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We report a case of non-familial juvenile primary aldosteronism (PA). Super-selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase-positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism. [ABSTRACT FROM AUTHOR]

Our group previously purified human and rat aldosterone synthase (CYP11B2 and Cyp11b2, respectively) from their adrenals and verified that it is distinct from steroid 11β-hydroxylase (CYP11B1 or Cyp11b1), the cortisol- or corticosterone-synthesizing enzyme. We now describe their distributions immunohistochemically with specific antibodies. In rats, there is layered functional zonation with the Cyp11b2-positive zona glomerulosa (ZG), Cyp11b1-positive zona fasciculata (ZF), and Cyp11b2/Cyp11b1-negative undifferentiated zone between the ZG and ZF. In human infants and children (<12 years old), the functional zonation is similar to that in rats. In adults, the adrenal cortex remodels and subcapsular aldosterone-producing cell clusters (APCCs) replace the continuous ZG layer. We recently reported possible APCC-to-APA transitional lesions (pAATLs) in 2 cases of unilateral multiple adrenocortical micro-nodules. In this review, we present 4 additional cases of primary aldosteronism, from which the extracted adrenals contain pAATLs, with results of next generation sequencing for these lesions. Immunohistochemistry for CYP11B2 and CYP11B1 has become an important tool for the diagnosis of and research on adrenocortical pathological conditions and suggests that APCCs may be the origin of aldosterone-producing adenoma. [ABSTRACT FROM AUTHOR]

Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults. [ABSTRACT FROM AUTHOR]

Three potassium channels have been associated with primary aldosteronism (PA) in rodents and humans: KCNK3 (TASK-1), KCNK9 (TASK-3), and KCNJ5 (Kir3.4). Mice with deficiency in Kcnk3 and Kcnk9 have elevated aldosterone production and blood pressure. In humans, adrenal tumors with somatic mutations in KCNJ5 cause PA. However, there are very few reports on the expression patterns of these genes in humans versus rodents. Herein, we compared human and rat mRNA expression (by quantitative real-time polymerase chain reaction (qPCR) and protein levels (by immunohistochemistry) across three tissues (adrenal, brain, heart) and two laser-captured adrenal zones (zona glomerulosa, zona fasciculata). Our findings show that expression patterns of KCNK3, KCNK9, and KCNJ5 are inconsistent between rats and humans across both tissues and adrenal zones. Thus, species variation in the expression of PA-related potassium channels indicates an evolutionary divergence in their role in regulating adrenal aldosterone production. [ABSTRACT FROM AUTHOR]

Abstract: We recently identified hundreds of transcripts with differential expression in rat zona glomerulosa (zG) and zona fasciculata. Although the genes up-regulated in the zG may be playing important roles in aldosterone production, the relationship between most of these genes and aldosterone production has not been uncovered. Because aldosterone, in the presence of a high sodium diet, is now considered a significant cardiovascular risk factor, in this review we performed gene ontology and pathway analyses on the same microarray data to better define the genes that may influence zG function. Overall, we identified a number of genes that may be involved in aldosterone production through transforming growth factor β (TGF-β), WNT, calcium, potassium, and ACTH signaling pathways. The list of genes we present in the current report may become an important tool for researchers working on primary aldosteronism and aldosterone-related cardiovascular diseases. [Copyright &y& Elsevier]

Background: Immune checkpoint inhibitors (ICIs) are effective in some cancer patients; however, they may show no efficacy in others. Predictive biomarkers are crucial for appropriately selecting the patients who receive ICI therapy. This study aimed to clarify the predictors of disease progression in urothelial carcinoma (UC) patients treated with an ICI, pembrolizumab. Methods: We analyzed the response patterns of 50 UC patients who were treated with pembrolizumab, as well as the association between survival and clinicopathological factors. Clinical factors included age, sex, body mass index, clinical courses, laboratory data, metastases, and adverse events. Pathological factors included special variant, squamous differentiation, programmed cell death ligand‐1 (PD‐L1) expression, CD8‐positive lymphocytes density, and CDKN2A/p16 homozygous deletion. Results: During pembrolizumab treatment, four (8%), 11 (22%), and eight (16%) patients achieved the best‐case scenarios of complete response, partial response, and stable disease, respectively. Twenty‐seven patients (54%) showed progressive disease. In this study, younger age, lower preoperative neutrophil‐to‐lymphocyte ratio (NLR), and positive PD‐L1 expression were significantly correlated with longer progression‐free survival and overall survival. Moreover, lower NLR and positive PD‐L1 expression were independently associated with longer OS in multivariate analysis. Conclusions: Based on our observations, lower NLR and positive PD‐L1 expression may be independent favorable prognostic markers in UC patients treated with pembrolizumab. These results suggest that both host and tumor status can reflect the effectiveness of pembrolizumab among patients with UC. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer. Methods: One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease. Results: Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer ( P < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters. Conclusions: The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy. [ABSTRACT FROM AUTHOR]

