Risedronate prevents persistent bone loss in prostate cancer patients treated with androgen deprivation therapy: Results of a 2-year follow-up study

Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that risedronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P0.0001, P0.0001, and P0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment. © 2011 Macmillan Publishers Limited All rights reserved

Cranial nerve deficit caused by skull metastasis of prostate cancer: three Japanese castration-resistant prostate cancer cases

金沢大学附属病院泌尿器科We report 3 Japanese patients with cranial nerve deficit caused by skull metastasis of prostate cancer (PCa). Case 1 was a 75-year-old patient with a chief complaint of diplopia. The cause of diplopia was right oculomotor nerve palsy from the skull metastasis. External beam radiation therapy (EBRT) to the whole brain, 40 Gy in 20 fractions, was performed and the diplopia improved. Case 2 was a 72-year-old patient with a chief complaint of facioplegia. Bone scintigraphy and computed tomography (CT) of the head revealed right occipital bone metastasis of PCa resulting in right facial nerve palsy. EBRT to the right occipital bone, 50 Gy in 25 fractions, with daily oral dexamethasone (DEX) was performed and facioplegia showed complete recovery. At 12 months after onset, the patient was followed-up with no symptoms. Case 3 was a 74-year-old patient with a chief complaint of diplopia. Diffusion-weighted magnetic resonance imaging (MRI) and positron emission tomography (PET) showed right petrous bone metastasis resulting in right abducent nerve palsy. EBRT to the right petrous bone, 44 Gy in 22 fractions, with oral DEX was performed and diplopia showed complete recovery. At 13 months after onset, the patient was followed-up with no symptoms. MRI and PET may detect PCa metastasis in the skull base more clearly than other imaging modalities. EBRT with 40-50 Gy in 20-25 fractions in association with corticosteroid administration may be reasonable treatment of patients with metastatic PCa who develop cranial nerve dysfunction. © 2010 Japan Society of Clinical Oncology

Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone

金沢大学附属病院泌尿器科金沢大学附属病院泌尿器科One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5a-reductase inhibitor dutasteride appears to function not only as a 5a-reductase inhibitor but also as a 3b-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis. © 2009 Society for Endocrinology

Role of surgical resection in adult urological soft tissue sarcoma: 25-Year experience

金沢大学附属病院泌尿器科The effect of chelating ligands on iron (Fe) uptake and growth of radish (Raphanus sativus L.) was investigated. The ethylenediaminetetraacetic acid (EDTA) increased 55Fe uptake in roots of radish though its subsequent translocation from roots to shoots and leaves did not increase. About 70%-80% of the total 55Fe was distributed in the roots while about 5%-15% and 11%-17% were in shoots and leaves, respectively. The EDTA increased iron uptake into the roots of radish, but not in the above ground parts of the plant. The growth of radish (Raphanus sativus L.) decreased drastically in alkaline condition (pH > 9), even though the concentration of iron was sufficient in the growth medium. The growth of radish was enhanced successfully by the addition of hydroxyiminodisuccinic acid (HIDS) and EDTA. This might be because HIDS and EDTA solubilize iron from its precipitation with hydroxides at higher pH, and increase iron bioavailability. The influence of EDTA and HIDS on radish growth was comparable. Increase of radish growth by ethylenediaminedisuccinic acid (EDDS) and methylglicinediacetic acid (MGDA) was less than those by EDTA and HIDS. Considering the reproducibility of the radish growth (biomass production) at pH 10, HIDS is supposed to be more effective compared to EDTA. © Taylor & Francis Group, LLC

Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen

金沢大学附属病院泌尿器科Objectives: To analyze the clinical effects of flutamide as a second-line anti-androgen for combined androgen blockade in patients with castration-resistant prostate cancer (CRPC) initially treated with bicalutamide as a first-line anti-androgen. Methods: Our study population consisted of 16 patients with CRPC who were treated with flutamide (375 mg daily) as second-line hormonal therapy. Dehydroepiandrosterone (DHEA), androstenedione, androstenediol, testosterone and dihydrotestosterone were measured to investigate the relationship between plasma androgens and outcome following treatment. Furthermore, adrenal androgen levels in a medium of adrenal cancer cell line were also measured. Results: Second-line hormonal therapy using flutamide resulted in a reduction of the prostate-specific antigen (PSA) level in 14 (87.5%) of 16 patients. A PSA decline greater than 50% was observed in 8 (50%) of the 16 patients. The duration of median responsiveness was 6.25 months. PSA elevation of baseline androstenediol level was a predictive factor of PSA responsiveness. The lower DHEA group improved the duration of responsiveness to flutamide. In vitro, 3 μmol/L flutamide suppressed DHEA, androstenedione and androstenediol synthesis compared with bicalutamide in a medium of adrenal cancer cell line. Conclusions: Our data show that flutamide suppresses the adrenal androgens in comparison with bicalutamide. The responsiveness and response duration of flutamide can be predicted in patients with a higher baseline androstenediol level and a lower DHEA level. Metabolites from adrenal androgens contribute to the progression of prostate cancer. © 2010 The Japanese Urological Association

