Dose-escalated Salvage Whole-pelvic Radiotherapy for Biochemical Recurrence After Radical Prostatectomy for High-risk Prostate Cancer.

Background/Aim: To investigate the institutional experience of dose-escalated salvage whole-pelvic radiotherapy (WPRT) with the simultaneous integrated boost (SIB) technique in patients with biochemical recurrence (BCR) after radical prostatectomy for high-risk prostate cancer. Patients and Methods: This retrospective study included 21 patients with BCR who received radical prostatectomy for high-risk prostate cancer and underwent salvage RT. Clinical target volume (CTV) of the whole pelvis (CTV56) included the prostate bed, common iliac, external iliac, internal iliac, and obturator lymph node regions. The boost CTV (CTV66) included the prostate bed. Planning target volumes (PTV) were generated by adding a margin of 6-8 mm to CTV (PTV56 and PTV66). Doses of 56.1 and 66 Gy in 33 fractions were delivered to PTV56 and PTV66, respectively. Results: The 5-year biochemical progression-free survival, overall survival, and cause-specific survival rates were 72%, 94%, and 94%, respectively. A grade 3 late genitourinary toxicity event of gross hematuria was observed in one patient (4%). Acute and late toxicities of grade ≥3, other than gross hematuria, were not observed in any patient. Conclusion: Dose-escalated salvage WPRT using the SIB technique provides appropriate tumor control without increasing the incident of significant toxicities.

Predictive factors of nivolumab plus ipilimumab treatment efficacy in metastatic renal cell carcinoma patients.

OBJECTIVE: Nivolumab plus ipilimumab is a recommended first-line therapy regimen for metastatic renal cell carcinoma. However, it is not clear which patient characteristics are associated with its effectiveness. METHODS: We retrospectively examined 67 metastatic renal cell carcinoma patients treated with nivolumab plus ipilimumab as a first-line therapy in multiple institutions from September 2018 to August 2022. We analyzed the relationships between survival outcomes and patient-related variables, including paraneoplastic symptoms. We also analyzed the relationships between changes in symptoms and parameters and outcomes. RESULTS: Of the 67 patients, 32 patients had paraneoplastic symptoms. The median progression-free survival was 14.9 months and median overall survival was 43.3 months. The objective response rate was 49.25% (33 patients), including two patients with complete response. Patients with cytoreductive nephrectomy, bone metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with short progression-free survival in the univariate analysis. Multivariate analysis of these factors showed that the presence of paraneoplastic symptoms at treatment initiation remained an independent predictor of progression-free survival. Of the 32 patients with paraneoplastic symptoms at treatment initiation, 12 patients had symptomatic improvement and 20 did not. The 1-year progression-free survival rates were significantly longer in improved patients compared with those with no improvement. CONCLUSIONS: Patients without cytoreductive nephrectomy and with bone metastasis, liver metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with shorter progression-free survival. The presence of paraneoplastic symptoms was an independent predictor of progression-free survival. Improvement in paraneoplastic symptoms may reflect the treatment efficacy of nivolumab plus ipilimumab.

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.

Efficacy and Safety of Brachytherapy for Localized Prostate Cancer in Renal Transplant Recipients.

BACKGROUND: Prostate cancer is common among male renal transplant recipients and can present challenges for medical management and patient survival. It is imperative to have a comprehensive understanding of available treatment options in this population to determine the most effective and safe therapies. Brachytherapy, a safe and effective treatment for localized prostate cancer, has not been sufficiently studied in this patient population. Therefore, this study aimed to evaluate the safety and effectiveness of brachytherapy in treating prostate cancer in renal transplant recipients. METHODS: We retrospectively reviewed our brachytherapy database to identify patients with a previous history of renal transplantation who underwent seed implantation for localized prostate cancer. Long-term prostate-specific antigen control and treatment-related toxicity, including graft dysfunction and urinary and rectal complications, were assessed and compared with published outcomes. Results were analyzed to evaluate the efficacy and safety of seed implantation in this patient population. RESULTS: We identified 2 patients with previous renal transplantation who underwent permanent seed implantation for localized prostate cancer. Follow-ups ranged from 53 to 57 months, and both patients remained free of prostate-specific antigen progression with normal graft function. No acute and late complications occurred. CONCLUSION: Brachytherapy is a safe and effective treatment option for post-renal transplant prostate cancer. Given the paucity of reports on brachytherapy in this population, the findings of this study, despite a small sample size, contribute to the increasing body of evidence supporting the use of brachytherapy in this patient population.

Sarcomatoid renal cell carcinoma with an inferior vena cava tumor thrombus that was completely resected by robot-assisted laparoscopic radical nephrectomy after neoadjuvant therapy nivolumab plus ipilimumab: a case report.

We here present a patient with a sarcomatoid renal cell carcinoma complicated by inferior vena cava tumor thrombus that we treated with nivolumab plus ipilimumab. This resulted in shrinkage of the tumor, enabling complete resection by robot-assisted laparoscopic radical nephrectomy. The patient is still alive with no evidence of recurrence.

Partial penectomy for severe penile ulceration caused by cholesterol crystal embolization.

Introduction: Cholesterol crystal embolism is a rare microembolic disease caused by cholesterol crystals that can present with various symptoms after vascular surgery, catheterization, or anticoagulation therapy. We report a case of penile ulceration caused by cholesterol crystal embolism. Case presentation: A 72-year-old man undergoing maintenance dialysis for end-stage renal failure presented with penile pain and a black glans ulcer. Despite low-density lipoprotein apheresis, he was referred to our hospital because of lack of improvement. Based on his medical history and clinical presentation, including artificial vascular replacement and right toe amputation, cholesterol crystal embolism was suspected and partial penectomy was performed, thus confirming the diagnosis. Penile pain resolved after surgery, and he was discharged on Day 10. Unfortunately, he died after small bowel perforation developed 2 months after surgery. Conclusion: Penile ulcers caused by cholesterol crystal embolism may indicate the severity and progression of disease and typically require surgical intervention.

[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.

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.

Initial experience in robot-associated radical nephrectomy with inferior vena cava tumor thrombectomy.

Background: Renal cell carcinoma (RCC) is often locally invasive and may extend from the renal vein into the inferior vena cava (IVC) as a venous tumor thrombus (VTT). Radical nephrectomy with IVC tumor thrombectomy (IVC-TT) via an open approach has been shown to carry high morbidity and mortality. Recently, robot-associated radical nephrectomy (RARN) has been developed with the aim of improving the performance and outcomes of surgery for RCC with IVC-VTT. Methods: We here present four patients who had right RCC with IVC-VTT and underwent RARN with IVC-TT in Nagasaki University Hospital. All four patients had level II IVC-TT and underwent RARN with IVC-TT using a da Vinci Xi surgical system. The procedure comprised performing the Kocher maneuver, exposing the right renal artery in the aortocaval region dorsal to the left renal vein, exposing, mobilizing, and clipping the IVC, clamping and incising the IVC, and removing the kidney with the VTT en bloc. Results: The mean tumor size was 83.1 (range, 50.1-115.2) mm and the mean length of the VTT within the IVC 41.6 (range, 25.3-44.3) mm. The mean console time was 290 (range, 287-367) minutes and the mean blood loss was 200 (range, 175-260) mL and no patient required blood transfusion. Conclusions: Our initial experience of the procedure of RARN with IVC-TT for level II IVC-VTT is that it is safe and has acceptable perioperative outcomes and complications.

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.

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.

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.

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.

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.

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.