presented with a 3-week history of dysuria, suprapubic pain, and pain at the tip of the penis postmicturition. Initial investigations revealed that he had microhematuria, and an ultrasound with computed tomography scan of the abdomen showed a bladder mass. Transurethral resection of the bladder tumor was performed and the patient received a single dose of intravesical mitomycin postoperatively. Results of histopathological examination revealed high-grade bladder TCC (G3pT1), and the patient was managed with intravesical BCG for 2 weeks following the surgery. Four weekly cycles of BCG were administered uneventfully; however, before the fifth instillation, the patient complained of urethral discharge, bilateral conjunctivitis, and low back pain. Reiter's syndrome was diagnosed as a rare but known complication of BCG instillation and the BCG immunotherapy was withheld. The patient was treated with nonsteroidal antiinflammatory drugs (for back pain) and eye ointment (for conjunctivitis) and his condition improved. This case report of Reiter's syndrome should be highlighted as a rare but significant complication of BCG immunotherapy and urologists should have a high index of suspicion to diagnose this rare complication.

Matched MeSH terms: Urinary Bladder Neoplasms/drug therapy*; Urinary Bladder Neoplasms/pathology; Urinary Bladder Neoplasms/surgery
Fulltext o-Vanillin Derived Schiff Bases and Their Organotin(IV) Compounds: Synthesis, Structural Characterisation, In-Silico Studies and Cytotoxicity

Yusof ENM, Latif MAM, Tahir MIM, Sakoff JA, Simone MI, Page AJ, et al.

Int J Mol Sci, 2019 Feb 15;20(4).
PMID: 30781445 DOI: 10.3390/ijms20040854

Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph₂SnCl₂ or Me₂SnCl₂ with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R₂Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me₂Sn(S2MoVa), Me₂Sn(S4MoVa) and Me₂Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C₂NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext Comparing CxBladder to Urine Cytology as Adjunct to Cystoscopy in Surveillance of Non-muscle Invasive Bladder Cancer-A Pilot Study

Chai CA, Yeoh WS, Rajandram R, Aung KP, Ong TA, Kuppusamy S, et al.

Front Surg, 2021;8:659292.
PMID: 34055868 DOI: 10.3389/fsurg.2021.659292

Purpose: Guidelines advocate cystoscopy surveillance (CS) for non-muscle invasive bladder cancer (NMIBC) post-resection. However, cystoscopy is operator dependent and may miss upper tract lesions or carcinoma in-situ (CIS). Urine cytology is a common adjunct but lacks sensitivity and specificity in detecting recurrence. A new mRNA biomarker (CxBladder) was compared with urine cytology as an adjunct to cystoscopy in detecting a positive cystoscopy findings during surveillance cystoscopy in our center. Materials and Methods: Consented patients older than 18, undergoing CS for NMIBC, provide paired urine samples for cytology and CxBladder test. Patients with positive cystoscopy findings would undergo re-Trans Urethral Resection of Bladder Tumor (TURBT). Results: Thirty-five patients were enrolled from April to June 2019. Seven contaminated urine samples were excluded. The remaining cohort of 23 (82%) and 5 (18%) females had a mean age of 66.69 (36-89). Eight (29%) patients with positive cystoscopy finding underwent TURBT. All 8 patients also had positive CxBladder result. This shows that CxBladder has a sensitivity and negative predictive value (NPV) of 100%, specificity of 75% and positive predictive value (PPV) of 62% in predicting a positive cystoscopy finding. TURBT Histo-pathological findings showed Low-grade Ta NMIBC in one patient (4%), and 7 (25%) patients had inflammatory changes. Urine cytology was only positive in one patient with a positive cystoscopy finding. This led to a sensitivity of merely 13% and NPV of 74%, while specificity and PPV was 100% in predicting a positive cystoscopy finding. Conclusion: CxBladder had high NPV and sensitivity which accurately predicted suspicious cystoscopy findings leading to further investigation. It has great potential for use as adjunct to cystoscopy for surveillance of NMIBC.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext Validation of oligonucleotide microarray gene expression profiles by real-time PCR using SYBR-Green 1 fluorescence

Nik Norliza Nik Hassan, Rozita Rosli, Abdul Munir Abdul Murad, Nor Kaslina Kornain, Sabariah, A.R., Rohan Malek Johan, et al.

