Publications by authors named "Tomomi Kamba"

137 Publications

Clinical impact of detecting low-frequency variants in cell-free DNA on treatment of castration-resistant prostate cancer.

Clin Cancer Res 2021 Sep 15. Epub 2021 Sep 15.

Department of Urology, Hirosaki University Graduate School of Medicine.

Purpose: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from CRPC patients and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%.

Experimental Design: This prospective, multicenter cohort study enrolled CRPC patients eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pre-treatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF {greater than or equal to} 0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied.

Results: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious , , and variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in or [hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.24-5.11; = 0.0091] and (HR, 3.74; 95% CI, 1.60-8.71; = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable.

Conclusions: Detecting low-frequency ctDNA variants with a VAF < 1% is important to identify clinically informative genomic alterations in CRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2328DOI Listing
September 2021

Surveillance of urachal abscess in the Kyushu-Okinawa area of Japan.

Int J Urol 2021 Jul 21. Epub 2021 Jul 21.

Department of Urology, Faculty of Medicine, Saga University, Saga, Japan.

Objective: To report a multicenter experience with the management of urachal abscess treatment in Japan.

Methods: This was a retrospective study of 263 cases of urachal abscess managed at 12 university hospitals in the Kyushu-Okinawa region over a 10-year period. Age, sex, abscess size, clinical symptoms, type of urachal remnants, and treatment were collected and analyzed.

Results: The average age was 29.8 ± 18.1 years, with males accounting for approximately two-thirds of the study population. The average abscess size was 1.7 cm (range 0-11 cm). The most common presenting symptom was umbilical secretion (66%), followed by abdominal pain (46%). A total of 127 patients (48.3%) were treated with antibiotics alone, whereas 136 patients (51.7%) received surgical treatment. The surgical approach was laparotomy in 75 patients (61.0%) and laparoscopic surgery in 48 patients (39.0%). Regarding the type of urachal remnant, the urachus sinus (180 patients) accounted for 68.4% of the total.

Conclusions: To our knowledge, this study represents the first report on urachal abscess treatment in Japan. Our data show that the clinical symptoms might vary depending on the type of urachus remnant. It should be noted that gross hematuria, a characteristic symptom of urachal cancer, is rare in patients with urachal abscess.
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http://dx.doi.org/10.1111/iju.14637DOI Listing
July 2021

High T-cell infiltration in tumor tissue and younger age predict the response to pembrolizumab in recurrent urothelial cancer.

Med Mol Morphol 2021 Jun 16. Epub 2021 Jun 16.

Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Targeting the programmed cell death-1 signaling pathway has been approved for the anti-cancer therapy in several cancers including urothelial cancer. To determine predictive factors of the responsiveness to pembrolizumab in urothelial cancer patients, a retrospective study that used clinical information and paraffin-embedded samples obtained from patients diagnosed with urothelial cancer between 2015 and 2020 were performed. Seventeen patients who underwent total cystectomy or nephroureterectomy of the primary lesion and were treated with pembrolizumab for chemo-resistant disease were enrolled, and immunohistochemical analysis was performed. A key difference in the characteristics between the non-responder group and the responder group was the age of the patients (74 vs. 63 years, p = 0.0194). Although there was no statistically significant difference, the histological subtype with sarcomatoid and micropapillary components was only seen in the non-responder group, and squamous differentiation and lymph node metastasis were only seen in cases with a complete response. In the results of immunohistochemistry, the density of CD8-positive T-cells and Tregs was significantly increased in the responder group than in the non-responder group. In conclusion, younger age and a high number of tumor-infiltrating lymphocytes were predictive factors of a good response to immune checkpoint inhibitors, although further studies with more enrolled patients are necessary.
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http://dx.doi.org/10.1007/s00795-021-00292-8DOI Listing
June 2021

HLA-DR and CD74 Expression and the Immune Microenvironment in Renal Cell Carcinoma.

Anticancer Res 2021 Jun;41(6):2841-2848

Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;

Background/aim: Expression of human leukocyte antigen (HLA) class I and II and CD74, which functions as a chaperone of MHC class II, play essential roles in T-cell recognition. The aim of this study was to elucidate the association between the HLAs and CD74, and their correlation with the infiltrated immune cells in renal cell carcinoma (RCC).

