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Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.

Context The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters (APCCs) that strongly express aldosterone synthase (CYP11B2) are frequently found in adult adrenals and harbor somatic mutations that are also detected in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCCs are not well understood. Objective This study aimed to analyze the transcriptome of APCCs at single-cell resolution and infer the developmental trajectory. Methods Single-cell RNA sequencing (scRNA-seq) of 2 adult adrenals was performed. Results Immunohistochemical analyses confirmed the 2 adrenals had APCCs. scRNA-seq data of 2928 adrenal cells were obtained and 1765 adrenocortical cells were identified based on unsupervised clustering and the marker gene expression. The adrenocortical cells were divided into 6 clusters, of which 3 clusters (923 cells) were composed of APCC/ZG cells. By further subclustering, the APCC/ZG cells were divided into 3 clusters (clusters C1, C2, and C3), we finally identified APCC cluster (C3) and ZG cluster (C1). Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis inferred the developmental direction from cluster ZG-cluster-C1 to APCC-cluster-C3. The scRNA-seq additionally revealed that many CYP11B2-positive cells were positive for CYP11B1 and/or CYP17A1, which were essential for cortisol but not for aldosterone production. Conclusions Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel to APCC.

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Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC.Implications:Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

Supplemental Figure S1. Representative images of TFE3 immunohistochemistry of renal papillae and renal pelvis (a, b), ureters (c, d), and bladders (e, f) from a 10-month-old PRCC-TFE3; KSP-Cre- (a, c, e) mouse and a PRCC-TFE3; KSP-Cre+ (b, d, f) mouse. S2, S3, S4, S5. Supplemental Table S1. (a) List of top 50 significantly upregulated (q-value < 0.05, fold change > 2) genes in kidneys from 4 month old PRCC-TFE3; KSP-Cre+ mice. (b) List of significantly downregulated (q-value < 0.05, fold change < 1/2) genes in kidneys from 4 month old PRCC-TFE3; KSP-Cre+ mice. Supplemental Table S2 (a) List of top 50 significantly upregulated (q-value < 0.05, fold change > 2) genes in kidneys from 7 month old PRCC-TFE3; KSP-Cre+ mice. (b) List of top 50 significantly downregulated (q-value < 0.05, fold change < 1/2) genes in kidneys from 7 month old PRCC-TFE3; KSP-Cre+ mice. Supplemental Fig. S2 Gene Set Enrichment Analysis (GSEA) of microarray data from 4 month old PRCC-TFE3; KSP-Cre+ mouse kidneys (n=4) vs 4 month old PRCC-TFE3; KSP-Cre- mouse kidneys (n=4) (a, b, c, g, h, i) and 7 month old PRCC-TFE3;KSP-Cre+ mouse kidneys (n=4) vs 7 month old PRCC-TFE3; KSP-Cre- mouse kidneys (n=3) (d, e, f, j, k, l). Supplemental Table S3 List of commonly upregulated genes in PRCC-TFE3; KSP-Cre+ mouse kidneys (4 month old and 7 month old) and TFEB overexpressed mouse kidneys (P0 and P14, Calcagni et al. Supplemental Fig. S3 Gene Set Enrichment Analysis (GSEA) of microarray data from 4 month old PRCC-TFE3; KSP-Cre+ mouse kidneys (n=4) vs 4 month old PRCC-TFE3; KSP-Cre- mouse kidneys (n=4) (a) and 7 month old PRCC-TFE3;KSP-Cre+ mouse kidneys (n=4) vs 7 month old PRCC-TFE3; KSP-Cre- mouse kidneys (n=3) (b). Marginal (a) and significant (b) enrichment of genes associated with KRAS activation in kidneys from PRCC-TFE3; KSP-Cre+ mice. Supplemental Fig. S4. The immunohistochemical staining of Tfe3 (a), Gpnmb (b), and Ret (c) on PRCC-TFE3;KSP-Cre- kidneys and PRCC-TFE3;KSP-Cre+ kidneys was semiquantified and scored as (-), (1+) and (2+). Supplemental Fig. S5. Volcano plot of gene expression changes for 4 month-old (a) and 7 month-old (b) PRCC-TFE3; KSP-Cre- kidneys and PRCC-TFE3; KSP-Cre+ kidneys.

