[Clinical Outcome of Surgical Resection for Renal Cell Carcinoma with Inferior Vena Cava Tumor Thrombus].

We analyzed 45 patients who were diagnosed with renal cell carcinoma with inferior vena cava tumor thrombus (IVC) and underwent surgical resection at Nagasaki University Hospital during the 17 years from March 2003 to November 2020. The median overall survival (OS) was 68.5, 53.5, 45.7, and 20.4 months, respectively, according to the tumor thrombus level (Lv) of I, II, III and IV, with a median level of (P＝0.025). In multivariate analysis, pathological sarcomatoid changes were associated with risk of tumor recurrence in the postoperative complete remission group, and IVC thrombus level above Lv III was associated with poor prognosis in the postoperative incomplete remission group. On postoperative systemic treatment for the postoperative recurrence group and the incomplete remission group, overall survival was significantly prolonged in cases using immune checkpoint inhibitors. The results of surgical treatment of renal cell carcinoma with IVC tumor embolization were analyzed. Patients who underwent surgical resection and achieved postoperative complete remission had a relatively long prognosis with a median OS of more than 6 years. In contrast, patients with metastases, especially those with postoperative incomplete remission group, had a poor prognosis despite surgical resection, depending on the patient's situation.

[A Retrospective Study on the Malignancies after Renal Transplantation].

Detection of post-transplant malignant tumors and the analysis of the associated risk factors is important for monitoring the progress after renal transplantation. In this study, we retrospectively examined the medical records of 298 patients who underwent renal transplantation at two facilities in Nagasaki Prefecture (Nagasaki University Hospital and National Hospital Organization Nagasaki Medical Center). Of the 298 patients, 45 (15.1%) patients had developed malignant tumors with 50 lesions. The most common type of malignant tumor was skin cancer (eight patients; 17.8%), followed by renal cancer (six patients; 13.3%), and pancreatic cancer and colorectal cancer, (four patients; 9.0% each). Five patients (11.1%) had multiple cancers, four of whom had skin cancer. The cumulative incidence within 10 and 20 years after renal transplantation was 6.0 and 17.9%, respectively. Univariate analysis identified age at transplantation and administration of cyclosporine and rituximab as risk factors, while multivariate analysis identified age at transplantation and administration of rituximab as independent factors. The administration of rituximab was associated with the development of malignant tumors. However, further investigation is required to establish the association with post-transplant malignant neoplasms.

Pathological Significance of Kidney and Brain Expressed Protein (KIBRA) in Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIM: Kidney and brain expressed protein (KIBRA), a member of the WW domain-containing protein family, has an important role in tumour growth and progression in various cancers. However, the pathological significance of KIBRA expression in clear cell renal cell carcinoma (ccRCC) tissues is not fully understood. The aim of this study was to clarify the pathological significance and prognostic roles of KIBRA expression in patients with ccRCC. MATERIALS AND METHODS: KIBRA immunoreactivity, proliferation index (PI; with anti-Ki-67 antibody), apoptotic index (AI; using anti-cleaved caspase-3), and large tumour suppressor kinases (LATS-2) were evaluated in 157 ccRCC specimens by immunohistochemistry. Fifty normal kidney tissues were also evaluated as controls. The relationships between KIBRA expression and these cancer-related variables as well as clinicopathological features and survival were analysed. RESULTS: Moderate to strong immunoreactivity of KIBRA was identified in all normal kidney tissues; however, ccRCC cells with strong KIBRA expression was rare. The immunoreactivity score (IRS) of KIBRA was negatively associated with grade, T stage, tumour diameter, and metastasis. Kaplan-Meier survival curves showed that high KIBRA expression was a favourite predictor for overall survival. KIBRA IRS was negatively associated with PI and positively associated with the IRS of LATS-2 by univariate analysis. In addition, multivariate analysis showed that KIBRA was significantly associated with PI. CONCLUSION: KIBRA demonstrated important roles as a tumour suppressor in ccRCC. In addition, its expression was significantly associated with survival in these patients. Several such KIBRA-related functions were speculated to be modulated by cancer cell proliferation and LATS-2.

Impact of Mirabegron Administration on the Blood Pressure and Pulse Rate in Patients with Overactive Bladder.

