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15 pages, 5333 KiB

Open AccessArticle

Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder

by Yoshitaka Itami, Makito Miyake, Sayuri Ohnishi, Yoshihiro Tatsumi, Daisuke Gotoh, Shunta Hori, Yousuke Morizawa, Kota Iida, Kenta Ohnishi, Yasushi Nakai, Takeshi Inoue, Satoshi Anai, Nobumichi Tanaka, Tomomi Fujii, Keiji Shimada, Hideki Furuya, Vedbar S. Khadka, Youping Deng and Kiyohide Fujimoto

Diagnostics 2020, 10(1), 54; https://doi.org/10.3390/diagnostics10010054 - 20 Jan 2020

Cited by 12 | Viewed by 3787

Abstract

Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of [...] Read more.

Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RNA (siRNA) transfection, and then its effects on cell proliferation, invasion, and migration, and changes to epithelial-mesenchymal transition (EMT)-related proteins were evaluated. In our in vivo assays, tumor-bearing athymic nude mice subcutaneously inoculated with human UCB cells (MGH-U-3 or UM-UC-3) were treated by DAB2-targeting siRNA. Higher expression of DAB2 was associated with higher clinical T category, high tumor grade, and poor oncological outcome. The knock-down of DAB2 decreased both invasion and migration ability and expression of EMT-related proteins. Significant inhibitory effects on tumor growth and invasion were observed in xenograft tumors of UM-UC-3 treated by DAB2-targeting siRNA. Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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13 pages, 1100 KiB

Open AccessArticle

The Genes—Candidates for Prognostic Markers of Metastasis by Expression Level in Clear Cell Renal Cell Cancer

by Natalya Apanovich, Maria Peters, Pavel Apanovich, Danzan Mansorunov, Anna Markova, Vsevolod Matveev and Alexander Karpukhin

Diagnostics 2020, 10(1), 30; https://doi.org/10.3390/diagnostics10010030 - 08 Jan 2020

Cited by 12 | Viewed by 3652

Abstract

The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF [...] Read more.

The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, EGLN3, SAA1, CSF1R, C1QA, and FN1—through RT-PCR, in 56 ccRCC patients without metastases and with metastases. All of these, excluding CSF1R, showed differential and increased (besides SAA1) expression in non-metastasis tumors. The gene expression levels in metastasis tumors were decreased, besides CSF1R, FN1 (not changed), and SAA1 (increased). There were significant associations of the differentially expressed genes with ccRCC metastasis by ROC analysis and the Fisher exact test. The association of the NDUFA4L2, VWF, EGLN3, SAA1, and C1QA expression with ccRCC metastasis is shown for the first time. The CA9, NDUFA4L2, BHLHE4, and EGLN3 were distinguished as the strongest candidates for ccRCC metastasis biomarkers. We used an approach that presupposed that the metastasis marker was the expression levels of any three genes from the selected panel and received sensitivity (88%) and specificity (73%) levels with a relative risk of RR > 3. In conclusion, a panel of selected genes—the candidates in biomarkers of ccRCC metastasis—was created for the first time. The results might shed some light on the ccRCC metastasis processes. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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15 pages, 1290 KiB

Open AccessArticle

Prognostic Significance of Lymphocyte Infiltration and a Stromal Immunostaining of a Bladder Cancer Associated Diagnostic Panel in Urothelial Carcinoma

by Hideki Furuya, Owen T.M. Chan, Kanani Hokutan, Yutaro Tsukikawa, Keanu Chee, Landon Kozai, Keith S. Chan, Yunfeng Dai, Regan S. Wong and Charles J. Rosser

Diagnostics 2020, 10(1), 14; https://doi.org/10.3390/diagnostics10010014 - 28 Dec 2019

Cited by 8 | Viewed by 3115

Abstract

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder [...] Read more.

