Current Status of Prostate-specific Membrane Antigen-targeted Alpha Radioligand Therapy in Prostate Cancer.

Prostate cancer (PCa) is the most prevalent malignancy and leading cause of mortality in men. Despite the development of various drugs, such as novel androgen receptor signaling inhibitors and poly adenosine diphosphate-ribose polymerase inhibitors targeting homologous recombination repair-related genetic mutations, prognosis of metastatic castration-resistant prostate cancer remains unfavorable. However, recent advances in nuclear medicine have allowed for both imaging diagnostics and therapeutic interventions by targeting molecules specifically expressed in cancer cells with radioisotopes (RI). γ-rays are used in nuclear medicine imaging, whereas in therapy, α or ß-emitting RIs are administered to target cells in radiation therapy. PCa, in particular, exhibits the characteristic features of radioligand therapy, as the membrane protein prostate-specific membrane antigen (PSMA) is proportionally highly expressed in malignancy compared to normal tissues. The administered RI-labeled compound binds to PSMA, enabling specific targeting of PCa for treatment. Unlike ß-rays, α-rays have a shorter range and impart stronger energy to DNA, allowing α-particles to exhibit a higher linear energy transfer. Due to such characteristics, PSMA-targeted α radiotherapy is expected to have potent cytotoxic effects and fewer side effects on normal organs, making them more likely to be widely adopted in the future. However, reports on PSMA-targeted α radiotherapy differ in aspects, such as prior PSMA-targeted ß radiotherapy, the administered doses, and the number of treatment cycles. Therefore, in this review, we compile the reports on treatments utilizing α-emitting isotopes targeting PSMA in patients with PCa.

Bacteria-derived DNA in serum extracellular vesicles are biomarkers for renal cell carcinoma.

This is the first study to determine the clinical importance of circulating bacterial DNA in patients with renal cell carcinoma (RCC). We performed 16S rRNA metagenomic analysis of serum extracellular vesicles (EVs) from 88 patients with RCC and 10 healthy donors and identified three abundant bacterial DNA: Bacteroidia, TM7-1, and Sphingomonadales. Combining characteristic bacterial DNA information (three bacteria-derived DNA), a BTS index was created to diagnose patients with RCC. The BTS index showed high sensitivity not only in the discovery cohort, but also in the validation cohort, suggesting that it was useful as a screening test. Furthermore, in nivolumab treatment of RCC, patients with higher levels of Bacteroidia DNA in serum EVs had significantly poorer progression-free and overall survival than did those with lower levels. This study showed that circulating Bacteria-derived DNA could be used as a biomarker for RCC.

Comparative Effectiveness of Radiation Versus Radical Cystectomy for Localized Muscle-Invasive Bladder Cancer.

Purpose: Radical cystectomy (RC) with neoadjuvant chemotherapy is the most commonly recommended treatment for muscle-invasive bladder cancer (MIBC), yet RC with urinary diversion remains an invasive treatment. Although some patients with MIBC gain good cancer control with radiation therapy (RT), its effectiveness remains under discussion. Therefore, we aimed to reveal the effectiveness of RT compared with RC for MIBC. Methods and Materials: Using cancer registry and administrative data from 31 hospitals in our prefecture, we recruited patients with bladder cancer (BC) initially registered between January 2013 and December 2015. All patients received RC or RT, and none had metastases. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards model and log-rank test. Propensity score matching between the RC and RT groups was performed to examine the association of each factor with OS. Results: Among the patients with BC, 241 received RC and 92 received RT. Median ages of the patients receiving RC and RT were 71.0 and 76.5 years, respectively. Five-year OS rates were 44.8% for patients receiving RC and 27.6% for patients receiving RT (P < .001). Multivariate analysis for OS showed that older age, poorer functional disability, clinical node positive, and pathology of nonurothelial carcinoma were significantly associated with worse prognosis. A propensity score-matching model identified 77 patients with RC and 77 with RT. In this arranged cohort, there were no significant differences in OS between the RC and RT groups (P = .982). Conclusions: Prognostic analysis with matched characteristics showed that patients with BC receiving RT were not significantly different from those receiving RC. These findings could contribute to proper treatment strategies for MIBC.