There were 15 patients with Clavien-Dindo >=3a complications (9.6% of all the cases), and three patients with Clavien 4a complications (1.9%). From these factors with strong discriminative power (area under the curve 0.86), the nomogram was generated and its decision curve analysis showed apparently significant positive benefit for patients with a >10% threshold probability of post-adrenalectomy complications. [Extracted from the article]

Objectives Methods Results Conclusions In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) using oral 5‐aminolevulinic acid hydrochloride reduced residual tumors in high‐risk non‐muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD‐TURBT for intravesical recurrence after a second transurethral resection for high‐risk NMIBC.High‐risk NMIBC patients initially treated with PDD‐TURBT (PDD group) were prospectively registered between 2018 and 2020. High‐risk patients with NMIBC who were initially treated with white‐light TURBT (WL group) were retrospectively registered. Intravesical recurrence‐free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis.In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25–0.77). In subgroup analysis, PDD‐TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14–0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16–0.86), and no postoperative intravesical Bacillus Calmette‐Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13–0.58).PDD‐TURBT may reduce short‐term intravesical recurrence in patients with high‐risk NMIBC. [ABSTRACT FROM AUTHOR]

Renal myxomas are rare neoplasms. Only three cases have been convincingly diagnosed as renal myxoma. Here we report an additional case. The case was a 36-year-old man and he was discovered incidentally at the regular health-check for chronic hepatitis B. Computed tomography showed 8 cm low-density tumor in the lower pole of the left kidney. The tumor was slightly enhanced by contrast agents. Magnetic resonance imaging revealed the tumor as low intensity on T1-weighted imaging and high intensity on T2-weighted images. The tumor was enhanced by gadrinium enhancement homogeneously. The resected kidney contained semitranslucent, gelatinous, tan mass within the lower pole of the kidney. The microscopic examination showed the typical appearance of a myxoma, which consisted of large amounts of myxoid material containing a few uniformly scattered spindle cells The tumor cells showed immunoreactivity for vimentin but not for S-100 protein, epithelial membrane antigen, cytokeratin, alpha smooth muscle actin. [ABSTRACT FROM AUTHOR]

The author comments on an article published in a previous issue of the periodical which focused on the use of intermittent everolimus to treat renal angiomyolipoma (AML) associated with tuberous sclerosis complex. Topics discussed include the effectiveness of the treatment with everolimus, the release of patients from adverse events during drug holidays, and the optimal dosage of everolimus.

