Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Preoperative Immunonutrition Significantly Reduced Surgical Site Infection After Urinary Diversion for Invasive Bladder Cancer: A Retrospective Cohort Study.

BACKGROUND: Radical cystectomy and ileal conduit have a high incidence of surgical site infection. In this study, we evaluated the effects of preoperative immunonutrition on its incidence following these procedures. MATERIALS AND METHODS: We retrospectively enrolled 86 patients who underwent radical cystectomy and ileal conduit at our hospital between 2014 October and 2021 July. They were sequentially divided into the Immunonutrition group (n = 43) and Control group (n = 43). Patients in the Immunonutrition group drank 4 packs of IMPACT (Nestle, Japan) per day for 5 days before surgery. IMPACT contains arginine and eicosapentaenoic acid. We compared levels of plasma arginine and eicosapentaenoic acid before and after surgery and the rate of surgical site infection between the groups. Factors related to surgical site infection were analyzed using univariate and multivariable logistic regression analysis. RESULTS: No statistically significant differences were observed in patient characteristics between the groups except for surgical operative method (P < .001) and transfusion (P = .009). Levels of plasma arginine and eicosapentaenoic acid were significantly increased the day before surgery in the immunonutrition group (P < .001). However, the levels of plasma arginine on the day after surgery did not vary significantly between the groups. The incidence of surgical site infection was significantly lower in the immunonutrition group (P = .014). Multivariate analyses showed a significant association of surgical site infection with immunonutrition (OR = 0.14, CI 0.03-0.72, P = .019) and with ASA classification (OR = 4.76, CI 1.23-18.40, P = .024). CONCLUSIONS: Preoperative immunonutrition significantly reduced the incidence of surgical site infection following radical cystectomy and ileal conduit.

A comparative study on nivolumab and axitinib as secondary treatment in patients with metastatic renal cell carcinoma: A multi-institutional retrospective study in Japan.

OBJECTIVES: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. METHODS: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. RESULTS: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression-free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. CONCLUSIONS: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC.

Real-world efficacy and safety of nivolumab plus ipilimumab in untreated metastatic renal cell carcinoma, and the impact of previous nephrectomy on clinical outcome: Japanese multi-institutional retrospective study.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

Pilot study of an artificial intelligence-based deep learning algorithm to predict time to castration-resistant prostate cancer for metastatic hormone-naïve prostate cancer.

The object in this study is to develop an artificial intelligence-based deep learning algorithm for prediction of time to castration-resistant prostate cancer by combined androgen blockade therapy in metastatic hormone-naïve prostate cancer. We included 180 metastatic hormone-naïve prostate cancer patients who initially received combined androgen blockade. We first evaluated whether time to castration-resistant prostate cancer was a significant prognostic factor. Then, using the patients' needle-biopsy specimen images, we developed and validated our deep learning algorithm. The results are shown below. First, we confirmed that time to castration-resistant prostate cancer correlated with overall survival (P < 0.001). Next, we selected two groups by time to castration-resistant prostate cancer of >24 months (n = 18) and <6 months (n = 6) and developed a deep learning algorithm by artificial intelligence-based machine deep learning. In 16 other metastatic hormone-naïve prostate cancer patients used as an external validation set, we confirmed the prediction accuracy remained significant (P < 0.05). In conclusion, our obtained deep learning algorithm has high predictive ability for the effectiveness of combined androgen blockade.

A case of long-term complete remission of locally advanced T4 bladder cancer treated with pembrolizumab.

A 69-year-old man with a history of non-muscle invasive bladder cancer 12 years ago presented complaining of gross hematuria. He was diagnosed as having invasive T4 bladder cancer with invasion to a branch of the internal iliac artery and received platinum-based chemo-radiation therapy. However, the tumor progressed to extensively infiltrate the pelvic wall, and left leg pain and swelling developed. Pembrolizumab was started, which entirely resolved the tumor after 14 courses of treatment. Pembrolizumab was discontinued after 20 courses of treatment because of adverse events. However, the patient has remained in complete response for over 2 years after pembrolizumab cessation.

Recurrent urinary retention due to clots caused by a congenital renal arteriovenous malformation that forms a complex vascular network: Report of two cases.

INTRODUCTION: Repeated urinary retention due to clots caused by congenital renal arteriovenous malformation is rare. CASE PRESENTATION: A 40-year-old woman (case 1) and a 66-year-old man (case 2) experienced recurrent urinary retention due to clots. Neither patient had a history of renal trauma nor was taking any medications. Contrast-enhanced abdominal computed tomography revealed a large hematoma in the renal pelvis and ureter with no masses, stones, or vascular lesions and only dilated blood vessels in the arterial phase in case 1. Angiography of the kidney in both patients revealed an arteriovenous malformation, and embolization of the arteries feeding the arteriovenous malformation was performed. Soon after embolization, hematuria disappeared completely with no recurrence for 5 years in case 1 and 2 years in case 2. CONCLUSION: Congenital renal arteriovenous malformation should be considered as a cause of recurrent clot retention, and angiographic embolization of the feeding arteries can be an effective treatment.