Androgen replacement therapy for cancer-related symptoms in male advanced cancer patients : study protocol for a randomised prospective trial (ARTFORM study)

Recent studies reveal that hypogonadism with low serum androgen levels is associated with advanced cancer and induction of most cancer-related symptoms.We designed an ARTFORM study to evaluate the efficacy of androgen replacement therapy in male advanced cancer patients. The ARTFORM study is an investigatorinitiated, randomised controlled trial comparing intramuscle injection of testosterone enanthate with non-administration in male advanced cancer patients with non-curative locally advanced or metastatic lesions. Serum total and free testosterone levels are measured and patients with low testosterone level are randomised. The primary endpoint is the difference in validated health-related quality of life questionnaires at week 12. Trial registration of the ARTFORM study is assigned to University hospital Medical Information Network, Center identifier UMIN 000010939

Tissue-specific differentially methylated regions of the human VASA gene are potentially associated with maturation arrest phenotype in the testis

Numerous CpG islands containing tissue-specific differentially methylated regions (TDMRs) are potential methylation sites in normal cells and tissues. The VASA (also known as DDX4) gene is believed to be under the control of TDMRs. A total of 131 male patients with idiopathic azoospermia or severe oligospermia were evaluated histologically, and the methylation status of CpG islands in the VASA gene was screened. Genome DNAs were obtained from testicular biopsy and modified with sodium bisulfite, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied. This system is capable of analyzing both the methylated and unmethylated CpG island in the genome. The methylation analysis is conducted by an epigram as graphic data. On histological assessment, 17 of 131 patients revealed maturation arrest (MA).In all, 6 of the 17 patients showed particularly high VASA TDMR methylation rates, whereas the remaining 11 patients and controls had low methylation rates. This study may imply that the VASA TDMR methylation is significantly higher among patients with MA, in whom the VASA gene expression was silenced. This finding represents an important contribution to the molecular basis of meiotic arrest as one possible cause of idiopathic infertility. © 2009 The Japan Society of Human Genetics All rights reserved

Changes in penile length after radical prostatectomy: Investigation of the underlying anatomical mechanism

Objective: To measure changes in penile length (PL) over time before and after radical prostatectomy (RP), and to investigate the underlying mechanisms for these changes. Patients and Methods: The stretched PL (SPL) of 102 patients was measured before, 10 days after, and at 1, 3, 6, 9, 12, 18 and 24 months after RP. The perpendicular distance from the distal end of the membranous urethra to the midline of the pelvic outlet was measured on mid-sagittal magnetic resonance imaging (MRI) slice at three time points: preoperatively; 10 days after RP; and 12 months after RP. Pre- and postoperative SPLs were compared using paired Student\u27s t-test. Predictors of PL shortening at 10 days and at 12 months after RP were evaluated on univariate and multivariate analyses. Results: The SPL was shortest 10 days after RP (mean PL shortening from preoperative level: 19.9 mm), and gradually recovered thereafter. SPL at 12 months after RP was not significantly different from preoperative SPL. On MRI examination, the distal end of membranous urethra was found to have moved proximally (mean proximal displacement: 3.9 mm) at 10 days after RP, and to have returned to the preoperative position at 12 months after RP. On univariate analysis, only the volume of the removed prostate was a predictor of SPL change at 10 days after surgery; on multivariate analysis, the association was not statistically significant. No predictor of SPL change was found at 12 months after RP. Conclusion: The SPL was shortest at 10 days after RP and gradually recovered thereafter in the present study. Anatomically, the glans and corpus spongiosum surrounding the urethra are an integral structure, and the proximal urethra is drawn into the pelvis during urethrovesical anastomosis. This is the first report showing that slight vertical repositioning of the membranous urethra after RP causes changes in SPL over time. These results can help inform patients about changes in penile appearance after RP. © 2017 BJU International.Embargo Period 12 month

Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis

Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy