Paraganglioma with High Levels of Dopamine, Dopa Decarboxylase Suppression, Dopamine ß-hydroxylase Upregulation and Intra-tumoral Melanin Accumulation: A Case Report with a Literature Review.

Object Exclusively dopamine-producing pheochromocytoma/paraganglioma (PPGL) is an extremely rare subtype. In this condition, intratumoral dopamine ß-hydroxylase (DBH), which controls the conversion of norepinephrine from dopamine, is impaired, resulting in suppressed norepinephrine and epinephrine production. However, the rarity of this type of PPGL hampers the understanding of its pathophysiology. We therefore conducted genetic and immunohistological analyses of a patient with an exclusively dopamine-producing paraganglioma. Methods Paraganglioma samples from a 52-year-old woman who presented with a 29.6- and 41.5-fold increase in plasma and 24-h urinary dopamine, respectively, but only a minor elevation in the plasma norepinephrine level was subjected to immunohistological and gene expression analyses of catecholamine synthases. Three tumors carrying known somatic PPGL-related gene variants (HRAS, EPAS1) were used as controls. Whole-exome sequencing (WES) was also performed using the patient's blood and tumor tissue. Results Surprisingly, the protein expression of DBH was not suppressed, and its mRNA expression was clearly higher in the patient than in the controls. Furthermore, dopa decarboxylase (DDC), which governs the conversion of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) to dopamine, was downregulated at the protein and gene levels. In addition, melanin, which is synthesized by L-DOPA, accumulated in the tumor. WES revealed no PPGL-associated pathogenic germline variants, but a missense somatic variant (c.1798G>T) in CSDE1 was identified. Conclusion Although pre-operative plasma L-DOPA was not measured, our histological and gene expression analyses suggest that L-DOPA, rather than dopamine, might have been overproduced in the tumor. This raises the possibility of pathophysiological heterogeneity in exclusively dopamine-producing PPGL.

A case of juvenile-onset pheochromocytoma with KIF1B p.V1529M germline mutation.

In 2008, a familial noradrenergic pheochromocytoma (PCC) with a KIF1B germline mutation in exon 41 was reported in a 24-year-old female proband and her family. However, in 2020, the same research group reported that the cause of PCC in this family was a MAX germline mutation and was not due to the KIF1B mutation. In this study, we investigated the pathogenicity of a KIF1B germline mutation detected in a 26-year-old woman with juvenile-onset noradrenergic PCC. She was surgically treated and did not have a family history of PCC. We performed whole-exome sequencing, Sanger sequencing, and immunohistochemical and gene expression analyses of catecholamine-synthesizing enzymes. Three tumors with associated somatic mutations were used as the control group. Whole-exome sequencing revealed a p.V1529M KIF1B germline mutation in exon 41 in our patient, and no other associated germline and somatic mutations, including MAX, were detected. Sanger sequencing confirmed the presence of both mutant and wild-type alleles in the tumor. Among the catecholamine-synthesizing enzymes, the expression of phenylethanolamine-N-methyl transferase was suppressed. An in silico analysis of the p.V1529M mutation showed a score suggestive of pathogenicity. After evaluation with the international guideline for sequence variants, p.V1529M mutation was still classified as a variant with uncertain significance; however, our data, including the in silico analysis data, provided certain evidences that met the criteria supporting its pathogenicity. Therefore, this study can support future studies in proving the pathogenicity of the KIF1B p.V1529M mutation.

Effect of oxybutynin patch versus mirabegron on nocturia-related quality of life in female overactive bladder patients: A multicenter randomized trial.