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder cancer-associated diagnostic signature were chemokines, cytokines, or secreted proteins, we set out to report the stromal staining pattern of the diagnostic signature as well as CD3⁺ (T-cell) cell and CD68⁺ (macrophage) cell staining in human bladder tumors as a snapshot of the tumor immune landscape. Immunohistochemical staining was performed on 213 tumor specimens and 74 benign controls. Images were digitally captured and quantitated using Aperio (Vista, CA). The expression patterns were correlated with tumor grade, tumor stage, and outcome measures. We noted a positive correlation of seven of the 10 proteins (excluding A1AT and IL8 which had a negative association and VEGFA had no association) in bladder cancer. The overexpression of MMP10 was associated with higher grade disease, while overexpression of MMP10, PAI1, SDC1 and ANG were associated with high stage bladder cancer and CA9 was associated with low stage bladder cancer. Increased tumor infiltration of CD68⁺ cells were associated with higher stage disease. Overall survival was significantly reduced in bladder cancer patients’ whose tumors expressed eight or more of the 10 proteins that comprise the bladder cancer diagnostic panel. These findings confirm that the chemokines, cytokines, and secreted proteins in a urine-based diagnostic panel are atypically expressed, not only in the epithelial component of bladder tumors, but also in the stromal component of bladder tumors and portends a worse overall survival. Thus, when assessing immunohistochemical staining, it is important to report staining patterns within the stroma as well as the entire stroma itself. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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14 pages, 2346 KiB

Open AccessArticle

Down-Grading of Ipsilateral Hydronephrosis by Neoadjuvant Chemotherapy Correlates with Favorable Oncological Outcomes in Patients Undergoing Radical Nephroureterectomy for Ureteral Carcinoma

by Makito Miyake, Nagaaki Marugami, Yuya Fujiwara, Kazumasa Komura, Teruo Inamoto, Haruhito Azuma, Hiroaki Matsumoto, Hideyasu Matsuyama and Kiyohide Fujimoto

Diagnostics 2020, 10(1), 10; https://doi.org/10.3390/diagnostics10010010 - 23 Dec 2019

Cited by 6 | Viewed by 4584

Abstract

Few studies have analyzed the details of neoadjuvant chemotherapy (NAC)-induced changes in patients with upper tract urothelial carcinoma. This study aimed to describe the impact of down-grading ipsilateral hydronephrosis by NAC for ureteral carcinoma. An observational study was conducted in 32 patients with [...] Read more.

Few studies have analyzed the details of neoadjuvant chemotherapy (NAC)-induced changes in patients with upper tract urothelial carcinoma. This study aimed to describe the impact of down-grading ipsilateral hydronephrosis by NAC for ureteral carcinoma. An observational study was conducted in 32 patients with cT1-3N0M0 ureteral carcinoma treated with NAC and radical nephroureterectomy. Hydronephrosis was classified into five grades based on computed tomography findings. We focused on the differences between the baseline and post-NAC status of ipsilateral hydronephrosis, radiographic tumor response, and blood markers. Down-grading, no change, and up-grading was observed in 10 (31%), 21 (66%), and 1 (3%) patients, respectively. In univariate analysis, locally advanced disease (cT3), severe hydronephrosis (grade 3/4) at baseline, no change/up-grading of hydronephrosis after NAC, and pathological lymphovascular involvement were identified as potential prognostic factors of progression-free and cancer-specific survival after radical nephroureterectomy. Locally advanced disease (cT3) at baseline and no change/up-grading of hydronephrosis by NAC were independently associated with poor progression-free survival. Notably, none of the patients with NAC-induced down-grading of hydronephrosis died of ureteral carcinoma during the follow-up. We reported the prognostic impact of down-grading of ipsilateral hydronephrosis, which could serve as a useful aid or clinical marker for decision-making. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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9 pages, 395 KiB

Open AccessArticle

Comparison of Commercial ELISA Kits, a Prototype Multiplex Electrochemoluminescent Assay, and a Multiplex Bead-Based Immunoassay for Detecting a Urine-Based Bladder-Cancer-Associated Diagnostic Signature

by Hideki Furuya, Ian Pagano, Keanu Chee, Takashi Kobayashi, Regan S. Wong, Riko Lee and Charles J. Rosser

Diagnostics 2019, 9(4), 166; https://doi.org/10.3390/diagnostics9040166 - 29 Oct 2019

Cited by 13 | Viewed by 3295

Abstract

The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of clinical tests composed of multiple biomarkers. We investigated the diagnostic accuracy of the two multiplex protein array platforms for detecting a bladder-cancer-associated [...] Read more.

