Serum D-asparagine concentration adjusted for eGFR could serve as a novel screening tool for urothelial carcinoma.

The sensitivity of currently available screening tools for urothelial carcinoma (UC) remains unsatisfactory particularly at early stages. Hence, we aimed to establish a novel blood-based screening tool for urothelial carcinoma. We measured serum d-amino acid levels in 108 and 192 patients with and without UC individuals in the derivation cohort, and 15 and 25 patients with and without UC in the validation cohort. Serum d-asparagine levels were significantly higher in patients with UC than in those without UC (p < 0.0001). We developed a novel screening equation for the diagnosis of urothelial carcinoma using d-asparagine in serum and estimated the glomerular filtration rate (eGFR). Serum d-asparagine levels adjusted for eGFR exhibited high performance in the diagnosis of UC (AUC-ROC, 0.869; sensitivity, 80.6 %; specificity, 82.7 %), even in early-stage UC (AUC-ROC: 0.859, sensitivity: 83.3 %, specificity: 82.3 %), which were previously misdiagnosed via urinary occult blood or urine cytology. This established strategy combined with urinary occult blood, improves diagnostic ability (sensitivity: 93.7 %, specificity: 70.1 %).

Clinical outcomes of first-line combination therapy with immune checkpoint inhibitor for metastatic non-clear cell renal cell carcinoma: a multi-institutional retrospective study in Japan.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC). METHODS: We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups. RESULTS: Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9 months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75 years was significantly higher compared to that in patients aged < 75 years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively). CONCLUSION: This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75 years with respect to clinical prognosis.

The presence of lymph node metastases and time to castration resistance predict the therapeutic effect of enzalutamide for castration-resistant prostate cancer.

BACKGROUND: Enzalutamide is effective against castration-resistant prostate cancer (CRPC). However, it is unclear which patients would benefit more from enzalutamide treatment. Here, we analyzed patients who received enzalutamide as first-line therapy for CRPC and evaluated the factors that predict treatment response and prognosis. METHODS: We retrospectively analyzed 101 patients treated with enzalutamide for CRPC at our institution. As primary endpoints we regarded the prostate-specific antigen (PSA) response rate and PSA-progression-free survival (PSA-PFS) from the start of enzalutamide treatment. Laboratory and imaging data were analyzed to predict treatment efficacy. RESULTS: PSA reductions of ≥ 50% and ≥ 90% were observed in 78 (77%) and 47 (47%) patients, respectively, compared with the baseline. During the follow-up period, 67 (66%) patients showed PSA progression, with a median PSA-PFS of 11 months. Moreover, 31 patients (31%) died, with a median overall survival of 64 months. On multivariate analysis, lymph node metastases at the start of enzalutamide treatment [odds ratio (OR) 0.0575, 95% confidence interval (CI) 0.0105-0.316, p = 0.0010] and time to CRPC (OR 0.177, 95% CI 0.0428-0.731, p = 0.0167] were associated with ≥ 90% PSA response. Lymph node metastases (hazard ratio [HR] 3.00, 95% CI 1.48-6.09, p = 0.0023) and time to CRPC (HR 1.84, 95% CI 1.02-3.30, p = 0.0419) were also predictors of PSA-PFS on a multivariate model. CONCLUSIONS: Time to CRPC and lymph node metastasis were predictors of the PSA response rate and PSA-PFS.

Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium-223 (Ra-223) is a targeted alpha therapy that has been shown to prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. However, prognosis after Ra-223 administration varies among patients. The aim of the present study was to assess risk factors associated with the poor prognosis of patients treated with Ra-223. METHODS: We retrospectively reviewed patients' records of treatment with Ra-223 between October 2016 and December 2019. All patients had mCRPC, bone metastasis, and no known visceral metastases, and received up to six cycles of Ra-223 (55 kBq/kg). Prognostic factors for OS were analyzed by Cox proportional hazards model and log-rank test. RESULTS: We identified 42 patients who received at least one cycle of Ra-223 (median six cycles, range 1-6). Approximately two-thirds of patients had received at least two lines of therapy for mCRPC. The median age was 74 years, and the median follow-up duration was 13.6 months. The median OS time was 16.6 months. On multivariate analysis, PSA doubling time (PSADT) (0-3 months) at baseline, number of bone metastases (≥ 20), and treatment line of Ra-223 (4th-5th line) remained significantly correlated with the poor OS (HR 4.354, P = 0.003; HR 2.855, P = 0.020; and HR 4.871, P = 0.001, respectively). CONCLUSIONS: Our study demonstrated that a shorter PSADT, a heavier volume of bone metastases, and a later treatment line before Ra-223 are poor prognostic factors for mCRPC patients. These newly discovered risk factors may help select patients who potentially have long-term OS after Ra-223 treatment.

[A Case of IgG4-Related Disease Arising in Female Periurethra].

A 67-year-old female, with a past medical history of IgG4-related Mikulicz disease, was referred to our department for a periurethral mass revealed by contrast-enhanced computed tomography. She presented with weak urine flow a half year before the first consultation. Magnetic resonance imaging (MRI) revealed a periurethral mass, 39×39×29 mm, extending from the bladder neck to the urethral meatus. Serum IgG4 level was elevated to 580 mg/dl. Histological examination by the transvasinal biopsy revealed a lymphocytic infiltrate with IgG4-positive plasmacytoid predominance, leading to the diagnosis of IgG4-related disease arising in the periurethra. She was treated with prednisolone for 4 months, and urinary disturbance disappeared. MRI showed that the periurethral mass decreased in size.

[A Case of Myocardial Metastasis of Renal Cell Cancer Treated with Nivolumab].

The patient a 48-year-old male, underwent nephrectomy for clear cell renal cell carcinoma. After surgery, the patient was treated sequentially with sunitinib, axitinib, and everolimus for multiple pulmonary metastases and iliopsoas muscle metastasis. After 16 months, subcutaneous metastasis and left ventricular myocardial metastasis developed without any symptoms. He was treated with pazopanib for these metastases. However, no shrinkage was seen and bone metastasis in right acetabulum appeared. After radiation therapy (20 Gy/5 Fr) for right acetabulum, nivolumab was administered for myocardial metastasis and subcutaneous metastasis. Significant shrinkage of metastases was seen after 3 courses of nivolumab and the patient's condition remained stable after 31 courses of nivolumab.

[A Case of Ipsilateral Multifocal Renal Cell Carcinoma Treated with Robot-Assisted Partial Nephrectomy].

A 55-year-old male was referred to our hospital for left lower back pain. Computer tomography suggested a left ureteral stone and two left renal tumors at ventral and lateral sites. The ventral tumor measured 7 mm, and it showed intense early enhancement. On the other hand, the lateral tumor measured 22 mm, and it was enhanced weakly. We performed a single-stage robot-assisted partial nephrectomy, because he had chronic renal insufficiency and the two tumors appeared to be different types of renal cell carcinoma. Pathological examination revealed the ventral tumor was clear cell renal cell carcinoma, while the lateral tumor was papillary renal cell carcinoma. He is free of recurrence 1 year and 2 months after operation.

[Two Cases of Clear Cell Adenocarcinoma Arising in Urethral Diverticulum].

We report two cases of clear cell adenocarcinoma arising in the urethral diverticulum. Case 1 occurred in a 79-year-old woman presenting with complaints of frequent micturition. Magnetic resonance imaging (MRI) revealed a localized urethral diverticular tumor. Transurethral resection of the tumor was performed, and the final histopathological diagnosis was clear cell adenocarcinoma. Anterior pelvic exenteration was performed. She had no recurrence 15 months after surgery. Case 2 occurred in a 79-year-old woman presenting with urinary incontinence. As in Case 1, MRI and histopathological findings of transurethral resection of the tumor revealed clear cell adenocarcinoma in the urethral diverticulum. Anterior pelvic exenteration and ileal conduit formation were performed. She had no recurrence 16 months after surgery. Clear cell adenocarcinoma in the urethral diverticulum is very rare. We review 17 cases of clear cell adenocarcinoma arising in the urethral diverticulum in Japan.

