Hiroji Uemura

Prostate cancer: a comparative study of 11C-choline PET and MR imaging combined with proton MR spectroscopy.

PurposeProstate cancer is difficult to visualise in its early stages using current imaging technology. The present study aimed to clarify the utility of 11C-choline PET for localising and evaluating cancer lesions in patients with prostate cancer by conducting a prospective comparison with magnetic resonance (MR) imaging combined with proton MR spectroscopy.MethodsPET and MR imaging combined with proton MR spectroscopy were performed in 20 patients with prostate cancer. Correlations among the metabolite ratio of choline + creatine to citrate (Cho+Cr/Ci) on MR spectroscopy, serum PSA and maximum standardised uptake value (SUVmax) of 11C-choline were assessed. The location of the primary lesion was assessed by the site of SUVmax and the laterality of the highest Cho+Cr/Ci ratio and confirmed by examination of surgical pathology specimens (n=16).ResultsPET exhibited a diagnostic sensitivity of 100% (20/20) for primary lesions, while the sensitivities of MR imaging and MR spectroscopy were 60% (12/20) and 65% (13/20), respectively. Weak linear correlations were observed between SUVmax and serum PSA (r=0.52, p<0.05), and between SUVmax and Cho+Cr/Ci ratio (r=0.49, p<0.05). Regarding the localisation of main primary lesions, PET results agreed with pathological findings in 13 patients (81%) (κ=0.59), while MR spectroscopy results were in accordance with pathological findings in eight patients (50%) (κ=0.11).ConclusionThis preliminary study suggests that 11C-choline PET may provide more accurate information regarding the localisation of main primary prostate cancer lesions than MR imaging/MR spectroscopy. A further clinical study of 11C-choline PET in a large number of patients suspected of prostate cancer will be necessary to determine the clinical utility of 11C-choline PET in patients who clinically require biopsy.

Telomerase Activity in Primary Prostate Cancer

PURPOSE Telomerase activity has been detected in a wide variety of human tumor types. We analyzed the telomerase activity in association with the acquisition of prostate cancer. MATERIALS AND METHODS Telomerase activity in prostate tissues was examined by PCR-based telomeric repeat amplification protocol (TRAP) assay. RESULTS Among 31 primary prostate cancers, 28 tissue samples (90%) displayed telomerase activity. The relative level of telomerase activity was associated with the pathological differentiation. High levels of telomerase activity were more frequently detected in poorly differentiated prostate cancer. None of the 10 samples taken from prostates with benign prostatic hyperplasia (BPH) or normal prostates expressed telomerase activity. In another 10 BPH samples obtained from prostate tissue adjacent to cancerous tissue, one of 10 samples (10%) showed weak telomerase activity. Furthermore, we investigated this activity in human prostate cancer cell lines (PC-3, LNCaP, and DU145) and all showed very high activity compared to normal human tissue samples. Four lymph nodes and one bone metastasis also exhibited extremely high telomerase activity. CONCLUSIONS The present results indicate that telomerase activity might be a marker for detecting malignancy of the prostate and evaluating the malignant potential of prostate cancer.

Stable Suppression of Tumorigenicity by Pin1-Targeted RNA Interference in Prostate Cancer

Purpose: The peptidyl-prolyl isomrase Pin1 plays a catalytic role in oncogenesis in solid cancers, including prostate cancer. In the present study, we sought to determine the potential of Pin1-targeted gene silencing in inhibiting cellular growth and tumorigenicity in prostate cancer. Experimental Design: A retrovirus-mediated RNA interference targeting Pin1 was expressed in PC3 and LNCaP cells, and cell growth and several transformed properties were investigated. Results: The stable expression of Pin1-specific small interfering RNA constructs in PC3 and LNCaP cells significantly reduced cellular proliferation, colony formation, migration, and invasion but strongly enhanced the apoptotic response induced by serum depletion or treatment with anticancer agents. Furthermore, Pin1 depletion significantly suppressed tumorigenic potential in athymic mice, resulting in the inhibition of both tumor growth and angiogeneisis. Conclusions: These results strongly suggest that Pin1 plays an important role not only in tumorigenesis but also in the maintenance of the transformed phenotype in prostate cancer cells. Hence, Pin1 may serve as a promising therapeutic target, particularly for recurrent prostate tumors.

PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines.

Extensive allelotyping studies have implicated several tumor‐suppressor loci on chromosomes 3p, 5q, 6q, 8p, 9pq, 10q, 11q, 14q, 17p, 18q and 19p in human kidney tumorigenesis. The PTEN (also called MMAC1 and TEP1) gene, a candidate tumor suppressor located at chromosome 10q23.3, is mutated in a variety of sporadic malignancies as well as in patients with Cowden disease. To investigate the potential role of the PTEN gene in renal tumorigenesis, we searched for abnormalities of the gene in 68 primary renal‐cell carcinomas (RCCs) as well as in 17 renal carcinoma–derived cell lines, using DNA‐SSCP, sequencing and microsatellite analysis. Five of 68 (7.5%) primary RCCs exhibited intragenic mutations (3 missense, 1 deletion and 1 splice‐site), and 1 of 17 (5.9%) cell lines had an insertion mutation. Loss of heterozygosity of the PTEN gene occurred in 25% of primary RCCs, including the 3 cases with intragenic mutation and the 1 PTEN‐mutated cell line. Clinical and histopathological examinations revealed that 4 of the 5 primary tumors with PTEN mutation were high‐grade, advanced clear‐cell RCCs with distant metastases or renal vein tumor invasions, resulting in poor prognostic courses. The other was a low‐stage papillary/chromophilic RCC. Our data suggest that PTEN mutation is observed in a subset of RCCs and that, especially in clear‐cell RCCs, it occurs as a late‐stage event and may contribute to the invasive and/or metastatic tumor phenotype.

