[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.

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.

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.

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.

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.

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.

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial.

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.

Pathological significance and prognostic role of LATS2 in prostate cancer.

BACKGROUND: Large tumor suppressor 2 (LATS2) is an important regulator of the Hippo pathway and it plays crucial roles in cell survival and behaviors. Herein, we evaluated the pathological roles of LATS2 in prostate cancer (PC), for which very little information is available. METHODS: Cell proliferation, migration, and invasion in response to the siRNA-mediated knockdown (KD) LATS2 expression were evaluated in two PC cell lines (LNCaP and PC3). The expression of LATS2 in specimens from 204 PC patients was investigated immunohistochemically, and the relationships between its expression and clinicopathological features, proliferation index (PI; measured using an anti-KI-67 antibody), and biochemical recurrence (BCR) were investigated. RESULTS: KD of LATS2 increased the growth, migration, and invasion in LNCaP cells and only increased migration in PC3 cells. The expression of LATS2 was negatively associated with the grade group, T, N, M stage, and PI. In addition, the expression of LATS2 was a useful predictor of the histological effects of neoadjuvant hormonal therapy and BCR-free survival periods. A multivariate analysis model including clinicopathological features showed that negative expression of LATS2 had a significantly higher risk of BCR (odds ratio = 2.95, P < 0.001). CONCLUSIONS: LATS2 acts as a tumor suppressor in PC. LATS2 expression is a useful predictor for BCR. LATS2-related activities are possibly dependent on the androgen-dependency of PC cells. Therefore, we suggest that LATS2 could be a potential therapeutic target and a useful predictor for outcome in patients with PC.

Pathological Roles of Prostaglandin E2-specific E-type Prostanoid Receptors in Hormone-sensitive and Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Prostaglandin (PG) E2 mediates malignant aggressiveness by binding to four specific E-type prostanoid receptors (EP1R - 4R). This study aimed to clarify the pathological significance of EPRs in hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: EP1R - 4R expression was examined in 102 HSPC and 27 CRPC specimens. The relationships between their expression and proliferation index (PI), apoptotic index (AI), and vascular endothelial growth factor (VEGF)-A expression were analyzed. RESULTS: EP4R expression in CRPC was significantly higher compared to that in HSPC, even in advanced disease (T3/4, N1, and/or M1). EP4R expression was significantly correlated with PI, AI, and VEGF-A expression in CRPC. Such significant relationships were not detected between EP1R - 3R and CRPC. CONCLUSION: EP4R expression in CRPC was significantly higher than that in HSPC and was associated with cancer cell proliferation, apoptosis, and pro-angiogenetic potential.

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.

Intravesical injection of onabotulinumtoxinA in neurogenic overactive bladder patients with human T-cell leukemia virus type 1-associated myelopathy: A single-institution case series.

INTRODUCTION: Neurogenic overactive bladder is a main feature of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis. We successfully performed intravesical onabotulinumtoxinA therapy for refractory neurogenic overactive bladder due to human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis. CASE PRESENTATION: We retrospectively reviewed four neurogenic overactive bladder patients with human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis who underwent bladder wall injections of onabotulinumtoxinA from April to October 2020. All patients were female. Their median age was 66 (range, 63-71) years. They were previously treated with ß3-adrenergic receptor agonists or anticholinergic drugs alone or in combination for ≥12 weeks. However, insufficient results were obtained. After 4 weeks of intravesical onabotulinumtoxinA therapy, overactive bladder symptoms improved and maximum cystometric capacity increased in all cases. CONCLUSION: Intravesical onabotulinumtoxinA therapy may be useful for treating refractory overactive bladder due to human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis.

Stage-specific Embryogenic Antigen-4 Expression in Castration-resistant Prostate Cancer and its Correlation With the Androgen Receptor.

BACKGROUND/AIM: Stage-specific embryonic antigen (SSEA)-4 plays important roles in the malignant aggressiveness of various cancers. The aim of this study was to investigate the pathological characteristics of SSEA-4 in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: SSEA-4 expression and its pathological roles were evaluated in five prostate cancer (PC) cell lines and 27 CRPC tissues. The relationship between SSEA-4 and the androgen receptor (AR) was also examined. RESULTS: SSEA-4 expression was detected in AR-negative cells (PC3, DU145, and AICaP1) but was not detected in AR-positive cells (LNCaP and AICaP2). SSEA-4 expression in human CRPC tissues was significantly higher than that in locally advanced or metastatic hormone sensitive PC (HSPC) tissues. A negative correlation was also detected between SSEA-4 and AR in CRPC tissues but not in HSPC tissues. CONCLUSION: SSEA-4 was over-expressed in CRPC and the changes were mediated by complex mechanisms that related to the AR and hormonal therapy.

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.

Efficacy of propiverine hydrochloride for urinary incontinence after robot-assisted or laparoscopic radical prostatectomy.

INTRODUCTION: To clarify the efficacy and safety of propiverine hydrochloride for incontinence after robot-assisted laparoscopic prostatectomy (RALP)/laparoscopic radical prostatectomy (LRP), along with changes in the urethral pressure profile (UPP) and quality of life in patients treated with propiverine hydrochloride. MATERIALS AND METHODS: In this randomized, comparative study, 104 patients who were aware of urinary incontinence after RALP or LRP were assigned to receive propiverine hydrochloride (treatment group) or not (controls). Pad test results, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores, and UPP results [including maximum urethral closure pressure (MUCP) and functional urethral length (FUL)], were recorded immediately and at 6 months postoperatively. RESULTS: No serious intraoperative complications or adverse events were caused by propiverine hydrochloride. The pad-test negative rate was significantly greater in the treatment group than in controls (89.1% vs. 73.2%, p = 0.044). Changes in ICIQ-SF scores and MUCP were significantly greater in the treatment group than in controls [-6.5 vs. -4.5 points (p = 0.021), and +49.5 vs. +28.7 mmHg (p = 0.038), respectively]. FUL change did not significantly differ between groups [+4.5 vs. +3.8 mm (p = 0.091)]. In univariate logistic regression analyses, body mass index (BMI), MUCP, and treatment with propiverine hydrochloride were significantly associated with continence status. In multivariate analyses, BMI and MUCP were independently associated with continence status [odds ratio (OR), 1.266; 95% confidence interval (CI), 1.047-1.530 (p = 0.015), and OR, 0.986; 95% CI, 0.973-0.999 (p = 0.042), respectively]. CONCLUSIONS: Treatment with propiverine hydrochloride alleviated urinary incontinence while improving patient symptoms and quality of life after RALP or LRP.