Real-world Outcomes of Tyrosine Kinase Inhibitors Immediately After Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit for patients with cancer. However, the clinical outcomes of subsequent tyrosine kinase inhibitors (TKIs) after ICI failure in patients with metastatic renal cell carcinoma (mRCC) remain unclear. PATIENTS AND METHODS: We retrospectively examined 38 patients with mRCC who started TKIs immediately after nivolumab with (combination group) or without ipilimumab (nivolumab group) between September 2016 and July 2019. RESULTS: Of the 38 patients, 16 and 11 achieved partial response and stable disease, respectively, resulting in a 42.1% objective response rate and 71.1% disease control rate. The median progression-free survival (PFS) from TKI initiation was 8.8 and 12.9 months in the nivolumab and combination groups, respectively. PFS and overall survival were significantly longer in patients with long-term responses to previous ICI treatment (p=0.0152 and p=0.0155, respectively). CONCLUSION: TKIs demonstrate adequate anti-tumour activity after treatment with ICIs in real-world settings.

The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study.

BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were correlated with favorable clinical outcome in patients with melanoma. However, in metastatic renal cell carcinoma (mRCC) patients, there have been few reports about the correlation between irAEs and clinical efficacy of anti-programmed cell death protein-1 (PD-1) therapy. METHODS: We retrospectively investigated 160 mRCC patients who started nivolumab monotherapy between September 2016 and July 2019. IrAEs were defined as patients' AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy. We compared the data of patients who received nivolumab into two groups based on the occurrence of irAEs and assessed clinical efficacy in both groups. RESULTS: Of all mRCC patients, 47 patients (29.4%) developed irAEs. In patients who developed irAEs, the objective response rate and disease control rate were 38.8% and 77.6%, which were significantly higher when compared to that in patients without irAEs (p = 0.012 and p < 0.001, respectively). Furthermore, the incidence of irAEs was significantly associated with an increase in progression-free survival (PFS) [Hazard ratio (HR) = 0.4867; p = 0.0006] and overall survival (OS) (HR = 0.526; p = 0.0252). Importantly, PFS and OS seemed to be similar in patients who discontinued treatment because of irAEs and in those who did not discontinue because of irAEs (p = 0.36 and p = 0.35, respectively). CONCLUSION: Development of irAEs strongly correlates with clinical benefit for mRCC patients receiving nivolumab monotherapy in real-world settings.

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

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

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

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

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

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

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

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

Renal cell carcinoma in a horseshoe kidney treated with robot-assisted partial nephrectomy.

Horseshoe kidney is one of the most common congenital renal fusion anomalies and the incidence of renal cell carcinoma in horseshoe kidney is predicted to be approximately 5.2/100000 individuals. Because horseshoe kidney merges malformations and vascular changes, open surgery is the standard for treatment. There are no reports of robot-assisted partial nephrectomy (RAPN) for renal cell carcinoma in horseshoe kidney. We describe for the first time the safety and the utility of RAPN in a horseshoe kidney with renal cell carcinoma.

High diagnostic efficacy of 5-aminolevulinic acid-induced fluorescent urine cytology for urothelial carcinoma.

BACKGROUND: In general, urine cytology is often problematic because of its low sensitivity, especially for low-grade urothelial carcinoma (UC) in clinical practice. To improve the sensitivity, we focused on 5-aminolevulinic acid (5-ALA), because recent studies suggested that 5-ALA-induced urine cytology can be used for photodynamic diagnosis. In this study, we evaluated the diagnostic efficacy of 5-ALA-induced fluorescent urine cytology for UC. METHODS: We included in this study 318 patients comprising 158 non-cancer patients, 84 bladder tumor patients, and 76 upper urinary tract urothelial carcinoma (UUT-UC) patients treated in our institution from March 2013 to September 2018. Using the same voided urine sample, we compared sensitivity and specificity between conventional urine cytology and 5-ALA-induced fluorescent urine cytology. RESULTS: Overall, the sensitivity of 5-ALA-induced fluorescent urine cytology was significantly higher than that of conventional urine cytology (86.9% vs. 69.4%; p = 0.0002), and the specificity was equivalently high (96.2% vs. 95.6%; p = 1.0). In subgroup analysis, the high sensitivity of 5-ALA-induced fluorescent urine cytology was also detected regardless of age, sex, and tumor type. However, in terms of stage and grade, differences were only detected in patients with less than pTa stage (89.2% vs. 52.1%; p = 0.0001) and low-grade tumor (91.5% vs. 51.1%; p < 0.0001). CONCLUSIONS: 5-ALA-induced fluorescent urine cytology was significantly more effective for UC diagnosis when compared with the conventional cytology, especially in patients with low-stage and low-grade tumors. These findings indicate that 5-ALA-induced fluorescent urine cytology may potentially be a very useful tool for clinical use.

[CLINICAL STUDY OF INTEGRATED URINARY CARE TO SUPPORT SELF-RELIANCE AGAINST URINARY DYSFUNCTION WITH INVOLVEMENT BY UROLOGISTS].

