Association of TUSC1 and DPF3 gene polymorphisms with male infertility.

PURPOSE: Recently, genome-wide association studies of a Hutterite population in the USA revealed that five single nucleotide polymorphisms (SNPs) with a significant association with sperm quality and/or function in ethnically diverse men from Chicago were significantly correlated with family size. Of these, three SNPs (rs7867029, rs7174015, and rs12870438) were found to be significantly associated with the risk of azoospermia and/or oligozoospermia in a Japanese population. In this study, we investigated whether the rs10966811 (located in an intergenic region between the TUSC1 and IZUMO3 genes) and rs10129954 (located in the DPF3 gene) SNPs, previously related to family size, are associated with male infertility. In addition, we performed association analysis between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility. METHODS: We genotyped 145 patients with infertility (including 83 patients with azoospermia and 62 with oligozoospermia) and 713 fertile controls by PCR-RFLP technique for polymorphism. Because rs10966811 has no restriction sites, the SNP rs12376894 with strong linkage disequilibrium was selected as an alternative to rs10966811. RESULTS: There was a statistically significant association between rs12376894 proxy SNP of rs10966811 and oligozoospermia. Also, a statistically significant association between rs10129954 and azoospermia, and oligozoospermia was observed. When we assessed the relationship between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility traits, we found that rs12348 in TUSC1 was significantly associated with azoospermia and oligozoospermia, but rs2772579 in IZUMO3 was not associated with male infertility. CONCLUSION: We found that the polymorphisms in TUSC1 and DPF3 displayed strong associations with male infertility.

Erratum: An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies.

[This corrects the article DOI: 10.1093/hropen/hox002.][This corrects the article DOI: 10.1093/hropen/hox002.].

An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies.

STUDY QUESTION: Are the single nucleotide polymorphisms (SNPs) rs2075230, rs6259 and rs727428 at the sex hormone-binding globulin (SHBG) locus, which were identified by genome-wide association studies (GWASs) for testosterone levels, associated with testosterone levels in Japanese men? SUMMARY ANSWER: The SNP rs2075230, but not rs6259 and rs727428, is significantly associated with testosterone levels in Japanese men. WHAT IS ALREADY KNOWN: Previous GWASs have revealed that rs2075230 is associated with serum testosterone levels in 3495 Chinese men and rs6259 and rs727428 are associated with serum testosterone levels in 3225 men of European ancestry. STUDY DESIGN SIZE AND DURATION: This is an independent validation study of 1687 Japanese men (901 in Cohort 1 and 786 in Cohort 2). PARTICIPANTS/MATERIALS SETTING AND METHOD: Cohort 1 (20.7 ± 1.7 years old, mean ± SD) and Cohort 2 (31.2 ± 4.8 years) included samples obtained from university students and partners of pregnant women, respectively. The three SNPs were genotyped using either TaqMan probes or restriction fragment length polymorphism PCR. Blood samples were drawn from the cubital vein of the study participants in the morning, and total testosterone and SHBG levels were measured using a time-resolved immunofluorometric assay. Association between each SNP and testosterone levels was evaluated by meta-analysis of the two Japanese male cohorts. MAIN RESULTS AND THE ROLE OF CHANCE: The age of the two cohorts was significantly different (P < 0.0001). We found that rs2075230 was significantly associated with serum testosterone levels (ß STD = 0.15, P = 7.2 × 10-6); however, rs6259 and rs727428 were not (ß STD = 0.17, P = 0.071; ß STD = 0.082, P = 0.017, respectively), after adjusting for multiple testing in a combined analysis of two Japanese male cohorts. Moreover, rs2075230, rs6259 and rs727428 were significantly associated with high SHBG levels (ß STD = 0.22, P = 3.4 × 10-12; ß STD = 0.23, P = 6.5 × 10-6 and ß STD = 0.21, P = 3.4 × 10-10, respectively). LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: This study had differences in the age and background parameters of participants compared to those observed in previous GWASs. In addition, the average age of participants in the two cohorts in our study also differed from one another. Therefore, the average testosterone levels, which decrease with age, between studies or the two cohorts were different. WIDER IMPLICATIONS OF THE FINDINGS: The three SNPs have a considerable effect on SHBG levels and hence may indirectly affect testosterone levels. STUDY FUNDING/COMPETING INTERESTS: This study was supported partly by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (26462461) (to Y.S.) and (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.) and the Takeda Science Foundation (to A.Ta.). There are no conflicts of interest to declare.