Background: To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT).Methods: Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis.Results: Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69-186 mmHg) and 124 mmHg (range, 69-186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43-140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p < 0.05) and general anesthesia (OR 14.435, p < 0.05) as significantly associated with an increased risk of hypotension incidence. Use of calcium antagonist showed significant negative associations with hypotension (OR 0.183, p < 0.05). Decision tree analysis showed presence of general anesthesia, age ≥ 74 years and American Society of Anesthesiologists physical status (ASA-PS) ≥2 as the most important discriminators.Conclusions: General anesthesia and hypertension were independent risk factors related to ALA-induced hypotension. In contrast, use of calcium antagonists was identified as a factor associated with reduced risk of ALA-induced hypotension. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions The aim of this study was to compare clinical outcomes between patients receiving second TUR after initial white‐light transurethral resection of bladder tumor (WL‐TURBT) and initial photodynamic diagnosis (PDD)‐assisted TURBT.A total of 1007 patients were divided into four groups based on the treatment pattern: WL‐TURBT with second TUR (161 patients, WL‐second group) or without second TUR (540 patients, WL‐alone group) and PDD‐TURBT with second TUR (112 patients, PDD‐second group) or without second TUR (194 patients, PDD‐alone group). Oncologic outcomes (bladder cancer recurrence, progression, urothelial cancer‐specific mortality) and rates of residual tumor and risk stratification of non‐muscle‐invasive bladder cancer (NMIBC) after second TUR were evaluated.After propensity score‐matching 121 patients were included each in the WL‐alone and WL‐second groups, and 63 patients each in the PDD‐alone and PDD‐second groups. In the WL group, the second TUR was significantly associated with improved progression‐free (p = 0.012) and urothelial cancer‐specific free survival (p = 0.011), but not with recurrence‐free survival (p = 0.93). Patients initially treated with PDD‐TURBT, and with a tumor diameter <30 mm and multifocality had a relatively high benefit from second TUR. The rates of residual tumor and risk stratification of NMIBC did not significantly differ between WL‐TURBT and PDD‐TURBT groups.Our findings suggested that a second TUR could be omitted after an initial PDD‐TURBT in selected patients with high‐risk NMIBC. [ABSTRACT FROM AUTHOR]

Background: Among patients with non-muscle-invasive bladder cancer (NMIBC), systematic reviews showed lower recurrence rate in patients treated with photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) than with white-light (WL) TURBT. However, the result is not consistent between clinical trials and the significance of preoperatively available factors in disease recurrence after PDD-TURBT remains unclear. Methods: The present study retrospectively analyzed 1174 NMIBC patients who underwent TURBT and were followed up for ≥ 6 months. Among 1174 patients, 385 and 789 underwent PDD-TURBT with oral 5-aminolevulinic acid (the PDD group) and WL-TURBT (the WL group), respectively. Recurrence-free survival (RFS) was compared between the PDD and WL groups before and after propensity score matching, and the impact of several baseline parameters on RFS between the 2 groups was investigated after matching. Results: Before propensity score matching, RFS was significantly longer in the PDD group than in the WL group (P = 0.006). After matching, 383 patients were included in both groups, and RFS was significantly longer in the PDD group than in the WL group (P < 0.001). In the cohort after matching, RFS between the two groups was compared in each subgroup classified according to baseline parameters, including age, sex, history of previous or concomitant upper urinary tract urothelial carcinoma, preoperative urinary cytology, tumor multiplicity, and tumor size, and significantly longer RFS was observed in the PDD group in all subgroups, except for the patients with tumors ≥ 30 mm (P = 0.21). Conclusion: These results suggest that PDD-TURBT prolongs RFS in NMIBC patients, except for those with tumors ≥ 30 mm. [ABSTRACT FROM AUTHOR]

Objectives: Bladder cancer, especially non‐muscle invasive bladder cancer (NMIBC), is one of the most costly cancers owing to its long‐term management. Photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) reduces the risk of intravesical recurrence. However, its impact on healthcare economics in Japan remains unclear. We evaluated the comprehensive medical costs of Japanese healthcare economics regarding PDD‐TURBT. Methods: This large‐scale, multicenter, retrospective study included a dataset of 1531 patients who were diagnosed with primary NMIBC who underwent initial TURBT between April 2006 and June 2021. A one‐to‐one propensity‐score matching analysis was used for an unbiased comparison based on postTURBT follow‐up periods. The total medical costs, including hospitalization, surgical procedures for TURBT and salvage radical cystectomy, adjuvant intravesical therapies, and follow‐up examinations, were compared between white light (WL)‐TURBT and PDD‐TURBT groups. Results: After propensity‐score matching, 468 patients each of WL‐ and PDD‐TURBT groups were matched. Total costs were 510 337 128 and 514 659 328 ¥ in WL‐ and PDD‐TURBT groups, respectively. The costs of adjuvant intravesical therapies, follow‐up examinations, and salvage radical cystectomy in PDD‐TURBT group were equivalent to or lower than those in WL‐TURBT group. Furthermore, total costs of high‐ and highest‐risk NMIBC in PDD‐TURBT group were either equivalent or lower compared to those in WL‐TURBT group. Conclusions: The total costs associated with PDD‐TURBT were higher compared to WL‐TURBT, while there is the potential of PDD‐TURBT to reduce the burden on healthcare economics in limited cases. [ABSTRACT FROM AUTHOR]

The CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations. [ABSTRACT FROM AUTHOR]

Background: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. Methods: Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. Expected outcome: Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. Trial registration: The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021. [ABSTRACT FROM AUTHOR]

Background: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. Methods: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. Results: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6–13.8) months and 11.0 (7.9–12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22–0.98; p = 0.010; HR, 0.32; 95% CI, 0.12–0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. Conclusions: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC. [ABSTRACT FROM AUTHOR]

Objectives: Transurethral resection of bladder tumor with photodynamic diagnosis has been reported to result in lower residual tumor and intravesical recurrence rates in non‐muscle invasive bladder cancer. We aimed to evaluate the usefulness of photodynamic diagnosis‐transurethral resection of bladder tumor combined with oral 5‐aminolevulinic acid hydrochloride for high‐risk non‐muscle invasive bladder cancer. Methods: High‐risk non‐muscle invasive bladder cancer patients with an initial photodynamic diagnosis‐transurethral resection of bladder tumor (photodynamic diagnosis group) were prospectively registered between 2018 to 2020. High‐risk non‐muscle invasive bladder cancer cases with a history of initial white‐light transurethral resection of bladder tumor (white‐light group) were retrospectively registered. Propensity score‐matching analysis was used to compare residual tumor rates, and factors that could predict residual tumors at the first transurethral resection of bladder tumor were evaluated. Results: Analyses were conducted with 177 and 306 cases in the photodynamic diagnosis and white‐light groups, respectively. The residual tumor rates in the photodynamic diagnosis and white‐light groups were 25.7% and 47.3%, respectively. Factor analysis for predicting residual tumors in the photodynamic diagnosis group showed that the residual tumor rate was significantly higher in cases with a current/past smoking history, multiple tumors, and pT1/pTis. When each factor was set as a risk level of 1, cases with a total risk score ≤1 showed a significantly lower residual tumor rate than cases with a total risk score ≥2 (8.3% vs 33.3%, odds ratio 5.46 [1.81–22.28]). Conclusions: In high‐risk non‐muscle invasive bladder cancer cases, the odds of a residual tumor after initial photodynamic diagnosis‐transurethral resection of bladder tumor were 0.39‐fold that of the odds of those after initial white‐light transurethral resection of bladder tumor. A risk stratification model could be used to omit the second transurethral resection of bladder tumor in 27% of the cases. [ABSTRACT FROM AUTHOR]

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies. [ABSTRACT FROM AUTHOR]

Aims: Xp11 rearrangement in renal cell carcinoma (RCC) typically involves gene fusion to the gene encoding transcription factor E3 (TFE3), a member of the microphthalmia‐associated transcription factor family on chromosome Xp11.2. Dual‐colour break‐apart fluorescence in‐situ hybridisation (FISH) is recommended to confirm histological diagnoses. Recently, RNA‐binding motif protein 10 (RBM10), encoded by a gene on chromosome Xp11.3, was identified as a chimeric partner of TFE3; thus, RBM10–TFE3 fusion results from paracentric inversion. RBM10–TFE3 RCC may yield a false‐negative result in FISH analysis of TFE3 expression. The aim of the present study was to investigate the clinicopathological features of RBM10–TFE3 RCC. Methods and results: Ten patients with RBM10–TFE3 RCC aged 31–71 years were investigated. Histological analysis, immunostaining, dual‐colour break‐apart FISH for TFE3, reverse transcription polymerase chain reaction and sequencing analysis were performed. No patient had a history of exposure to chemotherapy. Two of these patients died of RCC, and three were alive but developed metastases. Microscopically, the tumours were composed of a mixed architecture of tubulocystic and papillary patterns with scattered psammoma bodies. The tumours showed strong nuclear immunoreactivity for TFE3. FISH showed consistent closely spaced split signals in the RCCs of four patients, and polysomic signals with occasional closely spaced split signals in the RCCs of six patients. Of the latter six patients, five had renal failure, and four developed tumours in kidneys subjected to haemodialysis. Conclusions: The present study suggests that the carcinogenesis of RBM10–TFE3 RCC in some, but not all, patients may be associated with chronic kidney disease. The aggressive nature of RBM10–TFE3 RCC should be considered, as five patients experienced metastases. [ABSTRACT FROM AUTHOR]

