Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma.

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11ß-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated ß-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11-mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause.

Incidental finding of extramammary Paget's disease during active surveillance for early-stage prostate cancer in a prostate biopsy.

Introduction: Skin tissue contamination within transcutaneous visceral organ biopsies is seldom found. We encountered a rare case of extramammary Paget's disease incidentally diagnosed by prostate biopsy during active surveillance for prostate cancer. Case presentation: A 71-year-old Japanese patient was diagnosed with prostate cancer, and active surveillance was selected. After 1 year, prostate biopsy was performed by a transperitoneal approach, and 16 biopsy cores were taken. One biopsy core contained skin tissue showing extramammary Paget's disease. Careful skin examination confirmed the presence of an extramammary Paget's disease lesion in the left perineum, and curative surgical resection was performed. Recurrence and metastasis did not occur after 6 months of follow-up. Conclusion: Although the perianal region is a common site of extramammary Paget's disease, early-stage extramammary Paget's disease is often asymptomatic. Thus, during a transcutaneous biopsy, it is important to consider the appearance of the skin and the pathological features of migrating skin tissue.

Effectiveness and Safety of a Mixture of Nobiletin and Tangeretin in Nocturia Patients: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study.

Nobiletin and tangeretin (NoT) are flavonoids derived from the peel of Citrus depressa, and they have been found to modulate circadian rhythms. Because nocturia can be considered a circadian rhythm disorder, we investigated the efficacy of NoT for treating nocturia. A randomized, placebo-controlled, double-blind, crossover study was conducted. The trial was registered with the Japan Registry of Clinical Trials (jRCTs051180071). Nocturia patients aged ≥50 years who presented nocturia more than 2 times on a frequency-volume chart were recruited. Participants received NoT or a placebo (50 mg once daily for 6 weeks), followed by a washout period of ≥2 weeks. The placebo and NoT conditions were then switched. Changes in nocturnal bladder capacity (NBC) were the primary endpoint, and changes in nighttime frequency and nocturnal polyuria index (NPi) were secondary endpoints. Forty patients (13 women) with an average age of 73.5 years were recruited for the study. Thirty-six completed the study, while four withdrew. No adverse events directly related to NoT were observed. NoT had little effect on NBC compared with the placebo. In contrast, NoT significantly changed nighttime frequency by -0.5 voids compared with the placebo (p = 0.040). The change in NPi from baseline to the end of NoT was significant (-2.8%, p = 0.048). In conclusion, NoT showed little change in NBC but resulted in decreased nighttime frequency with a tendency toward reduced NPi.

[Evaluation of Patients with Localized Prostate Cancer in whom Long-Term Successful Androgen Deprivation Therapy was Ceased].

We evaluated the clinical course of patients with localized prostate cancer in whom long-term successful androgen deprivation therapy (ADT) was ceased. Study subjects were 24 patients with stage B prostate cancer who were initially treated with ADT for a median duration of 93 months. The median age at the cessation of ADT was 84 years. The median nadir serum prostate specific antigen (PSA) level was 0.022 ng/ml. The median duration of follow-up from the cessation of ADT was 31 months. During follow-up, five patients showed PSA elevation of ≥2 ng/ml from the nadir. Serum testosterone level was tested in 20 patients, and five showed testosterone recovery ≥0.5 ng/ml. Seven patients died from diseases other than prostate cancer, but there were no deaths caused by prostate cancer. This study demonstrated that long-term successful ADT for localized prostate cancer could be ceased with adequate follow-up evaluation.

Impact of the severity of urethrovesical anastomotic leakage on urinary continence following robot-assisted laparoscopic prostatectomy.

We assessed whether the severity of anastomotic urinary leakage detected during routine cystourethrography after robot-assisted laparoscopic prostatectomy (RALP) affects urinary continence recovery. Around 302 patients who underwent RALP between August 2013 and May 2019 were included retrospectively. According to routine cystourethrographic findings obtained on the sixth or eighth postoperative day, which indicated leakage severity, patients were divided into three groups: no-leakage, grade 1 (linear shaped leakage, but not spreading), and grade 2 (spreading strip-shaped leakage). The preoperative factors and intraoperative factors were compared between no-leakage and leakage group (grade 1 and grade 2). Continence recovery was compared between the three groups. Continence recovery was defined as no pad used or one security pad used in a day. Cystourethrography revealed anastomotic urinary leakage in 44 patients (14.5%), of which 20 patients (6.6%) had grade 1 leakage and 24 patients (7.9%) had grade 2 leakage. On multivariate logistic regression analysis, the only significant predictor for urethrovesical anastomotic urinary leakage on cystourethrography following RALP was intraoperative anastomotic leakage (OR 5.306; 95% CI 1.530-18.398, p = 0.009). Continence recovery rates for no-leakage, grade 1 leakage, and grade 2 leakage groups were 11%, 20%, and 25% after 1 month (P = 0.131); 25%, 25%, and 45.8% after 3 months (P = 0.474); 44.6%, 55%, and 60.8% after 6 months (P = 0.184); and 63.1%, 87.5%, and 78.2% after 12 months (P = 0.095), respectively. In conclusion, urinary leakage in urethrovesical anastomosis, even at its severity, had no negative effects on continence recovery after RALP.

A case of pyelocalyceal diverticulum urothelial carcinoma that was difficult to distinguish from cystic renal cell carcinoma preoperatively.