A replication study of a candidate locus for follicle-stimulating hormone levels and association analysis for semen quality traits in Japanese men.

In men, follicle-stimulating hormone (FSH) acts on the seminiferous tubules and enhances spermatogenesis. Recently, a candidate locus (rs2414095) for FSH levels was identified by a genome-wide association study (GWAS) in Chinese men. The rs2414095 single-nucleotide polymorphism (SNP) is found on the third intron of the cytochrome P450, family 19, subfamily A, peptide 1 (CYP19A1) gene encoding an aromatase. In the present study, we performed a replication study in 1687 Japanese men (901 from cohort 1 and 786 from cohort 2) to assess whether this SNP is associated with circulating FSH levels. Furthermore, we investigated whether the rs2414095 SNP is correlated with semen quality traits in 2015 Japanese men (1224 from cohort 1 and 791 from cohort 2). The rs2414095 SNP was significantly associated with circulating FSH levels (ßSTD=0.15, P=9.7 × 10-5), sperm concentration (ßSTD=0.073, P=0.032) and total sperm number (TSN) (ßSTD=0.074, P=0.027) in a combined analysis of the two Japanese male cohorts. We successfully replicated, in Japanese men, the results of the previous GWAS for the rs2414095 SNP in Chinese men, and found that the rs2414095 SNP was related with sperm production.

An association study of four candidate loci for human male fertility traits with male infertility.

STUDY QUESTION: Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER: rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY: Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION: This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 10(6)/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE: The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION: Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS: The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare.

Lack of replication of four candidate SNPs implicated in human male fertility traits: a large-scale population-based study.

STUDY QUESTION: Are the four candidate loci (rs7867029, rs12870438, rs7174015 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with semen quality traits in a Japanese population? SUMMARY ANSWER: The four single nucleotide polymorphisms (SNPs) rs7867029, rs12870438, rs7174015 and rs724078 have no association with semen parameters in a meta-analysis of two Japanese male cohorts. WHAT IS KNOWN ALREADY: Four (rs7867029, rs12870438, rs7174015 and rs724078) of the SNPs associated with family size or birth rate in the GWAS of a Hutterite population in the USA were associated with semen parameters in ethnically diverse men from Chicago, USA. STUDY DESIGN, SIZE, DURATION: This is a replication study in a total of 2015 Japanese subjects, including 791 fertile men and 1224 young men from the general population. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a replication study in two cohorts to assess whether the SNPs rs7867029, rs12870438, rs7174015 and rs724078 are associated with sperm concentration, semen volume, total sperm numbers, total motile sperm numbers or sperm motility. The rs12870438 SNP was detected by restriction fragment length polymorphism PCR while rs7174015, rs724078 and rs7867029 SNPs were genotyped using TaqMan probes. MAIN RESULTS AND THE ROLE OF CHANCE: This study indicated that none of the four SNPs rs7867029, rs12870438, rs7174015 and rs724078 displayed a significant association with semen parameters in the meta-analysis of two Japanese male cohorts. LIMITATIONS, REASONS FOR CAUTION: Only four SNPs identified in the Hutterite GWAS were examined for associations with semen quality traits in a Japanese population. In addition, the linkage disequilibrium structures around the testing markers were different between ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: Locus mapping studies using a set of tagging SNPs across the loci will be necessary in populations with larger sample sizes in order to understand the contribution of specific genes to semen quality. STUDY FUNDING/COMPETING INTEREST S: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.), and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare.

Y chromosome gr/gr subdeletion is associated with lower semen quality in young men from the general Japanese population but not in fertile Japanese Men.

Several case-control studies have investigated whether Y chromosome haplogroups or deletions are associated with spermatogenic failure. However, the relationships between Y chromosome haplogroups or deletions and semen quality in general population have not been elucidated. In this study, we assessed relationships between Y chromosome haplogroups or deletions and semen parameters in 791 fertile Japanese men and 1221 young men from the general Japanese population. We found that the haplogroup D2 (M55 lineage) was significantly associated with lower semen parameters, especially total motile sperm count (P = 0.00051, beta = -0.097), in men from the general population but not in fertile men. In addition, we found that the gr/gr subdeletion was associated with semen quality and in particular, strongly associated with decreased sperm motility (P = 0.00041, beta = -3.14) and total motile sperm count (P = 0.00031, beta = -0.099) in men from the general population but not in fertile men. The combined analysis of fertile Japanese men and men from the general Japanese population showed that the haplogroup D2 (M55 lineage) and the gr/gr subdeletion were strongly associated with reduced sperm motility (P = 0.00056, beta = -2.71, and P = 7.7 × 10(-5), beta = -3.05, respectively) and that haplogroup O2b1 was strongly associated with elevated sperm motility (P = 0.00089, beta = 2.94). These observations add further support for the view that the gr/gr subdeletion diminishes sperm motility that consequently may result in male infertility.

Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study.

OBJECTIVES: To provide information of semen quality among normal young Japanese men and indicate the frequency of reduced semen quality. DESIGN: Cross-sectional, coordinated studies of Japanese young men included from university areas. The men had to be 18-24 years, and both the man and his mother had to be born in Japan. Background information was obtained from questionnaires. Standardised and quality-controlled semen analyses were performed, reproductive hormones analysed centrally and results adjusted for confounding factors. SETTING: Four study centres in Japan (Kawasaki, Osaka, Kanazawa and Nagasaki). PARTICIPANTS: 1559 men, median age 21.1 years, included during 1999-2003. OUTCOME MEASURES: Semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. RESULTS: Median sperm concentration was 59 (95% CI 52 to 68) million/ml, and 9% and 31.9% had less than 15 and 40 million/ml, respectively. Median percentage of morphologically normal spermatozoa was 9.6 (8.8 to 10.3)%. Small, but statistically significant, differences were detected for both semen and reproductive hormone variables between men from the four cities. Overall, the semen values were lower than those of a reference population of 792 fertile Japanese men. CONCLUSIONS: Assuming that the investigated men were representative for young Japanese men, a significant proportion of the population had suboptimal semen quality with reduced fertility potential, and as a group they had lower semen quality than fertile men. However, the definitive role-if any-of low semen quality for subfertility and low fertility rates remain to be investigated.

TFE3-renal carcinoma in an adult patient: a case with strong expression of phosphorylated hepatocyte growth factor (HGFR)/Met.

TFE3-renal carcinoma is rare in adults. Patients with this disease often have a poor prognosis, because it has reached an advanced stage at presentation, and there is lack of an effective therapy. The exact mechanism of its malignant behavior is still unclear. In recent years, a significant relationship between TFE3 fusion protein and hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase activity was reported in several malignancies. We previously reported that phosphorylation of HGFR/Met was associated with malignant aggressiveness and survival in patients with conventional RCC. Here, using immunohistochemical techniques, we examined two types of phosphorylated HGFR/Met (pY1234/1235 and pY1349) in a specimen of a 29-year-old man with TFE3-renal carcinoma. Strong expression of both proteins was detected in carcinoma cells, but not in normal kidney tissues. In addition, they were expressed more strongly in TFE3-renal carcinoma than in conventional RCC. Although tumor was diagnosed at T1N0M0 and the patient received radical nephrectomy, the tumor metastasized to multiple organs, and he died 2 years after surgery. We speculate that upregulated phosphorylation of HGFR/Met could be partly associated with the malignant aggressiveness and poor survival of this patient.

Long-term follow up of patients with invasive bladder carcinoma receiving combined cisplatin-based intra-arterial chemotherapy and radiotherapy.

OBJECTIVES: Combined cisplatin-based intra-arterial chemotherapy and radiotherapy is an effective treatment for patients with locally invasive bladder carcinoma. We report long-term follow-up data regarding definitive treatment of locally invasive bladder carcinoma, regardless of whether bladder preservation was possible. METHODS: The follow-up data from 24 patients (18 males and six females; aged, 31-85 years; median, 73 years) with invasive bladder carcinoma, between 1993 and 2003, was examined. The clinical stages of the patients ranged T2-T4, all N0M0, and involved 13 patients at T2 (T2a, T2b), seven patients at T3 and four patients at T4. Combined cisplatin-based intra-arterial chemotherapy and radiotherapy was performed. RESULTS: The 5-year overall survival rate and cancer-specific survival rate for all patients were 81.6% and 85.6%, respectively. When the patients were divided into complete response (CR) of 10 patients and non-CR groups of 14 patients, the 5-year overall survival rate for the CR group was 87.5%, while that of the non-CR group was 78.6% (P = 0.58). The tumor grade of the CR group was significantly lower than that of the non-CR group (P = 0.01). When the non-CR group was divided into radical cystectomy and non-radical cystectomy groups, the 5-year overall survival rate for the radical cystectomy group (100%) was higher than that of the non-radical cystectomy group (70%). CONCLUSION: This combined chemo-radiotherapy was effective for local invasive bladder carcinoma, leading to the possibility of bladder preservation using this therapy.

