Differentially expressed genes associated with high metabolic tumor volume served as diagnostic markers and potential therapeutic targets for pancreatic cancer.

BACKGROUND: The lack of distinct biomarkers for pancreatic cancer is a major cause of early-stage detection difficulty. The pancreatic cancer patient group with high metabolic tumor volume (MTV), one of the values measured from positron emission tomography-a confirmatory method and standard care for pancreatic cancer, showed a poorer prognosis than those with low MTV. Therefore, MTV-associated differentially expressed genes (DEGs) may be candidates for distinctive markers for pancreatic cancer. This study aimed to evaluate the possibility of MTV-related DEGs as markers or therapeutic targets for pancreatic cancer. METHODS: Tumor tissues and their normal counterparts were obtained from patients undergoing preoperative 18F-FDG PET/CT. The tissues were classified into MTV-low and MTV-high groups (7 for each) based on the MTV2.5 value of 4.5 (MTV-low: MTV2.5 < 4.5, MTV-high: MTV2.5 ≥ 4.5). Gene expression fold change was first calculated in cancer tissue compared to its normal counter and then compared between low and high MTV groups to obtain significant DEGs. To assess the suitability of the DEGs for clinical application, the correlation of the DEGs with tumor grades and clinical outcomes was analyzed in TCGA-PAAD, a large dataset without MTV information. RESULTS: Total RNA-sequencing (MTV RNA-Seq) revealed that 44 genes were upregulated and 56 were downregulated in the high MTV group. We selected the 29 genes matching MTV RNA-seq patterns in the TCGA-PAAD dataset, a large clinical dataset without MTV information, as MTV-associated genes (MAGs). In the analysis with the TCGA dataset, MAGs were significantly associated with patient survival, treatment outcomes, TCGA-PAAD-suggested markers, and CEACAM family proteins. Some MAGs showed an inverse correlation with miRNAs and were confirmed to be differentially expressed between normal and cancerous pancreatic tissues. Overexpression of KIF11 and RCC1 and underexpression of ADCY1 and SDK1 were detected in ~ 60% of grade 2 pancreatic cancer patients and associated with ~ 60% mortality in stages I and II. CONCLUSIONS: MAGs may serve as diagnostic markers and miRNA therapeutic targets for pancreatic cancer. Among the MAGs, KIF11, RCC1, ADCY, and SDK1 may be early diagnostic markers.

Deciphering the Role of ERBB3 Isoforms in Renal Cell Carcinoma: A Comprehensive Genomic and Transcriptomic Analysis.

ERBB3, a key member of the receptor tyrosine kinase family, is implicated in the progression and development of various human cancers, affecting cellular proliferation and survival. This study investigated the expression of ERBB3 isoforms in renal clear cell carcinoma (RCC), utilizing data from 538 patients from The Cancer Genome Atlas (TCGA) Firehose Legacy dataset. Employing the SUPPA2 tool, the activity of 10 ERBB3 isoforms was examined, revealing distinct expression patterns in RCC. Isoforms uc001sjg.3 and uc001sjh.3 were found to have reduced activity in tumor tissues, while uc010sqb.2 and uc001sjl.3 demonstrated increased activity. These variations in isoform expression correlate with patient survival and tumor aggressiveness, indicating their complex role in RCC. The study, further, utilizes CIBERSORTx to analyze the association between ERBB3 isoforms and immune cell profiles in the tumor microenvironment. Concurrently, Gene Set Enrichment Analysis (GSEA) was applied, establishing a strong link between elevated levels of ERBB3 isoforms and critical oncogenic pathways, including DNA repair and androgen response. RT-PCR analysis targeting the exon 21-23 and exon 23 regions of ERBB3 confirmed its heightened expression in tumor tissues, underscoring the significance of alternative splicing and exon utilization in cancer development. These findings elucidate the diverse impacts of ERBB3 isoforms on RCC, suggesting their potential as diagnostic markers and therapeutic targets. This study emphasizes the need for further exploration into the specific roles of these isoforms, which could inform more personalized and effective treatment modalities for renal clear cell carcinoma.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