Background and Objectives: To determine changes in the blood pressure (BP) and pulse rate (PR) before and after the administration of mirabegron in real-world clinical practice for patients with overactive bladder (OAB). Materials and Methods: This study was conducted in patients newly diagnosed with OAB. Before and 12 weeks after mirabegron treatment, we evaluated the effects on BP and PR. An overall examination was conducted, and the patients were divided into two groups according to their age: a young group (<65 years old) and an old group (≥65 years old). Results: A total of 263 patients were enrolled in this study. In the overall and intragroup comparisons, the systolic BP (SBP) did not change significantly after mirabegron administration. However, an increase in SBP of ≥10 mmHg was observed in 53 (20.2%), 4 (7.4%), and 49 (23.4%) in the entire group, young group, and old group, respectively (p = 0.009). Regarding diastolic BP, a significant decrease after the treatment was detected in entire (71.2 ± 11.4 versus 69.8 ± 10.7 mmHg; p = 0.041) and old patients (71.5 ± 10.6 versus 69.5 ± 10.2 mmHg; p = 0.012). There was no significant change in PR in our study population. Further examination using a propensity match score revealed that age was the risk factor for the increase in SBP after mirabegron administration. Conclusions: Mirabegron does not have any adverse effects on BP and PR. However, since some patients in this study had elevated SBP after administration, we suggest regular BP monitoring during mirabegron treatment.

Effects of ß3 Agonists and Anticholinergic Drugs on Defecation in Patients With Overactive Bladder.

BACKGROUND/AIM: In clinical practice, constipation is one of the most frequent adverse events caused by drugs for overactive bladder (OAB). The occurrence of constipation greatly deteriorates the patient's quality of life. The aim of the study was to evaluate and compare the effects of three commonly used ß3 agonists and anticholinergic drugs on the defecation status in patients with OAB. PATIENTS AND METHODS: We retrospectively reviewed the defecation status in patients who received mirabegron, solifenacin, or fesoterodine for OAB. We evaluated changes in the (a) urological parameters using the OAB symptom score (OABSS) and (b) defecation status using the Bristol Stool Form Scale (BSFS) and constipation scoring system (CSS) following 12 weeks of drug administration. RESULTS: We analyzed data from 165 patients (mirabegron=56, fesoterodine=52, and solifenacin=57). The solifenacin group showed a significant decrease in BSFS (from 3.2±1.0 at baseline to 2.3±12 post-treatment) and an increase in hardened stools (p<0.001). Elimination worsened as assessed by almost all items, and the total modified CSS scores worsened significantly from 4.8±2.6 points at baseline to 8.O±4.8 points after 12 weeks of solifenacin treatment (p<0.001). The mirabegron group showed no changes in any of the CSS items. In the fesoterodine group, the CSS scores for "completeness" and "assistance" increased significantly after treatment (p<0.001 and p=0.013, respectively). CONCLUSION: All three drugs were effective for OAB. Mirabegron had almost no effect on constipation; fesoterodine, an anticholinergic drug, also had hardly any effect on defecation.

Preservation of Split Renal Function After Laparoscopic and Robot-assisted Partial Nephrectomy.

BACKGROUND/AIM: To analyze the effects of laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN) for the treatment of renal cell carcinoma (RCC) on subsequent split renal function using renal scintigraphy. PATIENTS AND METHODS: We retrospectively analyzed data from 174 patients who underwent LPN or RAPN by a single surgeon, and assessed their total and split renal function before and 6 months after each procedure. Split renal function was analyzed using 99mTc-2,3 dimercaptosuccinic acid renal imaging and calculated as the total estimated glomerular filtration rate (eGFR) × uptake ratio on the surgical side/uptake ratio on the contralateral side. RESULTS: LPN or RAPN were performed in 51 (29.3%) and 123 (70.7%) participants, respectively. Their median eGFRs before and after surgery were 32.76 and 27.74 ml/min/1.73 m2, respectively, and 70 of them (40.2%) showed a preservation of split eGFR of >90%, which was used to define a successful procedure. Participants who underwent a successful procedure had significantly lower RENAL nephrometry scoring system (RNS) scores and fewer of them had external tumors. Successful procedures were associated with shorter warm ischemia time, were more likely to be RAPN, and less likely to involve parenchymal suturing. Multivariate analysis showed that a low RNS score and parenchymal suturing were significant independent predictors of split renal function following partial nephrectomy (PN). CONCLUSION: Preoperative RNS score and the use of parenchymal suturing are significantly associated with a preservation of split renal function of >90% in patients who undergo PN for the treatment of RCC.

Preoperative Predictors of Lymph Node Invasion and Biochemical Recurrence in High-risk Prostate Cancer.