Materials And Methods: We retrospectively investigated the expression of HLA-A/B/C, HLA-DR, and CD74 in 38 patients with advanced RCC (T3/T4), and evaluated their correlations with CD4 and CD8-positive T-cell infiltration using immunohistochemistry.

Results: The expression of HLA-A/B/C, HLA-DR, and CD74 on cancer cells was observed in 37, 20, and 31 patients, respectively. The density of CD8- and CD4-positive T cells showed a positive correlation with HLA-DR expression. The density of CD4-positive lymphocytes was significantly associated with CD74 expression.

Conclusion: The expression of HLA-DR, rather than CD74, on cancer cells was potentially associated with the anti-cancer immune microenvironment.
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http://dx.doi.org/10.21873/anticanres.15065DOI Listing
June 2021

Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a.

Prostate 2021 02 24;81(3):147-156. Epub 2020 Dec 24.

Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Background: The treatment of castration-resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a-C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses.

Methods: C5aR and PD-L1 were immunostained in the prostate cancer (PC) tissues. The relationship of PC C5aR expression to clinicopathological parameters was analyzed. CRPC cell lines were examined for C5aR expression by real-time reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. C5a effects were examined on CRPC cell glutamine consumption, proliferation, invasion, and PD-L1 expression.

Results: PC cells expressed C5aR in 83 of the 161 patients (52%) and in three of the six CRPC patients. Basal cells, but not luminal cells, of noncancerous prostate glands expressed C5aR. Three CRPC cell lines expressed C5aR. C5a increased CRPC cell glutamine consumption 2.1-fold, proliferation 1.3-1.6-fold, and invasion 2-3-fold in a C5a-concentration and a C5aR-dependent manner. High expression of C5aR did not relate to the PC patients' clinical parameters but the PD-L1-positive rate was higher in the C5aR high-expression patients (37.5%) compared to low- or no expression patients (17.8%), and double-positive PC cells were present. C5a increased CRPC cell PD-L1 production 1.4-fold and cell-surface expression 2.6-fold.

Conclusions: C5aR expression of PC cells in patients' tissues and C5a augmentation of C5aR-dependent CRPC proliferation, invasion, and PD-L1 expression suggested participation of the C5a-C5aR system in CRPC promotion and evasion from antitumor immune responses. Targeting this signaling pathway may provide a useful therapeutic option for CRPC.
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http://dx.doi.org/10.1002/pros.24090DOI Listing
February 2021

Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

Cancer Med 2021 01 27;10(1):119-134. Epub 2020 Oct 27.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.
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http://dx.doi.org/10.1002/cam4.3578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826464PMC
January 2021

Difficulty in differential diagnosis for renal cancer with microscopic papillary architecture: overlapped pathological features among papillary renal cell carcinoma (RCC), mutinous tubular and spindle cell carcinoma, and unclassified RCC. Lessons from a Japanese multicenter study.

Jpn J Clin Oncol 2020 Oct;50(11):1313-1320

Department of Urology, National Defense Medical College, Saitama, Japan.

Objectives: In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC.

Methods: We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features.

Results: All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5 years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3 years.

Conclusion: Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs.
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http://dx.doi.org/10.1093/jjco/hyaa114DOI Listing
October 2020

Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

Int J Clin Oncol 2021 Jan 18;26(1):169-177. Epub 2020 Sep 18.

Department of Urology, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan.

Background: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC.

Methods: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed.

Results: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069).

Conclusions: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.
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http://dx.doi.org/10.1007/s10147-020-01784-wDOI Listing
January 2021

Solitary recurrence of prostate cancer surrounded by seminal vesicle/vas deferens-like epithelium.

IJU Case Rep 2020 Sep 30;3(5):171-173. Epub 2020 Jul 30.

Department of Nephro-urologic Surgery Mie University Hospital Tsu Japan.

Introduction: Clinical recurrence of prostate cancer after curative treatment with a limited number of metastases is often termed as oligorecurrence. We report a case of solitary recurrence of prostate cancer surrounded by epithelium of the seminal vesicle or vas deferens.

Case Presentation: A 54-year-old man diagnosed with localized prostate cancer underwent radiation therapy. Six years later, imaging studies detected a solitary recurrence. We performed metastasectomy, and histopathological examination revealed the metastatic lesion surrounded by the epithelium of the seminal vesicle or vas deferens. Surgical resection achieved a complete biochemical response.

