Fumitaka Koga

Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness

ObjectivesThe diagnostic performance of diffusion-weighted magnetic resonance imaging (DW-MRI) in bladder cancer and the potential role of apparent diffusion coefficient (ADC) values in predicting pathological bladder cancer phenotypes associated with clinical aggressiveness were investigated.MethodsOne hundred and four bladder cancer patients underwent DW-MRI and T2-weighted magnetic resonance imaging (T2W-MRI) before transurethral resection. The image sets were reviewed by two independent radiologists. ADC values were measured in 121 eligible tumours.ResultsIn detecting patients with bladder cancer, DW-MRI exhibited high sensitivity equivalent to that of T2W-MRI (>90%). Interobserver agreement was excellent for DW-MRI (κ score, 0.88) though moderate for T2W-MRI (0.67). ADC values were significantly lower in high-grade (vs. low-grade, P < 0.0001) and high-stage (T2 vs. T1 vs. Ta, P < 0.0001) tumours. At a cut-off ADC value determined by partition analysis, clinically aggressive phenotypes including muscle-invasive bladder cancer (MIBC) and high-grade T1 disease were differentiated from less aggressive phenotypes with a sensitivity of 88%, a specificity of 85% and an accuracy of 87%.ConclusionDW-MRI exhibits high diagnostic performance in bladder cancer with excellent objectivity. The ADC value could potentially serve as a biomarker to predict clinical aggressiveness in bladder cancer.

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis.

Significance TNF receptor-associated protein (TRAP1) is found predominantly in mitochondria. A possible direct impact of TRAP1 on mitochondrial metabolism remains unexplored. We used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1 deficiency promotes increased mitochondrial respiration, fatty acid oxidation, tricarboxylic acid cycle intermediates, ATP and reactive oxygen species, while concomitantly suppressing glucose metabolism. TRAP1 deficiency also results in strikingly enhanced cell motility and invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.

Impact of C-Reactive Protein Kinetics on Survival of Patients with Metastatic Renal Cell Carcinoma

BACKGROUND Pretreatment C-reactive protein (CRP) level has been shown to be prognostic for metastatic renal cell carcinoma (mRCC). OBJECTIVES To demonstrate that CRP would be a biomarker for mRCC, we evaluated the impact of CRP kinetics on survival. DESIGN, SETTING, AND PARTICIPANTS One hundred eight patients with mRCC were treated from 1994 to 2007 with a median follow-up period of 18 mo (interquartile range: 7-40 mo). INTERVENTION All patients underwent multimodal therapeutic intervention. MEASUREMENT Patients were divided into three groups according to CRP kinetics. Patients whose pretreatment CRP levels were <5mg/l, patients whose pretreatment CRP levels were >5mg/l and normalized (<5mg/l) at least one time during treatment, and patients whose pretreatment CRP levels were >5mg/l and never normalized were assigned to nonelevated, normalized, and non-normalized CRP groups, respectively. The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined. RESULTS AND LIMITATIONS In 61 of the 108 patients (56%), CRP levels were elevated at the diagnosis of mRCC. During treatment, CRP levels were normalized in 30 of 61 patients (49%), whereas CRP levels remained elevated in the remaining 31 patients. Overall survival rates were significantly different between nonelevated, normalized, and non-normalized CRP groups (p<0.001) with 2-yr survival rates of 69%, 55%, and 4%, respectively. In multivariate analysis, CRP kinetics was an independent significant factor for overall survival. Normalized CRP period was significantly correlated with overall survival period in 78 patients who died of disease. Since this is a small retrospective study on patients within the past era of immunotherapy, larger confirmatory studies in the current era of targeted therapy are needed. CONCLUSIONS CRP can be a novel, widely available biomarker for patients with mRCC.