Aim: To evaluate the preoperative predictors of pathological lymph node (LN) metastasis and prognostic factors for postoperative biochemical recurrence (BCR) in robot-assisted radical prostatectomy with extended pelvic LN dissection in patients with D'Amico high-risk prostate cancer (PCa). Patients and Methods: Overall, 107 patients with D'Amico high-risk PCa underwent robot-assisted radical prostatectomy with extended pelvic LN dissection without neoadjuvant or adjuvant therapy. BCR was defined as a prostate-specific antigen (PSA) level ≥0.2 ng/ml. Moreover, BCR-free survival rates were determined using Kaplan-Meier analysis. Logistic regression analysis was used to evaluate preoperative predictors of pathological LN metastasis. Cox regression analysis was used to evaluate the effects of preoperative and pathologic variables on BCR. Results: The median follow-up was 21 months, and the 5-year BCR-free survival rate was 59.8%. The positive LN rate was 21.5%. In multivariate analysis, the percentage of positive cores was a significant preoperative predictor of positive LNs. Patients with >50% positive cores (p=0.004) and PSA density (PSAD) >0.5 ng/ml/cc (p=0.005) had a high risk of having ≥3 positive LNs. In multivariate analysis, PSAD >0.5% was a significant preoperative predictor of BCR. Among the postoperative predictors, the number of positive LNs was significantly associated with BCR. Patients with ≥3 positive LNs (n=7) had significantly lower BCR-free survival rates than patients with one or two positive LNs (n=16) (p<0.001). Patients with >50% positive cores and PSAD >0.5 ng/ml/cc had a risk for a high number of positive LNs (≥3) that was strongly associated with shorter BCR-free survival (p<0.001). Conclusion: The percentage of positive cores may be useful as a preoperative predictor of pathological LN metastasis in patients with high-risk PCa. Patients with >50% positive cores and PSAD >0.5 ng/ml/cc were found to have a high risk for ≥3 positive LNs and shorter BCR-free survival.

Pathological Significance and Prognostic Role of WWC1 in Upper Urinary Tract Urothelial Cancer.

BACKGROUND/AIM: WW and C2 domain-containing 1 (WWC1) protein is a suppressor of malignancies. However, there is no information on the pathological significance of WWC1 in upper urinary tract cancer (UTUC). PATIENTS AND METHODS: In this study, WWC1 immunoreactivity was investigated in 152 non-metastatic UTUC samples. The relationships between WWC1 expression and grade, pT stage, proliferative index (using an antibody to Ki-67), and the immunohistochemical expression of matrix metalloproteinase (MMP)-2 and -9 were evaluated. RESULTS: WWC1 expression was negatively associated with tumor grade and pT stage (p<0.001). Positive expression of WWC1 was a better predictor of the UTUC recurrence and subsequent metastasis, and the multivariate analysis showed that WWC1 expression was a significant predictor of subsequent metastasis (hazard ratio=0.29, p=0.020). WWC1 expression inversely correlated with the proliferative index (odds ratio=2.59, p=0.023) and expression of MMP9 (odds ratio=2.19, p=0.040) but not with MMP2 expression, by multivariate analyses. CONCLUSION: WWC1 expression was negatively associated with malignant aggressiveness via the suppression of cancer cell proliferation and MMP9 expression in patients with UTUC. This suggests WWC1 to be a useful predictor and novel therapeutic target in patients with UTUC.

Relationship between Urinary Calcium Excretion and Lower Urinary Tract Symptoms.

To date, few detailed studies have been conducted on the convenient and useful markers for the prevalence of lower urinary tract symptoms (LUTS), including overactive bladder (OAB) and nocturia. A high level of calcium (Ca) excretion (hypercalciuria) is indicative of lifestyle-related diseases such as hypertension, which are associated with the onset of LUTS. Hence, in this study we attempted to clarify the relationship between urinary Ca excretion and OAB, nocturia, and nocturnal polyuria in adults. The present study showed that patients with hypercalciuria frequently experienced OAB, nocturia, and nocturnal polyuria. In addition, this study revealed that the severity of LUTS is significantly associated with urinary Ca excretion and that hypercalciuria is an important risk factor for OAB, nocturia, and nocturnal polyuria.

Escherichia coli ST131 isolated from urological patients can acquire plasmid-mediated extended spectrum ß-lactamase from other bacteria with high frequency.

