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.

Diagnostic and prognostic significance of tartrate-resistant acid phosphatase type 5b in newly diagnosed prostate cancer with bone metastasis: A real-world multi-institutional study.

OBJECTIVES: Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients. METHODS: We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b). RESULTS: A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p < 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p < 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95). CONCLUSIONS: Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma.

Perioperative systemic chemotherapy improves the prognosis of upper tract urothelial carcinoma (UTUC). The first objective of this study was to verify whether perioperative circulating tumor DNA (ctDNA) analysis using a pan-cancer gene panel and next-generation sequencing could identify patients with poor prognosis who require perioperative chemotherapy. Second, we investigated whether ctDNA is useful for minimal residual disease (MRD) detection and treatment monitoring in UTUC. This study included 50 patients with untreated UTUC, including 43 cases of localized UTUC. We performed targeted ultradeep sequencing of plasma cell-free DNA (cfDNA) and buffy coat DNA and whole-exome sequencing of cancer tissues, allowing exclusion of possible false positives. We attempted to stratify the prognosis according to the perioperative ctDNA levels in patients with localized UTUC. In patients with metastatic UTUC, ctDNA was evaluated before, during, and after systemic treatment. In total, 23 (46%) of 50 patients with untreated UTUC were ctDNA positive, and 17 (40%) of 43 patients with localized UTUC were ctDNA positive. Of the detected TP53 mutations, 19% were false positives due to clonal hematopoiesis of indeterminate potential. Among preoperative risk factors, only the preoperative ctDNA fraction>2% was a significant and independent risk factor associated with worse recurrence-free survival (RFS). Furthermore, the existence of ctDNA early points after the operation was significantly associated with worse RFS, suggesting the presence of MRD. ctDNA also showed a potential as a real-time marker for systemic therapy in patients with metastatic UTUC. Detection of ctDNA may indicate potential metastasis and guide decisions on perioperative chemotherapy.

Early dynamics of circulating tumor DNA predict clinical response to immune checkpoint inhibitors in metastatic renal cell carcinoma.

OBJECTIVES: Detection of genomic alterations in circulating tumor deoxyribonucleic acid of peripheral blood can guide the selection of systemic therapy in cancer patients. The predictive significance of circulating tumor deoxyribonucleic acid in metastatic renal cell carcinoma remains unclear, especially for patients treated with immune checkpoint inhibitors. METHODS: In this study, we collected plasma samples before and 1 month after commencing nivolumab monotherapy or nivolumab plus ipilimumab therapy from 14 metastatic renal cell carcinoma patients. We performed circulating tumor deoxyribonucleic acid genomic profiling in plasma cell-free deoxyribonucleic acid by next-generation sequencing using a commercially available pan-cancer panel (Guardant360 CDx). Additionally, we also performed whole exome sequencing of tumor tissues and compared the concordance of genomic profiles with circulating tumor deoxyribonucleic acid. RESULTS: Nine patients had circulating tumor deoxyribonucleic acid in pretreatment plasma samples with a total of 20 mutations (15 single nucleotide variants, three insertions/deletions, and two copy number amplification). VHL (30.0%) was the most frequently mutated gene, followed by TP53 (20.0%), and 45.0% of circulating tumor deoxyribonucleic acid mutations were concordant with somatic mutations in tumor tissues. Patients with decreasing circulating tumor deoxyribonucleic acid mutant allele frequency had better progression free survival when compared to those with increasing mutant allele frequency (P = 0.0441). CONCLUSIONS: Our findings revealed that early circulating tumor deoxyribonucleic acid dynamics can serve as a predictive biomarker for response to immune checkpoint inhibitors in metastatic renal cell carcinoma patients.

[Left Essential Renal Hematuria, that Cannot Be Stopped by Ureteroscopy, Successfully Treated with the Instillation of Hydrogen Peroxide into the Renal Pelvis : A Case Report].

We report a case of left essential renal hematuria successfully treated with the instillation of hydrogen peroxide into the renal pelvis. A 68-year-old man was referred to our hospital with the chief complaint of gross hematuria. Our diagnosis was left renal essential hematuria. We could not find the bleeding point using a flexible ureteroscope. Due to prolonged gross hematuria, we performed instillation of hydrogen peroxide into the renal pelvis and the gross hematuria completely disappeared. Retrograde hydrogen peroxide instillation therapy is useful and safe for essential renal hematuria.

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

Fragmentation of cell-free DNA is induced by upper-tract urothelial carcinoma-associated systemic inflammation.

Reliable biomarkers for upper-tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive blood biomarker for various types of cancer. We investigated the utility of plasma cfDNA as a blood biomarker in UTUC patients. The fragment size of plasma cfDNA was shorter and the concentration of plasma cfDNA was higher in UTUC patients than in healthy controls. The fragment size of plasma cfDNA had a moderate accuracy of diagnosing UTUC (area under the curve [AUC] = 0.72), and multivariate analysis indicated that the fragment size of plasma cfDNA was significantly associated with the presence of UTUC (odds ratio = 0.807, 95% confidence interval [CI] 0.653-0.955, P = .024). Furthermore, we found that the size of plasma cfDNA shortens alongside disease progression (P < .001). The fragment size of plasma cfDNA in UTUC patients may be an auxiliary tool for the diagnosis of UTUC patients. We also found a high correlation between the fragmentation of plasma cfDNA and serum levels of three inflammatory cytokines (TNFα [r = -.837], interleukin-6 [IL-6] [r = -.964], interleukin-1 receptor antagonist [IL-1ra] [r = -.911]), which were reported to associate with poor prognosis. Also, we found that the proportion of short fragments of cfDNA was significantly increased in the supernatant of peripheral blood mononuclear cells (PBMCs) from healthy controls cultured in media containing TNFα. These results supposed that cancer-associated systemic inflammation, especially tumor necrosis factor-α (TNFα), may contribute to the fragmentation of plasma cfDNA in UTUC patients.

[A Case of Primary Central Nervous System Lymphoma that Developed during the Treatment of Castration-Resistant Prostate Cancer].

A 64-year-old man was diagnosed with metastatic prostate cancer (cT3bN0M1b) and treated with combined androgen blockade. After two years and three months, he developed castration-resistant prostate cancer. Multiple lung metastases appeared after the administration of five courses of docetaxel and four courses of cabazitaxel therapy. Pulmonary metastases disappeared following rechallenge with docetaxel. Enzalutamide administration was initiated because docetaxel had to be discontinued due to adverse events. Although enzalutamide lowered the prostate specific antigen value, the patient staggered while walking and developed homonymous hemianopsia. Magnetic resonance imaging revealed a brain tumor. Although the brain tumor was considered to have metastasized from the prostate cancer, it was diagnosed as a primary central nervous system lymphoma using open-ended tumor biopsy. The brain tumor was eliminated with whole-brain irradiation. Thereafter, he has been treated with enzalutamide for 3 years without clinical progression of either disease.

Solitary fibrous tumor mimicking adrenal tumor concomitant with contralateral adrenal pheochromocytoma: A case report of surgical resection after long-term observation.

INTRODUCTION: Solitary fibrous tumors (SFT) usually originate from the pleura and rarely occur in the retroperitoneum. There were few reports of SFT around the adrenal gland and its long-term clinical behavior remains unknown. PRESENTATION OF CASE: A 62-year-old woman with bilateral adrenal tumors was referred to our department in 2008. She had elevated urinary normetanephrine. Metaiodobenzylguanidine scintigraphy showed uptake in the right adrenal gland. The tumor in the right adrenal gland was 5 cm in diameter. The patient underwent right adrenalectomy and was diagnosed with pheochromocytoma. The left tumor was 3 cm in diameter and diagnosed as benign using imaging. However, its size gradually increased to 10 cm over 7 years after surgery. The catecholamine hormones were within normal range. The patient underwent the tumor resection and left partial adrenalectomy. A steroid cover was given temporarily after surgery for prophylactic purposes. The histological diagnosis was solitary fibrous tumor. There was no recurrence 2 years after surgery. DISCUSSION: There have been only nine case reports of SFTs that were diagnosed as adrenal tumor by clinical imaging in the English literature. Total adrenalectomy was performed in all patients with a unilateral tumor. One patient with bilateral tumors underwent partial adrenalectomy. CONCLUSION: SFT in the periadrenal region is difficult to differentiate from adrenal tumor. However, tumor resection with partial adrenalectomy should be considered for enlarged tumor with less aggressive behavior in patients with a history of contralateral adrenalectomy.

[A Case of Retroperitoneal Liposarcoma in which Magnetic Resonance Imaging was Useful in the Decision of Resection of Primary and RecurrentTumors].

A 47-year-old female was referred to our hospital because of retroperitoneal tumor which was detected by computer tomography (CT). Since the tumor was considered to be benign by magnetic resonance imaging (MRI), she was followed by MRI every 3 months. The site of the tumor was gradually increased, and 15 months after presentation, a lesion with high signal intensity on diffusion weighted image (DWI) appeared in the tumor. At that time, we performed tumor resection considering the tumor to be malignant. Pathological diagnosis was dedifferentiated liposarcoma. Three years and two months after the operation, liposarcoma recurred in the left retroperitoneal space. Because it showed low signal intensity on DWI, which was compatible with well-differentiated liposarcoma, further follow-up was carried out. Eleven months after the recurrence, a lesion with high signal intensity on DWI appeared in the tumor. We performed tumor resection again, leading to pathological diagnosis of recurrence of dedifferentiated liposarcoma. She remained free of disease at 4 months after surgery.

[A Case of Fulminant Hepatitis after Administration of Abiraterone Acetate].

A 77-year-old man with castration-resistant prostate cancer (CRPC) received abiraterone acetate in October 2014. He visited our outpatient clinic because of general malaise and anorexia 27 days after starting abiraterone acetate. The lab test showed hepatic dysfunction (aspartate transaminase, AST 440 U/l, alanine transaminase, ALT 420 U/l) and the elevation of liver enzymes continued on the next day even after stopping abiraterone acetate. Three days later, he was hospitalized due to severe elevation of liver enzymes (AST 1,171 U/l, ALT 1,487 U/l) , and the decreased prothrombin activity (60.5%). The result of the lab test were negative for viral and autoimmune hepatitis. Three days after admission, he entered hepatic coma (grade III) and prothrombin activity decreased (23.2%) , compatible with fulminant hepatitis. Plasma exchange and steroid pulse therapy were started the next day, but he died 39 days after starting abiraterone acetate. In addition, the result of drug-induced lymphocyte stimulation test performed 3 days before his death was possibly positive.

[A Case of Castration-Resistant Prostate Cancer with Fatal Convulsive Seizure after Administration of Enzalutamide].

Enzalutamide, an androgen receptor antagonist, is a standard drug for the treatment of castrationresistant prostate cancer. A 77-year-old man developed a seizure after administration of enzalutamide. The patient presented with general fatigue and high fever approximately 5 weeks after oral administration of enzalutamide. Several days later, a seizure attack occurred at home, resulting in cardiopulmonary arrest. The patient was taken to the hospital emergency room but could not be resuscitated. We described a 63-year-old man who was diagnosed with clinical T1c prostate cancer, with a Gleason score of 6 (3＋3), and a preoperative prostate-specific antigen (PSA) level of 5. 27 ng/ml. Radical prostatectomy(RP) was performed and final pathologyshowed Gleason score 3＋4, pT2c with negative surgical margin. In spite of suggested surgical radicality, PSA was 3.32, 4.78, 5.93 ng/ml, at 1, 2, and 3 months after RP, respectively. However, radiological investigation revealed no metastasis. Because of this clinical discrepancy, we checked the PSA-α1-antichemotrypsin level and found it to be ≦0.1 ng/ml. From these results, false PSA elevation caused byinterference of positive heterophilic antibodies was suggested and demonstrated byseveral immunoassays.

[A Subcutaneous Metastasis from Renal Pelvic Carcinoma Growing Rapidly after radical Nephrectomy : A Case Report].

A 78-year-old man was admitted to our department for a right renal mass detected by computed tomography which was accompanied by right hypochondriac pain. Dynamic computed tomography demonstrated a 7cm hypovascular right renal mass invading the liver. No metastatic disease was evident. Transabdominal nephrectomy and partial hepatectomy were performed under the diagnosis of right renal cell carcinoma in July 2014. Pathological examination revealed right renal pelvic carcinoma with liver invasion. After the operation, a subcutaneous nodule in the right forearm rapidly grew in one week. A needle biopsy revealed that it was a metastasis of the urothelial carcinoma. Additionally, lung metastases and lymph node swelling were detected. The patient received two courses of combination chemotherapy (gemcitabine, carboplatin) in August 2014. The subcutaneous metastasis was decreased, but it was not effective for other metastases. Two courses of another combination chemotherapy (methotrexate, vinblastine, epirubicin, calboplatin) were performed. It was effective for all metastatic lesions. During the third course, the patient developed melancholia and rejected additional therapy. He died in March 2015 due to disease progression.

[Etoposide and Carboplatin Effective for Treatment of Small Cell Carcinoma of Prostate : A Report of Two Cases].

Case 1 : A 76-year-old man consulted a physician because of pollakisuria, decline of urinary stream. A high level of serum prostate specific antigen (PSA) was detected and he came to our hospital. He was diagnosed to have prostate cancer, cT3aN0M1b, and was treated with combined androgen blockage (CAB). Two years and nine months later, postrenal failure appeared and serum level of neuron-specific enolase (NSE) was 162 ng/ml. We performed re-biopsy of prostate, and pathological examination indicated small cell carcinoma of the prostate. We treated him with combination chemotherapy comprised of etoposide and carboplatin, which was effective. Serum level of NSE was decreased and computed tomography showed reduction of the prostate volume and metastasis. Case 2 : An 84-year-old man was treated at a hospital with radiation therapy and CAB, because of prostate cancer. He came to our hospital with bladder tamponade. We performed transurethral coagulation and transurethral biopsy. Pathologically it proved to be small cell carcinoma of the prostate. The stage was cT4N1M1a, NSE and pro-gastrin-releasing peptide (Pro-GRP) levels were high. The same treatment given to him as in case 1, effectively decreased the metastasis and the level of serum NSE.

[A Case of Retroperitoneal Tumor in the Adrenal Area Turned Out to Be Schwannoma Mimicking an Adrenal Malignant Tumor].

A 76-year-old woman was found to have bilateral suprarenal tumors, 6.5 cm in diameter on the right side, and 2.4 cm in diameter on the left side, by ultrasonography, computed tomography, and magnetic resonance imaging. Strong accumulation of fluorodeoxyglucose in these tumors was found on positron emission tomography. Since it mimicked an adrenal malignant tumor, we performed right adrenalectomy. The pathological diagnosis of the removed mass was benign schwannoma, consistent of the Antoni type A. The left suprarenal tumor was not removed and she has been followed up for 18 months without any recurrence or tumor increase.

[Epithelioid Angiomyolipoma of the Kidney: A Case Report].

Herein we report a case of epithelioid angiomyolipoma of the kidney which is a rare subtype of angiomyolipoma. A 68-year-old man without a history of tuberous sclerosis complex (TSC) was referred to our department with a 40 × 84 mm left renal tumor incidentally detected by computed tomography. Computed tomography demonstrated a left renal heterogeneous mass which was enhanced at the early phase and washed out at the late phase. A tumor thrombus was seen extending into the main renal vein. No metastatic disease was evident. Thus, on the diagnosis of renal cell carcinoma, the patient underwent a left radical nephrectomy. Pathological examination showed that this tumor was composed predominantly of epithelioid cells, with a few blood vessels and adipose tissue and was diagnosed as epithelioid angiomyolipoma. He shows no disease progression for 6 months after the operation.