Diagnosing and Prognosing Bone Metastasis in Prostate Cancer: Clinical Utility of Blood Biomarkers.

Bone metastasis (BM) may occur in any type of cancer. The diagnosis of patients with BM has increased due to improved imaging technologies and advances in cancer drug therapy that have prolonged the survival time of cancer patients. BM may be asymptomatic in the early stages; however, as the disease progresses, it causes pain, fracture, neurological symptoms associated with spinal cord compression, hypercalcemia, and other specific symptoms that significantly impair the patient's quality of life (QOL). Imaging modalities have disadvantages, such as high cost, radiation exposure, and bone pain associated with holding posture for imaging test; further, they are time-consuming. Hence, patients with BM require convenient and useful biomarkers. However, no blood biomarkers generally useful for diagnosis and therapeutic monitoring of BM are established. Prostate cancer (PC) and breast cancer, in particular, are among the most prone to BM because BM occurs in approximately 70% of patients with advanced disease. Herein, we reviewed various potential bone turnover markers and liquid biopsy for diagnosis and prognosis prediction in patients with BM of PC based on PubMed literature search. The usefulness of conventional bone turnover markers of BM in PC is limited, and cut-off values vary. In the future, the creation of algorithms using these conventional markers and multiple tests, such as liquid biopsy and imaging tests, will help to develop highly accurate techniques for the diagnosis of BM.

The presence of lymph node metastases and time to castration resistance predict the therapeutic effect of enzalutamide for castration-resistant prostate cancer.

BACKGROUND: Enzalutamide is effective against castration-resistant prostate cancer (CRPC). However, it is unclear which patients would benefit more from enzalutamide treatment. Here, we analyzed patients who received enzalutamide as first-line therapy for CRPC and evaluated the factors that predict treatment response and prognosis. METHODS: We retrospectively analyzed 101 patients treated with enzalutamide for CRPC at our institution. As primary endpoints we regarded the prostate-specific antigen (PSA) response rate and PSA-progression-free survival (PSA-PFS) from the start of enzalutamide treatment. Laboratory and imaging data were analyzed to predict treatment efficacy. RESULTS: PSA reductions of ≥ 50% and ≥ 90% were observed in 78 (77%) and 47 (47%) patients, respectively, compared with the baseline. During the follow-up period, 67 (66%) patients showed PSA progression, with a median PSA-PFS of 11 months. Moreover, 31 patients (31%) died, with a median overall survival of 64 months. On multivariate analysis, lymph node metastases at the start of enzalutamide treatment [odds ratio (OR) 0.0575, 95% confidence interval (CI) 0.0105-0.316, p = 0.0010] and time to CRPC (OR 0.177, 95% CI 0.0428-0.731, p = 0.0167] were associated with ≥ 90% PSA response. Lymph node metastases (hazard ratio [HR] 3.00, 95% CI 1.48-6.09, p = 0.0023) and time to CRPC (HR 1.84, 95% CI 1.02-3.30, p = 0.0419) were also predictors of PSA-PFS on a multivariate model. CONCLUSIONS: Time to CRPC and lymph node metastasis were predictors of the PSA response rate and PSA-PFS.

Diagnostic and prognostic significance of tartrate-resistant acid phosphatase type 5b in newly diagnosed prostate cancer with bone metastasis: A real-world multi-institutional study.

OBJECTIVES: Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients. METHODS: We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b). RESULTS: A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p < 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p < 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95). CONCLUSIONS: Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

Anticancer maintenance chemotherapy prolonged prognosis of metastatic urothelial carcinoma patients: A single institute retrospective study using propensity score matching.

