Kazuhiko Orikasa

Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary

In the present study, we searched for genetic alterations of the entire coding region of PTEN/MMACl, a recently isolated candidate tumor suppressor gene, in 178 specimens from Japanese patients with various malignant tumors by the polymerase chain reaction‐single strand conformation polymorphism method. The samples consisted of 11 glioblastoma multiformes (GBMs), 14 astrocytomas, 47 breast cancers, 25 non‐small cell lung cancers, 9 small cell lung cancers, 8 pancreatic cancers, 24 renal cell carcinomas, 20 ovarian cancers, and 20 metastatic lung tumors from various organs. Only one somatic frameshift mutation at codon 319 was observed in one (9%) of eleven GBMs. Our results suggest that mutation of the PTEN/MMAC1 gene does not play a major role in carcinogenesis, at least in the tumor types from Japanese patients analyzed in this study.

Prospective Randomized Phase II Trial of a Single Early Intravesical Instillation of Pirarubicin (THP) in the Prevention of Bladder Recurrence After Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma: The THP Monotherapy Study Group Trial

PURPOSE We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

Isolation and characterization of the novel gene, TU3A, in a commonly deleted region on 3p14.3→p14.2 in renal cell carcinoma

We previously identified a 700-kb region of common allelic loss on 3p14.3→p14.2 in renal cell carcinoma (RCC). We further analyzed this region and constructed a sequence ready bacterial artificial chromosome (BAC) contig. This region was totally covered by six overlapping BAC clones and was roughly estimated to be 700 kb. Furthermore, we isolated a gene in this region that we termed TU3A. This gene encodes a protein consisting of 144 amino acids. Homology search did not show any significant similarities with known genes or proteins. Northern analysis with normal tissue identified a 3.0-kb transcript that was expressed ubiquitously. Although our mutation search using 37 primary RCCs as well as five RCC cell lines failed to detect any somatic alterations in the TU3A gene, two of five RCC cell lines had totally lost its expression. Considering the fact that we found no genetic alterations in TU3A, it is possible that some epigenetic alteration may have suppressed its expression.

Infrequent genetic alterations of the PTEN gene in Japanese patients with sporadic prostate cancer

AbstractProstate cancer is a major cause of cancer death among elderly men in America, Europe, and Japan. However, the molecular mechanism of carcinogenesis is not yet well characterized. Frequent loss of heterozygosity (LOH) on chromosome 10q was reported in prostate cancer, and a candidate tumor suppressor gene, PTEN, was isolated on chromosome band 10q23.3. To investigate the genetic alterations of PTEN, we examined 45 primary prostate cancer specimens. LOH at the PTEN locus was observed in two (11.1%) of 18 tumors. However, no mutations were observed in any of the primary prostate cancers. These data suggest that mutation of the PTEN gene does not play a major role in prostate carcinogenesis of Japanese patients.

Identification of a 700-kb Region of Common Allelic Loss in Chromosome Bands 3p14.3–p21.1 in Human Renal Cell Carcinoma

The short arm of chromosome 3 is considered to harbor one or more of the tumor suppressor genes taking part in the genesis of renal cell carcinoma (RCC). To define the localization of such putative tumor suppressor gene(s), we studied specific allelic loss on chromosome 3p by using 84 samples of RCC with nine microsatellite markers. We defined two commonly deleted regions in 3p14.3-p21.2: (1) region A, a 2-cM region between D3S1313 and D3S1592, and (2) region B, a 2-cM region between D3S1581 and D3S1289. The most frequent loss of heterozygosity was observed at D3S1067 (33 of 59, 55.9%), which is within region A. We further focused on region A and constructed a yeast artificial chromosome (YAC) contig and found that one YAC clone, which was 700-kb in size, harbored the entire region A. Using cosmid clones isolated from this contig, we also performed fluorescence in situ hybridization analysis and found that two of the tumors were homozygously deleted in this region. Our results strongly suggest the existence of a tumor suppressor gene in this region.