Buletin Persatuan Genetik Malaysia, 2008;14(1):1-16.
MyJurnal

DNA microarray technology has permitted large scale parallel analysis of gene expression of several diseases, including cancers. Real-time PCR has become a well-established procedure for
quantifying levels of gene expression. We evaluated Real-Time PCR to validate differentially expressed genes identified by DNA arrays. Gene expression of three different grade of transitional cell carcinoma (TCC) of human bladder cancer was determined using microarray slide containing cancer-related genes. Data obtained were sorted according based on the ratios between Cy3 and Cy5 dyes used and revealed 119, 235 and 183 differentially expressed genes in TCC WHO Grades I, II and III, respectively. Real-time PCR used SYBR Green-1 dye detection to validate relative change in gene expression. Real- Time PCR confirmed the change in gene expression of 17 of 28 (75%) genes identified by microarray. Real-Time PCR also suggest that genes identified by microarray with two or higher fold change cannot be eliminated as false nor be accepted as true without validation. Real-Time PCR based on SYBR Green- 1 is well-suited to validate DNA array results because it is quantitative, rapid and requires less RNA compared to the conventional assays.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

Foth M, Ismail NFB, Kung JSC, Tomlinson D, Knowles MA, Eriksson P, et al.

J Pathol, 2018 Nov;246(3):331-343.
PMID: 30043421 DOI: 10.1002/path.5143

Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext Radiation dose enhancement effects of superparamagnetic iron oxide nanoparticles to the t24 bladder cancer cell lines irradiated with megavoltage photon beam radiotherapy

Rosmazihana Mat Lazim, Raizulnasuha Ab Rashid, Wan Nordiana Rahman, Binh. T.T. Pham, Brian S. Hawkett, Moshi Geso

Jurnal Sains Nuklear Malaysia, 2018;30(2):30-38.
MyJurnal

Therapeutic application of metallic nanoparticles such as gold nanoparticles have been extensively investigated and intriguing finding have been reported. Superparamagnetic iron oxide nanoparticles (SPION) could also potentially have therapeutic properties that can be exploited to enhance radiotherapy outcome. In this study, investigations on the dose enhancement effects inflicted by SPIONs under irradiation with megavoltage photon beam radiotherapy were conducted. T24 human bladder cancer cell lines were pretreated with 1 mMol/L of SPION and irradiated with 6 MV and 10 MV photon beam at different doses.The non-treated cells irradiation was used as a control. Clonogenic assay was performed to determine the cell survival. Linear quadratic (LQ) model are used as fitting curve and does enhancement factors (DEF) were extrapolated from the curves. The cytotoxicity indicated cell growth normally after 72 hours and no long term cytotoxicity effects of SPIONs towards the cells were observed. The dose enhancement effects were observed for both 6 MV and 10 MV photon beam with DEF obtained 1.71 and 2.50, respectively. This reduction of cell colonies growth could be resulted from the interaction that induced free radical and reactive oxygen species (ROS) by megavoltage photon beams. The SPIONs were therefore act as multifunction nanoparticle both in diagnostic agent and radiotherapy as radiation dose enhancer, thus clearly qualified as future theranostic agents.

Matched MeSH terms: Urinary Bladder Neoplasms
Systematic Review and Meta-Analysis on the Impact of Hexaminolevulinate- Versus White-Light Guided Transurethral Bladder Tumor Resection on Progression in Non-Muscle Invasive Bladder Cancer

Gakis G, Fahmy O

Bladder Cancer, 2016 Jul 27;2(3):293-300.
PMID: 27500197

Introduction: Although there is evidence that hexaminolevulinate (HAL)-based transurethral bladder tumor resection (TURBT) improves the detection of Ta-T1 non-muscle-invasive bladder cancer (NMIBC) as well as carcinoma in situ there is uncertainty about its beneficial effects on progression. Material and Methods: A systematic literature search was conducted according to the PRISMA statement to identify studies reporting on HAL- vs. white-light (WL-) based TUR-BT in non-muscle invasive bladder cancer between 2000 and 2016. A two-stage selection process was utilized to determine eligible studies. Of a total of 294 studies, 5 (4 randomized and one retrospective) were considered for final analysis. The primary objective was the rate of progression. Results: The median follow-up for patients treated with HAL- and WL-TURBT was 27.6 (1-55.1) and 28.9 (1-53) months, respectively. Of a total of 1301 patients, 644 underwent HAL- and 657 WL-based TURBT. Progression was reported in 44 of 644 patients (6.8%) with HAL- and 70 of 657 patients (10.7%) with WL-TURBT, respectively (median odds ratio: 1.64, 1.10-2.45 for HAL vs. WL; p = 0.01). Data on progression-free survival was reported in a single study with a trend towards improved survival for patients treated with HAL-TURBT (p = 0.05). Conclusions: In this meta-analysis the rate of progression was significantly lower in patients treated with HAL- vs. WL-based TURBT. These results support the initiation of randomized trials on HAL with progression as primary endpoint.