Conclusion: We presented with a case of prostate cancer metastasis surrounded by the epithelium of the seminal vesicle or vas deferens.
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http://dx.doi.org/10.1002/iju5.12168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469812PMC
September 2020

Remarkable antitumor effect of nivolumab in a patient with metastatic renal cell carcinoma previously treated with a peptide-based vaccine.

IJU Case Rep 2020 Mar 9;3(2):44-48. Epub 2020 Jan 9.

Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.

Introduction: The safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer-specific peptide vaccines have not yet been established.

Case Presentation: A 71-year-old female metastatic renal cell carcinoma patient with multiple lung and pleural metastases. She had been treated with interferon alpha, sunitinib, axitinib, and pazopanib sequentially, but no clinical efficacy was observed. She participated in a clinical trial using cancer-specific peptide vaccine therapy. Initially no antitumor effect was observed, and vaccine therapy was ceased after two courses. But 3 months after the start of nivolumab, remarkable tumor shrinkage was observed at all metastatic sites, which resulted in almost complete response at 6 months. At 10 months, nivolumab was stopped due to cellulitis at the peptide vaccine inoculation site. Intriguingly, even after nivolumab discontinuation, complete response was maintained for more than 1 year.

Conclusion: We experienced a remarkable antitumor effect by nivolumab in a patient who was previously treated with vaccine therapy.
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http://dx.doi.org/10.1002/iju5.12139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292193PMC
March 2020

Renal metastasis from intrahepatic cholangiocarcinoma.

Int Cancer Conf J 2020 Apr 8;9(2):66-71. Epub 2020 Jan 8.

Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 Japan.

Metastases to the kidney are extremely rare and intrahepatic cholangiocarcinoma (ICC) is difficult to treat. In this study, we report a case of renal metastasis from ICC. A 72-year-old man who had been followed-up for chronic hepatitis C was diagnosed with ICC in the segment 8 and underwent S8 segmentectomy in 2014. During follow-up, the serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were slightly elevated, and abdominal contrast-enhanced computed tomography revealed a low-density mass preceded by rim enhancement in the arterial phase measuring 1.5 × 1.5 cm in the segment 6, and a hypovascular mass measuring 2.2 × 2.0 cm in the upper pole of the left kidney in 2017. He underwent partial hepatectomy and partial nephrectomy. Based on postoperative histological findings combined with immunohistochemical analysis, the tumors both in the liver and kidney were diagnosed as recurrent ICC.
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http://dx.doi.org/10.1007/s13691-019-00398-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109215PMC
April 2020

[The Safety of Laparoscopic Radical Cystectomy during Initial Phases in a Japanese Multicenter Cohort].

Hinyokika Kiyo 2019 Nov;65(11):439-444

The Department of Urology, Graduate School of Medicine, Kyoto University.

We evaluated the safety of laparoscopic radical cystectomy (LRC) during initial phases and its learning curve in a Japanese multicenter cohort by studying 436 patients who underwent LRC with no robot assistance at 10 institutions in Japan. We divided the patients into three groups according to cumulative surgical volume at each institution (first 10 cases, 11-30 cases, after 31 cases in each institution), and compared perioperative and pathologic variables among the three groups. The first, second, and third groups included 100, 166, 170 patients, respectively. The preoperative variables were similar in the three groups except for the rate of neoadjuvant chemotherapy. The methods of LRC procedure, such as urinary diversion, the extent of lymph node dissection, and concomitant urethrectomy or nephroureterectomy, were similar in the three groups. Mean operative time was 629, 562 and 531 minutes, respectively, and mean blood loss was 755, 650 and 435 ml, respectively. Both values decreased over time with the institution's experience. There was no significant difference among the three groups in the rate of positive surgical margin, the number of retrieved lymph nodes, and the rate of intra- and postoperative complications. LRC was safely performed during initial phases with an acceptable complication rate and without compromising oncological results, although operative time was longer and blood loss increased.
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http://dx.doi.org/10.14989/ActaUrolJap_65_11_439DOI Listing
November 2019

Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity.

Genes Dev 2019 12 14;33(23-24):1641-1656. Epub 2019 Nov 14.

Department of Molecular Genetics, Graduate school of Medical science, Kumamoto University, Kumamoto 860-8556, Japan.

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8 T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.
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http://dx.doi.org/10.1101/gad.329417.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942048PMC
December 2019

Differential predictive factors for cardiovascular events in patients with or without cancer history.

