Diagnostic performance and safety of NMK36 (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid)-PET/CT in primary prostate cancer: multicenter Phase IIb clinical trial.

OBJECTIVE: We performed a multicenter Phase IIb clinical trial of NMK36, a novel amino acid analog for positron emission tomography containing trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid, to evaluate its safety and diagnostic performance for primary prostate cancer. METHODS: Sixty-eight subjects with primary prostate cancer scheduled for radical prostatectomy or hormone therapy underwent whole-body positron emission tomography/computed tomography after injection of NMK36. The diagnostic performances of NMK36-positron emission tomography/computed tomography were evaluated for (i) regional lymph node metastasis: comparison with contrast-enhanced computed tomography under setting reference standard (histopathology or 6-month follow-up), (ii) bone metastasis: concordance rate with conventional imaging (combination of bone scintigraphy and contrast-enhanced computed tomography) and (iii) primary lesion: comparison with histopathological findings. RESULTS: The accuracy of NMK36-positron emission tomography/computed tomography and contrast-enhanced computed tomography for regional lymph node metastasis were 85.5 and 87.3%, respectively. NMK36-positron emission tomography/computed tomography showed positive findings for regional lymph nodes with short-axis diameters of 5-9 mm at 23 regions in 13 patients of hormone therapy cohort, but they were not confirmed with reference standard in this study. The concordance rate of NMK36-positron emission tomography/computed tomography with conventional imaging for bone metastases was 83.3%, and seven patients had positive findings only by NMK36-positron emission tomography/computed tomography. The sensitivity and specificity of NMK36-positron emission tomography/computed tomography for primary lesion in six-segment analysis was 92.5 and 90.1%, respectively. Seven of non-serious adverse events were observed in six patients. CONCLUSIONS: This study showed the comparable diagnostic performance of NMK36-positron emission tomography/computed tomography compared with conventional imaging. Some lesions of lymph node and bone were positive solely by NMK36-positron emission tomography/computed tomography, which needs to be confirmed with reference standard in future study to evaluate the usefulness of NMK36-positron emission tomography/computed tomography in staging prostate cancer.

The clinical trial on the safety and effectiveness of the photodynamic diagnosis of non-muscle-invasive bladder cancer using fluorescent light-guided cystoscopy after oral administration of 5-aminolevulinic acid (5-ALA).

OBJECTIVE: To examine the utility and safety of photodynamic diagnosis (PDD) after oral administration of 5-aminolevulinic acid (5-ALA) (ALA-PDD) of non-muscle-invasive bladder cancer (NMIBC) using fluorescent-light (FL)-cystoscopy. METHODS: The study was a single-arm, open-label, multi-center prospective study on ALA-PDD of NMIBC, with safety as the primary endpoint and efficacy as the secondary endpoint. Diagnostic potential was evaluated through comparisons with the conventional diagnostic method using a white-light (WL)-source. Clinically recommended doses were also examined. Oral administration of 5-ALA (1.0g/50mL) was performed 180-240min before FL-cystoscopy, and positive or negative results were judged using a WL-source and based on presence or absence of red fluorescence on exposure to a blue FL-source. RESULTS: Regarding safety, the adverse drug reactions were observed as grade 1 pruritus in 1 patient (0.6%). As for efficacy, specificity and positive predictability were lower than those of a WL-source, but sensitivity was higher with a FL-source than with a WL-source. The proportion of patients with tumors detected only by FL-cystoscopy was greater than the proportion of patients with tumors detected only by conventional WL-cystoscopy. Moreover, not only sensitivity, but also the proportion of patients with tumors detected only by FL-cystoscopy, was highest among patients who received 5-ALA at ≧20mg/kg/body. CONCLUSIONS: ALA-PDD was shown to be safe and effective. Furthermore, diagnostic accuracy of PDD increased with increased dose of 5-ALA, and the recommended dose was determined as ≧20mg/kg/body in the present study.

Oral 5-aminolevulinic acid mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A randomized, double-blind, multicentre phase II/III study.