Cancer-associated fibroblasts induce an aggressive phenotypic shift in non-malignant breast epithelial cells via interleukin-8 and S100A8.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with tumor progression in breast cancer. Although crosstalk between breast cancer cells and CAFs has been studied, the effect of CAFs on non-neoplastic breast epithelial cells is not fully understood to date. Here, we investigated the effect of CAFs on aggressive phenotypes in non-neoplastic MCF10A breast epithelial cells. CAFs induced epithelial-to-mesenchymal transition (EMT) and invasive phenotype in MCF10A cells. S100A8, a potential prognostic marker in several cancers, was markedly increased in MCF10A cells by CAFs. S100A8 was crucial for CAFs-induced invasive phenotype of MCF10A cells. Among cytokines increased by CAFs, interleukin (IL)-8 induced S100A8 through transcription factors p65 NF-κB and C/EBPß. In a xenograft mouse model with MCF10A cells and CAFs, tumor was not developed, suggesting that coinjection with CAFs may not be sufficient for in vivo tumorigenicity of MCF10A cells. Xenograft mouse tumor models with MDA-MB-231 breast carcinoma cells provided an in vivo evidence for the effect of CAFs on breast cancer progression as well as a crucial role of IL-8 in tumor growth and S100A8 expression in vivo. Using a tissue microarray of human breast cancer, we showed that S100A8 expression was correlated with poor outcomes. S100A8 expression was more frequently detected in cancer-adjacent normal human breast tissues than in normal breast tissues. Together, this study elucidated a novel mechanism for the acquisition of invasive phenotype of non-neoplastic breast cells induced by CAFs, suggesting that targeting IL-8 and S100A8 may be an effective strategy against breast cancer.

Immunohistochemical and genetic characteristics of HPV-associated endocervical carcinoma with an invasive stratified mucin-producing carcinoma (ISMC) component.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described entity of human papillomavirus (HPV)-associated endocervical adenocarcinoma with phenotypic plasticity and aggressive clinical behavior. To identify the cell of origin of ISMC, we investigated the immunohistochemical expression of cervical epithelial cell markers (CK7, PAX8, CK5/6, p63, and CK17), stemness markers (ALDH1 and Nanog), and epithelial-mesenchymal transition (EMT) markers (Snail, Twist, and E-cadherin) in 10 pure and mixed type ISMCs with at least 10% of ISMC component in the entire tumor, seven usual type endocervical adenocarcinomas (UEAs), and seven squamous cell carcinomas (SCCs). In addition, targeted sequencing was performed in 10 ISMCs. ISMC was significantly associated with larger tumor size (p = 0.011), more frequent lymphovascular invasion and lymph node metastasis (p < 0.001), higher FIGO stage (p = 0.022), and a tendency for worse clinical outcomes (p = 0.056) compared to other HPV-associated subtypes. ISMC showed negative or borderline positivity for PAX8, CK5/6, and p63, which were distinct from UEA and SCC (p < 0.01). Compared to UEA and SCC, ISMC showed higher expression for ALDH1 (p = 0.119 for UEA and p = 0.009 for SCC), Snail (p = 0.036), and Twist (p = 0.119), and tended to show decreased E-cadherin expression (p = 0.083). In next-generation sequencing analysis, ISMC exhibited frequent STK11, MET, FANCA, and PALB2 mutations compared to conventional cervical carcinomas, and genes related to EMT and stemness were frequently altered. EMT-prone and stemness characteristics and peripheral expression of reserve cell and EMT markers of ISMC suggest its cervical reserve cell origin. We recommend PAX8, CK5/6, and p63 as diagnostic triple biomarkers for ISMC. These findings highlight the distinct biological basis of ISMC.

Genetic characteristics of gastric-type mucinous carcinoma of the uterine cervix.