This study aimed to evaluate the therapeutic benefit of novel androgen receptor-targeted agents (ARTAs) in castration-resistant prostate cancer (CRPC) with bone metastases in Japan.In followup to our prospective observational study (PROSTAT-BSI) from 2012 to 2018 on metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic CRPC (mCRPC) before docetaxel initiation, we conducted this sub-analysis to investigate the benefit of ARTAs after clinical recurrence on overall survival (OS) in the real-world clinical setting in Japan. In this study, we compared patients who were treated with ARTA with those who received only vintage hormone therapy including docetaxel after clinical recurrence.In the mHSPC group, 69 patients became mCRPC and were treated with or without ARTAs. No significant difference was observed in prostate-specific antigen (PSA) progression-free survival between the ARTA (+) and ARTA (-) groups; however, OS after clinical recurrence was significantly better in the ARTA (+) group than in the ARTA (-) group (median OS 31.9 vs. 23.0 months; p0.01).The ARTAs are beneficial even after mHSPC recurrence in Japanese patients in the real-world clinical setting. Since ARTAs are beneficial after clinical recurrence, it may be better to switch to ARTAs whenever necessary based on PSA response after combined androgen blockade therapy, considering the adverse effects and cost. This approach may be suitable to reduce overtreatment in Japanese patients with mHSPC.

CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC.Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy.The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR.Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

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.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.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]).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.

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.

Adrenocortical carcinoma (ACC) is a rare malignancy with a very poor prognosis. A 77-year-old man underwent imaging studies due to poorly controlled hypertension, which revealed a mass measuring 43 mm in diameter near the left adrenal gland. There were no findings indicative of pheochromocytoma. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed for the preoperative pathological evaluation, and the findings indicated a possibility of ACC. Based on these results, curative surgery was performed. If the diagnosis of pheochromocytoma is excluded, then EUS-FNA for adrenal lesions is relatively safe. It can also be used for the preoperative diagnosis of ACC.

Objective To investigate whether dose reductions in cisplatin due to renal dysfunction were associated with worse clinical outcomes in metastatic urothelial carcinoma (UC) patients. Patients and methods One hundred and fifty one metastatic UC patients who received first‐line gemcitabine plus cisplatin (GC) salvage chemotherapy without a previous history of peri‐surgical chemotherapy were included in this retrospective study. Patients with endogenous creatinine clearance of 60 mL/min or more were treated with a full dose of cisplatin, while those with 45‐59 and 30‐44 mL/min were treated with 75% and 50% doses, respectively. Patients were divided into three groups based on the average administered dose of cisplatin of 100% (Group A, N = 43), 99%‐75% (Group B, N = 59), and less than 75% (Group C, N = 49), and therapeutic responses and the toxicity of GC were compared. Results Complete response rates were 9.3%, 13.6%, and 14.3% in groups A, B, and C, respectively. One‐year progression‐free survival rates were 22.9%, 31.1%, and 36.7% in groups A, B, and C with no significant differences. One‐year cancer‐specific survival rates were 56.1%, 71.1%, and 68.3% in groups A, B, and C with no significant differences. A multivariate Cox's regression analysis showed that the dose of cisplatin was not an independent prognostic factor for disease progression and cancer death. Furthermore, there were no significant differences in the incidence of severe adverse events. Conclusions Dose reductions in cisplatin due to renal dysfunction did not worsen clinical outcomes for metastatic UC.

Technological innovations in single-photon emission computed tomography (SPECT) have enabled a more accurate quantitative evaluation of the uptake, and the standardized uptake value (SUV) can be measured as a semi-quantitative value, as in positron emission tomography. Nevertheless, the reliability of the SUV of bone SPECT has not been well established. The purpose of this study is to evaluate the test–retest repeatability of the SUV of bone SPECT/CT in clinical settings. This prospective study recruited patients with prostate cancer planning to receive bone SPECT/CT for the evaluation of bone abnormality between August 2017 and September 2019. Bone images were acquired twice by an integrated SPECT/CT scanner (Symbia Intevo, Siemens) within a 4- to 10-day interval. The maximum SUV (SUVmax) and peak SUV (SUVpeak) were calculated for the volumes of interests on the normal bone areas, degeneration/fracture lesions, and metastatic lesions. To determine repeatability, we calculated statistical indicators, including intraclass correlation coefficient (ICC), repeatability coefficient (RC), and mean absolute percentage difference (MAPD). For the ICC, the 95% confidential interval (CI) was also calculated, and an ICC of ≥ 0.8 was defined as an almost perfect correlation. Twelve male patients were enrolled in the study (58–86 years; median, 71 years), and a total of 229 volumes of the interest were included in the analyses. The ICCs were 0.968 [95% CI (0.959, 0.975)] for SUVmax and 0.976 [95% CI (0.969, 0.981)] for SUVpeak. The RCs of the relative difference were 30.7% for SUVmax and 27.6% for SUVpeak, and the MAPDs (± standardized deviation) of all lesions were 12.3 ± 9.9% for SUVmax and 11.5 ± 8.3% for SUVpeak. The RCs and the MAPDs showed comparable value with the previous report regarding repeatability studies on PET. An almost perfect correlation was demonstrated by repeated SUVmax and SUVpeak measured by quantitative integrated SPECT/CT. The quantitative values could be reliable indicators in patient management.