[Seminal Vesicle Abscess Associated with Zinner Syndrome].

We report a case of seminal vesicle abscess associated with Zinner syndrome. A 26-year-old male was admitted to our hospital because of fever and right scrotal swelling. Ultrasound showed an enlarged epididymis and color Doppler ultrasound showed increased vascularity in the epididymis. We diagnosed the case as acute epididymitis and started intravenous antibiotic therapy. Four days after admission, remittent fever persisted and blood culture was positive for Staphylococcus aureus. We performed computed tomography, which showed a right seminal vesicle cyst abscess and right renal agenesis. Our diagnosis was an abscess associated with Zinner syndrome. Transrectal ultrasound-guided transperineal drainage was performed 30 days after admission because seminal vesicle abscess could not be controlled by conservative treatment. Eight days after the procedure, the patient was discharged. One year after the procedure, recurrence of seminal vesicle abscess has not been observed.

[A CASE OF ABO INCOMPATIBLE LIVING KIDNEY TRANSPLANTATION IN A PATIENT WITH SELECTIVE IgA DEFICIENCY].

We report a case of ABO incompatible living kidney transplantation in a 45-year-old man with selective IgA deficiency. He has been on hemodialysis for 1 year due to chronic renal failure. Although the serum anti-IgA antibody was negative, he has experienced anaphylactic reaction to red blood cell product in the past. Before the transplantation, we performed double filtration plasmapheresis for two times, but didn't performed plasma exchange, considering the possibility of producing anti-IgA antibody and anaphylactic reaction. He underwent kidney transplantation from his mother without anaphylactic reaction, following to the recirculation of renal blood flow. He was discharged on the 29th postoperative day when the serum creatinine level was 1.2 mg/dL. The graft function was stable at 8 months after transplantation with no evidence of rejection and infection.

Association of Androgen Receptor and PD-L1 Expression in Upper Urinary Tract Urothelial Carcinoma.

BACKGROUND/AIM: The response to immune checkpoint inhibitors (ICIs) or enfortumab vedotin is limited in patients with upper urinary tract urothelial carcinoma (UTUC), and the development of new targeted therapy for UTUC is eagerly needed. Several biomarkers, including programmed cell death-ligand 1 (PD-L1), have already been reported as predictors of response to ICIs therapy for UTUC. Recently, several studies have shown that steroid hormone receptors, including the androgen receptor (AR), are associated with progression of urothelial carcinoma. MATERIALS AND METHODS: We prepared tissue microarrays (TMA) from paraffin blocks of UTUC specimens in 99 non-metastatic UTUC patients who underwent radical nephroureterectomy. With these TMA sections, we performed immunohistochemical staining for PD-L1 and AR and examined PD-L1 and AR expression levels in tumor cells. In addition, we analyzed the correlation between these markers and clinical prognosis in UTUC cases. RESULTS: PD-L1 was positive in 24 (24%) of the 99 samples, whereas AR was positive in 20 (20%) patients. AR-negative samples had significantly higher PD-L1 expression level than that the AR-positive samples (mean value 4.70% versus 2.55%, p=0.0324). Among AR-positive cases, patients with absence of PD-L1 expression had significantly lower cancer-specific survival (CSS) than that in PD-L1 expression-positive cases (p=0.049), although PD-L1 expression had no significant impact on CSS in AR-negative cases (p=0.920). CONCLUSION: Our findings suggest that AR is the promising target for UTUC treatment, especially in PD-L1-negative cases.

Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management.

Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9-43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93-11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01-0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13-11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68-15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Bacteria-derived DNA in serum extracellular vesicles are biomarkers for renal cell carcinoma.

This is the first study to determine the clinical importance of circulating bacterial DNA in patients with renal cell carcinoma (RCC). We performed 16S rRNA metagenomic analysis of serum extracellular vesicles (EVs) from 88 patients with RCC and 10 healthy donors and identified three abundant bacterial DNA: Bacteroidia, TM7-1, and Sphingomonadales. Combining characteristic bacterial DNA information (three bacteria-derived DNA), a BTS index was created to diagnose patients with RCC. The BTS index showed high sensitivity not only in the discovery cohort, but also in the validation cohort, suggesting that it was useful as a screening test. Furthermore, in nivolumab treatment of RCC, patients with higher levels of Bacteroidia DNA in serum EVs had significantly poorer progression-free and overall survival than did those with lower levels. This study showed that circulating Bacteria-derived DNA could be used as a biomarker for RCC.

Partial nephrectomy for a Bosniak IV cystic renal mass mimicking a simple renal cyst adjacent to a solid renal tumor.

INTRODUCTION: Renal tumors are often associated with renal cysts. Meanwhile, in some cases there are challenging issues of how to diagnose renal cystic tumors and to decide surgical procedures. CASE PRESENTATION: A 75-year-old man was referred to our department for a 21-mm tumor by his left kidney. Contrast-enhanced computed tomography showed an intense contrast uptake the tumor, which was adjacent to a 64-mm unilocular renal cyst with no contrasting effects. It was clinically diagnosed as renal cell carcinoma, stage T1aN0M0, and treated with robot-assisted partial nephrectomy, for both the solid tumor and the adjacent cyst. Pathological findings revealed a tumor cell clump within the cyst wall, concurrent with the renal cell carcinoma. The patient has remained free of disease at 1 year after surgery. CONCLUSION: A partial nephrectomy that includes the entire cyst wall should be considered for renal tumor associated with unilocular renal cyst.

Renal cell carcinoma with central nervous system demyelination caused by nivolumab.

INTRODUCTION: Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition. CASE PRESENTATION: A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress. CONCLUSION: Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.

FAN score comprising fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio is a prognostic marker of urothelial carcinoma patients treated with pembrolizumab.

It is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20-3.76, p = 0.010), albumin-bilirubin score (HR 1.91, 95% CI 1.27-2.88, p = 0.002), and neutrophil-lymphocyte ratio (HR: 1.84, 95% CI 1.22-2.79, p = 0.004) were independent significant prognostic factors. We established a 'FAN score' that included these three aforementioned items, which were assigned one point each. We divided patients into the 0-1 point (n = 116) and 2-3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19-1.83, p < 0.001) along with the Eastern Cooperative Oncology Group Performance Status. The FAN score was also a prognostic factor of progression-free survival (PFS) (HR: 1.25, 95% CI 1.01-1.54, p = 0.036) along with the presence of liver metastasis. In the validation cohort, the FAN score was a significant prognostic factor for CSS (HR: 1.48, 95% CI 1.19-1.85, p = 0.001) and PFS (HR: 1.29, 95% CI 1.02-1.62, p = 0.034). We established the FAN score as a prognostic marker for patients with mUC treated with pembrolizumab.

Acute myocardial infarction caused by tumor embolus originating from upper tract urothelial carcinoma: a case report.

Coronary emboli from malignant tumors rarely cause acute myocardial infarction. We report the case of a patient with tumor embolism from an upper tract urothelial carcinoma that caused acute myocardial infarction via a patent foramen ovale. Coronary blood flow was restored by embolus aspiration without stenting. Clinicians must consider malignant tumor embolism as a possible cause of acute myocardial infarction.

Robot-Assisted Laparoscopic Prostatectomy in a Prostate Cancer Patient Undergoing Continuous Ambulatory Peritoneal Dialysis.