Immunohistochemical analysis of connexin43 expression in infertile human testes.

Connexin43 (Cx43) is abundantly expressed in mammalian testes and implicated in the regulation of cell-to-cell interaction between germ cells and Sertoli cells, which is essential to the normal process of spermatogenesis. In the present study, we investigated the relation between Cx43 expression and the degree of spermatogenesis in infertile human testes. Immunohistochemical analysis of Cx43 was performed on testicular biopsies from 29 patients with azoospermia (n=23) and severe oligospermia (n=6), who gave informed consent to this experiment. The degree of testicular spermatogenesis was evaluated by Johnsen score. In the interstitium, immunostaining for Cx43 was localized to some focal parts of plasma membrane between neighboring Leydig cells. In seminiferous tubules with normal spermatogenesis, Cx43 expression was found between Sertoli cells and germ cells. However, Cx43 expression in maturation arrest was decreased and located mainly in the basal compartment of seminiferous tubules. Finally, there was a significant positive correlation between histological score of spermatogenesis and intensity of Cx43 (p=0.0294). These data suggest that the alteration of Cx43 expression may be involved in spermatogenic impairment, and that the communication between Sertoli cells and germ cells through Cx43 may be important for maturation of spermatogenesis.

Tumor lymphangiogenesis in transitional cell carcinoma of the upper urinary tract: association with clinicopathological features and prognosis.

PURPOSE: Lymph node metastasis is an important prognostic factor in many types of cancer. Recently several specific markers for lymphatic endothelium were developed that facilitate the quantification of lymphangiogenesis in human cancer tissues. We investigated the clinical and prognostic significance of lymphangiogenesis in patients with transitional cell carcinoma of the upper urinary tract. MATERIALS AND METHODS: We measured lymph vessel density and relative lymphatic vascular area in 125 specimens by quantitative immunohistochemical staining for D2-40 antibody (DakoCytomation, Glostrup, Denmark). These parameters were examined in the intratumor and peritumor areas, and measured using image analysis software. RESULTS: Peritumor lymph vessel density and peritumor lymphatic vascular area correlated with lymph node metastasis and tumor grade. In the intratumor area lymphatic vessels were detected in only 16.0% of specimens. However, the presence of intratumor lymphatic vessels was associated with lymph node metastasis (p = 0.002). Multivariate analysis identified high peritumor lymphatic vascular area and the presence of intratumor lymphatic vessels as significant and independent factors of metastasis-free survival after surgery (OR = 5.11, p = 0.020 and OR = 2.92, p = 0.025, respectively). Multivariate analysis also identified the presence of intratumor lymphatic vessels as the only independent predictive factor of cause specific survival (OR = 3.89, p = 0.049). CONCLUSIONS: Lymphangiogenesis may have important roles in tumor metastasis and survival in patients with transitional cell carcinoma of the upper urinary tract. Quantification of lymphatic vessels, especially peritumor lymphatic vascular area and intratumor lymphatic vessels, was useful for predicting metastasis-free survival. In addition, the presence of intratumor lymphatic vessels was an independent predictor of cause specific survival.

Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract.

The prostaglandin E2 receptor, EP4 receptor (EP4R), plays an important role in the development of transitional cell carcinoma of the upper urinary tract (TCC-UUT). However, the clinical significance of other EP receptors (EP1R-3R) is not clear. Furthermore, the pathological function of EP receptors in such patients is not understood. In the present study, we examined the expression of EP1R-3R in 101 TCC-UUT tissues by immunohistochemistry. Furthermore, we defined the relationship between cyclooxygenase (COX)-2 and EP receptor expression, proliferation index (PI), microvessel density (MVD), and expression of metalloproteinase-2 (MMP-2), urokinase-type plasminogen activator (uPA), and exon v6 containing CD44 isoform (CD44 v6) by multivariate analysis. The expression of EP1R, EP2R, and EP3R was positive in 20 (19.8%), 26 (25.7%), and 14 (13.9%) tumor samples, respectively. Expression of these receptors was not associated with pathological findings or survival. COX-2 and EP4R were independently associated with MVD and MMP-2, and uPA or PI and MMP-2, respectively. Other EP receptors were not influenced by any factors. Our results suggest that EP1R-3R play a minimal role in cancer progression in patients with TCC-UUT. On the other hand, EP4R regulates tumor progression via cancer cell proliferation and MMP-2, distinct from COX-2.