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.

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.

Introduction Pembrolizumab cause immune-related adverse events. We herein report a case of advanced bladder cancer, who treated with pembrolizumab and exhibited intriguing clinical course. Case presentation A 63-year-old man with bladder carcinoma was treated by radical cystectomy, however, the bladder carcinoma recurred and invaded to the rectum. He was treated by combination therapy using gemcitabine and cisplatin, which were not effective for the tumor. He subsequently underwent treatment with pembrolizumab. In several 30 days, he suffered from the symptoms of myasthenia gravis. Serum levels of creatine kinase, its isozyme creatine kinase-myocardial band, and troponin I were elevated. Electrocardiography showed a right bundle branch block. These findings suggested that he was myasthenia gravis with general myositis and presumable myocarditis. Oral prednisolone administration significantly attenuated these findings. The tumor drastically shrunk only by the single injection of pembrolizumab. Conclusion Early intervention with corticosteroid was effective for neuromuscular complications due to pembrolizumab.

Background/Aim: Patients with metastatic renal cell carcinoma (RCC) with cardiac metastasis have had poor outcomes in the era of molecular targeted therapy. There are few reported outcomes for patients with cardiac metastasis of RCC treated with immune checkpoint inhibitors (ICIs). Case Report: A 32-year-old female presented with metastatic RCC (unclassified type) with contralateral renal and cardiac metastases, as well as renal hilar lymph node metastases (cT4N2M1). An (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) computed tomographic (CT) scan was useful in diagnosing cardiac metastasis. Nivolumab plus ipilimumab achieved prominent shrinkage of almost all tumors except for one cardiac tumor. FDG-PET/CT scan also revealed the marked attenuation of FDG uptake in each tumor. In addition, a needle biopsy of the remaining primary renal tumor was pathologically observed to have no viable cancer cells. Conclusion: This successful case suggests that ICIs might provide a better outcome even for patients with cardiac metastasis of RCC, and that FDG-PET/CT scan might be useful for therapeutic assessment, as well as diagnosis.

To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy.Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups.Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group.In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group.

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.

Introduction Pazopanib, a tyrosine kinase inhibitor, and nivolumab, an immune checkpoint inhibitor, are both considered to cause hepatotoxicity with different pathophysiology. We report a case in which a patient died of severe hepatotoxicity who was presumed to have been caused by the administration of nivolumab followed by pazopanib for metastatic renal cell carcinoma. Case presentation A 74-year-old male with metastatic renal cell carcinoma was treated with nivolumab as a third-line treatment. However, nivolumab was subsequently discontinued, as it caused severe thyroiditis. About 2 months after the final dose of nivolumab was administered, pazopanib was initiated as a fourth-line treatment. The patient suffered from lethal hepatic failure and died 18 days after the initiation of pazopanib treatment. An autopsy revealed that CD8-positive lymphocytes had infiltrated the thyroid gland and liver. Conclusion The patient was considered to have died of severe hepatic failure due to the aggravation of mild nivolumab-induced immune-related hepatitis by pazopanib.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

Background/aim The purpose of this retrospective study was to identify the predictive biomarkers of response to pretreatment for patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. Materials and methods The subjects were 54 patients treated with nivolumab for mRCC with a clear cell component (mccRCC) between September 2016 and February 2018. We analyzed the impact of serum biomarkers (lactate dehydrogenase [LDH], neutrophil-to-lymphocyte ratio, and C-reactive protein) on patients treated with nivolumab. We adopted the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model using six clinical factors (0=favorable, 1 or 2=intermediate, 3 to 6=poor risk groups, respectively). Results The prognostic risk classification (non-poor vs. poor) and serum LDH levels were correlated with the objective response of nivolumab treatment for mccRCC. Elevated serum LDH levels at baseline were an independent biomarker for progression-free survival (PFS) of mccRCC patients receiving nivolumab [HR=2.268 (95%CI=1.014-5.051), p=0.046]. Notably, high LDH levels were associated with a poorer PFS for patients in the favorable-risk group. Conclusion Serum LDH levels at baseline before nivolumab treatment were associated with the objective response and clinical outcome of nivolumab treatment.

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.