BACKGROUND: Photodynamic diagnosis (PDD) of non-muscle-invasive bladder cancer (NMIBC) following transurethral administration of a hexalated form of 5-aminolevulinic acid (5-ALA), 5-ALA hexyl ester, is widely performed in Western countries. In this study, effectiveness and safety of the oral administration of 5-ALA is assessed in a phase II/III study of PDD for NMIBC in comparison to those of conventional white-light endoscopic diagnosis. METHODS: Patients with NMIBC were allocated to two groups that were orally administered 10 and 20 mg/kg of 5-ALA under the double-blind condition. Effectiveness was evaluated by setting the primary endpoint to sensitivity. Safety was also analyzed. Moreover, clinically recommended doses of 5-ALA was also investigated as an investigator-initiated multicenter cooperative clinical trial in which five medical institutions participated. RESULTS: All 62 enrolled patients completed the clinical trial. The sensitivities of PDD were higher (84.4 and 75.8% in the 10 and 20 m g/kg-groups, respectively) than those of conventional endoscopic diagnosis (67.5 and 47.6%, respectively) (p = 0.014 and p < 0.001, respectively). Five episodes of serious adverse events developed in four patients; whereas a causal relationship with the investigational agent was ruled out in all episodes. CONCLUSION: This investigator-initiated clinical trial confirmed the effectiveness and safety of PDD for NMIBC following oral administration of 5-ALA. Both doses of 5-ALA may be clinically applicable; however, the rate of detecting tumors only by PDD was higher in the 20 mg/kg-group suggesting that this dose would be more useful.

The impact of HIF1α on the Per2 circadian rhythm in renal cancer cell lines.

In mammals, the circadian rhythm central generator consists of interactions among clock genes, including Per1/2/3, Cry1/2, Bmal1, and Clock. Circadian rhythm disruption may lead to increased risk of cancer in humans, and deregulation of clock genes has been implicated in many types of cancers. Among these genes, Per2 is reported to have tumor suppressor properties, but little is known about the correlation between Per2 and HIF, which is the main target of renal cell carcinoma (RCC) therapy. In this study, the rhythmic expression of the Per2 gene was not detectable in renal cancer cell lines, with the exception of Caki-2 cells. In Caki-2 cells, HIF1α increased the amplitude of Per2 oscillation by directly binding to the HIF-binding site located on the Per2 promoter. These results indicate that HIF1α may enhance the amplitude of the Per2 circadian rhythm.

Combination of hemoglobin, alkaline phosphatase, and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer.

BACKGROUND: We aimed to find the prognostic factors predicting overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) who had docetaxel (DTX) chemotherapy, and to construct a model predicting the optimum number of cycles of DTX. METHODS: A total of 279 CRPC patients who received DTX (≥50 mg/m(2)) every 3-4 weeks were studied retrospectively. Prognostic factors predicting treatment cycles as well as OS were analyzed, and a risk table for predicting treatment cycles was constructed. RESULTS: The longer treatment group (>10 cycles) had a significantly longer OS than the standard treatment group (p < 0.0001). Multivariate analysis demonstrated that a decrease of ≥50 % in prostate-specific antigen (PSA), serum markers at the start of DTX therapy [PSA, alkaline phosphatase (ALP), and C-reactive protein (CRP)], and the number of DTX courses were independent predictors of OS. The risk table employing the combination of three factors [ALP (cut-off 189 IU/L), hemoglobin (11.3 g/dL), and age (65 years) at the start of DTX therapy], and scoring based on the hazard ratio of each risk factor (ALP 4, hemoglobin 2, age 3) could effectively predict the probability of the length of DTX therapy, with lower score (0-6) predicting >10 cycles, and higher score (7-9) predicting ≤5 cycles (p < 0.0001). No significant difference was found regarding grade 3/4 adverse events between the two groups. CONCLUSION: A model using three factors prior to chemotherapy may be beneficial for deciding the duration of DTX therapy in patients with CRPC.

The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: a multi-institutional study.

BACKGROUND: Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. INTERVENTION: All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50mg/dl was defined as elevated. RESULTS AND LIMITATIONS: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤ 0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p<0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. CONCLUSIONS: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

Enhanced diagnostic accuracy for quantitative bone scan using an artificial neural network system: a Japanese multi-center database project.

