Initial experience of enfortumab vedotin in a patient with metastatic urothelial carcinoma on hemodialysis: Two case reports.

Introduction: Few studies have reported on administering enfortumab vedotin to patients with metastatic urothelial carcinoma and end-stage renal disease requiring hemodialysis. Case presentation: Case 1: An 85-year-old man underwent hemodialysis for progressive renal failure 4 months after right laparoscopic radical nephroureterectomy. Case 2: A 73-year-old man underwent hemodialysis after two laparoscopic radical nephroureterectomies for recurrent urothelial carcinoma. In both cases, enfortumab vedotin was administered due to postoperative recurrence and progression despite platinum-based chemotherapy and pembrolizumab. Partial response and disease progression were observed in cases 1 and 2, respectively. Adverse events included a mild skin rash in both patients and neutropenia in Case 1, both of which resolved with symptomatic treatment. Conclusion: The efficacy and safety of enfortumab vedotin in patients with metastatic urothelial carcinoma, and end-stage renal disease undergoing hemodialysis, were confirmed.

Relationship Between Overactive Bladder and Bone Fracture Risk in Female Patients.

BACKGROUND/AIM: Overactive bladder (OAB) has recently been recognized as an independent risk factor for falls and fractures. This study aimed to predict fracture risk in female patients with OAB symptoms. PATIENTS AND METHODS: We assessed and compared the fracture risk in newly diagnosed female patients with OAB to those without OAB using the Fracture Risk Assessment Tool (FRAX), and investigated the relationship between fracture risk and OAB severity. RESULTS: The present single-center, cross-sectional study included 177 female participants (79 with OAB, 98 without OAB). The OAB group was older (p=0.033) and shorter (p=0.010) compared to the non-OAB group. Compared to the non-OAB group, the OAB group had more patients with hypertension (p<0.001) and diabetes mellitus (p=0.011), as well as higher risks for major fractures (non-OAB group: 15.2±13.2%; OAB group: 23.6±14.1%; p<0.001) and hip fractures (non-OAB group: 6.3±11.0%; OAB group: 10.6±10.0%; p=0.007). In addition, those with moderate/severe OAB had the most significantly elevated risks for both major fractures (non-OAB group: 15.2±13.2%, mild-OAB: 17.6±12.5%, moderate/sever-OAB: 26.4±14.0%; p<0.001) and hip fractures (non-OAB group: 6.3±11.0%, mild-OAB: 6.5±7.6%, moderate/sever-OAB: 12.5±10.4%; p<0.001). Among the OAB symptoms, nocturia had the strongest correlation with fracture risk (major fracture, ρ=0.534; hip fracture, ρ=0.449; all p<0.001). CONCLUSION: Patients with severe OAB, and particularly severe nocturia, should be closely monitored with timely and aggressive symptom management; however, an interventional study incorporating the management of OAB symptoms is required to confirm whether the proactive management of OAB symptoms reduces the risk of fractures in older females.

Primary signet-ring cell carcinoma of the bladder treated with laparoscopic radical cystectomy: a case report.

Primary bladder adenocarcinomas comprise 0.5-2% of all epithelial bladder neoplasms. Of these, primary signet-ring cell carcinoma of the bladder is particularly rare, accounting for 0.24% of all bladder malignancies. This tumor is frequently diagnosed at an advanced stage and has a poor prognosis. No standard treatment has yet been established. We here report a patient in whom laparoscopic cystectomy following neoadjuvant chemotherapy was effective. Our patient was a 69-year-old man who had had microscopic hematuria, undergone transurethral resection of a mass in the bladder, and been diagnosed pathologically with a primary signet-ring cell carcinoma of the bladder. No metastases were detected on computed tomography. The patient was treated with a combination of paclitaxel, cisplatin, and gemcitabine prior to undergoing laparoscopic cystectomy. The histopathological diagnosis on this operative specimen was dysplasia and no metastases were detected in the dissected lymph nodes. Complete remission has now been maintained for 9 years.

Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model.

Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors. However, anti-carcinogenic effects of the EP receptor antagonist are unclear. In this study, we used a mouse model of PC. The mice were provided standard feed (control) or feed containing the EP1 receptor antagonist and were sacrificed at 10, 15, 30, and 52 weeks of age. Apoptosis was evaluated by immunohistochemical analysis using a cleaved caspase-3 assay. The incidence of cancer in the experimental group was significantly lower than that in the control group at 15, 30, and 52 weeks of age. The percentage of poorly differentiated PC cells was significantly lower in the experimental group than in the control group at 30 and 52 weeks of age. The percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age. These findings indicate that feeding with the addition of EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. We suggest that the EP1 receptor antagonist may be a novel chemopreventive agent for PC.

Ceruloplasmin Levels in Cancer Tissues and Urine Are Significant Biomarkers of Pathological Features and Outcome in Bladder Cancer.