Development, Validation, and Head-to-Head Comparison of Logistic Regression-Based Nomograms and Artificial Neural Network Models Predicting Prostate Cancer on Initial Extended Biopsy

OBJECTIVES Using cohorts examined by extended biopsy, we developed and validated multivariate models predicting prostate cancer on initial biopsy and examined whether these extended biopsy-based models outperform previously established models. METHODS Initial extended biopsy (median 22 cores) was performed in 1509 Japanese men including 1083 at Tokyo Medical and Dental University Hospital (TMDU) and 426 at Cancer Institute Hospital (CIH). Logistic regression-based nomograms 1 and artificial neural network (ANN) 1 incorporating age, digital rectal examination, and prostate-specific antigen (PSA) and free PSA, and nomogram 2 and ANN2 further incorporating transrectal ultrasound (TRUS) findings and prostate volume were constructed on the TMDU data. These and previously established models were externally validated on the CIH data set and predictive accuracy was compared directly. RESULTS Without TRUS-derived information, nomogram 1 outperformed the ANN1. With TRUS-derived information, nomogram 2 was more accurate than ANN2. External validation revealed applicability of the Western models to Japanese population, superiority of the nomograms over ANN models, and better predictive accuracy of our extended biopsy-based nomograms than the previous 6-10-core biopsy-based models. Using nomograms 1 and 2, 16% and 19% unnecessary biopsies would be saved at 95% sensitivity. CONCLUSIONS We developed new nomograms predicting prostate cancer on initial biopsy in men with PSA <20ng/ml. Predictive accuracy of these extended biopsy-based nomograms is better than those of previously established models based on 6-10-core biopsies. Our models might help clinicians to decide if a patient requires biopsy and to avoid unnecessary biopsies.

Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer.

OBJECTIVES To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DWI) in predicting therapeutic response to low-dose chemoradiotherapy (LCRT) against muscle-invasive bladder cancer (MIBC). Accurate assessment of response to induction therapy is an essential part of bladder-sparing therapeutic protocols against MIBC. However, conventional imaging studies are not useful in evaluating therapeutic response because of their inability to distinguish residual cancer from changes secondary to the treatment. METHODS Twenty patients with clinical T2-4aN0M0 bladder urothelial carcinoma (T2/T3/T4a: n = 10/8/2) who underwent induction LCRT comprising external beam radiotherapy to the bladder (40 Gy) concomitant with 2 cycles of cisplatin administration (20 mg/d for 5 days) followed by partial (n = 13) or radical cystectomy (n = 7) were prospectively enrolled. The patients underwent magnetic resonance imaging examinations with T2-weighted imaging (T2W), dynamic contrast-enhanced T1-weighted imaging (DCE), and DWI after LCRT. A finding of each protocol was compared with a pathologic finding of cystectomy specimen. RESULTS Pathologic examination of cystectomy specimens revealed pathologic complete response in 13 (65%) of the 20 patients. The sensitivity/specificity/accuracy of T2W, DCE, and DWI in predicting pathologic response was 43/45/44%, 57/18/33%, and 57/92/80%, respectively. Despite comparable sensitivity, DWI was significantly superior in specificity and accuracy to T2W (P = .03 and .02, respectively) and DCE (P = .002 for both). CONCLUSIONS This is the first study to show the feasibility of DWI over T2W and DCE for assessing therapeutic response to induction chemoradiotherapy against MIBC. The high specificity of DWI indicates that DWI is useful to accurately predict pathologic complete response, allowing more optimal patient selection in bladder-sparing protocols.

Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential

To evaluate the long‐term outcome of bladder papillary urothelial neoplasms of low malignant potential (PUNLMP).

High Diagnostic Ability of Multiparametric Magnetic Resonance Imaging to Detect Anterior Prostate Cancer Missed by Transrectal 12-Core Biopsy

