Microsatellite Instability Analysis (MSA) for Bladder Cancer: Past History and Future Directions

Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, colorectal, and bladder cancers; yet a landscape of instability events across a wider variety of cancer types is beginning to be discovered. The epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches to the detection of the MSI phenotype of tumors using NGS have been developed. Bladder cancer (here we refer to transitional carcinoma of the bladder) is a major cause of morbidity and mortality in the Western world. Cystoscopy, a gold standard for the detection of bladder cancer, is invasive and sometimes carries unwanted complications, while its cost is relatively high. Urine cytology is of limited value due to its low sensitivity, particularly to low-grade tumors. Therefore, over the last two decades, several new “molecular assays” for the diagnosis of urothelial cancer have been developed. Here, we provide an update on the development of a microsatellite instability assay (MSA) and the development of MSA associated with bladder cancers, focusing on findings obtained from urine analysis from bladder cancer patients as compared with individuals without bladder cancer. In our review, based on over 18 publications with approximately 900 sample cohorts, we provide the sensitivity (87% to 90%) and specificity (94% to 98%) of MSA. We also provide a comparative analysis between MSA and other assays, as well as discussing the details of four different FDA-approved assays. We conclude that MSA is a potentially powerful test for bladder cancer detection and may improve the quality of life of bladder cancer patients.

Download Full-text

Imaging of Bladder Cancer: Standard Applications and Future Trends

Medicina ◽

10.3390/medicina57030220 ◽

2021 ◽

Vol 57 (3) ◽

pp. 220

Author(s):

Rasha Taha Abouelkheir ◽

Abdalla Abdelhamid ◽

Mohamed Abou El-Ghar ◽

Tarek El-Diasty

Keyword(s):

Bladder Cancer ◽

Malignant Tumors ◽

Cancer Staging ◽

Low Grade ◽

Diagnostic Modality ◽

Positron Emission ◽

Standard Application ◽

Muscle Invasive ◽

Muscle Invasion ◽

Low Sensitivity

The evolution in imaging has had an increasing role in the diagnosis, staging and follow up of bladder cancer. Conventional cystoscopy is crucial in the diagnosis of bladder cancer. However, a cystoscopic procedure cannot always depict carcinoma in situ (CIS) or differentiate benign from malignant tumors prior to biopsy. This review will discuss the standard application, novel imaging modalities and their additive role in patients with bladder cancer. Staging can be performed with CT, but distinguishing between T1 and T2 BCa (bladder cancer) cannot be assessed. MRI can distinguish muscle-invasive from non-muscle-invasive tumors with accurate local staging. Vesical Imaging-Reporting and Data System (VI-RADS) score is a new diagnostic modality used for the prediction of tumor aggressiveness and therapeutic response. Bone scintigraphy is recommended in patients with muscle-invasive BCa with suspected bony metastases. CT shows low sensitivity for nodal staging; however, PET (Positron Emission Tomography)/CT is superior and highly recommended for restaging and determining therapeutic effect. PET/MRI is a new imaging technique in bladder cancer imaging and its role is promising. Texture analysis has shown significant steps in discriminating low-grade from high-grade bladder cancer. Radiomics could be a reliable method for quantitative assessment of the muscle invasion of bladder cancer.

Download Full-text

Microfluidic Assaying of Circulating Tumor Cells and its Correlation with Muscle Invasiveness and Tumor Grade of Urothelial Bladder Cancer

10.21203/rs.3.rs-267304/v1 ◽

2021 ◽

Author(s):