BACKGROUND/AIM: A previous report showed that immune complex-ceruloplasmin (CP) in urine is associated with carcinogenesis and malignant behavior in bladder cancer (BC). We investigated the pathological significance and prognostic roles of urine and tissue levels of CP protein in BC patients. MATERIALS AND METHODS: Urine CP levels were measured using an enzyme-linked immunosorbent assay in 97 patients. CP expression in BC tissues was evaluated by immunohistochemical analysis in 176 patient samples. RESULTS: Urine CP levels were positively associated with tumor grade and pT stage in non-muscle invasive BC (NMIBC). CP expression in BC tissues was positively associated with tumor growth and progression. Multivariate analysis demonstrated that high urine CP levels was an independent predictor of recurrence in the urinary tract in NMIBC (hazard ratio=2.87, p=0.016). CONCLUSION: CP-related markers, especially urine CP levels, are useful biomarkers of malignant potential and prognosis in NMIBC.

Detection of Novel Urine Markers Using Immune Complexome Analysis in Bladder Cancer Patients: A Preliminary Study.

BACKGROUND/AIM: Little is known on urine biomarkers that are associated with malignant behavior in patients with bladder cancer (BC). Our aim was to identify BC-related factors in urine samples using our original method "immune complexome analysis", based on detecting the immune complex (IC). PATIENTS AND METHODS: Immune complexome analysis was performed using urine samples from 97 BC patients, including 67 with non-muscle invasive BC (NMIBC). RESULTS: Eight IC-antigens were recognized as candidates for BC-related factors from 20,165 proteins. IC-serum albumin, -fibrinogen γ chain, -hemoglobin subunit α, -hemoglobin subunit ß, -ceruloplasmin, and fibrinogen ß chain were significantly associated with either pathological features and/or outcome. IC-ceruloplasmin was most widely associated with pathological features in all BC patients and lamina propria invasion and urinary tract recurrence in NMIBC. CONCLUSION: Based on detection of IC-antigens it was demonstrated that six IC-antigens, especially IC-ceruloplasmin, are potential urine biomarkers in BC.

Pathological Significance and Prognostic Roles of Thrombospondin-3, 4 and 5 in Bladder Cancer.

BACKGROUND/AIM: The pathological significance of thrombospondin (TSP)-1 and -2 in bladder cancer (BC) is well-known whereas that of TSP-3, 4 and 5 remains unclear. Our aim is to clarify the pathological significance and prognostic roles of TSP-3 to 5 expression in BC patients. PATIENTS AND METHODS: TSP-3 to 5 expression, proliferation index (PI), apoptotic index (AI) and microvessel density (MVD) were evaluated in 206 BC patients by immunohistochemical techniques. RESULTS: TSP-5 expression was positively associated with grade, T stage, metastasis, and worse prognosis. PI in TSP-5-positive tissues was significantly higher compared to negative tissues. In contrast, AI in TSP-5-positive tissues was significantly lower compared to negative tissues. Expressions of TSP-3 and 4 were not associated with any clinicopathological features, survival, PI, or AI. CONCLUSION: TSP-5 plays important roles in malignant behavior via cell survival regulation whereas the pathological significance of TSP-3 and TSP-4 in BC might be minimal.

Correction: Oral Intake of Royal Jelly Has Protective Effects against Tyrosine Kinase Inhibitor-Induced Toxicity in Patients with Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled Trial. Medicines, 2019, 6, 2.

We, the authors, wish to make the following correction to our published paper [...].

Erratum: Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

[This corrects the article DOI: 10.3892/mco.2020.2099.].

Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

Molecular targeted therapies are commonly used in patients with metastatic renal cell carcinoma (RCC). However, the efficacy and safety of these therapeutic interventions require enhancement to improve prognosis in these patients. Royal jelly (RJ) has anti-cancer effects and adverse events across a variety of types of malignancy. The present study investigated the detailed mechanism underlying the effects of oral administration of RJ in patients with advanced RCC that were treated with molecular targeted agents in a randomized clinical trial. The study cohort comprised 16 patients treated with RJ and 17 patients treated with a placebo. Serum levels of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß were measured using enzyme-linked immunosorbent assays. The results of the present study demonstrated a larger decrease in tumor size upon supplementing patients with RJ following molecular targeted therapy compared with that in patients administered with the placebo. Patients exhibited reduced anorexia and fatigue in the RJ group compared with the placebo group. The relative dose intensity for patients in the RJ group was higher than that in patients in the placebo group. Post- and pre-treatment ratios of the serum levels of TNF-α and TGF-ß in patients in the RJ group were lower than those in patients in the placebo group, and these ratios correlated with decreasing tumor size and frequency of anorexia or fatigue in patients. In conclusion, the results of the present study indicated that oral intake of RJ improved the efficacy and safety of molecular targeted therapy in patients with RCC and changed the levels of TNF-α and TGF-ß in the serum of patients, which is speculated to serve an important role in RJ-induced biological activities.

Pathological roles of c-Met in bladder cancer: Association with cyclooxygenase-2, heme oxygenase-1, vascular endothelial growth factor-A and programmed death ligand 1.

c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.

Efficacy of Tadalafil Therapy and Changes in Oxidative Stress Levels in Male Patients with Lower Urinary Tract Symptoms and Overactive Bladder.

OBJECTIVE: To evaluate the effects of tadalafil monotherapy on lower urinary tract symptoms, urodynamic parameters, and oxidative stress levels in male patients. METHODS: This prospective study included 53 male patients with urinary symptoms, who met the criteria for overactive bladder (OAB) (≥ 2 points for Q3 [urgency] in the OAB symptom score [OABSS] assessment and ≥ 3 points for the total score). The patients received 5 mg tadalafil orally once daily, and their symptoms were assessed before and after the 12-week treatment. The OABSS and international prostate symptom score (IPSS) were used to evaluate the subjective symptoms. The objective findings were assessed using uroflowmetry. Oxidative stress was assessed by determining urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels with an adjustment for urinary creatinine (CR) concentration. RESULTS: After tadalafil administration, total and individual indices of the OABSS assessment showed significant improvement. In addition, total storage and voiding symptoms that contributed to the IPSS were also significantly improved. The voided volume was increased, and the maximum flow rate was improved after tadalafil treatment (P = .002 and < 0.001, respectively). Urinary 8-OHdG/CR decreased from 12.4 ± 9.7 ng/mg CR to 7.6 ± 11.6 ng/mg CR (P < .001). In patients who showed OAB improvement and did not meet the criteria for OAB after the treatment (44 patients, 83.0%), the urinary 8-OHdG/CR level was significantly decreased from 11.6 ± 8.4 ng/mg CR to 6.4 ± 10.3 ng/mg CR (P < .001). CONCLUSIONS: Tadalafil treatment improves OAB symptoms and urodynamic parameters by decreasing oxidative stress level.

Four-weekly Low-dose Gemcitabine and Paclitaxel in Patients With Platinum-resistant Urothelial Cancer and Performance Status 2/3.

BACKGROUND/AIM: Immune check-point inhibitors are often unsuitable for patients with urothelial cancer with a poor performance status (PS 2 or 3). The aim of this study was to assess the safety and usefulness of combined therapy with low-dose gemcitabine and paclitaxel every 4 weeks. PATIENTS AND METHODS: Thirty patients were treated with gemcitabine (700 mg/m2 on day 1) and paclitaxel (70 mg/m2 on day 1) every 4 weeks. The predictive value of human antigen-R (HuR) and class III ß-tubulin (TUBB3) were also analyzed. RESULTS: There was no severe adverse event nor significant decrease in quality of life. The survival period of patients treated with this regimen was significantly longer than that of those treated with best supportive care. The expression pattern of HuR negativity and TUBB3 positivity predicted significantly worse overall survival. CONCLUSION: Our regimen was suitable as second-line therapy for patients with advanced platinum-resistant UC with a poor PS. However, a HuR-negative and TUBB3-positive expression pattern appears to confer poorer outcome.

The Pathological Significance and Prognostic Roles of Thrombospondin-1, and -2, and 4N1K-peptide in Bladder Cancer.

BACKGROUND/AIM: Thrombospondins (TSPs) play a role as inhibitors of angiogenesis under various pathological conditions. The aim of the study was to evaluate the pathological significance and prognostic role of the 4N1K-peptide (KRFYVVMWKK), which is derived from TSP-1 and -2, in bladder cancer. MATERIALS AND METHODS: Two-hundred and six bladder cancer tissues were examined for expression of TSP-1, TSP-2, and 4N1K-peptide by immunohistochemistry. Cancer cell proliferation, apoptosis, angiogenesis and matrix metalloproteinase (MMP)-9 immunoreactivity were also examined. RESULTS: Expression of TSP-2 and 4N1K-peptide was negatively associated with T stage, metastasis, and grade. TSP-2 expression was negatively associated with cancer cell proliferation and MMP-9 expression, whereas 4N1K-peptide was significantly associated with apoptosis, angiogenesis, and MMP-9 expression. Multivariate analysis showed that 4N1K-peptide expression was a significant predictor of metastasis (hazard ratio=3.90, p=0.002). CONCLUSION: TSP-2 and 4N1K peptide played important roles in malignant aggressiveness and progression of bladder cancer via complex mechanisms involving cell proliferation, apoptosis, angiogenesis, and MMP-9.

[A Case of Giant Adrenal Endothelial Cyst that was Discovered in Pregnancy and Caused Bleeding Three Years Later].

