Hideaki Kakinuma

Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus.

Background. The present study investigated the incidence of posttransplant diabetes mellitus (PTDM) and calculated the risk of developing PTDM under a tacrolimus-based immunosuppression based on clinical characteristics, tacrolimus pharmacokinetics, and genetic polymorphisms related to tacrolimus pharmacokinetics or diabetes mellitus. Methods. Seventy nondiabetic adult kidney recipients were studied. Patients with continuous high plasma glucose levels, over 6.5 mg/dl of hemoglobin A1c, or requiring insulin and/or oral antidiabetic agents for more than 3 months after transplantation 6 months postoperatively were diagnosed as having PTDM. Twelve genomic polymorphisms were assessed. Results. Six months after transplantation, 10 recipients (14.3%) developed PTDM. Positive risk factors were age (P=0.019) and body mass index (P=0.038). There were no significant differences in acute rejection rate, total steroid doses, tacrolimus pharmacokinetics or its related to genetic polymorphisms between the two groups. The frequency of PTDM was significantly higher in patients with the vitamin D receptor (VDR) TaqI t allele than in those with the TT genotype (P=0.013). On multivariate analysis, age over 50 years (odds ratio 9.28, P=0.003) and the presence of the VDR TaqI t allele (odds ratio 7.05, P=0.048) were correlated with the development of PTDM. Conclusion. The incidence of PTDM was 14.3% in our cohort. Age over 50 years was a risk factor. The presence of the VDR TaqI t allele may also be a risk factor for PTDM, suggesting that genotyping of diabetes-related polymorphisms is a possible method of predicting a patients risk for developing PTDM and would be a valuable asset in selecting appropriate immunosuppressive regimens for individuals.

Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer

Transcriptional silencing by CpG island hypermethylation of gene regulatory regions is one mechanism for inactivation of tumour suppressor genes. Chromosome 9q deletion is frequently found in transitional cell carcinoma (TCC) of the bladder and upper urinary tract and one of the putative tumour suppressor loci has been mapped to 9q32-33. A gene designated as DBCCR1 was identified in the candidate region and its mRNA expression is thought to be suppressed by hypermethylation. To understand the role of hypermethylation in TCC, we evaluated the methylation status of 20 CpG sites of the DBCCR1 5′-CpG island region in a total of 69 tumours from 45 patients, 21 normal urothelial specimens, and six bladder cancer cell lines. Aberrant hypermethylation levels were found in 36 (52%) of 69 tumours without any association with tumour grade or stage. Methylation was weakly detected in the normal urothelium in association with ageing. Although recurrent tumours tended to have higher methylation levels than the initial tumours, the methylation pattern was mostly maintained between multifocal TCCs in individual patients. The results suggest that hypermethylation of the DBCCR1 region is one of the earliest alterations in the development of TCCs and there may be an age-related hypermethylation-based field defect in normal urothelium. Methylator or methylation-resistant phenotype seems to be maintained during multifocal development or recurrence of most TCCs.

Targeted cancer chemotherapy with arterial microcapsule chemoembolization : review of 1013 patients

Abstract To evaluate the feasibility of intraarterial infusion of microencapsulated anticancer drugs (chemoembolization), collective data on 1013 cancer patients were reviewed. Ethylcellulose microcapsules containing mitomycin C (median total dose 20 mg), cisplatin (60 mg) or peplomycin (40 mg) were given to tumor-feeding arteries by bolus infusion in 79% of the patients and by fractionated infusion in the others, as a palliative (71%) or preoperative measure (29%). The target sites were the liver (42%), kidney (24%), intrapelvic organs (18%), lung (4%), head and neck (3%), bone (1%) and others (9%), excluding the central nervous system and gastrointestinal tract. The incidence of overall adverse effects ranged from 0.2 to 54.9%, but grade 2–3 hematological, renal and hepatic toxicities, local pain, abdominal discomfort, cutaneous reaction, remote embolization and infection were < 10%. Nine patients (0.9%) in the early stages of trials suffered serious complications including treatment-related death in two with critical underlying diseases of the target organs. The remaining patients recovered from the adverse effects, except for grade 2 cutaneous reactions, within 2 months by routine palliative measures. A ≥ 50% tumor reduction was seen in 28% of 427 evaluable tumors (42% for < 25-cm2 tumors and 20% for ≥ 25-cm2 tumors) with a median treatment number of one. The response rate depended on both the tumor size and the treatment number (P< 0.05), but it was not affected by prior therapies. Mitomycin C microcapsules produced a higher response rate. Complete or partial remission of intractable pain and genitourinary gross hemorrhage was found in two-thirds of eligible patients. The results indicate that this treatment modality, though restricted by catheter technique, can be applied to various tumor lesions with an acceptable morbidity and prospective trials are justified to evaluate the potential role of such a targeted chemotherapy.

Granulocyte Colony-Stimulating Factor Produced by Bladder Carcinoma of a Patient with Leukemoid Reaction did not Affect Proliferation of the Tumor Cells

Bladder carcinoma associated with leukemoid reaction, though it rarely occurs, is considered highly malignant and has proved to produce granulocyte colony-stimulating factor (G-CSF). Interest exists in whether G-CSF itself or G-CSF producing ability reflects the malignant potential of such a tumor, possibly through an autocrine mechanism. In a patient with invasive bladder carcinoma, we found that the tumor cells produced G-CSF responsible for a remarkable leucocytosis. However, we could not detect the rearrangement and amplification of the G-CSF gene nor the expression of G-CSF receptor in the tumor cells. Our immunohistological and molecular biological study failed to demonstrate a crucial role for G-CSF in mediating a growth advantage for the tumor.