Gastric-type mucinous carcinoma (GAS) is a recently established variant of endocervical mucinous adenocarcinoma that is characterized as being unrelated to HPV and having aggressive behavior and chemoresistance. GAS has a distinct morphology resembling nonneoplastic gastric glands or pancreaticobiliary adenocarcinoma, and their possible genetic similarity has been posed. In this study, next-generation sequencing was performed in 21 GAS cases using a customized panel including 94 cancer-associated genes. A total of 54 nonsynonymous somatic mutations were detected with an average mutation rate of 2.6 per lesion (range: 0-9). The most frequently mutated gene was TP53 (11/21, 52.4%), followed by STK11, HLA-B, PTPRS (4/21, 19.0%), FGFR4 (3/21, 14.3%), GNAS, BRCA2, ELF3, ERBB3, KMT2D, SLX4 (2/21, 9.5%), CDH1, EPCAM, KRAS, MLH1, RNF43, SNAI1, TWIST1, ZEB1, ZEB2, and so on (1/21, 4.8%). The mutated genes were mostly involved in signal transduction, DNA damage repair, and epithelial-mesenchymal transition (EMT). Correlation of TP53 mutation and p53 protein expression demonstrated that 31.3% with abnormal p53 expression harbored wild-type TP53. Compared to genetic features of gastric and pancreaticobiliary adenocarcinoma, TP53 mutations were frequent in both GAS and gastrointestinal adenocarcinoma. While KMT2D, ERBB3, and RNF43 mutations were shared between GAS and gastric adenocarcinoma, highly mutated genes in pancreatic ductal adenocarcinoma such as KRAS, SMAD4, and CDKN2A were rarely mutated in GAS. Of frequently mutated genes in cholangiocarcinoma, BAP1 and HLA-B were identified in GAS. Frequent EMT-related gene mutations suggested a possible role of EMT-related pathways in tumor dissemination and chemoresistance of GAS. In addition, GAS shared some genetic features with gastrointestinal adenocarcinoma. These findings provide a clue in understanding the biological basis of GAS.

Is Chest Computed Tomography Always Necessary Following Nephrectomy for Renal Cell Carcinoma? A Pilot Study in Single Tertiary Institution.

PURPOSE: We evaluated patterns of thoracic recurrence from renal cell carcinoma (RCC) following nephrectomy as a pilot study. METHODS: Data of consecutive 39 patients who had recurrent RCC in the abdomen or thorax following curative nephrectomy were evaluated. Recurrence sites were analyzed with abdomen and chest computed tomography (CT), or positron emission tomography/CT. All patients had no metastasis before initial nephrectomy. Recurrence was classified into 3 types according to the site of initially detected recurrence: (a) abdomen-only type, (b) abdomen and thorax type, and (c) thorax-only type. Vertebral level of recurrence site in the thorax-only level was investigated. University of California Los Angeles-Integrated Staging System was utilized for risk stratification (eg, low, intermediate, and high-risk). RESULTS: Rate of intermediate or high risk was 89.7% (37/39). Rate of thoracic recurrence, regardless of concurrent abdominal recurrence, was 71.8% (28/39). Rate of thorax-only type was 53.8% (21/39). In thorax-only type, median vertebral level of recurrence site was T10 (range, T3-T12), and no patient with low risk had metastasis above the T10 level alone. In intermediate or high risk, 89.2% (33/37) had at least a recurrent lesion at the level of T7 or lower. CONCLUSIONS: In low-risk patients, upper thoracic recurrence alone may be very rare after curative surgery. In majority of intermediate- or high-risk patients, initial recurrence may occur in the abdomen or lower thorax, which indicates abdomen CT covering T7 level may be an effective tool for postoperative follow-up in RCC.

A Clinical Trial of Combination Neoadjuvant Chemotherapy and Transoral Robotic Surgery in Patients with T3 and T4 Laryngo-Hypopharyngeal Cancer.

BACKGROUND: We conducted a prospective clinical trial of combination neoadjuvant chemotherapy, transoral robotic surgery (TORS), and customized adjuvant therapy in patients with locally advanced laryngo-hypopharyngeal cancer. METHODS: Between September 2008 and August 2016, 35 patients were enrolled in this clinical trial. RESULTS: Twenty patients had hypopharyngeal cancer and 15 had laryngeal cancer. Twenty-nine patients (82.9%) had T3 disease and six patients (17.1%) had T4 disease, while 12 patients (34.3%) had stage III disease and 23 patients (65.7%) had stage IV disease. The 3-year disease-specific survival rate was 82.4% and the 3-year disease-free survival rate was 69.48%. Decannulation was successful in 31 of 34 patients at an average of 18 days postoperatively. Among all patients, 83% exhibited a favorable subjective swallowing status, while five patients (14.4%) became dependent on feeding tubes. CONCLUSIONS: Neoadjuvant chemotherapy combined with TORS and customized adjuvant therapy, based on detailed pathological information, afforded favorable oncological outcomes and preserved organ functionalities in T3-T4 laryngo-hypopharyngeal cancer.

Combined Analysis of Biparametric MRI and Prostate-Specific Antigen Density: Role in the Prebiopsy Diagnosis of Gleason Score 7 or Greater Prostate Cancer.

OBJECTIVE: The objective of our study was to investigate the diagnostic performance of prebiopsy biparametric MRI (bpMRI) and prostate-specific antigen density (PSAD) for Gleason score (GS) 7 or greater prostate cancer (PCa). MATERIALS AND METHODS: Sixty-eight consecutive patients who underwent prebiopsy bpMRI and biopsy were included. Pathologic results of systemic and targeted biopsies were the reference standard. Qualitative analyses comprised Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and modified PI-RADSv2 (mPI-RADSv2). Quantitative analyses comprised mean apparent diffusion coefficient (ADC) of tumor, 10th percentile ADC of tumor, mean ADC ratio (ADCR) between benign tissues and PCa, and 10th percentile ADCR between benign tissues and PCa. The AUCs of the following combined models for GS 7 or greater PCa were investigated: model 1, PSAD and PI-RADSv2; model 2, PSAD and mPI-RADSv2; model 3, PSAD and mean ADC; model 4, PSAD and 10th percentile ADC; model 5, PSAD and mean ADCR; and model 6, PSAD and 10th percentile ADCR. RESULTS: The rate of GS 7 or greater PCa was 45.6% (31/68). AUCs of bpMRI parameters were 0.816 for PI-RADSv2, 0.838 for mPI-RADSv2, 0.820 for mean ADC, 0.823 for 10th percentile ADC, 0.780 for mean ADCR, and 0.763 for 10th percentile ADCR (p > 0.05 in all comparisons), whereas AUCs of prostate-specific antigen (PSA)-based parameters were 0.650 for PSA and 0.745 for PSAD (PSA vs PSAD, p = 0.017). AUCs of the combined models from 1 to 6 were 0.860, 0.880, 0.837, 0.844, 0.811, and 0.806, respectively, for biopsy GS 7 or greater PCa (p > 0.05 in all comparisons). CONCLUSION: Combined analysis of prebiopsy bpMRI and PSAD is useful for identifying GS 7 or greater PCa.

Solid Small Renal Mass Without Gross Fat: CT Criteria for Achieving Excellent Positive Predictive Value for Renal Cell Carcinoma.

OBJECTIVE: The purpose of this study was to evaluate CT criteria for achieving high positive predictive value (PPV) for renal cell carcinoma (RCC) in patients with solid small renal masses (SRMs) less than 4 cm without macroscopic fat. MATERIALS AND METHODS: One hundred fifty consecutive patients with a solid SRM without macroscopic fat (mean size ± SD, 2.5 ± 0.8 cm) who underwent CT including unenhanced, corticomedullary (CMP), and nephrographic phases (NP) were evaluated. Pathologically proven solid SRMs without macroscopic fat were classified into RCC (n = 131) and not RCC (n = 19). A "persistent low" sign was defined as a focal area or areas of low attenuation seen at the same location within the lesion on both CMP and NP imaging. Calcification, shape, and lesion attenuation on unenhanced CT were analyzed by two independent readers. RESULTS: PPV of CT criteria (calcification [criterion 1] or spherical shape, lower or equal attenuation, and persistent low sign [criterion 2]) for RCC was 98.3% (58/59) for reader 1 and 100% (53/53) for reader 2. Weighted kappa of interreader agreement was 1.000 for calcification, 0.966 of lower or equal attenuation, 0.834 for spherical shape, 0.823 for persistent low sign, and 0.829 for CT criteria. CONCLUSION: Interpretation of CT allowed reproducible and excellent PPV for RCC. Current CT criteria may effectively shorten the management process for solid SRMs without macroscopic fat by reducing unnecessary biopsy for a substantial number of RCCs showing typical CT findings.

Prognostic Significance of the Proportion of Ductal Component in Ductal Adenocarcinoma of the Prostate.

PURPOSE: In prostate cancer ductal adenocarcinoma is mixed with the usual acinar adenocarcinoma. However, to our knowledge whether the proportion of the ductal component affects oncologic outcomes is currently unknown. We investigated whether the proportion of the ductal component predicts oncologic outcomes in ductal adenocarcinoma. MATERIALS AND METHODS: We retrospectively reviewed clinical data on 3,038 patients with prostate cancer who underwent radical prostatectomy at our institution between 2005 and 2014. We excluded patients who received neoadjuvant or adjuvant treatment. Patients were stratified based on the proportion of the ductal component. We compared the probability of biochemical recurrence between groups and investigated how the proportion of the ductal component influences biochemical recurrence using Kaplan-Meier estimates and Cox regression models, respectively. RESULTS: Of 2,648 patients 101 (3.8%) had ductal adenocarcinoma and 2,547 (96.2%) had acinar adenocarcinoma. Freedom from biochemical recurrence in patients with ductal adenocarcinoma was significantly lower than in those with acinar adenocarcinoma (p <0.001). When ductal cases were stratified by the proportion of the ductal component, freedom from biochemical recurrence in the high ductal component group was significantly lower compared to that in the low ductal component group (30% or greater vs less than 30%, p = 0.023). On univariate and multivariate Cox regression analyses, a high ductal component was a significant predictor of biochemical recurrence (p <0.001). CONCLUSIONS: The prognosis for ductal adenocarcinoma can be stratified by the proportion of the ductal component. This marker could potentially be used as a surrogate for poor prognosis or as a determinant for adjuvant therapy.

A New Clinical Trial of Neoadjuvant Chemotherapy Combined With Transoral Robotic Surgery and Customized Adjuvant Therapy for Patients With T3 or T4 Oropharyngeal Cancer.

BACKGROUND: A prospective clinical trial of combination neoadjuvant chemotherapy, transoral robotic surgery (TORS), and customized adjuvant therapy for patients with locally advanced oropharyngeal cancer was conducted. METHODS: Between July 2009 and October 2016, 31 patients were enrolled in this clinical trial. RESULTS: The primary lesions were located in the tonsils of 27 patients and in the base of the tongue of 4 patients. Of the 31 patients, 16 (51.6%) were classified as T3 and 15 patients (48.4%) as T4a. Three patients (9.7%) had stage 3 disease, and 28 (90.3%) had stage 4 disease. The 5-year overall survival rate was 78.7%; the 5-year disease-specific survival rate was 85%; and the 5-year disease-free survival rate was 80.8%. At the final follow-up visit, 26 patients were alive with no evidence of disease, and 1 was alive with disease. Four patients died during the study: two of tumor-node-metastasis (TNM)-related disease and two of another condition. All the patients tolerated an oral diet at an average of 7.4 days postoperatively. At the subjective swallowing evaluation using the Functional Outcome Swallowing Scale score, 83.9% of the patients exhibited favorable outcomes. No patient was permanently dependent on a feeding tube. All the patients breathed and phonated in the absence of a permanent tracheotomy at the final follow-up evaluation. CONCLUSIONS: The treatment strategy in this study afforded good oncologic and functional outcomes for patients with locally advanced oropharyngeal cancer. Although future large-scale multicenter studies with longer follow-up periods are needed, this study showed that neoadjuvant chemotherapy combined with TORS is useful for treating advanced oropharyngeal cancer.

Prognostic Significance of Vas Deferens Invasion After Radical Prostatectomy in Patients with Pathological Stage T3b Prostate Cancer.

BACKGROUND: Seminal vesicle invasion (SVI) is associated with adverse clinical outcomes in prostate cancer (PCa) patients. Despite its anatomical similarity and close proximity to the seminal vesicle, the prognostic significance of vas deferens invasion (VDI) by PCa has not been elucidated. For these reasons, we investigated the impact of VDI on the oncological outcome of pT3b PCa in association with SVI. METHODS: We retrospectively reviewed the medical records of 3359 patients who had undergone a radical prostatectomy at our institution between January 2000 and December 2014 for PCa. Patients who received neoadjuvant or adjuvant treatment (radiation, androgen deprivation therapy, or both) and those without adequate medical records were excluded. A Kaplan-Meier analysis was performed to analyze biochemical recurrence-free survival (BCRFS), and a Cox regression model was used to test the influence of VDI on biochemical recurrence (BCR). RESULTS: Of 350 patients with pathologically confirmed SVI (pT3b), 87 (24.9%) had VDI, while the remaining 263 patients (75.1%) had isolated SVI. Compared with SVI patients without VDI, SVI patients with VDI were noted to have a significantly worse 5-year BCRFS (25.1 vs. 17.1%, respectively). VDI was a significant predictor of BCR in multivariate Cox regression analysis (hazard ratio 1.39, 95% confidence interval 1.02-1.90; p = 0.039). CONCLUSIONS: Our results shows that the prognosis of PCa with SVI might be further stratified by VDI status, thus suggesting the role of VDI either as a surrogate for poor prognosis or as a determinant for adjuvant therapy.

Diffusion-weighted imaging predicts upgrading of Gleason score in biopsy-proven low grade prostate cancers.

OBJECTIVE: To analyse whether diffusion-weighted imaging (DWI) predicts Gleason score (GS) upgrading in biopsy-proven low grade prostate cancer (PCa). PATIENTS AND METHODS: A total of 132 patients who had biopsy-proven low grade (GS < 7) PCa, 3T DWI results, and surgical confirmation were retrospectively included in the study. Clinical variables (prostate-specific antigen, greatest percentage of cancer in a biopsy core and percentage of positive cores) and DWI variables (minimum apparent diffusion coefficient [ADCmin ] and mean ADC [ADCmean ]) were evaluated. ADCmin was measured, by two independent, blinded readers, using a region of interest (ROI) of 5-10 mm2 at the area of lowest ADC value within a cancer, while ADCmean was measured using an ROI covering more than half of a cancer. Logistic regression and receiver-operating characteristic curve analyses were performed. RESULTS: The rate of GS upgrading was 46.1% (61/132). In both univariate and multivariate analyses, ADCmin and ADCmean were persistently significant for predicting GS upgrading (P < 0.05), whereas clinical variables were not (P > 0.05). In both readers' results, the area under the curve (AUC) of ADCmin was significantly greater than that of ADCmean (reader 1: AUC 0.760 vs 0.711; P < 0.001; reader 2: AUC 0.752 vs 0.714; P = 0.003). CONCLUSION: Our results showed that DWI may predict GS upgrading of biopsy-proven low grade PCa. The variable ADCmin in PCa may perform better than ADCmean .

Non-contrast magnetic resonance imaging for bladder cancer: fused high b value diffusion-weighted imaging and T2-weighted imaging helps evaluate depth of invasion.

OBJECTS: To investigate the utility of fused high b value diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) for evaluating depth of invasion in bladder cancer. METHODS: We included 62 patients with magnetic resonance imaging (MRI) and surgically confirmed urothelial carcinoma in the urinary bladder. An experienced genitourinary radiologist analysed the depth of invasion (T stage <2 or ≥2) using T2WI, DWI, T2WI plus DWI, and fused DWI and T2WI (fusion MRI). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were investigated. Area under the curve (AUC) was analysed to identify T stage ≥2. RESULTS: The rate of patients with surgically confirmed T stage ≥2 was 41.9% (26/62). Sensitivity, specificity, PPV, NPV and accuracy were 50.0%, 55.6%, 44.8%, 60.6% and 53.2%, respectively, with T2WI; 57.7%, 77.8%, 65.2%, 71.8% and 69.4%, respectively, with DWI; 65.4%, 80.6%, 70.8%, 76.3% and 74.2%, respectively, with T2WI plus DWI and 80.8%, 77.8%, 72.4%, 84.9% and 79.0%, respectively, with fusion MRI. AUC was 0.528 with T2WI, 0.677 with DWI, 0.730 with T2WI plus DWI and 0.793 with fusion MRI for T stage ≥2. CONCLUSION: Fused high b value DWI and T2WI may be a promising non-contrast MRI technique for assessing depth of invasion in bladder cancer. KEY POINTS: • Accuracy of fusion MRI was 79.0% for T stage ≥2 in bladder cancer. • AUC of fusion MRI was 0.793 for T stage ≥2 in bladder cancer. • Diagnostic performance of fusion MRI was comparable with T2WI plus DWI. • As a non-contrast MRI technique, fusion MRI is useful for bladder cancer.

PI-RADS version 2: quantitative analysis aids reliable interpretation of diffusion-weighted imaging for prostate cancer.