Medicine (Baltimore) 2019 Nov;98(44):e17602

Department of Cardiovascular Medicine, Graduate School of Medical Sciences.

Although attention has been paid to the relationship between malignant diseases and cardiovascular diseases, few data have been reported. Moreover, there have also been few reports in which the preventive factors were examined in patients with or without malignant disease histories requiring percutaneous coronary intervention (PCI).This was a retrospective, single-center, observational study. A total of 1003 post-PCI patients were divided into a malignant group, with current or past malignant disease, and a nonmalignant group. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, revascularization, and admission due to heart failure within 5 years of PCI. Kaplan-Meier analysis showed a significantly higher probability of the primary endpoint in the malignant group (P = .002). Multivariable Cox hazard analyses showed that in patients without a history of malignant, body mass index (BMI) and the presence of dyslipidemia were independent and significant negative predictors of the primary endpoint (BMI: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.53-0.99, P = .041; prevalence of dyslipidemia: HR 0.72, 95% CI 0.52-0.99, P = .048), and the presence of multi-vessel disease (MVD) and the prevalence of peripheral artery disease (PAD) were independent and significant positive predictors of the primary endpoint (prevalence of MVD: HR 1.68, 95% CI 1.18-2.40, P = .004; prevalence of PAD: HR 1.51, 95% CI 1.03-2.21, P = .034). In patients with histories of malignancy, no significant independent predictive factors were identified.Patients undergoing PCI with malignancy had significantly higher rates of adverse cardiovascular events but might not have the conventional prognostic factors.
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http://dx.doi.org/10.1097/MD.0000000000017602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946347PMC
November 2019

TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease.

Mol Cancer Res 2019 08 1;17(8):1613-1626. Epub 2019 May 1.

Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. IMPLICATIONS: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-1235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679785PMC
August 2019

MicroRNA-204-5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma.

Cancer Sci 2019 Jun 24;110(6):1897-1908. Epub 2019 May 24.

Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early-stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC-TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)-204-5p levels in urinary exosomes of 40-week-old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA-204-5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR-204-5p-containing exosomes. Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR-204-5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC-TFE3 fusion gene. These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.
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http://dx.doi.org/10.1111/cas.14026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549932PMC
June 2019

Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.

Sci Rep 2019 03 11;9(1):4030. Epub 2019 Mar 11.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.
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http://dx.doi.org/10.1038/s41598-019-40719-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411952PMC
March 2019

Impact of tumor size on patient survival after radical nephrectomy for pathological T3a renal cell carcinoma.

Jpn J Clin Oncol 2019 May;49(5):465-472

Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.

Purpose: We recently reported the results from a multi-institutional retrospective outcome study involving 814 patients with renal cell carcinomas (RCCs) who had undergone radical surgery and whose diagnoses were confirmed via a central pathological review. This study aimed to clarify the impact of tumor size on survival outcomes in patients with pT3aN0M0 RCC after radical nephrectomy using this cohort.

Methods: Using the Kaplan-Meier method, overall survival (OS), cancer-specific survival (CSS) and relapse-free survival (RFS) were estimated for 103 pT3aN0M0 patients. The differences in the OS, CSS and RFS according to tumor size were evaluated using the log-rank test. To identify independent prognostic factors that affected each survival outcome, clinicopathological factors were examined using univariate and multivariate analyses, and the Cox proportional hazards model.

Results: The OS, CSS and RFS rates for 26 patients with pT3a RCCs ≤4 cm were significantly better than those for 77 patients with pT3a RCCs that were 4-7 cm or >7 cm (P = 0.0064, 0.0169 and 0.0001, respectively). Tumor size and venous invasion were independent prognosticators for OS, CSS and RFS. The OS and CSS for patients with pT3a tumors ≤4 cm were comparable with those for patients with pT1 RCCs, and the RFS for patients with pT3a RCCs ≤4 cm was similar to that for patients with pT1b RCCs.

Conclusions: Tumor size significantly influenced the prognosis for patients with pT3aN0M0 RCC. This study's results suggest that the postoperative management of pT3a RCCs could be individualized according to tumor size.
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http://dx.doi.org/10.1093/jjco/hyy200DOI Listing
May 2019

Manipulation of Nephron-Patterning Signals Enables Selective Induction of Podocytes from Human Pluripotent Stem Cells.

J Am Soc Nephrol 2019 02 11;30(2):304-321. Epub 2019 Jan 11.