OBJECTIVES: To investigate the prevalence of the clonal group Escherichia coli ST131 in urologic patients, and to clarify the mechanisms underlying the high prevalence of the antimicrobial resistant genes in ST131. METHODS: We used 65 Escherichia coli strains collected from the Department of Urology, Nagasaki University Hospital, between January 2018 and December 2018. All of them underwent multilocus sequence typing and were analyzed for genes associated with quinolone resistance and extended-spectrum ß-lactamases. To compare ST131 and non-ST131 strains, bacterial conjugation experiments and intestinal colonization evaluations were performed. RESULTS: ST131 was the most dominant among all the strains, along with levofloxacin resistant strains, and extended-spectrum ß-lactamases positive strains (32%, 63%, and 73%, respectively). 12 out of 15 extended-spectrum ß-lactamases-producing Escherichia coli strains harbored CTX-M-9. In particular, all extended-spectrum ß-lactamases-producing ST131 strains possessed CTX-M-9. The proportions of ST131 strains with or without quinolone resistance-determining region mutations were significantly higher and lower, respectively, than that of non-ST131 strains (P = 0.0002 and P < 0.0001, respectively). When Klebsiella pneumoniae was used as a donor, three ST131 strains acquired extended-spectrum ß-lactamases a total of 16 times (six, four, and six times each), which was significantly more than that in one of the non-ST131 strains (two times). The amount of bacteria was significantly lower in the ST131 strains than in the non-ST131 strains administered to mice. Both the ST131 and non-ST131 strains increased again after the administration of vancomycin, even after the colony was not detected. CONCLUSIONS: These results support the mechanisms underlying the prevalence of ST131 strains in hospitals, particularly in urologic patients.

Evaluation of the Influence of a History of Childhood Nocturnal Enuresis on Nighttime Urinary Frequency and the Causes of Nocturia in Adults.

OBJECTIVE: To examine whether a history of nocturnal enuresis affects nighttime urinary frequency and to evaluate nocturia etiologies in adults. MATERIALS AND METHODS: A total of 143 participants with at least one episode of nocturia per night were included in this study. The self-reported questionnaire collected data on demographic characteristics, medical history, history of nocturnal enuresis in elementary school, lower urinary tract symptoms, and frequency-volume charts. RESULTS: A history of nocturnal enuresis was observed in 52.4% of participants. However, night-time urinary frequency was significantly lower in participants with a history of nocturnal enuresis in elementary school than in those without such history. On multivariate analysis, a history of nocturnal enuresis was also negatively associated with nighttime urinary frequency (P <.01). There was a collinearity effect between age and nighttime urinary frequency. A history of nocturnal enuresis did not affect the presence of nocturnal polyuria or overactive bladder in participants. However, sleep disturbances were fewer in participants with a history of nocturnal enuresis (odds ratio 0.404). CONCLUSION: A history of nocturnal enuresis might be negatively associated with nighttime urinary frequency due to fewer sleep disturbances. Further, progression of nocturia may depend on conditions, such as age and acquired diseases.

Alternative Treatment with Every-Other-Day Dosing of Sunitinib for Metastatic Renal Cell Carcinoma: Extended Follow-Up.

INTRODUCTION: We investigated the efficacy and safety of every-other-day dosing of sunitinib for the treatment of metastatic renal cell carcinoma (mRCC) with extended follow-up and the impact of immune checkpoint inhibitor (ICI) drugs. METHODS: Thirty-two patients received standard dosing treatment (standard group), and 32 received every-other-day treatment (experimental group). Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate. We also analyzed the clinical course of patients treated with nivolumab after sunitinib. RESULTS: The minimum follow-up was 42 months. Median PFS and OS were significantly longer in the experimental group compared with the standard group (27.6 vs. 6.2 and 87.1 vs. 24.6 months, respectively). The incidence of dose interruption of sunitinib caused by adverse events was significantly lower in the experimental group than in the standard group (28.1% vs. 56.3%, p = 0.042). Multivariate analysis showed that every-other-day dosing was a significant independent prognostic factor (p = 0.038), although nivolumab use was not (p = 0.232). Twelve patients were treated with nivolumab after sunitinib, and patients who did not respond to nivolumab tended to respond to pretreatment sunitinib for a long period. DISCUSSION/CONCLUSION: Long-term follow-up confirmed the efficacy and safety of every-other-day dosing of sunitinib for mRCC patients in the ICI era.

Intravesical mitomycin C (MMC) and MMC + cytosine arabinoside for non-muscle-invasive bladder cancer: a randomised clinical trial.

OBJECTIVES: To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy. PATIENTS AND METHODS: A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups. RESULTS: A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18-0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara-C groups, respectively, without a significant difference (P = 0.113). CONCLUSIONS: Our randomised clinical trial suggested that intravesical therapy with MMC and Ara-C is useful and safe for patients with intermediate-risk NMIBC. Increase in urinary pH with Ara-C is speculated as a mechanism for increased anti-cancer effects.