A 66-year-old Japanese male patient was referred to Saitama Medical University International Medical Center for treatment of bladder cancer (clinical stage T2 or higher without metastasis), and underwent radical cystectomy with pelvic lymphadenectomy. The histopathological diagnosis was high-grade urothelial carcinoma (pathological stage T2bN2, ly1, v0) and 2 cycles of adjuvant systemic chemotherapy (gemcitabine plus cisplatin) were administered. At 15 months after the operation, mediastinal and lung hilar lymph nodes and multiple bone metastases were identified on computed tomography imaging. After 3 cycles of the previous regimen as salvage systemic chemotherapy, the lymph node metastases had shrunk and the bone metastases were stable; therefore, further chemotherapy was planned. At 26 days after the initiation of the 4th cycle, the patient felt nausea and lower limb weakness. Spinal and brain magnetic resonance imaging with contrast medium revealed diffuse enhancement at the surface of the spinal cord and brain. In addition, abnormal signal intensity in the subarachnoid space was observed on fluid-attenuated inversion recovery imaging; therefore, the patient was diagnosed with meningeal carcinomatosis (MC). Treatment, including whole-brain radiotherapy, was planned for MC; however, the patient's condition rapidly worsened and he succumbed to the disease 14 days after the diagnosis of MC. The definitive diagnosis of MC was confirmed at autopsy. [ABSTRACT FROM AUTHOR]

The present case report describes a case of left renal clear cell carcinoma with brain, lung, para-aortic, and lymph node metastases (cT1bN1M1) in a 52-year-old Japanese male. The patient received sequential anticancer treatments with pazopanib, everolimus, and axitinib, but exhibited treatment-resistant tumor growth. Treatment with nivolumab resulted in a complete response in metastatic sites. However, the residual renal tumor, which was enhanced by contrast medium, required radical nephrectomy. Pathological analyses of the renal tumor revealed that it consisted of fibrotic and lymphocyte-infiltrated tissues in which morphological cancer cells were not detected. The majority of lymphocytes were cluster of differentiation (CD)8-positive, suggesting that cancer cells were attacked by these lymphocytes. Retrospective analyses of renal cell carcinoma tissues, which were biopsied before the anticancer treatment, revealed their infiltration by CD8-positive T cells. To the best of our knowledge, this is the first case report to examine renal tissue prior to and following treatment with nivolumab using immunohistochemical analysis. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the impact of metastatic sites and early tumor shrinkage (eTS) as prognostic predictive factors of metastatic renal cell carcinoma (mRCC) in molecular targeted therapy. A total of 209 advanced RCC cases treated with sorafenib, sunitinib, axitinib, pazopanib, temsirolimus and everolimus from our single institution were included in the present study. Several known prognostic predictive factors, including metastatic sites and the rate of eTS, were analyzed by Kaplan-Meier survival estimate analysis followed by Cox's proportional hazards model analysis. eTS was measured by three independent physicians. Four metastatic sites in the liver, bone, lymph nodes and brain as well as greater eTS were identified as potential independent predictors of overall survival (OS) in several cohorts: i) Metastatic RCC (n=194); ii) metastatic clear cell RCC (n=119); and iii) mRCC patients with eTS data (n=127). In sub-analyses of patients treated with each 1st line tyrosine kinase inhibitor, eTS was identified as a potentially potent predictor of OS in patients treated with axitinib. The liver, bone, lymph nodes, brain metastases and eTS were identified as independent predictive factors of OS by analyzing a limited Japanese cohort. [ABSTRACT FROM AUTHOR]

