Toshiki Ito

Impact of calcineurin inhibitors on urinary excretion of mycophenolic acid and its glucuronide in kidney transplant recipients.

Concomitant cyclosporine interacts with mycophenolic acid (MPA) through inhibition of the biliary excretion of its glucuronide (MPAG). The aim of this study was to evaluate the influence of calcineurin inhibitors on the plasma disposition and urinary excretion of MPA and MPAG in kidney transplant recipients. Twelve recipients treated with tacrolimus and 18 treated with cyclosporine at 30 days after transplantation were enrolled. AUC from 0 to 12 hours (AUC0–12) of MPA was significantly higher in tacrolimus‐treated than in cyclosporine‐treated recipients. In contrast, there was no significant difference in MPAG AUC0–12 between calcineurin inhibitor medications. Unbound fractions of MPA and MPAG did not change significantly in a comparison between the tacrolimus and cyclosporine treatments (0.90% vs 1.27% in MPA; 20.0% vs 19.3% in MPAG). The ratio of renal clearance to creatinine clearance (CLR/CLCr) of MPA was significantly lower in tacrolimus‐ than in cyclosporine‐treated recipients (0.054 vs 0.100). In contrast, no significant difference was observed in the CLR/CLCr of MPAG between the tacrolimus and cyclosporine treatments (0.19 vs 0.18). In conclusion, concomitant calcineurin inhibitors influenced the urinary excretion of MPA but not MPAG in kidney transplant recipients. The results suggest the presence of renal tubular secretion in the urinary excretion process of MPA.

Successful treatment for adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with laparoscopic adrenalectomy: a case series

IntroductionAdrenocorticotropic hormone-independent macronodular adrenal hyperplasia, characterized by bilateral macronodular adrenal hypertrophy and autonomous cortisol production, is a rare cause of Cushing’s syndrome. Bilateral adrenalectomy is considered the standard treatment for adrenocorticotropic hormone-independent macronodular adrenal hyperplasia but obliges the patient to receive lifetime steroid replacement therapy subsequently, and may increase the patient’s risk of adrenal insufficiency. These circumstances require surgeons to carefully consider operative strategies on an individual basis.Case presentationWe performed successful laparoscopic adrenalectomy on four patients with adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. Computed tomography scans showed bilateral adrenal enlargement in all patients. Case 1: a 56-year-old Japanese woman presented with obvious Cushing’s symptoms during treatment for diabetes mellitus and hypertension. Case 2: a 37-year-old Japanese man also presented with Cushing’s symptoms during treatment for diabetes mellitus and hypertension. These patients were diagnosed as Cushing’s syndrome caused by adrenocorticotropic hormone-independent macronodular adrenal hyperplasia based on endocrinologic testing, and underwent bilateral laparoscopic adrenalectomy. Case 3: an 80-year-old Japanese woman was hospitalized due to unusual weight gain and heightened general fatigue, and was diagnosed as Cushing’s syndrome caused by adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. She underwent unilateral laparoscopic adrenalectomy due to high operative risk. Case 4: a 66-year-old Japanese man was discovered to have bilateral adrenal tumors on medical examination. He did not have Cushing’s symptoms and was diagnosed as subclinical Cushing’s syndrome due to suppressed adrenocorticotropic hormone serum levels and loss of cortisol circadian rhythm without abnormal levels of serum cortisol. He underwent unilateral laparoscopic adrenalectomy. During follow-up, serum cortisol levels were within the normal range in all cases, and serum adrenocorticotropic hormone levels were not suppressed. Further, cases with Cushing’s syndrome experienced clinical improvement.ConclusionsWe were able to effectively treat adrenocorticotropic hormone-independent macronodular adrenal hyperplasia in patients with obvious Cushing’s symptoms by laparoscopic bilateral adrenalectomy, which promptly improved symptoms. Further, unilateral adrenalectomy was effective for treating an older patient at high operative risk and a patient with subclinical Cushing’s syndrome.

BK virus nephropathy: Clinical experience in a university hospital in Japan

Objectives:  To review the medical records of patients with BK virus nephropathy (BKVN) following kidney transplantation in our institution.

Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan

&NA; The present study included 222 patients with metastatic castration‐resistant prostate cancer. Of the 222 patients, 108 and 114 received an alternative androgen receptor‐axis‐targeted agent (ARATA) or docetaxel, respectively, after the failure of initial ARATA. We found that the oncologic outcomes, including the response rate, progression‐free survival, and overall survival, were significantly superior in the 114 patients receiving docetaxel compared with those of the 108 patients receiving ARATA. Background: The objective of the present study was to assess the oncologic outcomes of patients receiving second‐line therapy against metastatic castration‐resistant prostate cancer (mCRPC). Patients and Methods: The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor‐axis‐targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA‐to‐Enz, n = 49; Enz‐to‐AA, n = 59) and 114 received docetaxel (DTX; AA‐to‐DTX, n = 54; Enz‐to‐DTX, n = 60). Results: The prostate‐specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression‐free survival (PFS), and overall survival (OS) during second‐line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz‐to‐AA vs. AA‐to‐DTX and Enz‐to‐AA vs. Enz‐to‐DTX; PSA PFS, AA‐to‐Enz vs. Enz‐to‐AA, AA‐to‐Enz vs. AA‐to‐DTX, Enz‐to‐AA vs. AA‐to‐DTX, and Enz‐to‐AA vs. Enz‐to‐DTX; and OS, Enz‐to‐AA vs. AA‐to‐DTX and Enz‐to‐AA vs. Enz‐to‐DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis. Conclusion: Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA.