Inter/intra investigator variation in orchidometric measurements of testicular volume by ten investigators from five institutions.

AIM: To perform quality control studies on testicular volume measurements for a multi-center epidemiological study of male reproductive function. METHODS: We constructed a data matrix with a balanced assignment for 2 consecutive days by ten investigators (andrological career: 4-21 years) from five institutions and 12 male volunteers aged 20-26 years. Testicular volume was measured by Prader's orchidometer. A skilled technician also performed an ultrasound estimate of testicular volume. RESULTS: A statistically significant inter-investigator variation was found for both testes (P < 0.05). In addition, there was a statistically significant investigator-by-volunteer interaction in testicular volume measurement (P < 0.01). However, there was no statistically significant difference in the two measurements performed on consecutive days for either testis. The testicular volumes for both the right and left testes as estimated by ultrasonography were smaller than results using the orchidometer. However, there was no statistical significance (P > 0.05). The difference in experiences of the investigators did not significantly correlate with accuracy of measurements in either testis. CONCLUSION: The present study revealed significant differences in the results of estimation of testicular volume among the ten investigators, but intra-investigator variation was not considerable. Improved training and proper standardization of the measurement will be necessary before starting a multi-center study based on an andrological examination.

Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D.

PURPOSE: Lymph vessel density (LVD) and microvessel density (MVD) correlate with the malignant potential of tumors and patient survival. Vascular endothelial growth factors (VEGF)-A, VEGF-C, and VEGF-D could modulate LVD and MVD. We investigated the clinical and prognostic significance of LVD and MVD on lymphangiogenic and angiogenic function of VEGF-A, VEGF-C, and VEGF-D in human bladder cancer. EXPERIMENTAL DESIGN: We reviewed tissue samples from patients with nonmetastatic bladder cancer who had undergone transurethral resections (n = 126). The densities of D2-40-positive vessels (LVD) and CD34-positive vessels (MVD) were measured by a computer-aided image analysis system. Expression of VEGF-A, VEGF-C, and VEGF-D was examined by immunohistochemistry; survival analyses and their independent roles were investigated using multivariate analysis models. RESULTS: LVD was associated with tumor grade but not with pT stage. LVD was associated with metastasis-free survival (log rank P = 0.039), but was not an independent prognostic factor. Although MVD affected survival, the combination of high LVD and high MVD in tumors was an independent predictor of metastasis-free survival. Although VEGF-C expression was positively associated with both LVD and MVD, VEGF-D was associated only with LVD. VEGF-A expression was associated with MVD in univariate analysis, however, it was not an independent factor. CONCLUSIONS: Lymphangiogenesis and angiogenesis influence metastasis-free survival, and are regulated by VEGF-C and/or VEGF-D. Our results suggest that LVD and MVD are useful tools for the selection of postoperative management and treatment strategies in patients with bladder cancer.

Expression of cyclooxygenase-2 and EP4 receptor in transitional cell carcinoma of the upper urinary tract.

PURPOSE: Prostaglandin E2, produced by cyclooxygenase (COX)-2, affects the behavior of tumor cells possibly through 1 of the prostaglandin E2 receptors, the EP4 receptor (EP4R). The relationship between tumor development and EP4R in transitional cell carcinoma of the upper urinary tract (TCC-UUT) has not been fully understood. We determined the relationships between clinicopathological features and prognosis with expressions of COX-2 and EP4R in nonmetastatic TCC-UUT. MATERIALS AND METHODS: We examined expressions of COX-2 and EP4R by immunohistochemical technique in 101 patients. Histological features including tumor grade, pT stage and lymph node metastasis were examined using formalin fixed and paraffin embedded specimens from the radical operation. The predictive values of these expressions of prognosis were investigated by Kaplan-Meier curve and Cox proportional hazards analysis in multivariate model. RESULTS: Expression of COX-2 and EP4R was observed in 46 (45.5%) and 51 (50.5%) cases, respectively. Each expression was significantly associated with pT stage and grade. Patients with co-expression of these proteins had a higher frequency of extra-urinary tract recurrence (33.3%). Postoperative survival time of patients with co-expression of COX-2 and EP4R was significantly shorter than that of patients with other expression patterns (p <0.001). Although COX-2 or EP4R expression was not an independent factor for cause specific survival in a multivariate model, co-expression of these proteins was an independent one (odds ratio 12.26 and p = 0.0038). CONCLUSIONS: Co-expression of COX-2 and EP4R is a potentially useful marker for tumor progression and survival in patients with nonmetastatic TCC-UUT.