The quantification of aldosterone (ALD) in adrenal tributary venous blood serum/plasma combined with the super-selective adrenal venous sampling (ssAVS) technique is recognized as a definitive procedure for differentiation of the forms of primary aldosteronism (PA), identification of the affected segment(s) and operating decision-making. In this study, an enhanced throughput and sensitive method was developed and validated for the quantification of ALD in ssAVS serum samples by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with derivatization using the Girard P reagent (GP) isotopologues ( 2 H 0 - and 2 H 5 -GP). The right and left adrenal serum samples were separately pretreated and derivatized with either isotopologue. The two samples were then combined and injected together for LC/ESI-MS/MS analysis. Based on the mass differences between the isotopologues, the derivatized ALD in the two samples were quantified within a single run. This method enabled the reproducible (intra- and inter-assay relative standard deviations, 6.6% or lower) and accurate (98.2–107.0%) quantification of the serum ALD using a 25-μL sample, and the lower limit of quantification was 1.0 ng/mL. The developed method was used for the analysis of 11 pairs of ssAVS serum samples (total of 22 samples) of patients with ALD-producing adenoma and proven to have a satisfactory applicability; this method enabled the identification of the affected adrenal and the determination of the laterality of PA, and reduced the analysis time to about 2/3 compared to the previous method for 22 samples. [ABSTRACT FROM AUTHOR]

A 75-year-old Japanese male was referred to our institution for the evaluation of a left ureteral tumor in the ureterovesical junction. Computed tomography and pathologic examination under ureteroscopy revealed an invasive left ureteral urothelial carcinoma with left obturator nodal metastasis without distant metastasis. First, the patient underwent systemic chemotherapy (gemcitabine and cisplatin chemotherapy). We then performed left radical nephroureterectomy and extended lymph node dissection. Pathological examination revealed that the tumor was a high-grade invasive urothelial carcinoma with left common iliac and pelvic lymph node metastasis (pT3N2). Unfortunately, metastases appeared in the common iliac and para-aortic lymph nodes immediately after the operation; therefore, the previous first-line chemotherapy was readministered and second-line chemotherapy (gemcitabine and paclitaxel chemotherapy) was also performed. We also performed consolidative radiotherapy and salvage radiotherapy (boost, 20 Gy/10 fractions to the inferior para-aortic, and left common iliac regions containing swollen lymph nodes). The patient has shown no evidence of recurrence or metastasis even approximately 4 years after the initial diagnosis of advanced UUT-UC with lymph node metastasis. Our case suggests that consolidative or salvage radiotherapy combined with surgery and chemotherapy may provide clinical benefit for selected cases of advanced UUT-UC with lymph node metastasis. [ABSTRACT FROM AUTHOR]

18-Oxocortisol is the product of the metabolism of 11-deoxycortisol by the mitochondrial enzyme aldosterone synthase (CYP11B2). The traditional concept is that the CYP11B2 is exclusively expressed in zona glomerulosa cells and the 17α-hydroxylase (CYP17A1) enzyme, required to synthesize 11-deoxycortisol, is in the zona fasciculata of the human adrenal. It has been postulated that the substrate for 18-oxocortisol is either cortisol from the circulation or from zona fasciculata cells adjacent to the zona glomerulosa. P-glycoprotein, which is highly expressed in steroidogenic cells of the adrenal gland, efficiently expels cortisol from the cell. Double immunofluorescence staining for the CYP11B2 and CYP17A1 enzymes in 7 human adrenals demonstrated that a highly variable number of cells in different areas of the zona glomerulosa co-expressed both enzymes. In addition, there were a variable number of cells that exclusively expressed the CYP17A1 embedded within the zona glomerulosa surrounded by CYP11B2-expressing cells. 18-Oxocortisol in the media of human adrenocortical HAC15 cells was measured by ELISA after incubation with and without 10 nM of angiotensin II to stimulate CYP11B2 activity, with and without the 3β-hydroxysteroid dehydrogenase (HSD3B) inhibitor trilostane, and with variable amounts of cortisol or 11-deoxycortisol. Cortisol was a poor substrate, while 11-deoxycortisol was a significant substrate for the synthesis of 18-oxocortisol. These data suggest that the biosynthesis of 18-oxocortisol in the human adrenal is likely catalyzed by co-expression of the two crucial enzymes CYP17A1 and CYP11B2 in a small proportion of cells within the zona glomerulosa. It is also possible that 11-deoxycortisol diffusing from cells expressing only CYP17A1 interspersed with cells expressing the CYP11B2 enzyme may be a paracrine substrate in the synthesis of 18-oxocortisol. • Circulating cortisol is an unlikely substrate for the synthesis of 18-oxocortisol. • CYP11B2 and CYP17A1 are co-expressed in a few cells of the zona glomerulosa. • Cells expressing only CYP17A1 are also embedded within the zona glomerulosa. • 11-Deoxycortisol might be a paracrine substrate for the synthesis of 18-oxocortisol. [ABSTRACT FROM AUTHOR]