Functional Correlation of Trophinin Expression with the Malignancy of Testicular Germ Cell Tumor

Trophinin is a membrane protein that is potentially involved in human embryo implantation by mediating homophillic cell adhesion between trophoblastic cells and endometrial cells. Trophinin expression by maternal cells may be induced by the embryo that secretes human chorionic gonadotropin (hCG). Because the process of tumor metastasis resembles that of trophoblast invasion and proliferation during embryo implantation, we hypothesized that testicular cancers that synthesize hCG express trophinin thus becoming aggressive trophoblast-like cells. We screened paraffin-embedded orchiectomy specimens of 158 patients with testicular germ cell tumor by immunohistochemistry using antitrophinin antibody. This screening identified trophinin-positive specimens with the frequencies 39 of 91 (43%) in stage I, 14 of 24 (58%) in stage II, and 41 of 43 (95%) in stage III (P < 0.001). Thus, trophinin expression positively correlates with clinical stage. Remarkably, trophinin was found in all of the cases (33 of 33) with lung metastasis. The levels of serum hCG-β were significantly higher in the patients with trophinin-positive tumors than those with trophinin-negative tumors (P = 0.004). To determine whether trophinin promotes aggressiveness of the cell, trophinin-negative human seminona cell line JKT-1 was stably transfected with a mammalian expression vector containing trophinin cDNA. In vitro assays revealed that trophinin-expressing JKT-1-Tro cells are more invasive than JKT-1-mock cells, whereas there are no differences between JKT-1-Tro and JKT-1-mock in their proliferation activity. Upon orthotopic inoculation to athymic nude mice, JKT-1-Tro cells exhibited i.p. metastases in all of the mice (n = 5), whereas JKT-1-mock produced no metastases (n = 5). These results suggest strongly that trophinin enhances invasiveness of the cells and promotes metastasis of testicular germ cell tumor.

Serum sex steroid hormone levels and polymorphisms of CYP17 and SRD5A2: implication for prostate cancer risk.

Polymorphism of the steroid hormone-related genes might affect life-long androgen exposure, thus altering a risk of prostate cancer incidence. To evaluate the effect of the polymorphisms of CYP17 and SRD5A2 on serum steroid hormone levels, the 164 male Japanese cohort were tested for serum hormone levels and the genotype of the polymorphisms of CYP17 (T–C base substitution in the promoter region) and SRD5A2 (V89L). The linear trends across the CYP17 genotypes in serum-free testosterone and androstenedione levels were found, suggesting the importance of the polymorphism of CYP17 in determining the circulating androgen levels.

BCL10 is not a major target for frequent loss of 1p in testicular germ cell tumors

The deletion of chromosome 1p is one of the frequent genetic alterations found in testicular germ cell tumors (GCTs), suggesting the presence of a tumor suppressor gene. BCL10, which was identified as a gene altered in mucosa-associated lymphoid tissue lymphoma, has been mapped at 1p22. The gene has been reported to be mutated in a variety of human cancers. In this study, we investigated the allelic deletions on 1p and the mutation of BCL10 in 51 GCTs comprising 30 seminomas and 21 non-seminomatous germ cell tumors. Loss of heterozygosity (LOH) on 1p was tested using three microsatellite markers. The search for BCL10 mutations in each of the three exons was screened by a single-stranded conformation polymorphism (SSCP) analysis and samples with abnormal bandshifts were directly sequenced. LOH at at least one locus tested was found in 42% (21/49) of the tumors (43% of seminomas and 38% of NSGCTs). SSCP and direct sequence analyses revealed that there were single nucleotide polymorphisms at codon 5, 8, 162, and intron 1. However, there were no somatic mutations of BCL10 in the 51 tumors. In support of the previous studies, our results demonstrated that LOH on 1p is frequent in both seminomas and NSGCTs, indicating that there is an important tumor suppressor on 1p in GCT. However, the results indicate that BCL10 is not a candidate target gene of the 1p deletion.

Primary tumor of the ureteral stump following a nephrectomy for renal cell carcinoma

Background: A 64‐year‐old man presented with asymptomatic macroscopic hematuria during a follow up for a localized renal cell carcinoma (RCC), which was treated by a right radical nephrectomy 6 years earlier.

Transitional cell carcinoma in an ectopic ureter

We experienced an 82‐year‐old man with transitional cell carcinoma in an ectopic ureter draining into the prostatic urethra. Carcinoma arising from an ectopic ureter is very rare and a differential diagnosis is difficult. To our knowledge, our case is the third male case reported in the literature.

RADIONUCLIDE EVALUATION OF THE URETERO-ILEOCECO-PROCTOSTOMY (ILEOCECAL RECTAL BLADDER)

Technetium 99m diethylenetriaminepentaacetic acid renoscintigraphy was applied to 14 patients to obtain comprehensive information on the kidney and urinary tract 12.6 8.8 months (mean SD) after uretero‐ileoceco‐proctostomy (ileocecal rectal bladder) diversion. The total glomerular filtration rate (GFR) was within the normal range in all patients, and the diuretic renogram was normal in 19 of 28 kidneys, dilated‐nonobstructive in 7 and obstructive‐intermediate in 2. The mean colonic reflux was 16.6 18.4% of total excretion and the mean total residual in the colon and rectum was 38.815.5%. In the second study, performed 12.4 3.5 months later in 9 patients, the GFR of bilateral and individual kidneys remained stable, 17 of 18 kidneys were normal as judged by both renography and pyelography, and the occurrence and degree of colonic reflux decreased. There was a tendency for the rectal capacity to increase, while the total residual tended to decrease solely due to the decrease in colonic residual. These results indicate that the ileocecal rectal bladder functions well as an internal continent reservoir and that radionuclide investigation is a valuable and cost‐beneficial means for the follow‐up of urinary diversions.