Incidence of intraductal carcinoma, multifocality and bilateral significant disease in radical prostatectomy specimens from Japan and United States.

Significant differences, including epidemiologic, clinical, pathologic and genetic, exist between Asian and Caucasian prostate cancer. Detailed pathologic data are, however, scarce. We studied in detail and compared the pathological features of prostate cancer in radical prostatectomy specimens in 228 patients (117 Japan, 111 US). Japanese prostate cancer had a higher Gleason grade group (mean 2.67 vs. 2.42 US, P < 0.05), but lower pathological stage (72 % pT2 and 28 % pT3 vs 55 % pT2 and 45 % pT3 US, P < 0.05). Japanese cancer showed significantly more tumor foci (3.8 vs 2.9 US, P < 0.05), and higher incidence of bilateral significant disease (81.3 % vs. 66.7 % US, P < 0.05). The dominant tumor nodules in Japanese cases had higher Gleason grade group (mean 2.73 vs. 2.40 US, P < 0.05). The incidence of intraductal carcinoma was significantly higher in Japanese patients (35.3 % vs. 12.6 % US, P < 0.01), which was independent of Gleason score (7: 30.9 % Japan vs 11.8 % US, P < 0.01; ≥ 8: 87.5 % Japan vs 28.6 % US, P < 0.01) and tumor stage (pT2: 24.1 % Japan vs 6.6 % US, P < 0.01; pT3: 62.9 % Japan vs 20 % US, P < 0.01). These findings demonstrate distinct pathological features in prostate cancer between Japanese and Caucasian patients, and may have important diagnostic and therapeutic implications.

Prediction of prostate cancer recurrence using quantitative phase imaging: Validation on a general population.

Prediction of biochemical recurrence risk of prostate cancer following radical prostatectomy is critical for determining whether the patient would benefit from adjuvant treatments. Various nomograms exist today for identifying individuals at higher risk for recurrence; however, an optimistic under-estimation of recurrence risk is a common problem associated with these methods. We previously showed that anisotropy of light scattering measured using quantitative phase imaging, in the stromal layer adjacent to cancerous glands, is predictive of recurrence. That nested-case controlled study consisted of specimens specifically chosen such that the current prognostic methods fail. Here we report on validating the utility of optical anisotropy for prediction of prostate cancer recurrence in a general population of 192 patients, with 17% probability of recurrence. Our results show that our method can identify recurrent cases with 73% sensitivity and 72% specificity, which is comparable to that of CAPRA-S, a current state of the art method, in the same population. However, our results show that optical anisotropy outperforms CAPRA-S for patients with Gleason grades 7-10. In essence, we demonstrate that anisotropy is a better biomarker for identifying high-risk cases, while Gleason grade is better suited for selecting non-recurrence. Therefore, we propose that anisotropy and current techniques be used together to maximize prediction accuracy.

Association Between Progranulin and Gaucher Disease.

BACKGROUND: Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of ß-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. METHODS: Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed. FINDINGS: Serum PGRN levels were significantly lower in GD patients (96.65±53.45ng/ml) than those in healthy controls of the general population (164.99±43.16ng/ml, p<0.0001) and of Ashkenazi Jews (150.64±33.99ng/ml, p<0.0001). Four GRN gene SNPs, including rs4792937, rs78403836, rs850713, and rs5848, and three point mutations, were identified in a full-length GRN gene sequencing in 40 GD patients. Large scale SNP genotyping in 161 GD and 142 healthy controls was conducted and the four SNP sites have significantly higher frequency in GD patients. In addition, "aged" and challenged adult PGRN null mice develop GD-like phenotypes, including typical Gaucher-like cells in lung, spleen, and bone marrow. Moreover, lysosomes in PGRN KO mice exhibit a tubular-like appearance. PGRN is required for the lysosomal appearance of GCase and its deficiency leads to GCase accumulation in the cytoplasm. More importantly, recombinant PGRN is therapeutic in various animal models of GD and human fibroblasts from GD patients. INTERPRETATION: Our data demonstrates an unknown association between PGRN and GD and identifies PGRN as an essential factor for GCase's lysosomal localization. These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD.

Prostate Cancer Detection Using Computed Very High b-value Diffusion-weighted Imaging: How High Should We Go?