Locally advanced bladder cancer causes unpleasant symptoms such as irritative voiding symptoms, lower abdominal pain, gross hematuria and urinary retention, and lowers the quality of life. Treatment decisions in elderly patients may be difficult, as elderly patients are physically and psychologically different from younger patients. An 89-year-old male was referred to hospital for the treatment of an invasive bladder tumor with right hydronephrosis from tumor obstruction. The patient was elderly and did not have a good performance status; therefore curative radical cystectomy or chemotherapy was not indicated. Left retroperitoneoscopic ureterocutaneostomy was performed to alleviate gross hematuria and voiding difficulty. Intensity-modulated radiotherapy was administered 9 days after the surgery to control bleeding in the bladder tumor. After completing 8 days of radiotherapy, the patient was discharged from hospital. The patient exhibited no signs of either postrenal failure or gross hematuria for 7 months prior to mortality. Retroperitoneoscopic ureterocutaneostomy for very elderly patients with advanced bladder cancer with a poor performance status may be an important procedure for alleviating symptoms and improving quality of life. [ABSTRACT FROM AUTHOR]

• Aldosterone was quantified by LC/ESI-MS/MS for primary aldosteronism treatment. • Six adrenal venous serum samples were collected from each patient by ssAVS technique. • A sextet of Girard reagents was employed for the sample-multiplexing. • Aldosterone in 6 ssAVS samples could be quantified by a single run. • The method was successfully used to analyze the ssAVS samples from 8 patients. [Display omitted] The accurate quantification of aldosterone (ALD) in adrenal tributary venous serum/plasma collected by a super-selective adrenal venous sampling (ssAVS) technique has become a definitive procedure to identify the forms (laterality) of primary aldosteronism (PA) and the location of the affected segment(s), and to subsequently make the treatment decision. In this study, a stable isotope-dilution LC/ESI-MS/MS-based method was developed and validated for the determination of the ALD concentrations of the six ssAVS serum samples during a single run. A sextet of Girard reagents was used to convert ALD to the derivatives having different masses for each sample. Based on the validation tests, satisfactory specificity, precision and accuracy were observed and the matrix effect was found to be acceptable. The developed method was used for the analysis of the ssAVS serum samples from eight PA patients. The batch analysis of the six samples permitted the direct comparison of the ALD concentrations between the samples and enhanced to determine the laterality and location of the affected segment(s). The total analysis time after the sample purification was also reduced to 1/3 for the 24 samples by the sample-sextuplex procedure, which was also an advantage of the developed method. [ABSTRACT FROM AUTHOR]

• A quantitative MALDI-MS/MS method was developed for the serum cortisol. • Charged derivatization was employed for increasing the sensitivity. • Reproducible (intra- and inter-assay RSD ≤ 7.4%) quantification using a 20-μL sample. • The measured values by MALDI-MS/MS agreed well with those by LC/ESI-MS/MS or ECLIA. • The method was used for the analysis of peripheral and adrenal serum samples. Cortisol (CRT), the main glucocorticoid in humans, plays a crucial role in many physiological processes, therefore, the measurement of its serum level is of great clinical significance. Matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS) might be an effective approach for the quantification of CRT in serum due to its attractive properties, i.e. , high specificity, ease of use, ruggedness and rapid analysis. In this study, we developed a method to quantify the serum CRT by MALDI-MS/MS. This method employed the derivatization using a Girard-type reagent, 1-(hydrazinocarbonylmethyl)isoquinolinium chloride, which compensated for the lack of sensitivity. This method enabled the reproducible quantification of the serum CRT using a 20-μL sample (intra- and inter-assay relative standard deviations, 7.4% or lower), and the measurable range was 25–500 ng/mL. The serum CRT concentrations determined by the newly-developed MALDI-MS/MS method agreed well with those by liquid chromatography/electrospray ionization-MS/MS or electrochemiluminescence immunoassay. The MALDI-MS/MS method was used for the analysis of peripheral venous serum samples of healthy subjects and adrenal venous serum samples of patients with primary aldosteronism, and satisfactory results were obtained. [ABSTRACT FROM AUTHOR]