Guanghou Fu ◽

Kok Suen Cheng ◽

Anqi Chen ◽

Zhijie Xu ◽

Xiaoyi Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Risk Stratification ◽

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Tumor Grade ◽

Invasive Bladder Cancer ◽

Low Grade ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

Abstract Background: Bladder cancer is characterized by its frequent recurrence and progression. Effective treatment strategies need to be based on an accurate risk stratification, in which muscle invasiveness and tumor grade represent the two most important factors. Traditional imaging techniques provide preliminary information about muscle invasiveness but are lacking in terms of accuracy. Although as the gold standard, pathological biopsy is only available after the surgery and cannot be performed longitudinally for long-term surveillance. Methods: In this work, we developed a microfluidic approach that interrogates circulating tumor cells (CTCs) in the peripheral blood of bladder cancer patients to reflect the risk stratification of the disease. Results：In a cohort of 48 bladder cancer patients comprising 33 non-muscle invasive bladder cancer (NMIBC) cases and 15 muscle invasive bladder cancer (MIBC) cases, the CTC count was found to be considerably higher in the MIBC group compared with the NMIBC group (4.67 vs. 1.88 CTCs/3 mL, P=0.019), and was significantly higher in high-grade bladder cancer patients verses low-grade bladder cancer patients (3.69 vs. 1.18 CTCs/3mL, P=0.024). Conclusions: This microfluidic assay of CTCs is believed to be a promising complementary tool for the risk stratification of bladder cancer.Trial registration: This research was conducted under the approval of the Ethics Committee of the First Affiliated Hospital at Zhejiang University School of Medicine with the Registration No. 2015-218.

Download Full-text

Microsatellite instability profiling in Egyptian bladder cancer patients: A pilot study

Current Problems in Cancer ◽

10.1016/j.currproblcancer.2019.03.002 ◽

2019 ◽

Vol 43 (6) ◽

pp. 100472 ◽

Cited By ~ 1

Author(s):

Abdel-Rahman N. Zekri ◽

Hussein M. Khaled ◽

Mai B. Mohammed ◽

Fatma M. Diab ◽

Mona S. Abdellateif ◽

...

Keyword(s):

Bladder Cancer ◽

Pilot Study ◽

Microsatellite Instability ◽

Cancer Patients

Download Full-text

Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.572 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 572-572

Author(s):

Shaheen Riadh Alanee ◽

Zade Roumayah ◽

Musatafa Deebajah ◽

James O. Peabody ◽

Rodrigo Mora ◽

...

Keyword(s):

Flow Cytometry ◽

Bladder Cancer ◽

Single Cell ◽

Transitional Cell ◽

Low Grade ◽

High Grade ◽

Median Score ◽

Adaptive Genetic Algorithms ◽

Cell Flow Cytometry ◽

Carcinoma Of The Bladder

572 Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.

Download Full-text

A Single-Institutional Study of Human Immunodeficiency Virus-Related Bladder Cancer

10.21203/rs.3.rs-705534/v1 ◽

2021 ◽

Author(s):