The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of clinical tests composed of multiple biomarkers. We investigated the diagnostic accuracy of the two multiplex protein array platforms for detecting a bladder-cancer-associated diagnostic signature in samples from a cohort of 80 subjects (40 with bladder cancer). Banked urine samples collected from Kyoto and Nara Universities were compared to histologically determined bladder cancer. The concentrations of the 10 proteins (A1AT; apolipoprotein E—APOE; angiogenin—ANG; carbonic anhydrase 9—CA9; interleukin 8—IL-8; matrix metalloproteinase 9—MMP-9; matrix metalloproteinase 10—MMP10; plasminogen activator inhibitor 1—PAI-1; syndecan—SDC1; and vascular endothelial growth factor—VEGF) were monitored using two prototype multiplex array platforms and an enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s technical specifications. The range for detecting each biomarker was improved in the multiplex assays, even though the lower limit of quantification (LLOQ) was typically lower in the commercial ELISA kits. The area under the receiver operating characteristics (AUROC) of the prototype multiplex assays was reported to be 0.97 for the multiplex bead-based immunoassay (MBA) and 0.86 for the multiplex electrochemoluminescent assay (MEA). The sensitivities and specificities for MBA were 0.93 and 0.95, respectively, and for MEA were 0.85 and 0.80, respectively. Accuracy, positive predictive values (PPV), and negative predictive values (NPV) for MBA were 0.94, 0.95, and 0.93, respectively, and for MEA were 0.83, 0.81, and 0.84, respectively. Based on these encouraging preliminary data, we believe that a multiplex protein array is a viable platform that can be utilized as an efficient and highly accurate tool to quantitate multiple proteins within biologic specimens. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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14 pages, 2925 KiB

Open AccessArticle

A Potential Application of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Combined with Photodynamic Diagnosis for the Detection of Bladder Carcinoma in Situ: Toward the Future ‘MRI-PDD Fusion TURBT’

by Makito Miyake, Fumisato Maesaka, Nagaaki Marugami, Tatsuki Miyamoto, Yasushi Nakai, Sayuri Ohnishi, Daisuke Gotoh, Takuya Owari, Shunta Hori, Yosuke Morizawa, Yoshitaka Itami, Takeshi Inoue, Satoshi Anai, Kazumasa Torimoto, Tomomi Fujii, Keiji Shimada, Nobumichi Tanaka and Kiyohide Fujimoto

Diagnostics 2019, 9(3), 112; https://doi.org/10.3390/diagnostics9030112 - 04 Sep 2019

Cited by 5 | Viewed by 5204

Abstract

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients [...] Read more.

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients undergoing pre-surgical DCE-MRI and PDD-assisted endoscopic surgery accompanied by biopsies of the eight segmentations were analyzed. Immunohistochemical analysis of the biopsies revealed hypervascularity of CIS lesions, a cause of strong submucosal contrast-enhancement. It was found that 56 (16.2%) of 344 biopsies had pathologically proven CIS. In the DCE-MRI, the overall sensitivity and specificity for detecting CIS were 48.2% and 81.9%, respectively. We set out two different combinations of PDD and DCE-MRI for detecting CIS. Combination 1 was positive when either the PDD or DCE-MRI were test-positive. Combination 2 was positive only when both PDD and DCE-MRI were test-positive. The overall sensitivity of combinations 1 and 2 were 75.0% and 37.5%, respectively (McNemar test, vs PDD alone; p = 0.041 and p < 0.001, respectively). However, the specificity was 74.0% and 91.7%, respectively (vs PDD alone; both p < 0.001). Our future goal is to establish ‘MRI-PDD fusion transurethral resction of the bladder tumor (TURBT), which could be an effective therapeutic and diagnostic approach in the clinical management of high-risk disease. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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7 pages, 992 KiB