Department of Kidney Development, Institute of Molecular Embryology and Genetics, and

Background: Previous research has elucidated the signals required to induce nephron progenitor cells (NPCs) from pluripotent stem cells (PSCs), enabling the generation of kidney organoids. However, selectively controlling differentiation of NPCs to podocytes has been a challenge.

Methods: We investigated the effects of various growth factors in cultured mouse embryonic NPCs during three distinct steps of nephron patterning: from NPC to pretubular aggregate, from the latter to epithelial renal vesicle (RV), and from RV to podocyte. We then applied the findings to human PSC-derived NPCs to establish a method for selective induction of human podocytes.

Results: Mouse NPC differentiation experiments revealed that phase-specific manipulation of Wnt and Tgf- signaling is critical for podocyte differentiation. First, optimal timing and intensity of Wnt signaling were essential for mesenchymal-to-epithelial transition and podocyte differentiation. Then, inhibition of Tgf- signaling supported domination of the RV proximal domain. Inhibition of Tgf- signaling in the third phase enriched the podocyte fraction by suppressing development of other nephron lineages. The resultant protocol enabled successful induction of human podocytes from PSCs with >90% purity. The induced podocytes exhibited global gene expression signatures comparable to those of adult human podocytes, had podocyte morphologic features (including foot process-like and slit diaphragm-like structures), and showed functional responsiveness to drug-induced injury.

Conclusions: Elucidation of signals that induce podocytes during the nephron-patterning process enabled us to establish a highly efficient method for selective induction of human podocytes from PSCs. These PSC-derived podocytes show molecular, morphologic, and functional characteristics of podocytes, and offer a new resource for disease modeling and nephrotoxicity testing.
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http://dx.doi.org/10.1681/ASN.2018070747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362617PMC
February 2019

Advanced prostate cancer discovered with cancerous peritonitis: Case report.

Urol Case Rep 2019 Jan 22;22:31-33. Epub 2018 Oct 22.

Department of Urology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, 860-8556, Kumamoto, Japan.

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http://dx.doi.org/10.1016/j.eucr.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262798PMC
January 2019

Clinical Outcomes in Patients With Metastatic Papillary Renal-Cell Carcinoma: A Multi-Institutional Study in Japan.

Clin Genitourin Cancer 2018 12 11;16(6):e1201-e1214. Epub 2018 Aug 11.

Department of Urology, National Defense Medical College, Saitama, Japan.

Background: Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC.

Patients And Methods: This study included 51 patients who were diagnosed with PRCC at 14 institutions. Pathologic slides were reviewed by pathologists. The associations between clinical factors and overall survival (OS) were analyzed.

Results: Final pathologic diagnoses could be determined in 50 patients. Thirty-five tumors were diagnosed as PRCC (type 2 PRCC, 91.4%), and 15 were diagnosed as other histologic types. Targeted therapies (TTs) were provided to 25 mPRCC patients. Patients treated with TT survived significantly longer than those treated before the era of TT (median OS, 22.5 vs. 6.3 months; P = .0035). Median OS of patients who experienced stable disease for ≥ 9 months using single TT was 43.1 months. Patients treated with a tyrosine kinase inhibitor (TKI) as first-line TT survived longer after TT initiation than those treated with an mTOR inhibitor (median, 22.4 vs. 11.7 months; P = .2684). Patients treated with TKIs in both first- and second-line settings had significantly better survival after TT initiation than those treated with a TKI in one therapy line and an mTOR inhibitor in the other (31.4 vs. 12.9 months, P = .0172). Patients treated with a TKI as second-line TT survived significantly longer after second-line TT initiation than did those treated with an mTOR inhibitor (16.2 vs. 7.4 months, P = .0016).

Conclusion: Prognoses of patients with mPRCC were improved by TT, and TKIs appeared to be the treatment of choice in both the first- and second-line settings.
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http://dx.doi.org/10.1016/j.clgc.2018.07.028DOI Listing
December 2018

Intravesical prostatic protrusion is not always the same shape: Evaluation by preoperative cystoscopy and outcome in HoLEP.

Neurourol Urodyn 2018 09 10;37(7):2160-2166. Epub 2018 Aug 10.

Department of Urology, Kyoto University Hospital, Kyoto, Japan.

Aims: To examine how morphological differences in intravesical prostatic protrusion (IPP) predict outcome of Holmium laser enucleation of prostate (HoLEP) treatment.