RATIONALE AND OBJECTIVES: The aim of this study was to assess prostate cancer detection using a broad range of computed b-values up to 5000 s/mm(2). MATERIALS AND METHODS: This retrospective Health Insurance Portability and Accountability Act-compliant study was approved by an institutional review board with consent waiver. Forty-nine patients (63 ± 8 years) underwent 3T prostate magnetic resonance imaging before prostatectomy. Examinations included diffusion-weighted imaging (DWI) with b-values of 50 and 1000 s/mm(2). Seven computed DWI image sets (b-values: 1000, 1500, 2000, 2500, 3000, 4000, and 5000 s/mm(2)) were generated by mono-exponential fit. Two blinded radiologists (R1 [attending], R2 [fellow]) independently evaluated diffusion weighted image sets for image quality and dominant lesion location. A separate unblinded radiologist placed regions of interest to measure tumor-to-peripheral zone (PZ) contrast. Pathologic findings from prostatectomy served as reference standard. Measures were compared between b-values using the Jonckheere-Terpstra trend test, Spearman correlation coefficient, and generalized estimating equations based on logistic regression for correlated data. RESULTS: As b-value increased, tumor-to-PZ contrast and benign prostate suppression for both readers increased (r = +0.65 to +0.71, P ≤ 0.001), whereas anatomic clarity, visualization of the capsule, and visualization of peripheral-transition zone edge decreased (r = -0.69 to -0.75, P ≤ 0.003). Sensitivity for tumor was highest for R1 at b1500-3000 (84%-88%) and for R2 at b1500-2500 (70%-76%). Sensitivities for both pathologic outcomes were lower for both readers at both b1000 and the highest computed b-values. Sensitivity for Gleason >6 tumor was highest for R1 at b1500-3000 (90%-93%) and for R2 at 1500-2500 (78%-80%). The positive predictive value for tumor for R1 was similar from b1000 to 4000 (93%-98%) and for R2 was similar from b1500 to 4000 (88%-94%). CONCLUSIONS: Computed b-values in the range of 1500-2500 s/mm(2) (but not higher) were optimal for prostate cancer detection; b-values of 1000 or 3000-5000 exhibited overall lower performance.

Length of capsular contact for diagnosing extraprostatic extension on prostate MRI: Assessment at an optimal threshold.

PURPOSE: To evaluate the length of capsular contact of dominant lesions on multiparametric prostate magnetic resonance imaging (MRI) for predicting extraprostatic extension (EPE) and to determine a threshold value to apply in clinical practice. MATERIALS AND METHODS: Ninety patients undergoing 3T prostate MRI before prostatectomy were included. Two independent readers (R1, R2) recorded for each lobe the presence or absence of capsular irregularity on T2 -weighted imaging (T2 WI) and of overt measurable EPE. Readers also recorded the length of capsular contact of each lobe's dominant lesion for T2 WI and the apparent diffusion coefficient (ADC) map. Based on prostatectomy specimens, EPE was recorded for each lobe and classified as focal (single focus ≤0.5 mm in depth) vs. established. Receiver operating characteristic analysis, logistic regression, and kappa coefficients were used to assess interpretive approaches on a side-specific basis. RESULTS: The optimal thresholds were 6 mm and 7 mm of contact using T2 WI and ADC for any EPE, and 10 mm and 7 mm using T2 WI and ADC for nonfocal EPE (AUCs 81.0-82.5%). Capsular contact had higher sensitivity, yet lower specificity, than subjective interpretations for any EPE and for nonfocal EPE (all P ≤ 0.018, aside from any EPE for R2 using ADC). Length of contact exhibited more substantial gains in sensitivity (9-20% for any EPE; 34-41% for nonfocal EPE) than losses in specificity (6-13% for any EPE; 17-27% for nonfocal EPE) compared with subjective interpretations. Interreader agreement: 0.70 for assessments based on length of contact; 0.49-0.59 for subjective assessments. CONCLUSION: Length of capsular contact of dominant lesions can improve interreader agreement and sensitivity for EPE compared with subjective features, with relatively mild specificity loss.

Gleason score 3 + 4=7 prostate cancer with minimal quantity of gleason pattern 4 on needle biopsy is associated with low-risk tumor in radical prostatectomy specimen.