OBJECTIVES: To evaluate the therapeutic efficacy of anticancer maintenance chemotherapy for metastatic urothelial carcinoma. METHODS: We retrospectively compared the clinical outcomes of 74 patients with metastatic urothelial carcinoma who had been treated with or without anticancer maintenance chemotherapy between 2006 and 2020 at Osaka University Hospital. Progression-free survival and cancer-specific survival periods were calculated using the Kaplan-Meier method starting from the end date of induction chemotherapy. The backgrounds of patients who had treated with or without anticancer maintenance chemotherapy were adjusted using the propensity score matching method. RESULTS: Twenty-nine patients had undergone anticancer maintenance chemotherapy, whereas 45 patients had not. The median progression-free survival periods were 18.7 and 5.6 months (p = 0.0209), and the median cancer-specific survival periods were 25.1 and 15.2 months (p = 0.1299), in patients with or without anticancer maintenance chemotherapy respectively. In multivariate analysis, anticancer maintenance chemotherapy significantly prolonged both progression-free survival (hazard ratio 3.65, 95% confidence interval 1.96-6.78, p < 0.0001) and cancer-specific survival (hazard ratio 3.05, 95% confidence interval 1.62-5.76, p = 0.0006) in patients with partial response or stable disease after induction chemotherapy. Also, anticancer maintenance chemotherapy significantly prolonged both progression-free survival (13.1 months vs. 4.9 months, p = 0.0027) and cancer-specific survival (35.1 months vs. 11.8 months, p = 0.0044) in propensity score matched patients. CONCLUSIONS: Anticancer maintenance chemotherapy may be considered the treatment for metastatic urothelial carcinoma patients after induction chemotherapy.

EphA2 on urinary extracellular vesicles as a novel biomarker for bladder cancer diagnosis and its effect on the invasiveness of bladder cancer.

BACKGROUND: Urinary extracellular vesicles (uEVs) secreted from bladder cancer contain cancer-specific proteins that are potential diagnostic biomarkers. We identified and evaluated a uEV-based protein biomarker for bladder cancer diagnosis and analysed its functions. METHODS: Biomarker candidates, selected by shotgun proteomics, were validated using targeted proteomics of uEVs obtained from 49 patients with and 48 individuals without bladder cancer, including patients with non-malignant haematuria. We developed an enzyme-linked immunosorbent assay (ELISA) for quantifying the uEV protein biomarker without ultracentrifugation and evaluated urine samples from 36 patients with and 36 patients without bladder cancer. RESULTS: Thirteen membrane proteins were significantly upregulated in the uEVs from patients with bladder cancer in shotgun proteomics. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) was the only protein significantly upregulated in the uEVs of patients with bladder cancer, compared with that of patients with non-malignant haematuria. The EV-EphA2-CD9 ELISA demonstrated good diagnostic performance (sensitivity: 61.1%, specificity: 97.2%). We showed that EphA2 promotes proliferation, invasion and migration and EV-EphA2 promotes the invasion and migration of bladder cancer cells. CONCLUSIONS: We established EV-EphA2-CD9 ELISA for uEV-EphA2 detection for the non-invasive early clinical diagnosis of bladder cancer.

Circulating extracellular vesicles carrying Firmicutes reflective of the local immune status may predict clinical response to pembrolizumab in urothelial carcinoma patients.

Bacterial flora has clinical significance for the host. The metabolic environment created by this flora influences immunotherapy in urothelial carcinoma. However, there are no reports on the clinical significance of bacterial flora in the host bloodstream. We aimed to clarify the correlation between extracellular vesicle (EV)-derived blood microflora information and tumor immunological status in urothelial carcinoma (UC) patients. Serum samples were collected from 20 healthy donors, 50 patients with localized UC, and 31 patients with metastatic UC (mUC) who had undergone pembrolizumab treatment. Bacterial DNA in EVs was extracted from each sample. Metagenomic sequencing was performed after amplification of the V1-V2 region of the bacterial 16S rRNA gene. Using the matched tumor tissue and serum samples, we revealed that the smaller amount of peripheral EVs carrying Firmicutes DNA was significantly correlated with the higher number of infiltrating T cells within tumor tissues (CD3; p = 0.015, CD4; p = 0.039, CD8; p = 0.0084) and the higher expression of activation markers on their surface (ICOS on both CD4; p = 0.0013 and CD8 T cells; p = 0.016 and 4-1BB on CD4 T cells; p = 0.016). In terms of circulating metabolic information, L-Ser and L-Pro levels, which play important roles in T cell expansion and proliferation, were significantly higher in the Firmicutes-low group (p = 0.010). All of the patients with higher Firmicutes abundance had disease progression without any clinical response (p = 0.026) and significantly inferior prognosis for pembrolizumab therapy (p = 0.035). This is the first study on the importance of peripheral bacterial EVs in cancer patients treated with cancer immunotherapy.