Mucinous adenocarcinoma of the renal pelvis associated with transitional cell carcinoma in the renal pelvis and the bladder.

We report a case of mucinous adenocarcinoma of the renal pelvis associated with bladder carcinoma in situ (CIS). Transitional cell carcinoma (TCC) of the renal pelvis and CIS were also observed adjacent to the adenocarcinoma. Immunohistochemical assessment of the pelvic adenocarcinoma revealed positive expressions for mucin, epithelial membrane antigen, cytokeratin 7, cytokeratin 19 and carcinoembryonal antigen, but not vimentin or chromogranin. Based on the histopathological examinations, the adenocarcinoma of the renal pelvis in the present case may have a similar biological nature to conventional TCC and probably originated by development of pre-existing TCC of the renal pelvis.

Long-term effects of bacille Calmette-Guérin perfusion therapy for treatment of transitional cell carcinoma in situ of upper urinary tract.

OBJECTIVES: To report our experience with bacille Calmette-Guérin (BCG) perfusion therapy for transitional cell carcinoma in situ of the upper urinary tract. BCG perfusion therapy is widely used to treat transitional cell carcinoma in situ of the upper urinary tract. However, it has not yet been established as a standard treatment. METHODS: Ten patients diagnosed with transitional cell carcinoma in situ of the upper urinary tract were treated with BCG perfusion therapy from January 1990 to May 2002. BCG was instilled weekly for 6 weeks, with a median dose of 65 mg at 1.17 mg/mL (Tokyo 172 strain, dissolved in normal saline). RESULTS: The mean follow-up period was 50.9 months (range 12 to 134). The initial response to therapy was excellent, and cytology became negative in all patients after one course of BCG perfusion. Five patients developed recurrence after 5, 11, 24, 26, and 45 months, and all died after 46, 12, 41, 134, and 79 months, respectively. The mortality rate was 50% and was 100% in those with recurrence. The mean recurrence-free period was 22.2 months (range 5 to 45). Complications included bladder irritation-related symptoms in all patients, fever greater than 38 degrees C (n = 9), hematuria (n = 2), hydronephrosis (n = 2), and lumbago (n = 1) but all were transient and did not affect long-term prognosis. CONCLUSIONS: BCG perfusion therapy for carcinoma in situ of the upper urinary tract is safe, and the short-term response is excellent. However, the long-term results were not satisfactory. Therefore, this therapy should be considered experimental, although it may have potential benefits in delaying progression and possibly providing local control for patients in poor condition. Long-term studies are required for additional evaluation of BCG therapy.

Hearing impairment, undescended testis, circumferential skin creases, and mental handicap (HITCH) syndrome: a case report.

We report on a 3-year-old boy with circumferential skin creases as seen in Michelin tire baby syndrome (MTBS), hearing impairment, undescended testes, short stature, and mental handicap. Skin biopsy from the inguinal region showed degenerative collagen, which has never been found in MTBS. Similar clinical manifestations shared by our patient and a boy reported previously suggest a new clinical entity, in which degenerative collagen is etiologically involved. We propose an acronym to designate it: hearing impairment, undescended testis, circumferential skin creases, and mental handicap (HITCH) syndrome.

[Feasibility and change in the level of blood paclitaxel concentration after paclitaxel therapy for a hemodialysis patient with cisplatin resistant metastatic transitional cell cancer].

The patient was a 54-year-old woman with recurrent urinary tract cancer. A CT of the lung showed multiple nodules after bil-nephroureterectomy, cystectomy and combination chemotherapy with cisplatin (CDDP) and epirubicin (EPI). As second line chemotherapy for the patient, TXL was administered. She was hemodialized after operation, and there are few reports about paclitaxel (TXL) therapy for hemodialysis (HD) patients. Peak blood TXL concentration, about 1,200 ng/ml, was achieved 6 hours after the administration of TXL. The blood TXL concentration was 41 ng/ml 24 h after the administration of TXL. However, the TXL therapy was not repeated because of unacceptable neurological side effects. An almost 40% shrinkage in the size of the metastatic lung nodule was obtained after 1 cycle of treatment.