Anterior apical biopsy: Is it useful for prostate cancer detection?

Objectives:  To evaluate the utility of a 12‐core prostate biopsy protocol including apical anterior peripheral zone (AAPZ) cores.

Possible Relationship Between the Risk of Japanese Bladder Cancer Cases and the CYP4B1 Genotype

Cytochrome P450 4B1 (CYP4B1) is involved in the metabolism of several xenobiotics, such as 2-aminofluorene, 2-naphthylamine and benzidine. CYP4B1 allelic variants CYP4B1*1-*7 were recently identified. We thus hypothesized that CYP4B1 genotypes may modify bladder cancer risk. We examined the CYP4B1 genotypes in 169 bladder cancer cases and 190 hospital controls using a hybridization probe assay. Among the CYP4B1 genotypes observed, the most frequent genotypes in both the groups were CYP4B1*1/*1, *1/*2, *1/*3 and *2/*2. Logistic regression analysis revealed that the subjects carrying the CYP4B1*1/*2 or *2/*2 genotypes had a 1.75-fold increased risk of bladder cancer (95% CI=1.03-2.95, P = 0.038) compared with the subjects carrying the CYP4B1*1/*1 genotype. We demonstrated the first genetic study regarding the association of CYP4B1 with bladder cancer. Our results suggest that CYP4B1 genotypes might have an effect on the risk of bladder cancer.

Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer

Background:We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer.Methods:Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide.Results:Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49–85 years). Median PSA before ADT was 16.7 ng ml−1 (range, 0.3–3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028).Conclusions:One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

The Outcome of Prostate Cancer Screening in a Normal Japanese Population with PSA of 2–4 ng/ml and the Free/Total PSA Under 12%

OBJECTIVE No previous study has reported the numbers of prostate cancer (PC) patients existing among a normal Japanese population with prostate-specific antigen (PSA) < 4 ng/ml. The aim of this study was to elucidate the performance of %free PSA as a screening tool for a normal Japanese population with PSA of 2-4 ng/ml and to examine the characteristics of cancer detected using this criterion. METHODS We conducted a prospective, multi-center study to evaluate the performance of %free PSA among a normal Japanese population. We decided on a %free PSA cutoff value of 12% according to the preliminary results. A total of 5548 consecutive screening volunteers aged 50-79 years were enrolled in the project. Men with total PSA > 4 ng/ml, or men with total PSA of 2-4 ng/ml and %free PSA of < or =12% were indicated to undergo 12 core biopsies. RESULTS There were 826 (14.9%) men with PSA of 2-4 ng/ml. Among them, those with %free PSA of < or =12% numbered 100 (12.1%). Forty-nine out of 100 men (49%) received biopsy, and 16 PC patients were detected. Among 10 patients undergoing radical prostatectomy, seven were associated with extra-prostatic extension (pT3) or high-grade cancer (Gleason score > or = 8). CONCLUSIONS We confirmed the ability of %free PSA and demonstrated that there are considerable numbers of PC patients among the normal Japanese population with PSA of 2-4 ng/ml. We ascertained that cancers detected in this study had a variety of tumor characteristics, including those of an aggressive nature.

Spontaneous rupture of adrenal pheochromocytoma with capsular invasion

A 67‐year‐old Japanese man developed a sudden onset of severe right‐side upper abdominal pain, nausea and vomiting. On hospitalization, physical examination revealed sweating, tachycardia, hypertension and the appearance of peripheral vasoconstriction. An urgent computed tomography scan with contrast demonstrated a large hematoma in the right retroperitoneal space. A phentolamine test and an 131iodine metaiodobenzylguanidine scan suggested pheochromocytoma. An elective right adrenalectomy was successfully performed after pretreatment for sufficient volume replacement with continuous administration of α‐ and β‐adrenergic blocking agents. Pathological diagnosis was an adrenal pheochromocytoma 9.0 × 6.5 cm in diameter with evidence of capsular invasion, which could be associated with a tear in the capsule.