[Renal Cell Carcinomas in Patients on Chronic Dialysis].

Patients on chronic dialysis for end-stage renal disease (ESRD) show an increased incidence of renal cell carcinoma (RCC). We investigated the clinicopathological characteristics and outcomes of 54 patients who underwent nephrectomy for RCC due to ESRD between 1992 and 2019. The patients consisted of 44 men and 10 women, with a median age of 62.9 years. The median duration of dialysis before surgery was 12.9 years. The clinical stage of the 54 RCCs was stage I in 44, stage II in 1, stage III in 1, and stage IV in 8. With a median follow-up of 5.1 years after surgery, the 5-year cancer-specific and overall survival rates were 84.3 and 61.8%, respectively. Patients with symptomatic RCC had a longer period of dialysis, presented with larger tumors of higher grade and stage, and had worse prognosis compared with those with incidentally discovered RCC. Cox proportional hazards analysis performed with clinicopathological features and symptomatic/incidental detection showed that older age and symptomatic RCC were independently associated with worse overall survival. Our data show that early detection is important for a good prognosis.

Effect of oral intake of royal jelly on endothelium function in hemodialysis patients: study protocol for multicenter, double-blind, randomized control trial.

BACKGROUND: Hemodialysis (HD) is a common renal replacement therapy for patients with renal failure. Cardiovascular and cerebrovascular diseases are known to shorten survival periods and worsen the quality of life of HD patients. Atherosclerosis is a major cause of vascular diseases, and various factors such as abnormality of lipid metabolism and increased macrophage activity, oxidative stress, and endothelial dysfunction are associated with its pathogenesis and progression. Further, endothelial stem cells (ESCs) have been reported to play important roles in endothelial functions. Royal jelly (RJ) affects atherosclerosis- and endothelial function-related factors. The main aim of this trial is to investigate whether oral intake of RJ can maintain endothelial function in HD patients. In addition, the effects of RJ intake on atherosclerosis, ESC count, inflammation, and oxidative stress will be analyzed. METHODS: This will be a multicenter, prospective, double-blind, randomized controlled trial. We will enroll 270 participants at Nagasaki Jin Hospital, Shinzato Clinic Urakami, and Maeda Clinic, Japan. The participants will be randomized into RJ and placebo groups. The trial will be conducted according to the principles of the Declaration of Helsinki, and all participants will be required to provide written informed consent. The RJ group will be treated with 3600 mg/day of RJ for 24 months, and the placebo group will be treated with starch for 24 months. The primary endpoint will be the change in flow-mediated dilation (FMD), a parameter of endothelium function, from the time before treatment initiation to 24 months after treatment initiation. The secondary and other endpoints will be changes in FMD; ESC count; serum levels of vascular endothelial cell growth factor, macrophage colony-stimulating factor, 8-hydroxydeoxyguanosine, and malondialdehyde; the incidence of cardiovascular diseases, cerebrovascular diseases, and stenosis of blood access; and safety. DISCUSSION: This trial will clarify whether oral intake of RJ can maintain endothelial function and suppress the progression of atherosclerosis in HD patients. In addition, it will clarify the effects of RJ on ESCs, oxidative stress, and angiogenic activity in blood samples. TRIAL REGISTRATION: The Japan Registry of Clinical Trials  jRCTs071200031 .  Registered on 7 December 2020.

Pathological Significance of Macrophages in Erectile Dysfunction Including Peyronie's Disease.

Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many factors, such as fibrosis, lipid metabolism abnormalities, the immune system, and stem cells, play crucial roles in the etiology and development of ED. Although phosphodiesterase type 5 (PDE5) inhibitors are currently the standard treatment agents for patients with ED, they are effective only in a subgroup of patients. Therefore, further insight into the pathological mechanism underlying ED is needed to discuss ED treatment strategies. In this review, we focused on the biological and pathological significance of macrophages in ED because the interaction of macrophages with ED-related mechanisms have not been well explored, despite their important roles in vasculogenic and neurogenic diseases. Furthermore, we examined the pathological significance of macrophages in Peyronie's disease (PD), a cause of ED characterized by penile deformation (visible curvature) during erection and pain. Although microinjury and the subsequent abnormal healing process of the tunica albuginea are known to be important processes in this disease, the detailed etiology and pathophysiology of PD are not fully understood. This is the first review on the pathological role of macrophages in PD.