Background: Robot-assisted laparoscopic prostatectomy (RALP) has become the gold standard treatment for organ-confined prostate cancer. However, no proper surgical approach or appropriate postsurgical management of RALP has been established for a patient undergoing peritoneal dialysis. Here, we present a case of a peritoneal dialysis patient who underwent RALP and reinstated peritoneal dialysis with no trouble associated with peritoneal dialysis. Case Presentation: The patient was a 61-year-old man with organ-confined prostate cancer. He had been on peritoneal dialysis for 2 years. The peritoneal dialysis catheter was routed subcutaneously from the left lateral region into the abdominal cavity at the paramedian region. RALP was performed by the transperitoneal anterior approach. The surgical maneuver was not influenced by the peritoneal dialysis catheter at all. At the end of surgery, the incised peritoneum was sutured and closed tightly. After surgery, peritoneal dialysis was temporarily interrupted for 2 weeks. Then it was safely reinitiated with no complications. Conclusion: Transperitoneal RALP with complete peritoneal repair can be a standard treatment option for a prostate cancer patient undergoing peritoneal dialysis.

Case of pazopanib-induced thyrotoxicosis in a patient with metastatic renal cell carcinoma.

Pazopanib is an oral multi-targeted tyrosine kinase inhibitor and has been approved for metastatic renal cell carcinoma and advanced soft tissue sarcoma. To the best of our knowledge, pazopanib-induced thyrotoxicosis has never been reported. The patient was a 68-year-old woman with renal cell carcinoma and multiple metastases. Three weeks after pazopanib medication, she felt fatigue and palpitation. She was admitted because of liver chemistry abnormalities [AST 723 IU/L (normal range 7-37 IU/L); ALT 953 IU/L (normal range 3-33 IU/L)]. She showed abnormal thyroid function tests with suppressed TSH of 0.0585 µIU/mL, and elevated fT4 of 3.38 ng/dL. Ten days after admission, tachycardia appeared and fT3 and fT4 were elevated (fT3 27.85 pg/mL, fT4 2.58 ng/dL), and TSH was suppressed (0.0414 µIU/mL). Her thyroid ultrasound showed hypervascular thyroid gland without nodules. We diagnosed pazopanib-induced thyrotoxicosis. Because the fT3/fT4 ratio was high (10.8) and the thyroid was enlarged, we thought that her thyrotoxicosis might get worse. She was treated with medication of beta-blockers, hydrocortisone, and potassium iodide and thyrotoxicosis resolved. This report highlights that Pazopanib could induce thyrotoxicosis, and therefore, periodic surveillance of thyroid function is required during pazopanib therapy.

Quantitative measurements of oxidative stress in mouse skin induced by X-ray irradiation.

To find efficient methods to evaluate oxidative stress in mouse skin caused by X-ray irradiation, several markers and methodologies were examined. Hairless mice were irradiated with 50 Gy X-rays and skin homogenates or skin strips were prepared. Lipid peroxidation was measured using the skin homogenate as the level of thiobarbituric acid reactive substances. The level of lipid peroxidation increased with time after irradiation and was twice that of the control at 78 h. ESR spectra of skin strips showed a clear signal for the ascorbyl radical, which increased with time after irradiation in a manner similar to that of lipid peroxidation. To measure levels of glutathione (GSH) and its oxidized forms (GSSG) simultaneously, two HPLC methods, sample derivatization with 1-fluoro-2,4-dinitrobenzene and detection with a UV detector (method A) and no derivatization and detection with an electrochemical detector (method B), were compared and the latter was found to be better. No significant change was observed within 24 h after irradiation in the levels of GSH and GSSG measured by method B. The GSH/GSSG ratio may be a less sensitive parameter for the evaluation of acute oxidative stress caused by X-ray irradiation in the skin. Monitoring the ascorbyl radical seems to be a good way to evaluate oxidative stress in skin in vivo.