• DNA methylation is associated with excess cortisol and aldosterone. • Aldosterone-producing adenomas can cause hypercortisolemia. • Gene mutation and methylation analyses of CYP11B1 and CYP11B2 in APA were performed. • There was no association between hypercortisolemia and evaluated gene mutations. • CYP11B1 promoter methylation is involved in APA with hypercortisolemia. DNA methylation is associated with excess cortisol and aldosterone. The DNA encoding aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1), which catalyzes the final step of cortisol biosynthesis, is less methylated in aldosterone-producing adenomas (APA) and cortisol-producing adenomas (CPA), respectively. Several studies have reported specific gene mutations in APA and CPA, and some APAs also cause hypercortisolemia. The aim of this study was to clarify the molecular mechanisms of cortisol co-production in APA using genetic and epigenetic analyses. We evaluated 16 patients with APA between 2011 and 2018 at Kanazawa University Hospital (Ishikawa, Japan). The diagnostic criteria for hypercortisolemia were based on the guideline from the Endocrine Society. Gene mutation and DNA methylation analyses of the CYP11B2 and CYP11B1 promoters in APA were performed. Of the 16 patients with APA, six also had hypercortisolemia. In the genetic analysis, all six APAs with hypercortisolemia as well as eight of the 10 APAs without hypercortisolemia had a KCNJ5 mutation. In the epigenetic analyses, the methylation status of the CYP11B2 promoter was similar in the APAs with and without hypercortisolemia. However, in the APAs with hypercortisolemia, the CYP11B1 promoter was significantly less methylated, especially at two CpG sites near the Ad1/cAMP response element binding site within the CYP11B1 promoter. In conclusion, the genetic analysis revealed no association between hypercortisolemia and the evaluated gene mutations. However, the epigenetic analysis suggested that DNA methylation of the CYP11B1 promoter plays a role in concurrent hypercortisolemia and APA. [ABSTRACT FROM AUTHOR]

• Immunohistochemical examination using autopsy adrenals from elderly over 50 years old 85. • Expression of aldosterone synthase in zona glomerulosa attenuated in deceased elderly 85. • Aldosterone-producing cell clusters were less developed in deceased elderly 75. • Incidental aldosterone-producing adenoma was hardly observed in deceased elderly 80. • Inactive production of aldosterone was likely to have survival advantage 72. Immunohistochemistry of human aldosterone synthase (CYP11B2) has revealed that most of aldosterone is autonomously produced in aldosterone-producing cell clusters (APCCs) beneath the capsule of adult adrenals rather than physiologically in the zona glomerulosa (ZG). APCCs have been occasionally found to harbor a somatic mutation of ion channel/pump genes, and number and size of APCCs increase with age until 50 years old. Herein, the objective of the study was to examine APCC development in 106 autopsied adrenals from 85 elderly individuals who died at ages from 50 to 103 years. We obtained the following results: (1) physiological CYP11B2 expression in ZG were attenuated in more elderly persons; (2) number and size of APCCs decreased with age; (3) detachment of APCC from the capsule appeared to occur occasionally over the wide range of the ages; and (4) incidental micro aldosterone-producing adenomas (APAs) and possible APCC-to-APA transitional lesions (pAATLs) were found primarily in samples from persons aged 50–60 years but not in samples from more elderly persons; pAATL was a putative designation based on our previous results indicating that it consisted of subcapsular APCC-like portion and inner APA-like portions. Thus, the formation of the CYP11B2-expressing lesions as well as thickening of the ZG in the adrenals were inversely correlated with age of death in the individuals aged over 50 years. Considering that autopsy samples were used in this study, inactive production of aldosterone regardless of autonomous or physiological manners may have survival advantages in individuals aged over 50 years. [ABSTRACT FROM AUTHOR]