INTRODUCTION: Pyelocalyceal diverticulum is a rare disease sometimes difficult to distinguish from cysts. We report a case of urothelial carcinoma originating from a pyelocalyceal diverticulum, difficult to distinguish from cystic renal cell carcinoma preoperatively. CASE PRESENTATION: A 51-year-old Japanese man complained of gross hematuria. Computed tomography revealed a solid mass in one of the many cystic lesions in the left kidney. He was diagnosed with left cystic renal cell carcinoma and underwent retroperitoneal laparoscopic nephrectomy. Pathological examination revealed high-grade invasive urothelial carcinoma arising within the renal pyelocalyceal diverticulum. The definitive diagnosis was high-grade invasive urothelial carcinoma (pT3). In retrospect, the retrograde pyelography findings indicated the cyst and urinary tract connection. Residual ureterectomy and adjuvant chemotherapy were later performed. The patient has since been recurrence-free. CONCLUSION: Whether cystic renal cell carcinoma is suspected on imaging, pyelocalyceal diverticulum should be considered a differential diagnosis, though unlikely to be encountered in daily practice.

Use of surgical checklist during transurethral resection increases detrusor muscle collection rate and improves recurrence-free survival in patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To elucidate the therapeutic benefits of using a surgical checklist during transurethral resection for non-muscle-invasive bladder cancer. METHODS: A nine-item surgical checklist was established in January 2016 to assess disease risk and resection adequacy, and it was prospectively implemented into clinical practice. Patients diagnosed with non-muscle-invasive bladder cancer who underwent complete resection from January 2009 to August 2019 were included in this study. The presence of detrusor muscle in the transurethral resection specimen and the intravesical recurrence-free survival were compared between patients who underwent transurethral resection before and after surgical checklist implementation. RESULTS: A total of 125 patients who underwent transurethral resection after surgical checklist implementation were reviewed and compared with 125 patients who underwent transurethral resection before surgical checklist implementation. The use of the surgical checklist led to an increase in the proportion of transurethral resection specimens containing detrusor muscle (92% vs 69.6%, P < 0.01) and a decrease in the recurrence rate (19.2% vs 49.6%, P < 0.01). Multivariate analysis showed that transurethral resection without a surgical checklist was an independent predictive factor influencing the absence of detrusor muscle in the transurethral resection specimen (odds ratio 4.78, P < 0.01) and intravesical recurrence (hazard ratio 1.92, 95% confidence interval 1.14-3.23; P = 0.01). Kaplan-Meier plots showed that the recurrence-free survival rate was significantly lower when the surgical checklist was not used (log-rank test result P < 0.01). CONCLUSIONS: This study shows the therapeutic benefits of surgical checklist in improving the quality of resection during transurethral resection and reducing the recurrence rate in patients with non-muscle-invasive bladder cancer.

Impact of second transurethral resection on recurrence in patients with high-grade Ta bladder cancer.

OBJECTIVES: To clarify the potential therapeutic benefit of a second transurethral resection for high-grade Ta bladder cancer. METHODS: From January 2009 to August 2019, 521 patients with bladder tumors underwent initial transurethral resection procedures at Kagawa University Hospital. Patients diagnosed with high-grade Ta bladder cancer considered to have been resected completely were included in this study. Recurrence and progression rates were compared between patients who received a second transurethral resection and those who did not. RESULTS: We identified 97 eligible patients, including 22 patients who received a second transurethral resection. In terms of clinical characteristics, the proportion of patients with bladder cancer and upper urinary tract tumor history was lower in the second transurethral resection group than in the no second transurethral resection group (P < 0.01 and P = 0.03, respectively). The histopathological findings of 22 transurethral resection procedures were no cancer in 13 (59.2%), Ta in six (27.2%) and carcinoma in situ in three patients (13.6%). After the second transurethral resection, one patient (4.6%) had recurrent high-grade T1 bladder cancer. The no second transurethral resection group showed a 44% recurrence rate (33 patients), including five patients (6.7%) with progression, and consequently, had a higher rate of recurrence than in the second transurethral resection group (P < 0.01). Multivariate analysis showed that no second transurethral resection was the independent predictive factor influencing recurrence (hazard ratio 8.662, P = 0.04). The Kaplan-Meier curve showed that a second transurethral resection significantly decreased the recurrence rate than that of patients without a second transurethral resection (P < 0.01). CONCLUSIONS: A second transurethral resection can reduce the recurrence rate in high-grade Ta bladder cancer, showing a possible therapeutic benefit of this procedure.

Membranoproliferative pattern of glomerular injury associated with complement component 9 deficiency due to Arg95Stop mutation.

BACKGROUND: Arg95Stop mutation of exon 4 in complement component 9 (C9) gene is common in individuals in Japan with C9 deficiency (C9D); however, understanding of the influences of C9D on human glomerulonephritis remains elusive. METHODS: A total of 1288 patients with chronic kidney disease (CKD) were recruited from the hospitals in Niigata prefecture. They were screened for the Arg95Stop mutation of C9 gene by allele-specific PCR. RESULTS: We identified two individuals with C9D among 1,288 CKD patients, a frequency comparable to that of the general Japanese population (0.16%). Case 1 involved a 44-year-old man presenting with nephrotic proteinuria. The hemolytic activity of CH50 was low, and the concentration of C9 was not detected. Sequencing of exon 4 of the C9 gene showed the Arg95Stop mutation. Renal biopsy revealed diffuse global mesangial proliferation with extensive duplication of glomerular capillary walls. Mesangial, subendothelial and subepithelial deposits were noticed with light and electron microscopy. Immunofluorescent study showed predominant mesangial IgA deposition. Case 2 involved a 62-year-old man presenting with proteinuria and hematuria. His CH50 level was decreased. Renal biopsy revealed diffuse global mesangial proliferation with extensive duplication of glomerular capillary walls. Immune deposits were also confirmed. The percentage of C9D among patients with mesangial proliferation and duplication of GBM in this study was 5.1%. CONCLUSION: These results suggested that the lack of membrane attack complex because of an Arg95Stop mutation of the C9 gene predisposed patients to pathognomonic glomerulonephritis.