OBJECTIVES: To determine whether apparent diffusion coefficient (ADC) ratio aids reliable interpretation of diffusion-weighted imaging (DWI) for prostate cancer (PCa). METHODS: Seventy-six consecutive patients with PCa who underwent DWI and surgery were included. Based on pathologic tumour location, two readers independently performed DWI scoring according to the revised Prostate Imaging Reporting and Data System (PI-RADSv2). ADC ratios of benign to cancerous prostatic tissue were then measured independently and compared between cases showing concordant and discordant DWI scores ≥4. Area under the curve (AUC) and threshold of ADC ratio were analyzed for DWI scores ≥4. RESULTS: The rate of inter-reader disagreement for DWI score ≥4 was 11.8% (9/76). ADC ratios were higher in concordant vs. discordant DWI scores ≥4 (median, 1.7 vs. 1.1-1.2; p < 0.001). For DWI scores ≥4, the AUCs of ADC ratios were 0.970 for reader 1 and 0.959 for reader 2. In patients with an ADC ratio >1.3, the rate of inter-reader disagreement for DWI score ≥4 decreased to 5.9-6.0%. An ADC ratio >1.3 yielded 100% (reader 1, 54/54; reader 2, 51/51) positive predictive value for clinically significant cancer. CONCLUSION: ADC ratios may be useful for reliable interpretation of DWI score ≥4 in PI-RADSv2. KEY POINTS: • The ADC ratio correlated positively with DWI score of PI-RADSv2. • ADC ratio >1.3 was associated with concordant interpretation of DWI score ≥4. • ADC ratio >1.3 was associated with high PPV for clinically significant cancer. • ADC ratio is useful for reliable interpretation of DWI scoring in PI-RADSv2.

PI-RADS Version 2: Detection of Clinically Significant Cancer in Patients With Biopsy Gleason Score 6 Prostate Cancer.

OBJECTIVE: The purpose of this study was to analyze the utility of the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) in the detection of a clinically significant cancers in patients with prostate cancers with a biopsy Gleason score of 6. MATERIALS AND METHODS: A group of 182 consecutively registered patients with biopsy-proven prostate cancer with a Gleason score of 6 underwent MRI and radical prostatectomy. Clinically significant cancer was surgically defined as Gleason score of 7 or greater, tumor volume of 0.5 cm3 or greater, or tumor category T3 or greater. Clinical parameters (prostate-specific antigen level, greatest percentage of biopsy core, and percentage of positive cores) and the PI-RADSv2 ratings by three independent readers (experienced readers 1 and 2, inexperienced reader 3) were investigated. Cutoffs and the diagnostic performance of PI-RADSv2 for clinically significant cancer were analyzed. RESULTS: Clinically significant cancer was found in 87.4% (159/182) of patients. The cutoff PI-RADSv2 score for clinically significant cancer was 4 for readers 1 and 2 and 5 for reader 3. The AUCs were 0.829 and 0.853 for readers 1 and 2 (p < 0.001) and 0.602 for reader 3 (p = 0.067). For reader 1, sensitivity was 89.9% (143/159); specificity, 69.6% (16/23); positive predictive value, 95.3% (143/150); negative predictive value, 50.0% (16/32); and accuracy, 87.4% (159/182). The corresponding values for reader 2 were 81.1% (129/159), 82.6% (19/23), 97.0% (129/133), 38.8% (19/49), and 81.3% (148/182). For the experienced readers, 66.7-81.3% of patients with false-negative results had clinically significant cancers with tumor volume less than 1 cm3. CONCLUSION: PI-RADSv2 may help experienced readers identify clinically significant prostate cancers in patients with a biopsy Gleason score of 6. However, some small (< 1 cm3) clinically significant cancers can be missed when PI-RADSv2 is used.

Prognostic Significance of Macroscopic Appearance in Clear Cell Renal Cell Carcinoma and Its Metastasis-Predicting Model.

Prognostic significance of macroscopic appearance of clear cell renal cell carcinoma (ccRCC) has not yet been studied. This study aimed to define the prognostic significance of macroscopic appearance and to propose a prognostic model for post-operative metastasis in ccRCC. A total of 1,025 patients with ccRCC were analyzed for the development dataset. A separate cohort of 399 such patients was used as an external validation dataset. Macroscopic appearances were initially divided into four groups, but were later divided into two groups: a simple nodular group (700 cases, 68.3%) and an irregular outline group (325 cases, 32.7%). During the 66.1-month mean follow-up period, 98 patients (9.6%) developed metastasis. Univariate analysis revealed that metastasis was associated with older age, radical nephrectomy, larger tumor size, higher tumor grade and stage, and the irregular outline group. On multivariate analysis, age, tumor size, and macroscopic appearance remained as independent prognostic factors. These factors were used to build a prognostic model, which divided into three risk groups. The probabilities of 5-year metastasis-free survival in the low-, intermediate-, and high-risk groups were 98%, 83%, and 53%, respectively. The results showed prognostic significance of macroscopic appearance in ccRCC and propose a prognostic model to guide post-operative management of patients with ccRCC.

MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis.

BACKGROUND: We aimed to identify alteration of cancer-related miRNAs in HGPIN and PCa, and to investigate the clinical implications of HGPIN as a precancerous lesion of PCa. METHODS: Clinicopathologic analysis based on the status of HGPIN was performed in 388 patients who received radical prostatectomy between January 2005 and December 2008 in Severance Hospital. Among them, 10 paired HGPIN and PCa were prepared to perform miRNA microarray and quantitative real-time PCR. Fifty-two prostatectomy specimens were used to further validation of protein expression that was assessed by immunohistochemical staining (IHC) in matched non-neoplastic prostatic tissue (NPT), HGPIN, and PCa. Functional analysis was performed using a prostate normal cell line (RWPE-1) and two prostate cancer cell lines (LNCaP, PC-3) for comparison of expression of miR-155 and STAT3 mRNA before and after treatment of miR-155 mimetics/antagomir into each cell line. RESULTS: Patients with HGPIN had significantly less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower incidence of death, and longer overall survival compared to patients without HGPIN. MiR-155, miR-210, miR-153, and miR-200c were downregulated in HGPIN and PCa in common, compared to NPT. As putative target mRNAs, mRNA expression level of STAT3, ZEB1, and BACH1 was increased in PCa and HGPIN compared to NPT. mRNA expression level of ephrin-A3 was increased in PCa compared to NPT, and FGFRL1 was decreased in PCa compared to HGPIN and NPT. Protein expression assessed by IHC showed correlated results in STAT3, ZEB1, and ephrin-A3. Moreover, STAT3 and ZEB1 increased in a stepwise manner, from NPT to PCa. Treatment of miR-155 antagomir increased STAT3 mRNA expression in RWPE-1 cells, whereas treatment of miR-155 mimetics into PC-3 cells significantly decreased STAT3 expression. CONCLUSIONS: STAT3 and ZEB1 could be the key molecules altered at the early stages of carcinogenesis, especially in HGPIN. Prostate 76:937-947, 2016. © 2016 Wiley Periodicals, Inc.

Prostate Cancer: PI-RADS Version 2 Helps Preoperatively Predict Clinically Significant Cancers.

Purpose To retrospectively analyze whether Prostate Imaging Reporting and Data System (PI-RADS) version 2 is helpful for the detection of clinically significant prostate cancer. Materials and Methods Institutional review board approved this retrospective study. A total of 425 patients with prostate cancer who had undergone magnetic resonance (MR) imaging and radical prostatectomy were included. Preoperative parameters such as prostate-specific antigen, biopsy Gleason score, greatest percentage of the core, percentage of the positive core number, and score at PI-RADS version 2 with MR imaging were investigated. Two independent readers performed PI-RADS scoring. Clinically significant prostate cancer was defined as follows: (a) Gleason score of 7 or greater, (b) tumor volume of 0.5 cm(3) or greater, or a (c) positive extracapsular extension or seminal vesicle invasion. The reference standard was based on review of surgical specimen. Logistic regression was conducted to determine which parameters are associated with the presence of clinically significant cancer. Interreader agreement (ie, score ≥4 or not) was investigated by using κ statistics. Results At univariate analysis, all of the preoperative parameters were significant for clinically significant prostate cancer (P < .05). However, multivariate analysis revealed that PI-RADS score was the only significant parameter for both readers (reader 1: odds ratio = 28.170, P = .002; reader 2: odds ratio = 5.474, P = .007). The interreader agreement was excellent for PI-RADS score of 4 or greater (weighted κ = 0.801; 95% confidence interval: 0.737, 0.865). Conclusion The use of PI-RADS version 2 may help preoperatively diagnose clinically significant prostate cancer. (©) RSNA, 2016.