Methods: We analyzed 173 patients who had undergone HoLEP in our hospital. The protrusion shape was evaluated by outpatient preoperative flexible cystoscopy and classified into five groups: A, no protrusion; B, middle lobe only; C, unilateral lobe only; D, bilateral lobes; and E, B + C or B + D. Paired-match analysis that adjusted for preoperative International Prostate Symptom Score (IPSS) voiding/storage subscores and IPP was performed between the group with middle lobe protrusion (B + E) and the group without it (C + D).

Results: Type A prostate shape was found in 23 patients, type B in 14, type C in 31, type D in 71, and type E in 34. Groups with middle lobe protrusion (B and E) had better changes in the total IPSS (P < 0.05) and the IPSS storage subscore (P < 0.01). Pair matching identified 37 patients each with or without middle lobe protrusion. The group with middle lobe protrusion had significantly more improved total IPSS (-17.5 ± 7.5 vs -13.5 ± 8.3, P < 0.05) and IPSS storage subscore (-6.9 ± 3.4 vs -4.8 ± 3.3, P < 0.05) than did those without middle lobe protrusion.

Conclusions: Patients with middle lobe protrusion had greater IPSS improvement after HoLEP than those having comparable-length IPP but without middle lobe protrusion. IPP is not always the same shape and should be clinically divided into at least two groups.
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http://dx.doi.org/10.1002/nau.23428DOI Listing
September 2018

A pilot study of highly hypofractionated intensity-modulated radiation therapy over 3 weeks for localized prostate cancer.

J Radiat Res 2018 Sep;59(5):656-663

Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.

The purpose of this pilot study was to evaluate the feasibility of highly hypofractionated intensity-modulated radiation therapy (IMRT) in 15 fractions over 3 weeks for treating localized prostate cancer based on prostate position-based image-guided radiation therapy. Twenty-five patients with National Comprehensive Cancer Network (NCCN) very low- to unfavorable intermediate-risk prostate cancer were enrolled in this study from April 2014 to September 2015 to receive highly hypofractionated IMRT (without intraprostatic fiducial markers) delivering 54 Gy in 15 fractions over 3 weeks. Patients with intermediate-risk disease underwent neoadjuvant androgen suppression for 4-8 months. Twenty-four patients were treated with highly hypofractionated IMRT, and one was treated with conventionally fractionated IMRT because the dose constraint of the small bowel seemed difficult to achieve during the simulation. Seventeen percent had very low- or low-risk, 42% had favorable intermediate-risk, and 42% had unfavorable intermediate-risk disease according to NCCN guidelines. The median follow-up period was 31 months (range, 24-42 months). No Grade ≥3 acute toxicity was observed, and the incidence rates of Grade 2 acute genitourinary and gastrointestinal toxicities were 21% and 4%, respectively. No Grade ≥2 late toxicity was observed. Biochemical relapse was observed in one patient at 15 months, and the biochemical relapse-free survival rate was 95.8% at 2 years. A prostate-specific antigen bounce of ≥0.4 ng/ml was observed in 11 patients (46%). The highly hypofractionated IMRT regimen is feasible in patients with localized prostate cancer and is more convenient than conventionally fractionated schedules for patients and health-care providers.
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http://dx.doi.org/10.1093/jrr/rry060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151631PMC
September 2018

A family case with germline and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis.

J Clin Pathol 2018 Oct 30;71(10):936-943. Epub 2018 Jun 30.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aim: We examined the genetic alterations in a mother and son with multiple eosinophilic chromophobe renal cell carcinomas (chRCCs) showing no other features.

Methods: Germline DNA and bilateral renal cell carcinoma DNA were genetically analysed by whole-exome sequencing. Candidate gene alterations in the first patient's germline were investigated in her child's germline and the chRCCs.

Results: We detected several germline gene alterations in the mother. Among the identified alterations, and mitochondrial DNA mutations were also confirmed in her son. Regarding somatic alterations in bilateral chRCCs, no common candidate gene alteration was found.

Conclusion: To the best of our knowledge, this is the first report of whole-exome sequencing revealing bilateral eosinophilic chRCCs associated with tuberous sclerosis complex in a family case without classical phenotype. These results suggest that germline and mitochondrial DNA gene mutations may be involved in the development of chRCCs in some cases.
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http://dx.doi.org/10.1136/jclinpath-2018-205211DOI Listing
October 2018

Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation.

