Soichiro Yoshida

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.

11C-Choline Positron Emission Tomography in Prostate Cancer: Primary Staging and Recurrent Site Staging

Objectives: To evaluate the usefulness of 11C-choline positron emission tomography (PET) for primary staging and re-staging of prostate cancer. Patients and Methods:11C-choline PET, a total of 22 scans, was performed on 13 patients with histologically proven prostate cancer in primary staging (n = 6) and recurrent site staging; following radical prostatectomy (n = 5) and following radiation therapy (n = 3). In 1 patient, 11C-choline PET was performed in both primary staging and re-staging. Also, 3 patients histologically proven to have no malignant prostate were included. Results: Because urinary 11C-choline activity was low, it did not interfere with the visualization of pelvic structures. 11C-choline PET visualized normal prostate with a mean SUV of 2.99 (range 2.27–3.68) and primary prostate cancer as a hot spot in 5/6 scans with a mean SUV of 4.21 (range 2.99–6.2). In re-staging, 11C-choline PET was true positive in 9/16 scans and true negative in 2/16 scans. 5/16 scans in 2 patients were false negative with negative conventional imaging. Conclusions: In primary staging, 11C-choline PET may not be of use because of no reliable differential 11C-choline uptake of BPH and prostate cancer. On the other hand, 11C-choline PET may be of value in recurrent site staging and monitoring for the prostate cancer.

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.

Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats.

To investigate the effects of reactive oxygen species (ROS) on the micturition reflex in vivo, especially in bladder afferent signalling in rats, as several pathophysiological conditions in the urinary bladder (e.g. ischaemia/reperfusion and inflammation) are characterized by the formation of ROS.

Asymmetric Hsp90 N Domain SUMOylation Recruits Aha1 and ATP-Competitive Inhibitors

The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90s function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.

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.

Usefulness of Pre-biopsy Multiparametric Magnetic Resonance Imaging and Clinical Variables to Reduce Initial Prostate Biopsy in Men with Suspected Clinically Localized Prostate Cancer

PURPOSE We evaluated the usefulness of pre-biopsy multiparametric magnetic resonance imaging and clinical variables to decrease initial prostate biopsies. MATERIALS AND METHODS We prospectively evaluated 351 consecutive men with prostate specific antigen between 2.5 and 20 ng/ml, and/or digital rectal examination suspicious for clinically localized disease. All men underwent pre-biopsy multiparametric magnetic resonance imaging and initial 14 to 29-core biopsy, including anterior sampling. Three definitions of significant cancer were defined based on Gleason score and cancer volume (percent positive core and/or maximum cancer length). The overall cohort was divided into men at low risk-prostate specific antigen less than 10 ng/ml and normal digital rectal examination, and high risk-prostate specific antigen 10 ng/ml or greater and/or abnormal digital rectal examination. We evaluated the frequency of significant cancer according to magnetic resonance imaging and risk categories. Clinical variables as significant cancer predictors were analyzed using logistic regression. The sensitivity, specificity, and positive and negative predictive values of magnetic resonance imaging were calculated with or without clinical variables for significant cancer. RESULTS The frequency of significant cancer in men with negative vs positive magnetic resonance imaging was 9% to 13% vs 43% to 50% in the low risk group and 47% to 51% vs 68% to 71% in the high risk group. In men at low risk with negative magnetic resonance imaging prostate volume was the only significant predictor of significant cancer. In the low risk group the negative predictive value for significant cancer of a combination of positive magnetic resonance imaging and lower prostate volume (less than 33 ml) was 93.7% to 97.5%. CONCLUSIONS Pre-biopsy multiparametric magnetic resonance imaging along with prostate volume decreases the number of initial prostate biopsies by discriminating between significant cancer and other cancer in men with prostate specific antigen less than 10 ng/ml and normal digital rectal examination.

Diffusion‐weighted magnetic resonance imaging in the differentiation of angiomyolipoma with minimal fat from clear cell renal cell carcinoma

The aim of the present study was to evaluate diffusion‐weighted (DW) magnetic resonance imaging (MRI) in differentiating between minimal fat angiomyolipoma (MFAML) and clear cell renal cell carcinoma (CCRCC). Forty‐one solid renal tumors without visible macroscopic fat on unenhanced computed tomography images were evaluated by MRI, including DW‐MRI, and were diagnosed pathologically as CCRCC (n = 36) or MFAML (n = 5). To evaluate the heterogeneity of diffusion in each tumor, the signals of the tumors on DW‐MRI were analyzed subjectively and the apparent diffusion coefficient (ADC) values and histograms assessed objectively. Thirty‐three of 36 CCRCC (92%) exhibited a heterogeneous signal on DW‐MRI and several peaks in the ADC value histogram, whereas four of five MFAML exhibited a homogeneous signal on DW‐MRI and a single prominent peak in the histogram. The standard deviations of the ADC values were significantly smaller for MFAML than for CCRCC (P = 0.0015). In conclusion, DW‐MRI can be considered a useful and noninvasive addition to the preoperative differentiation of CCRCC and MFAML.