A 39-year-old woman was referred to our hospital after incidental detection of a hypoechoic abdominal mass on ultrasonography at the 11th week of gestation. Magnetic resonance imaging confirmed a 20 cm cystic lesion just cephalad to the left kidney. The patient delivered in the 40th week of gestation without complications. After 3 years of follow-up, she presented with acute left flank pain. Physical examination revealed pale palpebral conjunctiva and abdominal fullness. Contrast-enhanced computed tomography confirmed a 21 × 17 × 15 cm hemorrhagic cyst arising from the left adrenal gland. Laparoscopic left adrenalectomy was performed. Pathological examination revealed a vascular cyst (endothelial cyst) of the adrenal gland. Surgical intervention is indicated for large adrenal cysts which may cause bleeding into the cavity.

Oral Intake of Royal Jelly Has Protective Effects Against Tyrosine Kinase Inhibitor-Induced Toxicity in Patients with Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Although tyrosine kinase inhibitors (TKIs) are still recommended as the standard therapy in renal cell carcinoma (RCC), the high frequency of adverse events is a weakness of this therapy. Because royal jelly (RJ) possesses anti-inflammatory and antioxidant properties, we assessed its protective effects on TKI-induced toxicities in RCC patients. Methods: We enrolled 33 patients with advanced RCC who were assigned to start TKI therapy in combination with a randomized, double-blinded, placebo-controlled RJ trial consisting of a placebo group with 17 subjects and an RJ group with 16 subjects. Results: Fatigue and anorexia frequencies in the RJ group were significantly lower than in the placebo group (p = 0.003 and 0.015, respectively). A statistically significant correlation between RJ and fatigue or anorexia was detected in sunitinib-treated patients. The dose reduction- or discontinuation-free periods were significantly longer (p = 0.013) in the RJ group than in the placebo group. Furthermore, similar observations were made in sunitinib-treated patients (p = 0.016). Conclusions: Our clinical trial showed that RJ exerted protective effects against TKI-induced fatigue and anorexia and lowered TKI dose reduction or discontinuation. Hence, RJ is beneficial for maintaining the quality of life and medication compliance in TKI-treated RCC patients.

Anticancer Effects of Green Tea and the Underlying Molecular Mechanisms in Bladder Cancer.

Green tea and green tea polyphenols (GTPs) are reported to inhibit carcinogenesis and malignant behavior in several diseases. Various in vivo and in vitro studies have shown that GTPs suppress the incidence and development of bladder cancer. However, at present, opinions concerning the anticancer effects and preventive role of green tea are conflicting. In addition, the detailed molecular mechanisms underlying the anticancer effects of green tea in bladder cancer remain unclear, as these effects are regulated by several cancer-related factors. A detailed understanding of the pathological roles and regulatory mechanisms at the molecular level is necessary for advancing treatment strategies based on green tea consumption for patients with bladder cancer. In this review, we discuss the anticancer effects of GTPs on the basis of data presented in in vitro studies in bladder cancer cell lines and in vivo studies using animal models, as well as new treatment strategies for patients with bladder cancer, based on green tea consumption. Finally, on the basis of the accumulated data and the main findings, we discuss the potential usefulness of green tea as an antibladder cancer agent and the future direction of green tea-based treatment strategies for these patients.

Pathological significance and prognostic roles of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios in clear cell renal cell carcinoma.

The immune system is closely associated with malignant behavior in renal cell carcinoma (RCC). Therefore, understanding the pathological roles of immune cells in tumor stroma is essential to discuss the pathological characteristics of RCC. In this study, the clinical significance of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios were investigated in patients with clear cell RCC. The densities of CD57+, CD68+, and mast cells were evaluated by immunohistochemical techniques in 179 patients. Proliferation index, apoptotic index, and microvessel density were evaluated by using anti-Ki-67, anti-cleaved caspase-3, and anti-CD31 antibodies, respectively. The density of CD57+ cell was negatively correlated with grade, pT stage, and metastasis, although densities of CD68+ cell and mast cell were positively correlated. Ratios of CD68+ cell/CD57+ cell and mast cell/CD57+ cell were significantly correlated with grade, pT stage, and metastasis. Survival analyses showed that the CD68+ cell/CD57+ cell ratio was a significant predictor for cause-specific survival by multivariate analyses (hazard ratio = 1.41, 95% confidence interval = 1.03-1.93, P = .031) and was significantly correlated with proliferation index, apoptotic index, and microvessel density (r = .47, P <. 001; r = -.31, P < .001; and r = .40, P < .001, respectively). In conclusion, CD57+ cells, CD68+ cells, and mast cells played important roles in malignancy in clear cell RCC. The CD68+ cell/CD57+ cell ratio was strongly correlated with pathological features and prognosis in these patients because this ratio reflected the status of cancer cell proliferation, apoptosis, and angiogenesis.