Clinical characteristics of self-reported nocturia in patients with interstitial cystitis, and effects of bladder hydrodistention (with fulguration of Hunner lesions) on nocturia

The aim of this study was to investigate the clinical characteristics of nocturia in patients with interstitial cystitis (IC), and the effects of bladder hydrodistention (with fulguration of Hunner lesions) on nocturia.

Significance of De Ritis (Aspartate Transaminase/Alanine Transaminase) Ratio as a Significant Prognostic But Not Predictive Biomarker in Japanese Patients with Metastatic Castration-resistant Prostate Cancer Treated with Cabazitaxel

Background/Aim: To date, there have not been any established biomarkers predicting the efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the significance of the aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT) ratio (De Ritis ratio) as a biomarker for mCRPC patients receiving cabazitaxel. Patients and Methods: This study included 74 consecutive docetaxel-refractory mCRPC patients treated with cabazitaxel. It assessed the impact of the pretreatment De Ritis ratio, in addition to conventional clinicopathological parameters, on the oncological outcomes in these patients. Results: After treatment with cabazitaxel, 22 (29.7%) of the 74 patients achieved a prostate-specific antigen (PSA) response; however, there was no significant difference in the PSA response rate between patients with a low De Ritis ratio (<1.35) and those with a high ratio (≥1.35). In this series, the median periods of PSA progression-free survival (PFS) and overall survival (OS) after the introduction of cabazitaxel were 4.2 and 14.7 months, respectively. No significant difference was noted in PSA PFS between the low and high De Ritis ratio groups, whereas OS in the high De Ritis ratio group was significantly poorer compared with that in the low De Ritis ratio group. Univariate analysis showed the significant impact of the De Ritis ratio on OS, but not PFS, in these 74 patients. Furthermore, the De Ritis ratio, in addition to the performance status and lactate dehydrogenase level, was shown to be independently associated with OS on multivariate analysis. Conclusion: Assessment of the De Ritis ratio may provide useful prognostic, but not predictive, information on cabazitaxel therapy in mCRPC patients.

Significance of Age in Japanese Patients Receiving Sunitinib as First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: Comparative Assessment of Efficacy and Safety between Patients Aged <75 and ≥75 Years

Background/Aim: To date, it has not been well characterized whether sunitinib is effective in elderly patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to investigate the impact of age on clinical outcomes of mRCC patients receiving sunitinib. Patients and Methods: The efficacy and safety of first-line sunitinib in 154 consecutive mRCC patients were retrospectively compared between patients aged <75 (n=125) and ≥75 (n=29) years. Results: There were no significant differences in the major clinicopathological characteristics between younger and older patients; however, the reduction of the initial dose of sunitinib was significantly more frequent in older than younger patients. No significant difference in response rate, clinical benefit rate or proportion of patients going on to receive second-line therapy was noted between these two groups. Furthermore, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups, and no significant impact of age on PFS or OS was documented by the Cox proportional hazards regression analyses. Of several adverse events, only anemia and fatigue were significantly more frequently observed in older than younger patients. Although there was no significant difference in the incidence of dose reduction or discontinuation of sunitinib between the two groups, the interruption of sunitinib was more frequently required in older than younger patients. Conclusion: These findings suggest that advanced age alone should not be regarded as a contraindication to the introduction of sunitinib as first-line systemic therapy for mRCC patients.

Should Ipsilateral Solitary Adrenal Involvement in Renal Cell Carcinoma be Staged as M1

OBJECTIVE In 2009, the TNM classification of malignant tumors was revised, and the renewal of the T2-4 stage in renal cell carcinoma was adopted. To date, however, the staging of ipsilateral solitary adrenal involvement in renal cell carcinoma has not been sufficiently evaluated. METHODS We retrospectively reviewed the adrenal involvement in renal cell carcinoma among 1033 patients admitted to the Department of Urology at Hamamatsu University Hospital, Japan, and affiliated hospitals between 1978 and 2007. RESULTS We identified 23 of the 1033 patients (2.2%) with adrenal involvement in renal cell carcinoma. In renal cell carcinoma patients with adrenal involvement, a tendency for a high histological grade of tumor and lower overall survival (P< 0.0001) was observed. Ipsilateral solitary adrenal involvement was detected in 4 of the 23 patients (15%), whereas 2 of the 23 (9%) had direct invasion of the adrenal gland. All tumors in the 14 patients without ipsilateral solitary adrenal involvement and recurrent adrenal tumors were classified as Stage IV. The TNM classification of the four renal cell carcinoma patients with ipsilateral solitary adrenal involvement was determined to be either pT3N0M0 or pT1-3N0M1. Among the four patients with ipsilateral solitary adrenal involvement, three patients had recurrent tumors, despite complete surgical resection. Two of these patients died of metastatic renal cell carcinoma after 2 and 10 years of radical nephrectomy, respectively, whereas one was still alive with cancer 3 years after the initial radical nephrectomy. The fourth had no recurrence of renal cell carcinoma, but did develop synchronous gall bladder cancer (pT2N0M0) and bile duct cancer (pT2N0M0). CONCLUSIONS Adrenal involvement in primary renal cell carcinoma was observed more frequently in patients with advanced tumor stages. In the TNM classification system, we propose that ipsilateral solitary adrenal involvement in renal cell carcinoma should be staged as M1.