Matched MeSH terms: Urinary Bladder Neoplasms
The current status of checkpoint inhibitors in metastatic bladder cancer

Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G

Clin Exp Metastasis, 2016 Oct;33(7):629-35.
PMID: 27380916 DOI: 10.1007/s10585-016-9807-9

For many decades, no significant improvements could be achieved to prolong the survival in metastatic bladder cancer. Recently, systemic immunotherapy with checkpoint inhibitors (anti-PD-L1/anti-CTLA-4) has been introduced as a novel treatment modality for patients with metastatic bladder cancer. We conducted a systematic review according to the PRISMA statement for data published on the clinical efficacy of checkpoint inhibitors in metastatic bladder cancer. Clinical efficacy of anti PD-L1 therapy was investigated in prospective trials in a total of 155 patients. Patients with positive expression for PD-L1 tended towards better overall response rates (ORR) compared to those with negative expression (34/76 vs 10/73, 45 vs 14 %; p = 0.21). Among patients with PD-L1 positive tumors, those with non-visceral metastases exhibited significantly higher ORR compared to those with visceral metastases (82 vs 28 %; p = 0.001). For anti-CTLA4 therapy, there were no data retrievable on clinical efficacy. Although data on clinical efficacy of checkpoint inhibitors in metastatic bladder cancer are currently limited, the efficacy of these drugs might depend mainly on the metastatic volume and immune system integrity. Patients with PD-L1 positive tumors and non-visceral metastases seem to derive the highest benefit from therapy.

Matched MeSH terms: Urinary Bladder Neoplasms/drug therapy*; Urinary Bladder Neoplasms/genetics; Urinary Bladder Neoplasms/pathology
Fulltext Tumoral cystitis in children

Zulfiqar MA, Zaleha AM, Zulkifli I, Chia WY, Samad SA

Med J Malaysia, 1998 Sep;53(3):284-7.
PMID: 10968168

Three children aged 3-11 years had ultrasonography of the urinary tract for the investigation of dysuria and haematuria. A bladder mass was seen in these 3 children. One child had computed tomography scan, cystoscopy and bladder biopsy because rhabdomyosarcoma was considered. The biopsy revealed an inflammatory process. The urine culture of the other 2 children revealed E. coli. On ultrasonography, the inflammatory mass may appear homogeneously hypoechoic or may contain moderate level echoes. The mucosal surface of the mass may be smooth or lobulated. It is important to consider an infective cause for a bladder mass in children because computed tomography, cystoscopy and biopsy may be avoided.

Matched MeSH terms: Urinary Bladder Neoplasms/ultrasonography*
Fulltext Evaluation of CERS2 Gene as a Potential Biomarker for Bladder Cancer

Aldoghachi AF, Baharudin A, Ahmad U, Chan SC, Ong TA, Yunus R, et al.

Dis Markers, 2019;2019:3875147.
PMID: 31636736 DOI: 10.1155/2019/3875147

The ceramide synthase 2 (CERS2) gene has been linked to tumour recurrence and invasion in many different types of cancers including bladder cancer. In this study, the expression levels of CERS2 in bladder cancer cell lines were analysed using qRT-PCR and the protein expression in clinical bladder cancer histopathological specimens were examined via immunohistochemistry. The potential utility of CERS2 as a predictive biomarker of response to oncolytic virotherapy was assessed by correlating the CERS2 mRNA expression to IC50 values of cells treated with the Newcastle disease virus (NDV), AF2240 strain. This study demonstrates that CERS2 is differentially expressed in different types of bladder cancer cell lines and that the siRNA-mediated downregulation of the expression of CERS2 reduces the migratory potential of UMUC1 bladder cancer cells. However, there were no significant correlations between the expression levels of the CERS2 protein with bladder cancer grade/stage or between the IC50 values of cells treated with NDV and CERS2 expression. Although the utility of CERS2 expression may be limited, its potential as an antimigration cancer therapeutic should be further examined.

Matched MeSH terms: Urinary Bladder Neoplasms/metabolism*
Clinicopathological Features and Prognostic Value of Incidental Prostatic Adenocarcinoma in Radical Cystoprostatectomy Specimens: A Systematic Review and Meta-Analysis of 13,140 Patients

Fahmy O, Khairul-Asri MG, Schubert T, Renninger M, Stenzl A, Gakis G

J Urol, 2017 02;197(2):385-390.
PMID: 27569436 DOI: 10.1016/j.juro.2016.08.088

PURPOSE: There is controversy in the literature about the oncologic significance of incidental prostate cancer detected at radical cystoprostatectomy for bladder cancer.
MATERIALS AND METHODS: An online search was done for studies reporting incidental prostate cancer in cystoprostatectomy specimens. After following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines we identified a total of 34 reports containing 13,140 patients who underwent radical cystoprostatectomy for bladder cancer with no previous history of prostate cancer. A cumulative analysis was performed on the available data regarding prevalence, clinicopathological features and oncologic outcomes. RevMan, version 5.3 was used for data meta-analysis.
RESULTS: Of the 13,140 patients incidental prostate cancer was detected in 3,335 (24.4%). Incidental prostate cancer was significantly associated with greater age (Z = 3.81, p = 0.0001, d = 0.27, 95% CI -0.14-0.68), lymphovascular invasion of bladder cancer (Z = 2.07, p = 0.04, r = 0.14, 95% CI 0.09-0.18) and lower 5-year overall survival (Z = 2.2, p = 0.03). Among patients with clinically significant and insignificant prostate cancer those with clinically significant prostate cancer significantly more frequently showed a positive finding on digital rectal examination (Z = 3.12, p = 0.002, r = 0.10, 95% CI 0-0.19) and lower 5-year overall survival (Z = 2.49, p = 0.01) whereas no effect of age was observed (p = 0.15). Of 1,320 patients monitored for biochemical recurrence prostate specific antigen recurrence, defined as prostate specific antigen greater than 0.02 ng/ml, developed in 25 (1.9%) at between 3 and 102 months.
CONCLUSIONS: This meta-analysis suggests that incidental prostate cancer detected during histopathological examination of radical cystoprostatectomy specimens might be linked with adverse characteristics and outcomes in patients with invasive bladder cancer.

Matched MeSH terms: Urinary Bladder Neoplasms/surgery*
Immunohistochemical expression of NANOG in urothelial carcinoma of the bladder

Md Akhir MKA, Hussin H, Veerakumarasivam A, Choy CS, Abdullah MA, Abd Ghani F

Malays J Pathol, 2017 Dec;39(3):227-234.
PMID: 29279584 MyJurnal

Urothelial carcinoma is a common malignant neoplasm that has a poor prognosis and a high frequency of recurrence and metastasis. Constant disease surveillance with periodic and long term cystoscopy examination is necessary for management of the disease. However, the monitoring and therapy regimen is expensive, incurring a massive burden to patients and the government. Therefore, the development of specific biomarkers for urothelial carcinoma at an early stage and recurrence detection becomes a priority. Homeobox genes are a family of genes that are involved in tumourigenesis. They might be potential prognostic markers for urothelial carcinoma. The study investigated the expression pattern of NANOG which is one of a homeobox gene in different stages and grades of urothelial carcinoma. NANOG expressions were also correlated with patient demographic factors and clinicopathological parameters. The expression of NANOG in 100 formalin-fixed paraffin-embedded urothelial carcinoma tissues was determined by immunohistochemistry. Immunohistochemistry showed positive expression of NANOG in all specimens with detection in the cytoplasm, nuclei and the nuclear membrane of the cancer cells. The immunohistochemical expression of NANOG increased across stages and grades of the tumour. The expression of NANOG was not significantly associated with demographic factors; gender (p = 0.376), race (p = 0.718) and age (p = 0.058) as well as with most of the clinicopathological parameters; pathological stage (p = 0.144), grade (p = 0.625), lymph node involvement (p = 0.174) and distant metastasis (p = 0.228). However, NANOG expression showed significant correlation with tumour invasion (p = 0.019). We concluded that NANOG might be a potential biomarker for early diagnosis of urothelial carcinoma of the bladder.

Matched MeSH terms: Urinary Bladder Neoplasms/pathology*
Expression of AR, 5αR1 and 5αR2 in bladder urothelial carcinoma and relationship to clinicopathological factors

Hata S, Ise K, Azmahani A, Konosu-Fukaya S, McNamara KM, Fujishima F, et al.

Life Sci, 2017 Dec 01;190:15-20.
PMID: 28947209 DOI: 10.1016/j.lfs.2017.09.029

AIMS: Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored.
MAIN METHODS: The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT).
KEY FINDINGS: DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity.
SIGNIFICANCE: Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior.

Matched MeSH terms: Urinary Bladder Neoplasms/genetics*; Urinary Bladder Neoplasms/pathology
Abdominal wall reconstruction after resection of an enterocutaneous fistula with an island pedicled anterolateral thigh perforator flap. Case report

Ali F, Safawi EB, Zakaria Z, Basiron N

Clin Ter, 2013;164(5):413-5.
PMID: 24217827 DOI: 10.7417/CT.2013.1605

Entero-cutaneous fistula resulting from a locally invasive large bowel carcinoma is a difficult surgical challenge. En-bloc resection of the involved organs and the entero-cutaneous fistula tract with a healthy tissue margin will result in a composite abdominal wall defect that requires closure. Reconstructive surgical options include primary closure, components separation and the use of local, regional or free flaps with or without prosthetic mesh. We report a case of an abdominal enterocutaneous fistula secondary to a locally invasive sigmoid carcinoma, which was reconstructed with a pedicled antero-lateral thigh perforator (ALT) flap. To our knowledge, this is the first case of a malignant entero-cutaneous fistula, which was reconstructed with an ALT flap.

Matched MeSH terms: Urinary Bladder Neoplasms/diagnosis
Fulltext Targeting bladder cancer stem cells using Newcastle disease virus

Arcana Thirumorthy, De-Ming Chau, Khatijah Yusoff, Abhi Veerakumarasivam

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):24-24.
MyJurnal

Introduction: Bladder cancer is associated with high risk of tumour recurrence and therapeutic resistance. Cancer stem cells (CSC) within a particular tumour are postulated to drive tumorigenesis and influence tumour behaviour. Recent studies have shown that Newcastle disease virus (NDV) is able to selectively kill and exert a strong oncolytic effect against various cancer types. However little is known about the oncolytic effect of NDV against CSC. In this study, the oncolytic effect of NDV against putative bladder CSC was examined. Methods: Putative bladder CSC was selectively grown in the form of 3D-spheroids from six different bladder cancer cell lines. The spheroid cells were characterised for their stemness properties to ensure that these cells truly represent CSC. This was conducted via the analysis of CSC associated genes and cell surface markers expression. Subsequently, the oncolytic effect of the wild-type NDV-AF2240 strain against the bladder cancer spheroids was investigated. Results: All the spheroids expressed significantly high levels of CSC-associated genes. Flow-cytometry analysis revealed that the expression pattern of the CSC-associated surface markers was different in the spheroid cells; suggesting heterogeneity in the expression signatures of these cells. The infection of spheroids with NDV showed that the NDV was able to target bladder cancer spheroids but there was a spectrum of response across the different spheroids. Intriguingly, NDV was able to persistently infect bladder cancer spheroids that were not sensitive towards NDV infection as the presence of NDV viral genes were detected in the spheroid cells. The NDV persistently infected bladder cancer spheroids were resistant to superinfection and developed an antiviral state by expressing low levels of interferon-beta (IFN-b). NDV persistency of infection affects the process of epithelial to mesenchymal transition (EMT) of cancer cells as the spheroid forming ability of an established NDV persistently infected bladder cancer cell line, EJ28-PI was shown to be impaired. The EJ28-PI cells expressed significantly high levels of the EN2 gene. Knockdown of the EN2 expression reduced the viability of EJ28-PI cells; suggesting a role for EN2 in mediating NDV persistency of infection in cancer cells. Conclusion: Bladder CSC gene expression signatures influence the efficacy of NDV-mediated oncolysis. Our current work is focused on identifying genes and signalling pathways that influence NDV-mediated oncolysis us-ing whole-transcriptomic sequencing. The findings of this study can potentially be used to enhance the efficacy of NDV-mediated oncolysis and accelerate the translation of NDV as an oncotherapeutic agent in the clinic.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext Two Secreted Proteoglycans, Activators of Urothelial Cell-Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression

Papadaki V, Asada K, Watson JK, Tamura T, Leung A, Hopkins J, et al.