OBJECTIVES: To investigate the effect of oxybutynin patch versus ß3-adrenoceptor agonist mirabegron on nocturia-related quality of life in female overactive bladder patients. METHODS: In the present study, female overactive bladder patients were enrolled. The patients were randomly allocated into two groups: the oxybutynin patch group and the mirabegron group. Each of the drugs was given for 8 weeks. The changes in the total Nocturia Quality of Life Questionnaire score were evaluated. Parameters on a frequency volume chart were also evaluated. RESULTS: In total, 100 patients (51 oxybutynin patch, 49 mirabegron) were treated with oxybutynin patch or mirabegron. The changes in the Nocturia Quality of Life Questionnaire score 4 weeks after administration were 3.8 ± 18.6 and 8.7 ± 13.1 with the oxybutynin patch group and the mirabegron group, respectively, which were significantly higher than those at the baseline. Furthermore, the changes in the Nocturia Quality of Life Questionnaire score 8 weeks after administration were 4.3 ± 16.5 and 7.7 ± 12.3, respectively. A statistical difference was seen only in the mirabegron group. Regarding the Nocturia Quality of Life Questionnaire subscores, oxybutynin patch and mirabegron significantly improved the Nocturia Quality of Life Questionnaire bother/concern subscore 4 and 8 weeks after administration, whereas the Nocturia Quality of Life Questionnaire sleep/energy subscore was not significantly improved in each period. Eight weeks after administration, 24-h frequency, 24-h urinary urgency and mean voided urine volume were improved in both groups statistically. CONCLUSIONS: The oxybutynin patch improves quality of life, focusing mainly on nocturia by improving the bother/concern subscores of the Nocturia Quality of Life Questionnaire in the short term.

Genomic Profiling Identified ERCC2 E606Q Mutation in Helicase Domain Respond to Platinum-Based Neoadjuvant Therapy in Urothelial Bladder Cancer.

Genomic profiling of tumors enables therapeutic decisions, and identifying drug-matched mutations will prolong survival and prognosis. Here, we generated a custom panel for detecting genetic alterations in 19 patients with urothelial bladder cancer. This panel targeted 71 genes associated with urological cancer. Targeted sequencing was performed on formalin-fixed paraffin-embedded tumor tissues. Paired patient-matched tumor and blood samples were subjected to this analysis. A total of 142 somatic mutations were detected in 19 tumor tissues. At least one non-synonymous mutation was detected in all tumor tissues, and KDM6A, KMT2D, TP53, KMT2C, PIK3CA, and ERCC2 were recurrently mutated. Chromatin remodeling and epigenetic modifier genes are frequently mutated. Of 142 mutations, 69 mutations (49%) were annotated to have oncogenic potential. Furthermore, 74% of patients were expected to receive targeted therapy due to drug-matched mutations being identified in their tumors. Among this cohort, a patient harbored an ERCC2 helicase domain mutation and would be expected to respond to platinum-based therapy. As expected, the patient received carboplatin-containing neoadjuvant therapy with a remarkable response. Furthermore, tumor-derived mutations in urine were rapidly decreased after neoadjuvant therapy. These results suggested targeted sequencing could help to detect drug-matched somatic mutations and indicate single or combination therapy for cancer patients.

Genomic profile of urine has high diagnostic sensitivity compared to cytology in non-invasive urothelial bladder cancer.

Cytology is widely conducted for diagnosis of urothelial bladder cancer; however, its sensitivity is still low. Recent studies show that liquid biopsies can reflect tumor genomic profiles. We aim to investigate whether plasma or urine is more suitable for detecting tumor-derived DNA in patients with early-stage urothelial bladder cancer. Targeted sequencing of 71 genes was carried out using a total of 150 samples including primary tumor, urine supernatant, urine precipitation, plasma and buffy coat from 25 patients with bladder cancer and five patients with cystitis and benign tumor. We compared mutation profiles between each sample, identified tumor-identical mutations and compared tumor diagnostic sensitivities between urine and conventional cytology. We identified a total of 168 somatic mutations in primary tumor. In liquid biopsies, tumor-identical mutations were found at 53% (89/168) in urine supernatant, 48% (81/168) in urine precipitation and 2% (3/168) in plasma. The high variant allele fraction of urine was significantly related to worse clinical indicators such as tumor invasion and cytological examination. Although conventional cytology detected tumor cells in only 22% of non-invasive tumor, tumor diagnostic sensitivity increased to 67% and 78% using urine supernatant and precipitation, respectively. Urine is an ideal liquid biopsy for detecting tumor-derived DNA and more precisely reflects tumor mutational profiles than plasma. Genomic analysis of urine is clinically useful for diagnosis of superficial bladder cancer at early stage.

