Details of a Researcher - Kosaka, Takeo

Papers - Kosaka, Takeo

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Interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy: A case report

Yanai Y., Kosaka T., Hongo H., Oya M.

BMC Cancer (BMC Cancer) 19 ( 1 ) 2019.07

© 2019 The Author(s). Background: Interstitial pneumonitis is a rare reaction in a previously irradiated area of pulmonary or thoracic lesion after treatment with anticancer drugs such as taxanes. Case presentation: A 66-year-old man presented with a fever and dyspnea after treatment with cabazitaxel for castration-resistant prostate cancer. He was treated with an intravenous broad-spectrum antimicrobial agent, however he complained of dyspnea and had a pulse oximetric saturation of 80% while breathing room air. The patients had been treated for bone metastases with 37.5 Gy to the thoracic spine (Th 7) as a local radiotherapy. Radiological images showed pulmonary interstitial opacities in the irradiated field of the both lungs. The steroid pulse therapy was started. The patient's dyspnea disappeared and the interstitial opacities had also improved. Conclusions: This report is a case of interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy.

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Complete response with early introduction of cabazitaxel in a patient with multiple lung metastases of castration-resistant prostate cancer following the early detection of metastases using liquid biopsy: A case report

Kosaka T., Hongo H., Oya M.

BMC Cancer (BMC Cancer) 19 ( 1 ) 2019.06

© 2019 The Author(s). Background: Cabazitaxel (CBZ) chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) is believed to be palliative because the radiological response rate is low and a durable response is rare. Here, we describe a rare case of a patient with mCRPC who was treated with CBZ chemotherapy and showed a durable radiological response and a complete biochemical response. Case presentation: A 43-year-old man with prostate cancer and metastasis of the pubic bone underwent neoadjuvant androgen deprivation and docetaxel therapy, followed by laparoscopic prostatectomy, extended lymphadenectomy, and metastatectomy in 2014. Pathological examination revealed residual adenocarcinoma in the prostate and pubic bone (pathological T stage 3b, positive surgical margin). Following the operation, he received adjuvant radiation therapy (66 Gy) to the pelvic floor. His serum prostate-specific antigen (PSA) level decreased to < 0.01 ng/mL but gradually increased following docetaxel chemotherapy. Imaging findings indicated five tiny nodules in the bilateral lungs. Biopsy specimens are difficult to obtain and might not reflect the precise extent of the disease owing to heterogeneity in patients with CRPC. Thus, we performed liquid biopsy to isolate circulating tumor cells (CTCs), and overall 156 CTCs were detected per 7.5 mL. Almost all CTCs were androgen receptor-negative in the nucleus. We diagnosed the five nodules as lung metastases from docetaxel-resistant CRPC with few AR-signaling-dependent cancer cells. The patient was initiated on CBZ chemotherapy (25 mg/m2) according to the standard protocol in August 2016, instead of using a second-generation AR-targeting agent. After 2 cycles of CBZ chemotherapy, PSA level decreased to < 0.01 ng/mL and the lung metastases completely disappeared, with a reduced CTC count of < 5. To date, the patient has been receiving intermittent CBZ chemotherapy. Conclusions: We presented a rare case of a patient with mCRPC who was successfully treated with early CBZ chemotherapy. The early detection of metastasis using liquid biopsy enabled the introduction of early CBZ chemotherapy for docetaxel-resistant mCRPC.

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Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration

Shigeta K., Kosaka T., Hongo H., Yanai Y., Matsumoto K., Morita S., Mizuno R., Shinojima T., Kikuchi E., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 24 ( 5 ) 546 - 553 2019.05