Cancers (Basel), 2020 Nov 13;12(11).
PMID: 33202923 DOI: 10.3390/cancers12113362

Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial-mesenchymal transition (EMT), activated cell-cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.

Matched MeSH terms: Urinary Bladder Neoplasms
Hedgehog signalling molecule, SMO is a poor prognostic marker in bladder cancer

Mohd Ariffin K, Abd Ghani F, Hussin H, Md Said S, Yunus R, Veerakumarasivam A, et al.

Malays J Pathol, 2021 Apr;43(1):49-54.
PMID: 33903305

INTRODUCTION: Hedgehog (HH) pathway is an important signalling cascade for growth and patterning during embryonic development. Constitutive activation of Hedgehog pathway can be found in various types of malignancies including medulloblastoma, basal cell carcinoma, gastrointestinal, breast, pancreatic, prostate cancer and leukaemia. Little is known about the expression and role of Hedgehog signalling in bladder cancer.
MATERIALS AND METHODS: The purpose of this study was to investigate the immunohistochemical expression of SMO in 112 bladder cancer cases and determine their association with demographic and clinicopathological parameters. Bladder cancer tissues were obtained from the Hospital Kuala Lumpur.
RESULTS: SMO was expressed in the cytoplasm of all cases of bladder cancer. 6 cases (5.4%) showed low expression, while 106 cases (94.6%) showed high expression. Positive expression of SMO protein was correlated with a few variables which include grade and stage of tumour, lymph node metastasis and distant metastasis. SMO expression showed statistically significant association with higher grade (p=0.001) and higher stage (p=0.042) of bladder cancer. SMO expression also showed borderline association with lymph node metastasis (p=0.056).
CONCLUSION: These findings indicate that SMO expression may be a poor prognostic marker in bladder cancer.

Matched MeSH terms: Urinary Bladder Neoplasms
Fulltext Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes

Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al.

BMC Cancer, 2021 May 27;21(1):625.
PMID: 34044804 DOI: 10.1186/s12885-021-08345-y

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood.
METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR.
RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/β-catenin and KRAS signalling pathways were upregulated while the TGF-β signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV.
CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

Matched MeSH terms: Urinary Bladder Neoplasms
PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

Ismail AF, Oskay Halacli S, Babteen N, De Piano M, Martin TA, Jiang WG, et al.

Biochem. J., 2017 Mar 24;474(8):1333-1346.
PMID: 28232500 DOI: 10.1042/BCJ20160875

Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150 000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long-term prognosis. Thus, there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down-regulation of E-cadherin expression concomitant with a suppression of cell:cell junctions, and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell:cell junctions and the level of PAK5 expression. Interestingly, exogenous PAK5 has recently been described to be associated with cell:cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that, in both our own patient samples and a commercially available dataset, PAK5mRNA levels are reduced in human bladder cancer compared with normal controls. Taken together, the present study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression.

Matched MeSH terms: Urinary Bladder Neoplasms/enzymology; Urinary Bladder Neoplasms/metabolism*; Urinary Bladder Neoplasms/pathology
Protective Role of Natural Products in Cisplatin-Induced Nephrotoxicity

Ridzuan NRA, Rashid NA, Othman F, Budin SB, Hussan F, Teoh SL

Mini Rev Med Chem, 2019;19(14):1134-1143.
PMID: 30894108 DOI: 10.2174/1389557519666190320124438

Cisplatin is a widely used antineoplastic agent for the treatment of metastatic tumors, advanced bladder cancer and many other solid tumors. However, at higher doses, toxicities such as nephrotoxicity may appear. Cisplatin leads to DNA damage and subsequently renal cell death. Besides that, oxidative stress is also implicated as one of the main causes of nephrotoxicity. Several studies showed that numerous natural products: ginseng, curcumin, licorice, honey and pomegranate were able to reduce the oxidative stress by restoring the levels of antioxidant enzymes and also at the same time act as an anti-inflammatory agent. Furthermore, pre-treatment with vitamin supplementation, such as vitamin C, E and riboflavin markedly decreased serum urea and increased the levels of antioxidant enzymes in the kidney even after cisplatin induction in cancer patients. These natural products possess potent antioxidant and anti-inflammatory medicinal properties, and they can be safely used as a supplementary regime or combination therapy against cisplatin-induced nephrotoxicity. The present review focused on the protective role of a few natural products which is widely used in folk medicines in cisplatin-induced nephrotoxicity.

Matched MeSH terms: Urinary Bladder Neoplasms

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