BACKGROUND: Artificial neural network (ANN)-based bone scan index (BSI), a marker of the amount of bone metastasis, has been shown to enhance diagnostic accuracy and reproducibility but is potentially affected by training databases. The aims of this study were to revise the software using a large number of Japanese databases and to validate its diagnostic accuracy compared with the original Swedish training database. METHODS: The BSI was calculated with EXINIbone (EB; EXINI Diagnostics) using the Swedish training database (n = 789). The software using Japanese training databases from a single institution (BONENAVI version 1, BN1, n = 904) and the revised version from nine institutions (version 2, BN2, n = 1,532) were compared. The diagnostic accuracy was validated with another 503 multi-center bone scans including patients with prostate (n = 207), breast (n = 166), and other cancer types. The ANN value (probability of abnormality) and BSI were calculated. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) analyses were performed. RESULTS: The ROC analysis based on the ANN value showed significant improvement from EB to BN1 and BN2. In men (n = 296), the area under the curve (AUC) was 0.877 for EB, 0.912 for BN1 (p = not significant (ns) vs. EB) and 0.934 for BN2 (p = 0.007 vs. EB). In women (n = 207), the AUC was 0.831 for EB, 0.910 for BN1 (p = 0.016 vs. EB), and 0.932 for BN2 (p < 0.0001 vs. EB). The optimum sensitivity and specificity based on BN2 was 90% and 84% for men and 93% and 85% for women. In patients with prostate cancer, the AUC was equally high with EB, BN1, and BN2 (0.939, 0.949, and 0.957, p = ns). In patients with breast cancer, the AUC was improved from EB (0.847) to BN1 (0.910, p = ns) and BN2 (0.924, p = 0.039). The NRI using ANN between EB and BN1 was 17.7% (p = 0.0042), and that between EB and BN2 was 29.6% (p < 0.0001). With respect to BSI, the NRI analysis showed downward reclassification with total NRI of 31.9% ( p < 0.0001). CONCLUSION: In the software for calculating BSI, the multi-institutional database significantly improved identification of bone metastasis compared with the original database, indicating the importance of a sufficient number of training databases including various types of cancers.

Progesterone induced mesenchymal differentiation and rescued cystic dilation of renal tubules of Pkd1(-/-) mice.

Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary disease affecting the kidneys, is caused in 85% of cases by mutations in the PKD1 gene. The protein encoded by this gene, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment, which regulate the tissue architecture and differentiation. However, how such mutations result in the formation of cysts is still unclear. We performed a precise characterization of mesenchymal differentiation using PAX2, WNT4 and WT1 as a marker, which revealed that impairment of the differentiation process preceded the development of cysts in Pkd1(-/-) mice. We performed an in vitro organ culture and found that progesterone and a derivative thereof facilitated mesenchymal differentiation, and partially prevented the formation of cysts in Pkd1(-/-) kidneys. An injection of progesterone or this derivative into the intraperitoneal space of pregnant females also improved the survival of Pkd1(-/-) embryos. Our findings suggest that compounds which enhance mesenchymal differentiation in the nephrogenesis might be useful for the therapeutic approach to prevent the formation of cysts in ADPKD patients.

Significant Correlation between Chromosomal Aberration and Nuclear Morphology in Urothelial Carcinoma.

We aimed to identify whether there is any correlation between chromosomal/genetic changes, nuclear morphology and the histological grade of urothelial carcinomas of the urinary bladder. Morphometry and multicolour fluorescence in situ hybridisation (FISH) techniques were applied to 250 cells in five low-grade cases and 350 cells in seven high-grade cases of urothelial carcinoma. Compared with low-grade carcinomas, most high-grade cases showed larger and more variable nuclear size, more frequent polysomy of centromere enumeration probes (CEPs) 3, 7 and 17, and the loss of the 9p21 locus. The number of CEP signals in cells was increased as the nuclear area of the cells became larger. Cells with gains in two or more types of CEP had significantly larger nuclei than cells with normal FISH signal patterns. In conclusion, the present study indicates that there was a correlation between nuclear morphology and chromosomal/genetic changes which were related to histological grading. Thus, we show that differences in the chromosomal/genetic aberrations present in low- and high-grade tumours can affect not only nuclear morphology but also the histopathological and clinical behaviour of urothelial carcinomas.

[Biochemical markers of bone turnover. New aspect. Bone metabolic markers in prostatic carcinoma].

Hormonal therapy against prostatic carcinoma brings to osteoporotic change and alendronate is effective to suppress the change. Urinary NTX and serum ICTP are shown to be useful markers to react with hormonal therapy. But most of bone metabolic markers are not within normal range at the time of starting hormonal therapy. The program, which evaluate the effect of hormonal therapy against non-metastatic prostatic carcinoma, is strongly expected. And it is still a serious problem to be solved when we start, how to use, how long we use biphosphonates.

[The use of the PlasmaKinetic TUR system in the treatment of benign prostate hyperplasia: results of 1-year follow up].