Mengmeng Zhang ◽

Yanyan Zhang ◽

Zhiqiang Zhu ◽

Yu Zhang

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Clinical Characteristics ◽

Transitional Cell ◽

Invasive Bladder Cancer ◽

Low Grade ◽

High Grade ◽

Muscle Invasive Bladder Cancer ◽

Tumor Pathology ◽

Muscle Invasive

Abstract Purpose: We wished to investigate the clinical characteristics, treatments for tumor, pathology and outcomes of bladder cancer patients with HIV-infected.Patients and methods: We identified 10 cases of bladder cancer with HIV-infected from 2015 to 2020.We retrospectively investigated the clinical characteristics of the cases including demographic information, clinical presentation, TNM stage and so on. We investigated treatments for tumor, pathology, outcomes and HIV-relevant parameters during patients’ hospitalization course as well. Results: In our study, it was astonished to find that bladder cancer patients with HIV-infected were males at the median age of 51 years old, and no females were diagnosed on the contrary. Nine (90%)patients presented with painless gross hematuria, while one patient with incidental findings on ultrasonic examination. Six(60%) patients co-infected with another kind of infectious disease, four with syphilis, and two with HBV respectively. The median CD4+ T-lymphocyte cell count was 493/ul withthin 2 weeks prior to the diagnosis bladder cancer. Cystoscope examination manifested that the lesions were located in the trigonum of the bladder in four(40%)patients. All patients underwent surgeries successfully, six underwent transurethral resection of bladder tumor(TURBT),two of whom relapsed once, and one underwent TURBT twice due to recurrence and then RC and urethrectomy because of urethral invasion. All non muscle-invasive bladder cancer(NMIBC)patients received intravesical chemotherapy with pirarubicin 30mg for at least half year conventionally, and only one patient occurred mild adverse reaction of irritative symptoms of bladder. Pathologic analysis documented that all patients(100%) had transitional cell carcinoma(TCC). Tumor grade classification showed that three cases were identified with low grade TCC, and six cases with high grade or invasive TCC, two of whom occurred recurrence for once or twice respectively. One patient was identified with low grade TCC of primary tumor and high grade TCC of recurrent focal(Figure 2).Five cases(50%) were ascertained as (NMIBC) with pT1N0M0, while the rest five patients(50%) were muscle-invasive bladder cancer(MIBC) with at least pT2N0M0. During the median follow-up of 56 months (range from 5 months to 68 months) six cases(five were MIBC patients )died due to distant metastases. No patients acceptted adjuvent immunotherapy mainly due to the role of PD-1+ T cells in HIV transcription in treated aviremic individuals, concerns of unknown adverse effects and economic factors.Conclusions: It seemed like that bladder caner patients had higher tumor stage and more aggressive pathology. we did not find any evidence on the relationship between immunodeficiency and cancer progression because of relatively stable HIV status of this crew in our study. MIBC patients with HIV-infected really have worse outcomes, and more attention is warranted to pay to this special population in this situation when they present with hematuria extraordinarily.

Download Full-text

The predictive value of hENT 1 molecule for gemcitabine treatment in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15540 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15540-e15540

Author(s):

Didem Sener Dede ◽

Aydan Kilicaslan ◽

Muhammed Bulent Akinci ◽

Umut Demirci ◽

Gozde Tahtaci ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Predictive Value ◽

Stage Iv ◽

Response To Therapy ◽

Stage Iii ◽

Low Grade ◽

Nucleoside Transporter ◽

Control Tissue ◽

Significant Difference

e15540 Background: Human equilibrative nucleoside transporter 1 (hENT1) is the nucleoside transporter protein which plays the main role for transportation of gemcitabine into the cells. We aim to assess the predictive value of the hENT 1 molecule in bladder cancer patients treated with gemcitabine based chemoterapy. Methods: Clinically and histologically documented stage III and stage IV invazive bladder cancer patients were included in the study. The patients were assessed retrospectively. All patients were received gemsitabine-platine based chemotherapy as the first line treatment. Spesific hENT1 antibody staining was performed on the chemo-naive bladder tumor specimens immunuhistochemically. Vascular endotel and lymphocytes served as an external positive control for hENT 1 immunuhistochemistry. Staining intensity was graded as 0,absent; 1+, less intens than control tissue, 2, equally positive as control tissue; 3, more intense than control tissue. Tumor spesimens with having 3+ intensity staining in >50% of the tumor cells were accepted as showing high expression of hENT 1. Results: Fifty one patients were included in the study. The median age was 67 (range 41-85). Ninety two percent(n=52) of patients were male. Twenty six (46.4%) and 25 (44.6%) patients were stage III and stage IV disease at the beginning of the therapy, respectively. Thirty four (60.7%) patients were in neoadjuvant treatment group and 17 (30.4%) patients were in metastatic group. Tumor grades could be assessed in 33 patients; 2 (11.4%) were low grade and 31 (88%) were high grade. The median folllow up period was 13 (range 1-58) months. In neoadjuvant group 5 (14%) patients have low hENT 1 level and 21 (60%) patients have high hENT 1 level. In metastatic group 1 (5%) patients have low hENT1 level and 13 (95%) patients have high hENT 1 level. We found no statistically significant difference between hENT 1 low and hENT 1 high groups in terms of response to therapy in metastatic and neoadjuvant groups (p=0.426 and p=0.684 respectively). Conclusions: More stuides are needed to demonstrate the real role of hENT 1 molecule in terms of response to gemsitabine treatment.