Biological distinction between grades 2 and 3 with respect to intravesical recurrence in T1 high-grade bladder tumors: a retrospective study.

BACKGROUND: The pathological grading system for non-muscle-invasive bladder cancer is based on the WHO 2004/2016 classification system (low-grade: LG/high-grade: HG) and the WHO 1973 classification system (Grade 1: G1/Grade 2: G2/Grade 3: G3). Recently, the usefulness of combining both systems and classifying the tumors as LG/G1, LG/G2, HG/G2, and HG/G3 has been demonstrated. In this study, we compared the prognosis of intravesical recurrence in relation to different treatment intensities between HG/G2 and HG/G3 bladder cancers. METHODS: We retrospectively evaluated the clinical and therapeutic outcomes of 145 patients diagnosed with T1 HG bladder cancer between 2000 and 2020. We classified 145 patients into three groups: (1) patients with T1 HG/G2 and HG/G3 who received intravesical instillation therapy (n = 76), (2) patients with T1 HG/G2 who did not receive intravesical instillation therapy (n = 32), and (3) patients with T1 HG/G3 who did not receive intravesical instillation therapy (n = 37). RESULTS: The median intravesical recurrence-free survival for all patients was 34.2 months. The number of tumors, the presence of intravesical instillation therapy, and tumor grade were significant prognostic factors for intravesical recurrence in all cases. Groups 2 and 3 showed significantly worse prognosis than group 1 in the multivariate analysis. CONCLUSIONS: Regarding intravesical recurrence, intravesical instillation therapy is necessary for both T1 HG/G3 and T1 HG/G2 bladder cancers.

High-fat diet promotes prostate cancer growth through histamine signaling.

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma.

Perioperative systemic chemotherapy improves the prognosis of upper tract urothelial carcinoma (UTUC). The first objective of this study was to verify whether perioperative circulating tumor DNA (ctDNA) analysis using a pan-cancer gene panel and next-generation sequencing could identify patients with poor prognosis who require perioperative chemotherapy. Second, we investigated whether ctDNA is useful for minimal residual disease (MRD) detection and treatment monitoring in UTUC. This study included 50 patients with untreated UTUC, including 43 cases of localized UTUC. We performed targeted ultradeep sequencing of plasma cell-free DNA (cfDNA) and buffy coat DNA and whole-exome sequencing of cancer tissues, allowing exclusion of possible false positives. We attempted to stratify the prognosis according to the perioperative ctDNA levels in patients with localized UTUC. In patients with metastatic UTUC, ctDNA was evaluated before, during, and after systemic treatment. In total, 23 (46%) of 50 patients with untreated UTUC were ctDNA positive, and 17 (40%) of 43 patients with localized UTUC were ctDNA positive. Of the detected TP53 mutations, 19% were false positives due to clonal hematopoiesis of indeterminate potential. Among preoperative risk factors, only the preoperative ctDNA fraction>2% was a significant and independent risk factor associated with worse recurrence-free survival (RFS). Furthermore, the existence of ctDNA early points after the operation was significantly associated with worse RFS, suggesting the presence of MRD. ctDNA also showed a potential as a real-time marker for systemic therapy in patients with metastatic UTUC. Detection of ctDNA may indicate potential metastasis and guide decisions on perioperative chemotherapy.

Early dynamics of circulating tumor DNA predict clinical response to immune checkpoint inhibitors in metastatic renal cell carcinoma.