INTRODUCTION AND OBJECTIVE: The goal of this study was to evaluate the efficiency of the PlasmaKinetic (PK) system by comparing the preoperative and postoperative results in patients with benign prostate hyperplasia (BPH) treated in this hospital. METHODS: From June 2004 to November 2006, the PK system was utilized for 46 cases of TUR-P in this Hospital. The patients International prostate symptom score (IPSS), QOL score, uroflowmetry, measurement of residual urine amount and ultrasonography were compared before and after the surgery (first month, third month and first year). In addition, the operation times, urethral catheterization times, preoperative and postoperative hemoglobin and serum sodium values of the patients were compared before and after the operations. RESULTS: At 1 and 3 months and 1 year, the IPSS decreased from 28.2 +/- 7.4 to 6.1 +/- 5.9, 2.7 +/- 3.5 and 6.6 +/- 5.3, respectively. The QOL score, decreased from 5.4 +/- 1.0 to 0.9 +/- 1.2, 0.6 +/- 0.9 and 1.3 +/- 1.1, respectively. The maximum urinary flow increased from 3.7 +/- 4.0 ml/s to 19.5 +/- 9.6, 17.9 +/- 7.3 and 18.7 +/- 9.9 ml/s, respectively. The post void residual urine decreased from 104.8 +/- 83.6 ml to 19.4 +/- 25.0, 11.1 +/- 24.7 and 17.9 +/- 28.5 ml, respectively. CONCLUSIONS: Acceptable outcomes with normal recovery from TUR-P were obtained using the PK system.

[Clinical importance of guideline for decontamination of endoscopes in urological field: verification of 3 processes].

UNLABELLED: Clinical guideline for decontamination of endoscopes in urological field has not been provided, although endoscopic examination should be done in aseptic circumstance. MATERIAL AND METHOD: From decontamination processes, following 3 points were selected for verification: 1) Volume of residual water in flexible scope after rinsing, estimated by weight change. 2) Concentration of eluted disinfectant from flexible scope after standard rinsing procedure for gastrointestinal endoscope. 3) Observation of possible damage of telescope, caused by repeat autoclaving. RESULTS: Wet condition of flexible scope could be suspected in 60 hours in room temperature. Eluted disinfectants were detected, but in harmless level. Repeated autoclaving merely caused minor damage, which does not interfere clinical use. CONCLUSION: We obtained a couple of evidences with cautions in decontamination processes for endoscopes. Urgent requirement of standardization in this field should be discussed widely.

Langerhans cell histiocytosis on the penis: a case report.

BACKGROUND: Langerhans cell histiocytosis affects mainly young children and features an accumulation of CD1a+ dendritic Langerhans cells in the bone, skin, and other organs. A few cases of Langerhans cell histiocytosis on the penis have been reported in the literature. We present a case of Langerhans cell histiocytosis on the penis and review the similar cases in the literature. CASE PRESENTATION: The patient was a 13-year-old boy who had a history of lymph node, femur bone, and pituitary-thalmic axis lesions from Langerhans cell histiocytosis who noticed a painful nodule on the prepuce of his penis. The histological and immunohistochemical examination fulfilled the criteria of Langerhans cell histiocytosis. CONCLUSION: We herein describe the case reported of Langerhans cell histiocytosis on the penis.

Ectopic thyroid in an adrenal mass: a case report.

BACKGROUND: It is difficult to explain ectopic thyroid beneath the diaphragm because during the development the thyroid descends from the tongue to the anterior of the trachea. A few cases of ectopic lesions have been reported in the literature for abdominal organs including the adrenal glands, but the mechanism by which the thyroid components migrate into the abdomen has been poorly understood. CASE PRESENTATION: A 54-year-old woman was diagnosed as having an adrenal mass. Laparoscopic adrenalectomy was carried out. Microscopically, the mass was composed of normal adrenal and ectopic thyroid tissues. CONCLUSION: We herein describe the fourth case reported of ectopic thyroid in the adrenal gland.

Testicular seminoma after the complete remission of extragonadal yolk sac tumor : a case report.