Download Full-text

Disseminated BCG: Complications of Intravesical Bladder Cancer Treatment

Case Reports in Medicine ◽

10.1155/2014/362845 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3 ◽

Cited By ~ 3

Author(s):

Uyen To ◽

Joyce Kim ◽

David Chia

Keyword(s):

Bladder Cancer ◽

Hypersensitivity Pneumonitis ◽

Superficial Bladder Cancer ◽

Transitional Cell ◽

Low Grade ◽

Newly Diagnosed ◽

Insidious Onset ◽

Initial Symptoms ◽

Intravesical Bcg ◽

Carcinoma Of The Bladder

Intravesical bacillus Calmette-Guerin (BCG) has been established as an effective treatment of superficial bladder cancer (Parker and Kommu, 2013). However, major side effects, including pneumonitis, sepsis, and even death, may occur in <5% of patients (Gonzalez et al., 2003). Here we present a case of severe disseminatedMycobacterium bovisfollowing intravesical BCG administration. Our patient is a 76-year-old gentleman with newly diagnosed superficial transitional cell carcinoma of the bladder who recently received his first intravesical BCG treatment. He initially presented with hemoptysis and was found to have extensive patchy infiltrates bilaterally. He was treated for pneumonia with antibiotics and then with steroids for hypersensitivity pneumonitis but continued to deteriorate. Due to the temporal proximity of his exposure to BCG, we administered treatment for presumed disseminated BCG infection with rifampin, isoniazid, and ethambutol. Within a 48-hour period, the patient improved dramatically. The reported cases of infection from intravesical BCG illustrate an insidious onset with initial symptoms of low-grade fevers and cystitis but may progress to pneumonitis. If the symptoms persist for more than 7 days or if there is clinical deterioration, RIPE therapy (with rifampin, isoniazid, pyridoxine, and ethambutol) and a fluoroquinolone should be administered for a 6–9-month course along with steroids for 4–6 weeks (Naudžiunas et al., 2012).

Download Full-text

Novel serum peptide model revealed by MALDI-TOF-MS and its diagnostic value in early bladder cancer

The International Journal of Biological Markers ◽

10.1177/1724600820935473 ◽

2020 ◽

Vol 35 (3) ◽

pp. 59-66

Author(s):

Dapeng Ding ◽

Mingying Chen ◽

Xiaoguang Xiao ◽

Penglong Cao ◽

Shijun Li

Keyword(s):

Bladder Cancer ◽

Healthy Volunteers ◽

Cancer Patients ◽

Sensitivity And Specificity ◽

Diagnostic Model ◽

Low Grade ◽

Training Set ◽

Serum Peptide ◽

Auc Value ◽

Testing Set

Background: Bladder cancer is the ninth most common cancer worldwide and has high morbidity and mortality. We aimed to search for potential serum peptide biomarkers and establish a diagnostic model for early bladder cancer. Methods: A total of 67 bladder cancer patients and 64 healthy volunteers were randomly divided into a training set and testing set 1. There were 30 hematuria patients used as testing set 2. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on weak cation exchange magnetic beads was used to obtain and analyze the serum peptide profiles between bladder cancer patients and healthy volunteers in the training set. Serum peptide diagnostic model through a k-nearest neighbor algorithm, was established and validated, and significantly differentially expressed protein biomarkers were ultimately identified. Results: We constructed a diagnostic model containing five peptides (m/z 1954.9, m/z 2081.0, m/z 3938.3, m/z 3946.5, and m/z 4268.8). In the training set, the area under the curve (AUC) value of the five-peptide model was 0.923, and the sensitivity and specificity was 93.75% and 96.77%, respectively. In testing set 1, the sensitivity and specificity was 91.43% and 90.91%, respectively, and the specificity of testing set 2 was 73.33%. For early-stage bladder cancer, the sensitivity and specificity was 92.31% and 93.75%, respectively; the sensitivity of early low-grade bladder cancer was 90.00%; and the AUC value was 0.944. Conclusion: The five-peptide diagnostic model established in this study had high sensitivity and specificity, especially in the diagnosis of early bladder cancer, and could differentiate between healthy volunteers and hematuria patients.