OBJECTIVES: Detection of genomic alterations in circulating tumor deoxyribonucleic acid of peripheral blood can guide the selection of systemic therapy in cancer patients. The predictive significance of circulating tumor deoxyribonucleic acid in metastatic renal cell carcinoma remains unclear, especially for patients treated with immune checkpoint inhibitors. METHODS: In this study, we collected plasma samples before and 1 month after commencing nivolumab monotherapy or nivolumab plus ipilimumab therapy from 14 metastatic renal cell carcinoma patients. We performed circulating tumor deoxyribonucleic acid genomic profiling in plasma cell-free deoxyribonucleic acid by next-generation sequencing using a commercially available pan-cancer panel (Guardant360 CDx). Additionally, we also performed whole exome sequencing of tumor tissues and compared the concordance of genomic profiles with circulating tumor deoxyribonucleic acid. RESULTS: Nine patients had circulating tumor deoxyribonucleic acid in pretreatment plasma samples with a total of 20 mutations (15 single nucleotide variants, three insertions/deletions, and two copy number amplification). VHL (30.0%) was the most frequently mutated gene, followed by TP53 (20.0%), and 45.0% of circulating tumor deoxyribonucleic acid mutations were concordant with somatic mutations in tumor tissues. Patients with decreasing circulating tumor deoxyribonucleic acid mutant allele frequency had better progression free survival when compared to those with increasing mutant allele frequency (P = 0.0441). CONCLUSIONS: Our findings revealed that early circulating tumor deoxyribonucleic acid dynamics can serve as a predictive biomarker for response to immune checkpoint inhibitors in metastatic renal cell carcinoma patients.

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

Fragmentation of cell-free DNA is induced by upper-tract urothelial carcinoma-associated systemic inflammation.

Reliable biomarkers for upper-tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive blood biomarker for various types of cancer. We investigated the utility of plasma cfDNA as a blood biomarker in UTUC patients. The fragment size of plasma cfDNA was shorter and the concentration of plasma cfDNA was higher in UTUC patients than in healthy controls. The fragment size of plasma cfDNA had a moderate accuracy of diagnosing UTUC (area under the curve [AUC] = 0.72), and multivariate analysis indicated that the fragment size of plasma cfDNA was significantly associated with the presence of UTUC (odds ratio = 0.807, 95% confidence interval [CI] 0.653-0.955, P = .024). Furthermore, we found that the size of plasma cfDNA shortens alongside disease progression (P < .001). The fragment size of plasma cfDNA in UTUC patients may be an auxiliary tool for the diagnosis of UTUC patients. We also found a high correlation between the fragmentation of plasma cfDNA and serum levels of three inflammatory cytokines (TNFα [r = -.837], interleukin-6 [IL-6] [r = -.964], interleukin-1 receptor antagonist [IL-1ra] [r = -.911]), which were reported to associate with poor prognosis. Also, we found that the proportion of short fragments of cfDNA was significantly increased in the supernatant of peripheral blood mononuclear cells (PBMCs) from healthy controls cultured in media containing TNFα. These results supposed that cancer-associated systemic inflammation, especially tumor necrosis factor-α (TNFα), may contribute to the fragmentation of plasma cfDNA in UTUC patients.

[Usefulness of Fluorescent Urine Cytology in the Diagnosis of Urothelial Carcinoma].

Five-aminolevulinic acid, an amino acid that is metabolized in the cytoplasm to become protoporphyrin IX, is used in photodynamic diagnosis in various carcinomas because it accumulates in higher concentrations in tumor tissue than in normal tissue. 5-Aminolevulinic acid-induced fluorescent urine cytology is more sensitive than conventional urine cytology only in low grade urothelial carcinoma (UC), but it showed a tendency for higher sensitivity in high grade UC. To increase the number of patients and reconsider our previous findings, we compared the sensitivity and specificity of preoperative urine cytology and fluorescent urine cytology in 343 patients diagnosed as having UCs pathologically (215 bladder cancers, 128 upper tract UCs) and 197 non-cancer patients at Osaka Rosai Hospital from March 2013 to December 2019. The sensitivities of fluorescent urine cytology and conventional urine cytology were 81.1% and 63.3% (p<0.001), respectively, and specificities were 92.9% and 93.9% (p=0.84), respectively. The sensitivity of fluorescent urine cytology was superior to that of conventional urine cytology in both low grade UC (76.8% vs 41.1%, p<0.001) and high grade UC (83.1% vs 74.0%, p=0.023).