BACKGROUND: Between 2% and 5% of malignant germ-cell tumors in men arise at extragonadal sites. Of extragonadal germ cell tumors, testicular carcinoma in situ (CIS) are present in 31-42% of cases, and CIS are reported to have low sensitivity to chemotherapy in spite of the various morphology and to have a high likelihood of developing into testicular tumors. A testicular biopsy may thus be highly advisable when evaluating an extragonadal germ cell tumor. CASE PRESENTATION: A 36-year-old man was diagnosed as having an extragonadal non-seminomatous germ cell tumor, that was treated by cisplatin-based chemotherapy, leading to a complete remission. In the meantime, testicular tumors were not detected by means of ultrasonography. About 4 years later, a right testicular tumor was found, and orchiectomy was carried out. Microscopically, the tumor was composed of seminoma. CONCLUSIONS: We herein report a case of metachronous occurrence of an extragonadal and gonadal germ cell tumor. In the evaluation of an extragonadal germ cell tumor, a histological examination should be included since ultrasonography is not sufficient to detect CIS or minute lesions of the testis.

Nephrotic syndrome as a result of membranous nephropathy caused by renal cell carcinoma.

A 77-year-old woman was admitted for a renal biopsy to evaluate a case of nephrotic syndrome. In the course of the examination, a right renal tumor was incidentally found. We performed a right radical nephrectomy in advance of the renal biopsy. Histologically, the tumor was diagnosed as a renal cell carcinoma (clear cell carcinoma) and the non-neoplastic renal cell tissue showed membranous nephropathy (MN). After surgery, the nephrotic syndrome remitted without any further medical treatment and the MN was considered to be a malignancy associated syndrome. There have been few case reports in the literature regarding this association and we wish to describe another case.

Identification of a new target molecule for a cascade therapy of polycystic kidney.

Autosomal dominant polycystic kidney disease is a systemic disorder that primary affects the kidney which is characterized by the formation of fluid-filled cysts in both kidneys that leads to progressive renal failure. Mutated genes, polycystin-1 and polycystin-2, are identified, and evidence has emerged that polycystins are ion channels or regulators of ion channels. In spite of extensive characterization of polycystins, how polycystin channel signaling may be involved in cyst formation in ADPKD is still unclear. We found a mutant mouse which exhibits polycystic kidney and bone deformity in the course of making a transgenic mouse carrying the Drosophila sex-lethal gene. We identified a mutated gene Makorin1 by positional cloning. Makorin1 carries a typical RING-finger motif, suggesting that Makorin1 belongs to ubiquitinase E3 family. Makorin1 would open a new avenue to understand pathogenesis of polycystic kidney, and become a new therapeutic target of polycystic kidney.

Hypercalcemia upon recurrence of renal cell carcinoma producing parathyroid hormone-related protein.

We established a new renal carcinoma cell line that produces parathyroid hormone-related protein (PTHrP) and interleukin-6 in culture. The cellular production of PTHrP was confirmed by Northern blot analysis and immunofluorescence examination. Bone and lung metastases occurred simultaneously 3.5 years after surgery. The patient did not show hypercalcemia at this time, despite the presence of multiple osteolytic metastases. About 7 months after bone metastasis was first shown, serum PTHrP was detected by means of an immunoradiometric assay and the calcium level was found to be elevated to 3.29 mmol/l. The hypercalcemia was successfully controlled by i.v. administration of bisphosphonates.

Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice.

We investigated the mechanism of the anti-fibrotic effects of hepatocyte growth factor (HGF) in the kidney, with respect to its effect on connective tissue growth factor (CTGF), a down-stream, profibrotic mediator of transforming growth factor-beta1 (TGF-beta1). In wild-type (WT) mice with 5/6 nephrectomy (Nx), HGF and TGF-beta1 mRNAs increased transiently in the remnant kidney by week 1 after the Nx, returned to baseline levels, and increased again at weeks 4 to 12. In contrast, CTGF and alpha1(I) procollagen (COLI) mRNAs increased in parallel with HGF and TGF-beta1 during the early stage, but did not re-increase during the late stage. In the case of TGF-beta1 transgenic (TG) mice with 5/6 Nx, excess TGF-beta1 derived from the transgene enhanced CTGF expression significantly in the remnant kidney, accordingly accelerating renal fibrogenesis. Administration of dHGF (5.0 mg/kg/day) to TG mice with 5/6 Nx for 4 weeks from weeks 2 to 6 suppressed CTGF expression in the remnant kidney, attenuating renal fibrosis and improving the survival rate. In an experiment in vitro, renal tubulointerstitial fibroblasts (TFB) were co-cultured with proximal tubular epithelial cells (PTEC). Pretreatment with HGF reduced significantly CTGF induction in PTEC by TGF-beta1, consequently suppressing COLI synthesis in TFB. In conclusion, HGF can block, at least partially, renal fibrogenesis promoted by TGF-beta1 in the remnant kidney, via attenuation of CTGF induction.