A modified Gleason grading system as proposed in the 2005 International Society of Urological Pathology (ISUP) consensus meeting is the current grading system for prostate cancer. With this modified ISUP Gleason grading system, many Gleason score (GS) 6 cancers by the old grading system are upgraded to GS7 cancers on biopsy diagnosis even with minimal quantity (≤5%) of Gleason pattern 4 (GP4) component (GS7miniGP4). However, grade concordance between the core needle biopsy of GS7miniGP4 and the corresponding radical prostatectomy (RP) specimens has not been studied. In this study, we analyzed the pathologic features of 256 consecutive needle biopsies and their corresponding RP specimens. The quantity of GP4 was calculated as the percentage of total cancer for GS7 cancer in the biopsy. Of 256 biopsies, 88 (34.4%), 107 (41.8%), and 61 (23.8%) had a GS of 6, 3+4=7, and 4+3=7, respectively. Of 107 biopsies with GS 3+4=7, 22 (20.6%) are GS7miniGP4. Ten of 22 cases of G7miniGP4 in the biopsies (45%) had pathologically insignificant tumor in the RP. The quantity of GP4 in the GS7 biopsy significantly correlated with GS, pathologic stage, and total tumor volume in the corresponding RP. The GS, pathologic stages, total tumor volume, and insignificant tumor rate in RP were not significantly different between the biopsy groups of GS 3+3=6 and GS7miniGP4, whereas those parameters were significantly different between biopsy groups of GS 3+3=6 and GS 3+4=7 with GP4 6% to 50% and between biopsy groups of GS7miniGP4 and GS7 with GP4 6% to 50%. Our data demonstrate that pathologic parameters in the RP are similar between the biopsy groups of GS7miniGP4 and GS6, and the grading of cases with biopsy GS7miniGP4 is often downgraded in RP specimens. The clinical significance of minimal quantity (≤5%) of GP4 in biopsies with GS7 prostate cancer needs to be further evaluated, particularly because of its potential impact on clinical decisions between active surveillance versus surgery.

Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial.

IMPORTANCE: Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point. OBJECTIVE: To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. INTERVENTION: Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or, as placebo, calcium caseinate (n=90). MAIN OUTCOMES AND MEASURES: Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of ≥0.07 ng/mL) over the first 2 years following randomization and time to recurrence. RESULTS: The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53-1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation. CONCLUSION AND RELEVANCE: Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00765479.

Bilateral tubulocystic renal cell carcinomas in diabetic end-stage renal disease: first case report with cytogenetic and ultrastructural studies.

Tubulocystic renal cell carcinoma (TC-RCC) is a rare renal tumor composed of well-differentiated tubules and cysts lined by neoplastic cells with eosinophilic cytoplasm and prominent nucleoli. The origin of the tumor cells is still controversial. TC-RCC typically arises unilaterally. Involvement of both kidneys by multifocal TC-RCC has not been reported. In this study we report the first case of bilateral and multifocal TC-RCC. Immunohistochemical, cytogenetic and ultrastructural studies suggest TC-RCC is closely related to papillary RCC.

Expression of Sox10 and c-kit in sinonasal mucosal melanomas arising in the Chinese population.

Sinonasal mucosal melanomas (SNMM) of the head and neck regions are rare and aggressive malignancies. Although they can affect patients of any ethnicity, they are more numerous in Chinese patients. The diagnosis and treatment of these tumors can be challenging. Recent studies have reported that Sox10 is a sensitive melanocytic marker for cutaneous melanoma (Nonaka et al. in Am J Surg Pathol 32:1291-1298, 2008). In addition, a CD117 (c-kit) gene mutation has been identified in cutaneous melanomas, indicating that there may be potential therapeutic benefits of tyrosine kinase inhibitors, such as Imatinib. The purpose of this study was to detect and test the immunohistochemical expression of Sox10 and c-kit in mucosal melanomas (MM) arising in the nasal cavities of Chinese patients. Twenty eight patients with mucosal melanomas of the nasal cavity were treated in two major hospitals in China. All cases had been locally diagnosed as primary SNMM. We confirmed all diagnoses with positive immunohistochemical stains for S100 and HMB-45. Additionally, automated immunohistochemistry was performed using a goat polyclonal Sox10 antibody and a monoclonal c-kit antibody counterstained using a standard avidin-biotin complex method. Immunohistochemical positive expression of Sox10 was defined by nuclear stain; and positivity for c-kit resulted in a distinct membranous staining. The extent of nuclear positivity for Sox10 and membranous stain for c-kit was graded by 4 board certified pathologists as follows: 1+, 1-25 % of positive tumor cells; 2+, 25-50 %; 3+, 50-75 %; and 4+, ≥75 %. Sox10 nuclear expression was found in all cases (100 %), with 4+ staining in 26 out of 28 cases (92.8 %) and 3+ staining in two cases with (7.1 %). The overall positivity for S100 staining was 23 out of 28 (82.1 %), with 1+ staining in 10 cases, 2+ staining in 6 cases, 3+ staining in 7 cases, and no staining in 5 cases. The sensitivity and intensity of Sox10 immunohistochemistry were both higher than with S100 immunohistochemistry. Immunopositivity of membranous stain for c-kit (CD117) was seen in 24 out of 28 cases (85.7 %), including 6 tumors that were 4+, eight that were 3+, six that were 2+, and four that showed 1+ staining. Our results demonstrate that Sox10 is a sensitive marker for SNMM and it may possess diagnostic value in addition to that of S100 protein. The expression of c-kit in the majority of MMs suggests that it may be useful in the assessment of these tumors for potential treatment with tyrosine kinase inhibitors.