J Bone Miner Res 2018 10 26;33(10):1785-1798. Epub 2018 Jun 26.

International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.

Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn-deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF-κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn-deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn-deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn-Tfe3-Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.3477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220829PMC
October 2018

[Two Cases of Metastatic and Recurrent Non-Clear Cell Renal Cell Carcinoma Re-Diagnosed as Renal Mucinous Tubular and Spindle Cell Carcinoma during Long-Term Follow-Up].

Hinyokika Kiyo 2018 Mar;64(3):111-115

The Department of Urology, Kyoto University Hospital.

Renal mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, low-grade renal epithelial neoplasm. MTSCC has a lower malignant potential and shows relatively good prognosis, but can be difficult to distinguish from other renal cell carcinoma (RCC) subtypes. Here, we report two cases of metastatic and recurrent renal MTSCC diagnosed after long-term follow-up. Case 1 was a 79-year-old man with a history of macroscopic hematuria in whom a right kidney mass was detected and diagnosed as RCC (cT3bN0M0). After a radical nephrectomy, microscopic findings showed that the tumor consisted of spindle cells arranged in tubular patterns embedded in sarcomatoid tissues ; we diagnosed it as unclassified RCC with sarcomatoid differentiations (pT3aN0M0). Thereafter, metastases were twice detected and resected completely. The patient had no evidence of disease at his most recent follow-up, 10 years 1 month after the initial surgery. Case 2 was in a 72-year-old man in whom a right kidney mass, swollen lymph nodes, and a lung node were incidentally detected. This tumor was diagnosed as RCC (cT4N2M1), and radical nephrectomy and lymph node dissections were carried out. From the microscopic findings, we diagnosed papillary RCC type-2 (pT3aN2M1). After the surgery, pleural and bone metastases was detected. Despite sequential treatments with IFN-α and sunitinib, the patient suffered indolent-growing metastases and died at 5 years 6 months after operation. As these patients had relatively good prognoses despite assumed aggressive RCC subtypes, we reviewed their pathological findings. In both cases, tumor samples showed tubules lined by short cuboidal cells that were set within myxoid stromata and spindle cells ; we finally diagnosed these cases as renal MTSCC.
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http://dx.doi.org/10.14989/ActaUrolJap_64_3_111DOI Listing
March 2018

[Clinical Utility of Upper Urinary Tract Reconstruction by Ileal-Ureter Substitution].

Hinyokika Kiyo 2018 Mar;64(3):87-94

The Department of Urology, Kyoto University Graduate School of Medicine.

We retrospectively reviewed the indications and outcomes of ileal-ureter substitution cases for complex ureteral reconstruction. We analyzed the patient clinical characteristics, outcomes, and complications of eight patients who had ileal ureter substitution surgery at Kyoto University Hospital between 2009 and 2016. The median patient age was 55.5 years (36-79), and the median follow up period was 25.5 months (7-85). Seven patients had unilateral ureteral obstruction (right:left=4:3), and one had bilateral ureteral obstruction. The etiologies of the ureteral defects were ureteral stricture due to non-urologic malignant tumorinvasion (n=2), benign ureteral stricture (n=2), anastomotic stricture after cystectomy (n=2), and iatrogenic ureteral injury (n=2). The mean length of operation time was 384.7 minutes (median 323 minutes, 242-397), and the mean hospital stay was 32.9 days (median 31 days, 19-41). Simple anastomosis of an untailored ileal segment to ureter and bladder was performed in 5 cases, bilateral ureteral anastomosis to a single ileal segment in one case, and in the remaining two cases, the ileal ureter was anastomosed to ileal conduit or neobladder. A nipple valve was used as the antireflux mechanism, in 2 cases but not in the remaining 6 cases. The outcome was favourable in all cases with no stricture and no requirement for further intervention. There was no significant deterioration of renal function in any patient, and no metabolic abnormality was detected. The ileal-ureter substitution appears to be a reasonable option, allowing nephron sparing in complex ureteral reconstruction cases.
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http://dx.doi.org/10.14989/ActaUrolJap_64_3_87DOI Listing
March 2018

Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4 T cells expressing converged T-cell receptor genes .

Oncoimmunology 2018;7(4):e1415687. Epub 2018 Jan 5.

Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto, Japan.