Visualizing tissue distribution of steroid hormones is a promising application of MALDI mass spectrometry imaging (MSI). On-tissue chemical derivatization using Girard's T reagent has enhanced the ionization efficiency of steroids. However, discriminating between structural isomers with distinct bioactivities remains a challenge. Herein, we used ion trap MS/tandem MS (MS3) to distinguish a mineralcorticoid aldosterone (Aldo) and a glucocorticoid cortisol (F), from their structural isomers. Our method is also useful to detect hybrid steroids (18-hydroxycortisol [18-OHF] and 18-oxocortisol) with sufficient signal-to-noise ratio. The clinical applicability of the tandem MS method was evaluated by analyzing F, Aldo, and 18-OHF distributions in human adrenal glands. In such clinical specimens, small Aldo-producing cell clusters (APCCs) were identified and were first found to produce a high level of Aldo and not to contain F. Moreover, a part of APCCs produced 18-OHF, presumably converted from F by APCC-specific CYP11B2 activity. Catecholamine species were also visualized with another derivatization reagent (TAHS), and those profiling successfully discriminated pheochromocytoma species. These tandem MSI-methods, coupled with on-tissue chemical derivatization has proven to be useful for detecting low-abundance steroids, including Aldo and hybrid steroids and thus identifying steroid hormone-producing lesions.

Background International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

Introduction Aberrant cortical adrenal tissues are not generally identified in adults. Herein, we present a very rare case of an ectopic adrenal tumor located in the renal hilum that caused gross hematuria. Case presentation A 33-year-old man suddenly presented with asymptomatic gross hematuria. Abdominal computed tomography revealed a 35-mm mass in the left renal hilum encroaching the renal vein. Following the surgical removal with frozen section of the mass, his gross hematuria immediately improved. Pathological analysis of the specimen revealed the features adrenal adenoma. Immunohistochemical staining for key steroidogenic enzymes confirmed the adrenocortical origin without excessive hormone production. Conclusion This is the first case of an ectopic adrenocortical adenoma in the renal hilum that caused gross hematuria without hormonal symptoms.

Purpose of review Immunohistochemistry for aldosterone synthase (CYP11B2) has markedly provided a comprehensive picture of the adrenocortical diseases, particularly primary aldosteronism. The findings from CYP11B2-immunohistochemistry are consistent with the clinical courses of most patients with primary aldosteronism. We herein review the updated pathophysiology and usefulness of the method for understanding individual patients with different subtypes of primary aldosteronism. Recent findings After our discovery of aldosterone-producing cell clusters (APCCs) using the immunohistochemistry for CYP11B2, we found possible APCC-to-APA transitional lesions (pAATLs) in a few cases that had been hitherto classified as unilateral hyperplasia or multiple nodules. On the basis of morphological and functional features of pAATLs as well as distributions of somatic mutations within the lesions, we have made a hypothesis that APCC grows to APA via pAATL for one of developmental courses of APA. Recently, we successfully performed in-situ detection of aldosterone on adrenal tissue sections using a state-of-the-art technique, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-imaging). This method revealed in-situ synthesis of aldosterone in APCCs and APAs in addition to several other steroids. Summary CYP11B2 immunohistochemistry revealed the pathophysiology of aldosterone production in the past decade, especially formation of APCC in normal adrenals and pAATL that is a possible lesion developing from APCC to APA. The term 'idiopathic hyperaldosteronism' may soon become obsolete.

Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1–4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6–8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value ( m/z ). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.

This study investigated the clinical outcome of neoadjuvant androgen deprivation therapy followed by high dose rate brachytherapy (HDR-BT, called NEH) with external beam radiotherapy (EBRT) in high-risk prostate cancer (PCa) patients in our institution. : From 2007 to 2012, 192 high-risk PCa patients underwent neoadjuvant treatment-EBRT-NEH ( n = 192). Relations between clinical factors (prostate-specific antigen; PSA, cT stage, Gleason score) and biochemical recurrence were retrospectively analyzed. : The 5- and 7-year overall survival rates were 97.9 and 91.1%. By PSA levels (PSA 20 ng/ml, 20 ng/mlPSA≤50 ng/ml and PSA50 ng/ml), 5-year biochemical recurrence-free survival rates were 85.7, 84.7 and 54.5%, respectively. There were no significant differences between biochemical recurrence and cT stage or Gleason score. : We found that NEH can contribute to better biochemical recurrence free survival of high-risk PCa patients with PSA below 50 ng/ml. High-risk PCa patients with PSA over 50 ng/ml may require more aggressive local or systemic treatment.

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.