Open AccessArticle

Preoperative MRI Parameters Predict Urinary Continence after Robot-Assisted Laparoscopic Prostatectomy in Prostatic Cancer Patients

by Shinji Fukui, Yoriaki Kagebayashi, Yusuke Iemura, Yoshiaki Matsumura and Shoji Samma

Diagnostics 2019, 9(3), 102; https://doi.org/10.3390/diagnostics9030102 - 25 Aug 2019

Cited by 15 | Viewed by 3719

Abstract

We aimed to investigate whether preoperative MRI findings could predict the bladder neck location on postoperative cystography and recovery of urinary incontinence after robot-assisted laparoscopic radical prostatectomy (RALP). We retrospectively reviewed 270 consecutive patients who had complete preoperative data, including MRI, and underwent [...] Read more.

We aimed to investigate whether preoperative MRI findings could predict the bladder neck location on postoperative cystography and recovery of urinary incontinence after robot-assisted laparoscopic radical prostatectomy (RALP). We retrospectively reviewed 270 consecutive patients who had complete preoperative data, including MRI, and underwent postoperative observation for more than three months. Preoperative MRI parameters consisted of the membranous urethral length (MUL) and pubic symphysis-prostate apex length (PAL) on sagittal images. The bladder neck location on a postoperative cystography was defined as the lowest extension of the tapering contrast medium in the bladder, and its relation to the pubic symphysis (above (higher group) and below (lower group) the middle of the pubic symphysis height) was evaluated. Those who required no pad or a safety pad were defined as being continent. PAL was significantly shorter in the higher group than that in the lower group (25.5 vs. 29.1 mm; p < 0.0001). The continent group at three months had a significantly longer MUL and shorter PAL than those in the incontinent group (8.1 vs. 6.7 mm; p < 0.05, and 26.0 vs. 28.1 mm; p < 0.05, respectively). Preoperative MRI parameters could predict the bladder neck location on postoperative cystograms and the recovery of urinary incontinence after RALP. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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9 pages, 357 KiB

Open AccessArticle

The Preoperative Predictive Factors for Pathological T3a Upstaging of Clinical T1 Renal Cell Carcinoma

by Shinji Fukui, Makito Miyake, Kota Iida, Kenta Onishi, Shunta Hori, Yosuke Morizawa, Yoriaki Kagebayashi and Kiyohide Fujimoto

Diagnostics 2019, 9(3), 76; https://doi.org/10.3390/diagnostics9030076 - 15 Jul 2019

Cited by 7 | Viewed by 2810

Abstract

We aimed to determine the oncological outcomes of patients with clinical T1 renal cell carcinoma (RCC) upstaged to pathological T3a and to identify the preoperative predictive factors for upstaging. We retrospectively reviewed 272 patients with clinical T1 RCC who underwent surgical treatment. Thirty-three [...] Read more.

We aimed to determine the oncological outcomes of patients with clinical T1 renal cell carcinoma (RCC) upstaged to pathological T3a and to identify the preoperative predictive factors for upstaging. We retrospectively reviewed 272 patients with clinical T1 RCC who underwent surgical treatment. Thirty-three patients (12%) were upstaged to pathological T3a. These patients had a significantly larger tumor size on computed tomography (p < 0.0001), a higher aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (p = 0.037), and an elevated c-reactive protein (CRP) level (p = 0.014) preoperatively compared with those with pathological T1 RCC. On multivariate analysis, tumor diameter was the only significant preoperative predictive factor for upstaging [hazard ratio (HR), 3.61; 95% confidence interval (CI), 1.32–9.84; p = 0.01]. The AST/ALT ratio tended to be a preoperative predictive factor for upstaging, although it was not significant (HR, 2.14; 95% CI, 0.97–4.73; p = 0.06). Pathological T3a upstaging occurred in 25% of those with a tumor diameter ≥30 mm and a preoperative AST/ALT ratio ≥1.1. There was a significant correlation between pathological T3a upstaging and the number of preoperative risk factors (p = 0.0002). The preoperative tumor diameter and serum AST/ALT ratio can be predictive factors for pathological T3a upstaging in patients with clinical T1 RCC. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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Review