(Purpose) We reviewed 207 patients with urinary dysfunction who were managed by voiding care team at Osaka Rosai Hospital between November 2016 and June 2018. (Materials & methods) The study involved 112, 32, 24, 19, 10, 7, and 3 patients in the Urology, Orthopedics, Surgery, Internal Medicine, Neurosurgery, and Otorhinolaryngology departments, respectively. The average age was 72.7 years, ranging from 27 to 94 years, and the patients were170 males and 37 females. The average body mass index was 23.3, ranging from 11.6 to 43.7. The degree of activity of daily life (ADL) was distributed from J (independent ADL) to C (bedridden), and consisted of 132 in J category, 23 in A, 28 in B, 24 in C. Forty-seven patients had diabetes mellitus (DM), 36 had a cranial nerve disease, 25 had a history of urinary retention, 17 had indwelling urethral catheters on admission, 53 had an emergency hospital admission, and 174 underwent ≥1 operations during admission. (Results & conclusions) Among the 112 patients treated in the Urology department, 60 underwent robot-assist radical prostatectomy (RARP), 36 transurethral resection of prostate (TUR-P) and Holmium laser enucleation of the prostate (HoLEP), and 16 other procedures. A total of 93% were indwelling urethral catheter free, and 92% were pad-free (≤1 pad per day) at 1 year. In contrast, only 66% of the 95 patients in other departments were indwelling urethral catheter free at 1 year and were indwelling urethral catheter-free within 100 days, except for only one patient. The self-reliant voiding rate, including patients who have their indwelling urethral catheter removed or managed clean intermittent self-catheterization, was 91% at 1 year. A univariate analysis indicated that an ADL of J, independent ambulation, self-care/undiapered, self-reliant voiding score ≤4 (on a scale from 0 to 10, with higher score indicating a poorer ADL), and a urinary function ≤4 (on a scale from 0 to 10, with a higher score indicating greater urinary dysfunction) were significantly associated with freedom from urethral catheter. A multivariate analysis with Cox's proportional hazard model revealed a urinary function of ≤4 to be an independent good prognosticator for being catheter-free. Furthermore, a univariate analysis indicated that ADL J, a scheduled hospital admission, ≥1 operations during admission, independent ambulation, self-care/independent portable toilet, self-care/undiapered, self-reliant voiding score (≤4), and a urinary function of ≤4 were significantly associated with the acquisition of self-reliant voiding. A multivariate analysis with Cox's proportional hazard model revealed a self-reliant voiding of ≤4 to be an independent good prognosticator for self-reliant voiding. (Conclusions) Achieving freedom from an indwelling urethral catheter and acquiring a self-reliant voiding function are suggested to be very important for integrated urinary care.

Chronological changes in epidemiological characteristics of lower urinary tract urolithiasis in Japan.

OBJECTIVES: To determine changes and trends in the annual incidence and epidemiological aspects of lower urinary tract stones in Japan. METHODS: Data about patients who had been diagnosed by urologists in 2015 with first and recurrent lower urinary tract stones were collected from 301 hospitals approved by the Japanese Board of Urology. The estimated annual incidence according to sex, age and stone composition was compared with previous nationwide surveys between 1965 and 2005. RESULTS: The incidence of lower urinary tract stones in Japan has steadily increased from 4.7 per 100 000 in 1965 to 12.0 per 100 000 in 2015. However, the age standardized annual incidence of lower urinary tract stones has remained relatively stable over the same period at 5.5 per 100 000 and 6.0 per 100 000 in 1965 and 2015, respectively. The increase in incidence was most evident among individuals aged ≥80 years. The incidence of calcium oxalate stones has steadily increased among males and females, whereas that of infection-related stones has significantly decreased from 26.2% to 14.3% among men over the past 50 years. CONCLUSIONS: Nationwide surveys suggest a steady increase in the incidence of lower urinary tract stones over a 50-year period in Japan. This trend might reflect changes in the aging population and improved Japanese medical standards.

[Renal Pelvic Cancer with Delayed Diagnosis Due to Left Renal Injury : A Case Report].

We report a case of renal pelvic cancer found after left renal trauma. A 63-year-old man was admitted to our hospital because of gross hematuria after he had fallen down the stairs two days earlier. He had asymptomatic severe anemia (Hb : 3. 6 g/dl). Abdominal computed tomography (CT) scan revealed bilateral ureteropelvic stones, bilateral severe hydronephrosis and hematoma of the left upper renal pelvis. We diagnosed him with left renal pelvic hemorrhage by trauma, and transcatheter arterial embolization (TAE) was performed. After TAE, gross hematuria improved, but some hematuria continued to be noted. We suspected malignancy, and examined the patient with contrast-enhanced CT, transurethral resection and retrograde pyelography combined with urine cytology in the upper urinary tract, all with no evidence of malignancy. However, four months after the left renal injury, follow-up CT revealed multiple metastatic lesions. We performed a left nephrectomy, and the resulting pathological diagnosis was invasive urothelial carcinoma with squamous differentiation of the renal pelvis. We performed 7 courses of chemotherapy, but the multiple metastatic lesions progressed, and he died of the disease 19 months after the operation.