Malignant mixed epithelial and stromal tumor of the kidney: report of the first male case.

Mixed epithelial and stromal tumor of the kidney is a rare benign tumor that consists of both epithelial and stromal cells. To date, eight malignant cases have previously been reported in female patients only. We report the first case of malignant mixed epithelial and stromal tumor of the kidney in a male patient. A 67-year-old Japanese man receiving hormonal therapy for prostatic cancer was found to have a right renal cystic tumor and underwent right nephrectomy. Histologically, the tumor was composed of benign epithelial and stromal cells in addition to malignant undifferentiated stromal cells. Immunohistochemically, the malignant stromal component was positive for cluster of differentiation 99 and B-cell lymphoma 2, but no chimeric transcripts for synovial sarcoma were identified. Finally, a diagnosis of malignant mixed epithelial and stromal tumor of the kidney was recorded. Urologists and pathologists should recognize that malignant mixed epithelial and stromal tumors of the kidney might occur in male patients receiving hormonal therapy for prostatic cancer.

[Case report: instillation of povidone iodine for the treatment of idiopathic chyluria].

A 77-year-old woman who had never lived in a tropical area was referred to our hospital in November 2006 because of hypoproteinemia and chyluria. Cystoscopy revealed milky urine flowing from left ureteral orifice. Computed tomography showed small lymph nodes around the left side of the aorta but no carcinoma could be seen. We diagnosed her with idiopathic chyluria and recommended low fatty meals, but chyluria did not disappear. In March 2007 povidone iodine was instilled retrogradedly and chyluria disappeared immediately. As of December 2007, chyluria has not recurred.

[Case report: lymph node metastasis of micropapillary bladder tumor that completely responded to radiation therapy].

A 67-year-old woman was referred to our hospital in April 2003 because of a bladder tumor. Cystoscopy revealed a thumb tip size and wide based papillary tumor. TUR-Bt was performed. Histologically, the tumor was UC, G3 and pT1. There was no recurrence of tumor in bladder after that. 3 years later, she was referred again with high serum levels of CA19-9 and CEA. Computed tomography showed bilateral lymph node swelling in the pelvis. An open biopsy of the lymph node was done and it contained UC with a micropapillary component. Radiation therapy achieved completely response. Serum levels of CA19-9 and CEA were within normal limits. She has never had a recurrence of tumor until July 2007.

Bladder metastasis of renal cell carcinoma; a case study.

A 78-year-old man underwent left total nephroureterectomy, and histopathological examination revealed renal cell carcinoma (RCC) of clear cell subtype. Multiple lung metastases were observed, and immunotherapy using IFN-alpha was introduced after the operation. Gross hematuria was seen 1 year after the operation, and cystoscopy revealed a submucosal tumor in the bladder. Transurethral resection of the tumor was performed, and pathological diagnosis was metastasis from the RCC. Six months later, he died because of multiple metastases of the tumor. Thirty cases of metastasis of RCC to the bladder, including our case, have been reported in Japan.

Fate of tetraplegic patients managed by ileal conduit for urinary control: long-term follow-up.

BACKGROUND: A study was conducted to evaluate our experience of ileal-conduit formation in tetraplegic patients with special reference to late complications due to upper urinary tract stones and pyocystis. METHODS: Ileal-conduit formation was performed in 16 patients with tetraplegia to improve urinary management. The mean age at operation was 46 years (range 19-70) and the mean follow-up period was 8.7 years (range 2-17). We evaluated the results retrospectively from patients' medical records. RESULTS: Two patients died 2 years after the procedure and one patient died 8 years after the ileal-conduit formation. Five patients suffered from repeated renal or ureteral stone. In three of these cases, serious urinary tract infections developed whenever the stone caused an obstruction. Three patients received a cystectomy at the time of the ileal-conduit formation. Eight patients suffered from empyema of the bladder and in two of these cases a subsequent cystectomy was required. CONCLUSIONS: Ileal-conduit formation should be cautiously considered as an option in the urinary management of tetraplegic patients, particularly when more conservative management strategies have proved unsuccessful. However, an antirefluxing mechanism for the ileal conduit may be necessary, and a simultaneous cystectomy may improve the results.