Download Full-text

Identification of Prognosis-Related Genes in Bladder Cancer Microenvironment across TCGA Database

BioMed Research International ◽

10.1155/2020/9143695 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Xin Zhao ◽

Yu Tang ◽

Haoyu Ren ◽

Yi Lei

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cancer Patients ◽

Clinical Characteristics ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Cancer Prognosis ◽

Biological Behavior ◽

Low Grade ◽

Cancer Microenvironment

Background. Bladder cancer (BCa) is a common urothelial malignancy. The Cancer Genome Atlas (TCGA) database allows for an opportunity to analyze the relationship between gene expression and clinical outcomes in bladder cancer patients. This study is aimed at identifying prognosis-related genes in the bladder cancer microenvironment. Methods. Immune scores and stromal scores were calculated by applying the ESTIMATE algorithm. We divided bladder cancer patients into high and low groups based on their immune/stromal scores. Then, differentially expressed genes (DEGs) were identified in bladder cancer patients based on the TCGA database. We evaluated the correlation between immune/stromal scores and clinical characteristics as well as prognosis. Finally, we validated identified genes associated with bladder cancer prognosis through a cohort study in the Gene Expression Omnibus (GEO) database. Results. A higher stromal score was associated with female (vs. male p = 0.037 ), age > 65 (vs. age ≤ 65 p = 0.015 ), T3/4 (vs. T1/2, p < 0.001 ), N status p = 0.016 , and pathological high grade (vs. low grade P < 0.001 ). By analyzing DEGs, there were 1125 genes commonly upregulated, and 209 genes were commonly downregulated. Protein-protein interaction networks further showed the important protein that may be involved in the biological behavior and prognosis of BCa, such as FN1, CXCL12, CD3E, LCK, and ZAP70. A total of 14 DEGs were found to be associated with overall survival of bladder cancer. After validation by a cohort of 165 BCa cases with detailed follow-up information from GSE13507, 10 immune-associated DEGs were demonstrated to be predictive of prognosis in BCa. Among them, 5 genes have not been reported previously associated with the prognosis of BCa, including BTBD16, OLFML2B, PRRX1, SPINK4, and SPON2. Conclusions. Our study elucidated tight associations between stromal score and clinical characteristics as well as prognosis in BCa. Moreover, we obtained a group of genes closely related to the prognosis of BCa in the tumor microenvironment.

Download Full-text

Noninvasive Urine-Based Tests to Diagnose or Detect Recurrence of Bladder Cancer

Cancers ◽

10.3390/cancers13071650 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1650

Author(s):

Marine Charpentier ◽

Charly Gutierrez ◽

Thierry Guillaudeux ◽

Grégory Verhoest ◽

Rémy Pedeux

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Body Fluid ◽

Early Stage ◽

Ease Of Use ◽

High Rate ◽

Low Grade ◽

High Grade ◽

Liquid Biopsies

Liquid biopsies are increasingly used for the diagnosis and follow-up of cancer patients. Urine is a body fluid that can be used to detect cancers and others diseases. It is noninvasive and easy to collect. To detect Bladder Cancer (BC), cytology is the first assay used. It is an effective way to detect high grade BC but has a high rate of equivocal results, especially for low grade BC. Furthermore, cystoscopy is used to confirm cytology results and to determine cancer status. Cystoscopy is also effective but highly invasive, and not well accepted by patients, especially for BC follow-up. In this review we survey the numerous assays recently developed in order to diagnose BC at an early stage, and to facilitate the follow-up of patients. We discuss their effectiveness, ease of use, and applications. Finally, we discuss assays that, in the future, could improve the diagnosis and management of BC patients.

Download Full-text