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.

EphA2 on urinary extracellular vesicles as a novel biomarker for bladder cancer diagnosis and its effect on the invasiveness of bladder cancer.

BACKGROUND: Urinary extracellular vesicles (uEVs) secreted from bladder cancer contain cancer-specific proteins that are potential diagnostic biomarkers. We identified and evaluated a uEV-based protein biomarker for bladder cancer diagnosis and analysed its functions. METHODS: Biomarker candidates, selected by shotgun proteomics, were validated using targeted proteomics of uEVs obtained from 49 patients with and 48 individuals without bladder cancer, including patients with non-malignant haematuria. We developed an enzyme-linked immunosorbent assay (ELISA) for quantifying the uEV protein biomarker without ultracentrifugation and evaluated urine samples from 36 patients with and 36 patients without bladder cancer. RESULTS: Thirteen membrane proteins were significantly upregulated in the uEVs from patients with bladder cancer in shotgun proteomics. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) was the only protein significantly upregulated in the uEVs of patients with bladder cancer, compared with that of patients with non-malignant haematuria. The EV-EphA2-CD9 ELISA demonstrated good diagnostic performance (sensitivity: 61.1%, specificity: 97.2%). We showed that EphA2 promotes proliferation, invasion and migration and EV-EphA2 promotes the invasion and migration of bladder cancer cells. CONCLUSIONS: We established EV-EphA2-CD9 ELISA for uEV-EphA2 detection for the non-invasive early clinical diagnosis of bladder cancer.

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.

[A Long-Term Survival Case of Paraganglioma Treated with Repeated Surgical Resection].

We report a case of long-term survival in paraganglioma treated with repetitive surgery. A 32-year-old man was seen at the hospital because of hypertension and headache. On biochemical tests, elevated serum and urinary levels of noradrenaline were noted. Abdominal computed tomographic (CT) scan revealed a tumor 50 mm in diameter on the dorsal region of the inferior vena cava, superior to the renal artery. Our diagnosis was paraganglioma and we performed open resection of the tumor. Six years later, hypertension and headache appeared and abdominal computed tomography revealed tumors located in right renal hilus and para-aortic regions superior to aortic bifurcation, and ¹²³I-MIBG scintigraphy revealed uptake at the same sites. Therefore, we diagnosed the patient with recurrent pheochromocytoma and performed laparoscopic resection of the tumor. Surgical treatment was repeatedly performed for recurrence, and the symptoms due to hypersecretion of catecholamines could be controlled over a long period.

Proteomic analysis of urinary and tissue-exudative extracellular vesicles to discover novel bladder cancer biomarkers.

Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discover potential bladder cancer (BCa) biomarkers, however urine contains numerous EVs derived from the kidney and normal urothelial epithelium, which can obfuscate information related to BCa cell-derived EVs. In this study, we combined proteomic analysis of urinary EVs and tissue-exudative EVs (Te-EVs), which were isolated from culture medium of freshly resected viable BCa tissues. Urinary EVs were isolated from urine samples of 11 individuals (7 BCa patients and 4 healthy individuals), and Te-EVs were isolated from 7 BCa tissues. We performed tandem mass tag (TMT)-labeling liquid chromatography (LC-MS/MS) analysis for both urinary EVs and Te-EVs and identified 1960 proteins in urinary EVs and 1538 proteins in Te-EVs. Most of the proteins identified in Te-EVs were also present in urinary EVs (82.4%), with 55 of these proteins showing upregulated levels in the urine of BCa patients (fold change > 2.0; P < .1). Among them, we selected 22 membrane proteins as BCa biomarker candidates for validation using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis on urine samples from 70 individuals (40 BCa patients and 30 healthy individuals). Six urinary EV proteins (heat-shock protein 90, syndecan-1, myristoylated alanine-rich C-kinase substrate (MARCKS), MARCKS-related protein, tight junction protein ZO-2, and complement decay-accelerating factor) were quantified using SRM/MRM analysis and validated as significantly upregulated in BCa patients (P < .05). In conclusion, the novel strategy that combined proteomic analysis of urinary EVs and Te-EVs enabled selective detection of urinary BCa biomarkers.

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.

[Primary Pulmonary Cryptococcosis Mimicking Lung Metastases of Bladder Cancer : A Case Report].

A 70-year-old woman was diagnosed with bladder cancer (muscle invasive adenocarcinoma) via transurethral resection of bladder tumor in 2013. A month after the procedure, she underwent total cystectomy and ileal conduit diversion. Histopathological diagnosis was adenocarcinoma pTis pN0. In 2019, a computed tomography showed multiple nodules, each up to 1 cm in diameter, mainly in the right lower lobe. Metastatic lung cancer was suspected. She underwent thorascopic partial resection of the right lung, and was diagnosed with primary pulmonary cryptococcosis.

Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell-free DNA in upper tract urothelial carcinoma.

Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non-invasive test for detecting UTUC, but its sensitivity is low. A novel non-invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell-free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger-scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non-invasive diagnostic marker and reliable factor for tumor staging.

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma.

Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty-three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell-free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics-based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50-166 bp) to large (167-250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log-rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer-specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.

Expression level of CXCL7 in peripheral blood cells is a potential biomarker for the diagnosis of renal cell carcinoma.

There are no blood biomarkers for the diagnosis of renal cell carcinoma (RCC) in routine clinical use. We focused on the gene expression profile of peripheral blood cells obtained from RCC patients to discover novel biomarkers for RCC diagnosis. Using microarray analysis and quantitative verification, CXCL7 was shown to be significantly upregulated in the peripheral blood cells of RCC patients. Importantly, aberrant CXCL7 expression was confirmed even in peripheral blood cells obtained from early stage (pT1a) RCC patients, and the expression level of CXCL7 in peripheral blood cells was a potential independent biomarker for the diagnosis of RCC by receiver operating characteristic curve analysis (sensitivity, 70.0%; specificity, 64.0%; area under the curve = 0.722; multiple logistic regression analysis: odds ratio, 1.07; 95% confidence interval, 1.03-1.11; P = 0.0004). Moreover, CXCL7 expression in peripheral blood cells significantly decreased after resection of the primary tumor. CXCL7 is more highly expressed in PBMCs than in neutrophils from both healthy controls and RCC patients. Interestingly, CXCL7 expression in PBMCs from healthy volunteers was significantly elevated following coculture with RCC cells compared to those cocultured with normal cells as a control. These results suggest that aberrant CXCL7 expression in peripheral blood cells is induced by RCC cells and may serve as a novel biomarker in the diagnosis of RCC.

Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens.

BACKGROUND: Tumor-infiltrating macrophages, which are thought to be derived from blood monocytes, interact with tumor cells to promote cancer progression. The aim of this study was to assess the association of peripheral blood monocyte count with pathological findings and local tumor-infiltrating macrophages in prostatectomy specimens. METHODS: Preoperative peripheral blood monocyte counts were retrospectively assessed for their associations with pathological findings (pathological T stage, Gleason Score, extraprostatic extension, seminal vesicle invasion, and surgical margin) and biochemical recurrence of 248 patients who underwent radical prostatectomy. Local tumor-infiltrating macrophages were also evaluated immunohistochemically for their association with peripheral monocyte counts. RESULTS: The peripheral monocyte counts of the patients with extraprostatic extension, seminal vesicle invasion, or primary Gleason ≥4 were significantly higher than those of the patients without each of these pathological findings (P < 0.001, P = 0.034, and P = 0.004, respectively). Peripheral monocyte count was a significant predictor of adverse pathology and postoperative biochemical recurrence in localized prostate cancer by multivariate analysis (P = 0.001 and P = 0.041, respectively). Both the density and the count of tumor-infiltrating macrophages correlated significantly with the peripheral blood monocyte count (Spearman rank correlation coefficients were 0.463 and 0.649, respectively, P < 0.001). CONCLUSIONS: Peripheral blood monocyte count reflecting local tumor-infiltrating macrophages was a predictive factor for tumor progression and prognosis in patients with localized prostate cancer. Elucidating the mechanism of the interaction of peripheral monocytes with tumor-infiltrating macrophages is necessary.

[Emphysematous Cystitis and Acute Focal Bacterial Nephritis: A Case Report].

A 96-year-old woman was diagnosed with colitis in our hospital. Her past history was breast cancer and lung cancer but no diabetes mellitus. She suddenly complained of lower abdominal pain. Abdominal computed tomography (CT) revealed intramural gas in the bladder wall and multiple poor contrasting area in her right kidney, which suggested emphysematous cystitis and acute focal bacterial nephritis. Indwelling urethral catheter was performed for bladder drainage and the treatment with antibiotics started. Urine culture revealed Klebsiella pneumoniae and blood culture was negative. After 3 weeks, the abdominal CT confirmed the decrease of gas within the bladder wall and improvement of contrasting area in the right kidney.

[A Case of Perirenal Inflammatory Liposarcoma].

A 65-year-old man had been hospitalized for examination of melena at a separate facility. Computed tomography (CT) showed left renal mass and he was referred to our hospital. Magnetic resonance imaging (MRI) revealed a tumor without adipose components in the perirenal space. Preoperative diagnosis was retroperitoneal malignant tumor. Tumor excision and left nephrectomy were performed. Pathologic evaluation revealed inflammatory liposarcoma. He has been followed up for 10 months with no additional treatment and no evidence of local recurrence was seen.

[A case of solitary neurofibroma of spermatic cord].

We report a case of solitary neurofibroma of the spermatic cord. A 48-year-old man was referred to our hospital with a complaint of a left inguinal mass. Magnetic resonance imaging (MRI) demonstrated a solid mass in the left inguinal region. The tumor was removed. Histopathological diagnosis was neurofibloma. He had no other findings of Von Recklinghausen disease. Only a few cases of solitary neurofibromas of spermatic cord have been reported.

[A case of bronchogenic cyst treated as retroperitoneal tumor].

A 66-year-old man presented with a retroperitoneal mass found in a routine medical examination. He had no complaints and no medical history. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a cystic mass in the retroperitoneal space, attached to the left crus of the diaphragm, 5.5 cm in size. Retroperitoneal cystic tumor was diagnosed, and transperitoneal tumor resection was performed. Pathological findings revealed a cyst wall lined with ciliated epithelium and cartilage, diagnosed as a retroperitoneal bronchogenic cyst. The patient was in good health at 12 months after the surgery with no evidence of recurrence.

[Cardiorespiratory arrest due to acute pulmonary thromboembolism during chemotherapy for female urothelial carcinoma of urethra: a case report].

We report a case of deep vein thrombosis and acute pulmonary thromboembolism that occurred during chemotherapy for urethral carcinoma. A 68-year-old woman suffered from dysuria for a period of 2 years. When the symptoms worsened, a urethral catheter was placed and she was referred to our hospital for further examinations. Imaging analysis revealed a urethral tumor with multiple metastases. Pathological diagnosis on a specimen obtained from transurethral resection of the urethral mucosa was urothelial carcinoma and combined chemotherapy with gemcitabine and cisplatin was administered. On day 6 of the second course, the patient collapsed and was found to be in cardiorespiratory arrest. Cardiopulmonary resuscitation was successful and she received percutaneous cardiopulmonary support. Computed tomography at that time revealed a pulmonary embolism and deep vein thrombosis in the right popliteal vein. After her condition improved, an inferior vena cava filter was inserted to avoid further thromboembolism. The patient decided to continue the chemotherapy despite this episode. After the fourth course of combined chemotherapy, the urethral tumor and metastatic tumors were downsized, and she could urinate as she did before.

[A case of bladder cancer producing granulocyte colony-stimulating factor and interleukin-6 causing respiratory failure treated with neoadjuvant systemic chemotherapy along with sivelestat].

A 67-year-old man visited an urological clinic with a chief complaint of urination pain. Cystourethroscopy and magnetic resonance imaging (MRI) examination revealed a bladder tumor (cT3bN0M0). Marked leukocytosis and respiratory distress with pleural effusion appeared. Pulse steroid therapy improved the general condition partially. The patient was sent to our hospital for further examination. Serum granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were high and the pathological findings of bladder tumor obtained by transurethral resection (TUR) revealed an urothelial carcinoma that produced G-CSF and IL-6. Neoadjuvant systemic chemotherapy was performed along with use of steroid and sivelestat, which ameliorated the respiratory distress. After three courses of systemic chemotherapy, serum G-CSF and IL-6 normalized and cystoprostatectomy was performed. The patient has been in good health at 20 months after the surgery with no evidence of recurrence.

[A case of portal vein thrombosis during chemotherapy for bladder cancer].

A 53-year-old man was diagnosed with bladder cancer with pelvic and para-aortic lymph node metastases. The clinical stage was cT3bN2M1. He underwent radical cystectomy and ileal conduit construction and retroperitoneal lymph node dissection after showing a partial response to 4 cycles of chemotherapy with methotrexate,vinblastine,doxorubicin and cisplatin (MVAC). Pathology showed prostatic invasion and para-caval lymph node metastasis. Pathological stage was pT4N0M1. After 3 cycles of MVAC therapy as adjuvant chemotherapy,new lymph node metastasis was revealed. He showed a complete response after 4 cycles of chemotherapy with gemcitabine and cisplatin (GC). He received 6 additional cycles of GC chemotherapy. Follow-up computed tomographic scan 3 months after the last chemotherapy showed portal vein thrombosis. He was treated with anticoagulant therapy,which dissolved the thrombus.

[Cardiac tamponade due to pericardial metastasis from renal cell carcinoma : a case report].

A 52-year-old man received partial left nephrectomy for renal cell carcinoma (clear cell carcinoma, G1, pT1aN0M0) in January, 2003. After 7 years, he was diagnosed with mediastinal lymph node metastasis and we performed interferon-alpha therapy. After 7 months, he presented with dyspnea. Chest X rays showed a large globular cardiac shadow. Echocardiography revealed massive pericardial effusion with features of cardiac tamponade. Under echocardiographic guidance, 1, 020 ml hemorrhagic pericardial fluid was aspirated ; the fluid revealed class V and our diagnosis was pericardial metastasis of renal cell carcinoma. We performed treatment with sunitinib for 5 months after pericardiocectesis. Metastatic mediastinal lymph node size was maintained showing stable disease by computed tomography and cardiac effusion was not increased, but he died unexpectedly at home.

Osteosarcoma of the bladder: a case report.

BACKGROUND: Osteosarcoma arising from the bladder is extremely rare, with only 38 cases reported to our knowledge. It is often detected owing to hematuria, and is treated by surgery (for example, total cystectomy), radiation therapy, and chemotherapy; however, the prognosis is extremely poor. CASE PRESENTATION: An 83-year-old Japanese man underwent cystoscopy for postoperative follow-up of urothelial carcinoma of the bladder, which revealed a 2-cm nodular tumor on the right wall. He had a history of abdominal aortic aneurysm and hypertension, and had been smoking 15 cigarettes per day for 45 years. Seven years previously, the patient underwent transurethral resection of bladder tumor for a 5-cm tumor on the right wall of the bladder. The histopathological diagnosis was urothelial carcinoma. No recurrence had been detected since then. Transurethral resection of bladder tumor was performed, and the histopathological diagnosis was cystosarcoma. Because of his advanced age, we decided that it would be difficult to perform total cystectomy. We therefore performed a second transurethral resection of bladder tumor and found no residual tumor. At 29 months after surgery, the patient remains alive without recurrence. CONCLUSION: Bladder osteosarcoma has a poor prognosis. However, our case was detected early, and treatment with transurethral resection of bladder tumor alone resulted in long-term survival without recurrence.