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19 pages, 9947 KiB

Open AccessReview

Biomarkers for Bladder Cancer Diagnosis and Surveillance: A Comprehensive Review

by Rui Batista, Nuno Vinagre, Sara Meireles, João Vinagre, Hugo Prazeres, Ricardo Leão, Valdemar Máximo and Paula Soares

Diagnostics 2020, 10(1), 39; https://doi.org/10.3390/diagnostics10010039 - 13 Jan 2020

Cited by 74 | Viewed by 9432

Abstract

Bladder cancer (BC) ranks as the sixth most prevalent cancer in the world, with a steady rise in its incidence and prevalence, and is accompanied by a high morbidity and mortality. BC is a complex disease with several molecular and pathological pathways, thus [...] Read more.

Bladder cancer (BC) ranks as the sixth most prevalent cancer in the world, with a steady rise in its incidence and prevalence, and is accompanied by a high morbidity and mortality. BC is a complex disease with several molecular and pathological pathways, thus reflecting different behaviors depending on the clinical staging of the tumor and molecular type. Diagnosis and monitoring of BC is mainly performed by invasive tests, namely periodic cystoscopies; this procedure, although a reliable method, is highly uncomfortable for the patient and it is not exempt of comorbidities. Currently, there is no formal indication for the use of molecular biomarkers in clinical practice, even though there are several tests available. There is an imperative need for a clinical non-invasive testing for early detection, disease monitoring, and treatment response in BC. In this review, we aim to assess and compare different tests based on molecular biomarkers and evaluate their potential role as new molecules for bladder cancer diagnosis, follow-up, and treatment response monitoring. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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19 pages, 1900 KiB

Open AccessReview

Glycan Analysis as Biomarkers for Testicular Cancer

by Michal Hires, Eduard Jane, Michal Mego, Michal Chovanec, Peter Kasak and Jan Tkac

Diagnostics 2019, 9(4), 156; https://doi.org/10.3390/diagnostics9040156 - 22 Oct 2019

Cited by 3 | Viewed by 7332

Abstract

The U.S. Preventive Services Task Force does not recommend routine screening for testicular cancer (TC) in asymptomatic men, essentially because serological testicular cancer (TC) biomarkers are not reliable. The main reason is that two of the most important TC biomarkers, α-fetoprotein (AFP) and [...] Read more.

The U.S. Preventive Services Task Force does not recommend routine screening for testicular cancer (TC) in asymptomatic men, essentially because serological testicular cancer (TC) biomarkers are not reliable. The main reason is that two of the most important TC biomarkers, α-fetoprotein (AFP) and human chorionic gonadotropin (hCG), are not produced solely due to TC. Moreover, up to 40% of patients with TC do not have elevated serological biomarkers, which is why serial imaging with CT is the chief means of monitoring progress. On the other hand, exposure to radiation can lead to an increased risk of secondary malignancies. This review provides the first comprehensive account of the applicability of protein glycoprofiling as a promising biomarker for TC with applications in disease diagnostics, monitoring and recurrence evaluation. The review first deals with the description and classification of TC. Secondly, the limitations of current TC biomarkers such as hCG, AFP and lactate dehydrogenase are provided together with an extensive overview of the glycosylation of hCG and AFP related to TC. The final part of the review summarises the potential of glycan changes on either hCG and AFP as TC biomarkers for diagnostics and prognostics purposes, and for disease recurrence evaluation. Finally, an analysis of glycans in serum and tissues as TC biomarkers is also provided. Full article

(This article belongs to the Special Issue Urogenital Cancers: Diagnostic, Predictive, and Prognostic Markers)

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