DEP domain containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1) are human cancer testis antigens that are frequently overexpressed in urinary bladder cancer. In a phase I/II clinical trial, a DEPDC1- and MPHOSPH1-derived short peptide vaccine demonstrated promising efficacy in preventing bladder cancer recurrence. Here, we aimed to identify long peptides (LPs) derived from DEPDC1 and MPHOSPH1 that induced both T-helper (Th) cells and tumor-reactive cytotoxic T lymphocytes (CTLs). Stimulation of peripheral blood mononuclear cells (PBMCs) from healthy donors with the synthetic DEPDC1- and MPHOSPH1-LPs predicted to bind to promiscuous human leukocyte antigen (HLA) class II molecules by a computer algorithm induced specific CD4 T cells as revealed by interferon-γ enzyme-linked immunospot assays. Three of six LPs encompassed HLA-A2- or -A24-restricted CTL epitopes or both, and all six LPs stimulated DEPDC1- or MPHOSPH1-specific Th cells restricted by promiscuous and frequently observed HLA class II molecules in the Japanese population. Some LPs are naturally processed from the proteins in DCs, and the capacity of these LPs to cross-prime CTLs was confirmed using HLA-A2 or -A24 transgenic mice. The LP-specific and HLA class II-restricted T-cell responses were also observed in PBMCs from patients with bladder cancer. Repeated stimulation of PBMCs with DEPDC1-LPs and MPHOSPH1-LPs yielded clonal Th cells expressing specific T-cell receptor (TCR)-α and β genes. These DEPDC1- or MPHOSPH1-derived LPs may have applications in immunotherapy in patients with bladder cancer, and the TCR genes identified may be useful for monitoring of Th cells specific to LPs .
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http://dx.doi.org/10.1080/2162402X.2017.1415687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889196PMC
January 2018

CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis.

Cancer Sci 2018 May 14;109(5):1723-1730. Epub 2018 Apr 14.

Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

CD169 macrophages are suggested to play a pivotal role in establishing anti-tumor immunity. They capture dead tumor cell-associated antigens and transfer their information to lymphocsytes, including CD8 T cells, which is important for successful tumor suppression. This study aimed to determine the prognostic significance of CD169 macrophages residing in the tumor-draining lymph nodes from cases of bladder cancer. In this retrospective study, 44 bladder cancer patients who received radical cystectomy were examined. The abundance of CD169 macrophages in the regional lymph nodes and the number of CD8 T cells in the primary tumor were investigated by immunohistochemistry. A CD169 score was calculated based on the intensity of CD169 staining and the proportion of CD169 macrophages, and the scores were compared to the patients' clinicopathological parameters. A high CD169 score was significantly associated with low T stage and with a high number of CD8 T cells infiltrating into the tumor. The group with high CD169 expression had significantly longer cancer-specific survival than the group with low CD169 expression (5-year cancer-specific survival rate: 83.3% vs 31.3%). In a multivariate analysis, the CD169 score was identified as a strong and independent favorable prognostic factor for cancer-specific survival. Our findings suggest that CD169 macrophages in the lymph nodes enhance anti-tumor immunity by expanding CD8 T cells in bladder cancer. The CD169 score may serve as a novel marker for the evaluation of bladder cancer prognosis.
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http://dx.doi.org/10.1111/cas.13565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980134PMC
May 2018

Phenotypical change of tumor-associated macrophages in metastatic lesions of clear cell renal cell carcinoma.

Med Mol Morphol 2018 Mar 7;51(1):57-63. Epub 2017 Dec 7.

Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuouku, Kumamoto, 860-8556, Japan.

Macrophages are the main immune cells of the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). A high density of CD163 or CD204 tumor-associated macrophages (TAMs), rather than the density of total TAMs, is known to be linked to poor clinical outcome. In the present study, we investigated the phenotypical differences between the paired primary and metastatic lesions in ccRCC cases. Using immunostaining, the densities of CD163 and CD204 TAMs in metastatic lesions were found to be significantly lower compared to primary lesions, although the total number of TAMs was increased in metastatic lesions. Since CD163 and CD204 are considered to be the markers of an M2/protumor phenotype in macrophages, TAMs in metastatic lesions are suggested to have a greater M1/inflammatory function compared with those from primary lesions. These findings give new insights in regard to the immunological status of metastatic lesions of ccRCC.
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http://dx.doi.org/10.1007/s00795-017-0174-7DOI Listing
March 2018
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