PURPOSE We clarified the diagnostic ability of multiparametric magnetic resonance imaging to reveal anterior cancer missed by transrectal 12-core prostate biopsy based on the results of 3-dimensional 26-core prostate biopsy, which is a combination of transrectal 12-core and transperineal 14-core biopsies. MATERIALS AND METHODS The study population consisted of 324 patients who prospectively underwent prebiopsy multiparametric magnetic resonance imaging and then 3-dimensional 26-core prostate biopsy at a single institution. We defined transrectal 12-core negative cancer as cancer detected by transperineal 14-core but not transrectal 12-core prostate biopsy. We focused on cancer in the anterior region. Any findings suspicious for malignancy in the region anterior to the urethra on multiparametric magnetic resonance imaging were defined as an anterior lesion on imaging. Significant cancer was defined as a biopsy Gleason score of 4 + 3 or greater, a greater than 20% positive core and/or a maximum cancer length of 5 mm or greater. Associations between an anterior lesion on imaging and transrectal 12-core negative cancer were investigated. RESULTS The overall cancer detection rate on 3-dimensional 26-core prostate biopsy was 39% (128 of 324 cases), of which 28% (36 of 128) were transrectal 12-core negative cancers. An anterior lesion on prebiopsy multiparametric magnetic resonance imaging was identified in 20% of men overall (65 of 324). Of men with and without an anterior lesion on imaging 40% (26 of 65) and 3.8% (10 of 259), respectively, had transrectal 12-core negative cancer. Significant transrectal 12-core negative cancer was observed in 0.4% (1 of 259 men) without an anterior lesion on imaging. Prebiopsy multiparametric magnetic resonance imaging revealed an anterior lesion in 92% of cases (11 of 12) of significant transrectal 12-core negative cancer. CONCLUSIONS Prebiopsy multiparametric magnetic resonance imaging has the potential to efficiently select men who could advantageously undergo anterior samplings, in addition to transrectal 12-core prostate biopsy.

C‐reactive protein level predicts prognosis in patients with muscle‐invasive bladder cancer treated with chemoradiotherapy

To investigate the effect of C‐reactive protein (CRP) level on the prognosis of patients with muscle‐invasive bladder cancer treated with chemoradiotherapy (ChRT), as it is increasingly recognized that the presence of a systemic inflammatory response is associated with poor survival in various malignancies.

Sarcopenia as a prognostic biomarker of advanced urothelial carcinoma.

Objectives Sarcopenia, a novel concept reflecting the degenerative loss of skeletal muscle mass, is an objective indicator of cancer cachexia. We investigated its role as a prognostic biomarker in advanced urothelial carcinoma (UC) patients. Methods This retrospective study consisted of 88 UC patients with cT4 and/or metastases to lymph nodes/distant organs. Skeletal muscle index (SMI), an indicator of whole-body muscle mass, was measured from computed tomography (CT) images at the diagnosis. Sarcopenia was defined as SMIs of <43 cm2/m2 for males with body mass index (BMI) <25 cm2/m2, <53 cm2/m2 for males with BMI ≥25 cm2/m2, and <41 cm2/m2 for females. Predictors of overall survival (OS) were examined using Cox proportional hazard models. Results Sixty-seven patients (76%) died during the median follow-up of 13 months. The median OS rate was 13 months. Multivariate analysis revealed that SMI was a significant and independent predictor of shorter OS (hazard ratio (HR) 0.90, P <0.001). In the present cohort, 53 (60%) were diagnosed with sarcopenia. The median OS rates were 11 and 31 months for sarcopenic and non-sarcopenic patients, respectively (P <0.001). On multivariate analysis, sarcopenia was a significant and independent predictor of shorter OS (HR 3.36, P <0.001), along with higher C-reactive protein (CRP) (P = 0.001), upper urinary tract cancer (P = 0.007), higher lactate dehydrogenase (LDH) (P = 0.047), and higher alkaline phosphatase (ALP) (P = 0.048). Conclusion Sarcopenia, which is readily evaluated on routine CT scans, is a useful prognostic biomarker of advanced UC. Non-sarcopenic patients can expect long-term survival. Evaluating sarcopenia can be helpful for decision-making processes in the management of advanced UC patients.

Apparent diffusion coefficient value reflects invasive and proliferative potential of bladder cancer.

To elucidate a role of apparent diffusion coefficient (ADC) value as a biomarker of bladder cancer, we investigated its associations with Ki‐67 labeling index (LI) along with classical clinicopathological prognosticators.