Complete remission of metastatic renal cell carcinoma to the bone with sunitinib.

Target agents such as tyrosine kinase inhibitors have improved renal cell carcinoma (RCC) patient outcomes. However, complete remission (CR) with target agents is rare. Furthermore, CR of bone metastasis is much less common. We report a case of CR in bone and lung metastatic RCC. Radical nephrectomy was performed first, and clear cell RCC was diagnosed. Thereafter, sunitinib was started, and bone and lung metastases resolved entirely after 8 months of treatment. Sunitinib therapy was discontinued after 2 years because of the adverse event of proteinuria. However, the patient has remained in CR for over 1 year after sunitinib cessation.

[Late Recurrence of Seminoma Diagnosed by Endoscopic Ultrasound-Guided Fine Needle Aspiration in a Retroperitoneal Lymph Node].

The patient was a 43-year-old man. At 30 years of age, he underwent high-inguinal orchiectomy for a right testicular tumor and was diagnosed with seminoma pT1N0M0. The patient had been followed without additional treatment and had dropped out 7 years after surgery. At 43 years of age, abdominal ultrasonography performed for screening revealed a swollen 4 cm-wide intra-abdominal lymph node, and he was referred to our department. Abdominal contrast-enhanced computed tomography (CT) showed a mass with a 5 cm-wide contrast effect that contacted the anterior surface of the inferior vena cava from the duodenum to the aortic bifurcation. Histological examination by trans-duodenal ultrasound-guided fineneedle aspiration suggested late recurrence of seminoma. After receiving three courses of BEP (bleomycin, etoposide, and platinum) therapy, the patient underwent laparoscopic lymphadenectomy. Pathological examination showed no residual tumor, and the patient was free of recurrence at 13 months after surgery.

High performance of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology.

OBJECTIVES: To investigate the efficacy of selective upper tract urinary cytology using extracorporeal 5-aminolevulinic acid for the diagnosis of upper urinary tract urothelial carcinoma. METHODS: We evaluated 104 patients who underwent radical nephroureterectomy and were diagnosed pathologically as having upper urinary tract urothelial carcinoma between March 2013 and May 2019 in Osaka Rosai Hospital. Preoperatively, we collected upper tract urinary cytology from both sides, and compared the sensitivity and specificity between conventional urine cytology and 5-aminolevulinic acid-induced fluorescent urine cytology. RESULTS: The sensitivity of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology was significantly higher than conventional cytology (90.4% vs 66.3%, P < 0.001), whereas the specificity was equally high (100% vs 98.2%, P = 1.0). In more detailed analysis, the sensitivity of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology was significantly higher than that of conventional cytology unrelated to patients' age (<76 years: 90.2% vs 68.6%, P = 0.013; ≥76 years: 90.6% vs 64.2%, P = 0.021), sex (male: 89.2% vs 67.5%, P = 0.001; female: 95.2% vs 61.9%, P = 0.02) or pT stage (pT1 or less: 91.4% vs 69.0%, P = 0.005; pT2 or more: 89.1% vs 63.0%, P = 0.006), tumor grade (high grade: 91.0% vs 70.5%, P = 0.002; low grade: 88.5% vs 53.8%, P = 0.013), and tended to be more efficacious for tumors that could not be detected by imaging techniques (83.3% vs 50.0%, P = 0.075). CONCLUSIONS: 5-Aminolevulinic acid-induced fluorescent selective upper tract urinary cytology is more sensitive than conventional cytology for the diagnosis of upper urinary tract urothelial carcinoma, regardless of pT stage and tumor grade.