Usefulness of the 2005 International Society of Urologic Pathology Gleason grading system in prostate biopsy and radical prostatectomy specimens

To determine whether the 2005 International Society of Urologic Pathology (ISUP) Gleason Grading Consensus is clinically more useful than the conventional Gleason score (CGS), we compared the CGS and ISUP GS (IGS) of prostate needle biopsy (NB) and radical prostatectomy (RP) specimens, and evaluated the prognostic value of the ISUP GS.

aPKCλ/ι promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6

Understanding the mechanism by which hormone refractory prostate cancer (HRPC) develops remains a major issue. Alterations in HRPC include androgen receptor (AR) changes. In addition, the AR is activated by cytokines such as interleukin-6 (IL-6). Atypical protein kinase C (aPKCλ/ι) has been implicated in the progression of several cancers. Herein, we provide evidence that aPKCλ/ι expression correlates with prostate cancer recurrence. Experiments in vitro and in vivo revealed aPKCλ/ι to be involved in prostate cancer cell growth through secretion of IL-6. Further, aPKCλ/ι activates transcription of the IL-6 gene through NFκB and AP-1. We conclude that aPKCλ/ι promotes the growth of hormone independent prostate cancer cells by stimulating IL-6 production in an autocrine manner. Our findings not only explain the link between aPKCλ/ι and IL-6, implicated in the progression a variety of cancers, but also establish a molecular change involved in the development of HRPC. Further, aPKCλ/ι expression might be a biomarker for prostate cancer progression.

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

Background Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration‐resistant prostate cancer who were at high risk for the development of metastasis. Methods We conducted a double‐blind, placebo‐controlled, phase 3 trial involving men with nonmetastatic castration‐resistant prostate cancer and a prostate‐specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen‐deprivation therapy. The primary end point was metastasis‐free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Results A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis‐free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). Conclusions Among men with nonmetastatic castration‐resistant prostate cancer, metastasis‐free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)

Antiproliferative Efficacy of Angiotensin II Receptor Blockers in Prostate Cancer

An apparent low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors is reported; however, the molecular mechanisms have not been elucidated. Angiotensin-II (Ang-II) is well known to be associated with hypertension, as a main peptide of the renin-angiotensin system, and its detailed molecular mechanisms have recently been elucidated. For instance, Ang-II directly activates the mitogenic signal transduction pathway through the angiotensin-II type-1 (AT1) receptor in smooth muscle cells and cardiac myocytes. Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathways mediated by growth factors such as epidermal growth factor (EGF), through the AT1 receptor. Our studies demonstrated that an ARB had the potential for antiproliferative effects and inhibition of angiogenesis in prostate cancer cells. The AT1 receptor is categorized in the guanosine phosphate binding protein-coupled receptors (GPCRs), which are viewed as critical regulators of the interactions between epithelial and stromal cells. Hence, we consider that in overcoming prostate cancer, it is very important to inhibit GPCR signaling in cancer cells by ARBs. It is unclear how prostate cancer growth changes from being hormone dependent to independent, and no effective therapy has therefore been developed. Our clinical data revealed that ARB administration decreased prostate specific antigen (PSA) and improved performance status in patients with hormone-refractory prostate cancer. This review provides an insight into the key role of Ang-II and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.

Ureteroscopy assisted retrograde nephrostomy: a new technique for percutaneous nephrolithotomy (PCNL).

Study Type – Therapy (case series)

Alterations of p16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma.

The p16 gene encodes a 16-kDa cyclin kinase inhibitor, and the p14ARF gene a 14-kDa protein, which acts as a cell cycle regulator or tumor suppressor in human cancer cells. Both genes are mapped on chromosome 9p21. Previous studies have suggested that the p16 gene has important roles in head and neck squamous cell carcinoma. To clarify carcinogenesis in oral squamous cell carcinoma (OSCC), we examined 44 primary OSCCs for alterations of p16 and p14ARF mRNA expression, the methylation status of the p16 gene promoter, the loss of heterozygosity (LOH) at the 9p21 locus, and p16 and p14ARF gene mutations. Alterations of p16 and p14ARF mRNA expression were seen in 27 (61.4%) of 44 and 10 (22.7%) of 44 of OSCC samples, respectively. Methylation of the p16 gene promoter region was detected in 28 (63.6%) of 44 samples, and LOH at 9p21 locus was found in 30 (68.2%) of 44. p16 and p14ARF gene mutations were observed in 4 (9.0%) of 44 and 2 (4.5%) of 44 samples, respectively. Suspected homozygous deletion (HD) was seen in 9 (20.5%) of 44. All cases except one (97.7%) showed alterations in p16, p14ARF, and their locus. These data indicate that the status of p16 and p14ARF genes in OSCC is frequently influenced by methylation, gene mutation, and allelic deletions. Furthermore, these genes and their 9p21 locus have various roles in the pathogenesis of OSCC.