ISSN 13419625

© 2019, Japan Society of Clinical Oncology. Background: Our specific aim was to investigate the prognostic value of effective duration of first androgen deprivation therapy (ADT) and to evaluate the clinical impact on early docetaxel administration with oncological outcomes in castration-resistant prostate cancer (CRPC) patients treated with docetaxel. Methods: We identified 148 mCRPC patients who were treated with 75 mg/m2 docetaxel. We defined 16 months as the threshold for the effective duration of ADT, and defined 12 months as the cut-off time for starting docetaxel from the onset of CRPC. Univariate and multivariate analyses were conducted to investigate the prognostic indicators that influenced the survival outcomes. Results: Overall, 81 (54.7%) patients died. The median 1st ADT response was 22.2 months and the median time interval from CRPC onset to docetaxel treatment was 11.7 months. Multivariate analysis indicated that visceral metastasis, bone metastasis extent of disease (EOD) ≥ 2, and effective duration of ADT < 16 months were the independent prognostic indicators for progression-free survival (PFS). Referring to cancer-specific survival (CSS), besides visceral metastasis and effective duration of ADT < 16 months, late docetaxel treatment ≥ 12 months became as the predictors for poor prognosis. Among the ADT poor-responder group (ADT < 16 months), Kaplan–Meier method showed that 1-year and 2-year CSS rates were 96.0% and 80.0% in the patients who introduced docetaxel in early setting (< 12 months), which were significantly higher than those who introduced in late settings (93.6% and 30.8%, respectively, p < 0.001). Conclusion: CRPC patients who had poor response during 1st ADT would obtain survival benefit by introducing docetaxel treatment in early stage.

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Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer

Ogihara K., Kikuchi E., Okazaki S., Hagiwara M., Takeda T., Matsumoto K., Kosaka T., Mikami S., Saya H., Oya M.

Cancer Science (Cancer Science) 110 ( 4 ) 1431 - 1441 2019.04

ISSN 13479032

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9-xCT system in order to enhance cisplatin (CDDP)-induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer-specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho-p38 MAPK protein expression by SSZ with or without CDDP were assessed in MBT-2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT-2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT-2V cells by inhibiting CD44v9 expression and upregulating phospho-p38 MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT-2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.

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Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases

Uemura H., Uemura H., Nagamori S., Wakumoto Y., Kimura G., Kikukawa H., Yokomizo A., Mizokami A., Kosaka T., Masumori N., Kawasaki Y., Yonese J., Nasu Y., Fukasawa S., Sugiyama T., Kinuya S., Hosono M., Yamaguchi I., Akagawa T., Matsubara N.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 2019

ISSN 13419625

© 2019, The Author(s). Background: Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC. Methods: Patients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality. Results: Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5). Conclusions: In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

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Clinical outcome of high dose rate brachytherapy with external beam radiotherapy for high-risk prostate cancer: A single institutional retrospective study

Shirotake S., Makino S., Suzuki K., Araki R., Kosaka T., Nishimoto K., Oyama M., Kato S.

Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology) 49 ( 1 ) 87 - 91 2019

ISSN 03682811

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Objectives: This study investigated the clinical outcome of neoadjuvant androgen deprivation therapy followed by high dose rate brachytherapy (HDR-BT, called NEH) with external beam radiotherapy (EBRT) in high-risk prostate cancer (PCa) patients in our institution. Methods: From 2007 to 2012, 192 high-risk PCa patients underwent neoadjuvant treatment—EBRT—NEH (n = 192). Relations between clinical factors (prostate-specific antigen; PSA, cT stage, Gleason score) and biochemical recurrence were retrospectively analyzed. Results: The 5- and 7-year overall survival rates were 97.9 and 91.1%. By PSA levels (PSA ≤ 20 ng/ml, 20 ng/ml < PSA≤50 ng/ml and PSA > 50 ng/ml), 5-year biochemical recurrence-free survival rates were 85.7, 84.7 and 54.5%, respectively. There were no significant differences between biochemical recurrence and cT stage or Gleason score. Conclusions: We found that NEH can contribute to better biochemical recurrence free survival of high-risk PCa patients with PSA below 50 ng/ml. High-risk PCa patients with PSA over 50 ng/ml may require more aggressive local or systemic treatment.

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No significant impact of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer

Kosaka T., Hongo H., Watanabe K., Mizuno R., Kikuchi E., Oya M.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 82 ( 6 ) 1061 - 1066 2018.12

ISSN 03445704

© 2018, The Author(s). Background: The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. Materials and methods: This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel, focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. Results: Prostate-specific antigen (PSA) decline was observed in 27 patients (57.4%), including 19 (40.0%) achieving the response defined by PSA decline ≥ 30%. The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. Twenty (42.6%) were judged to have responded to cabazitaxel with a PSA decrease ≥ 30% from the baseline. A 30% PSA response to cabazitaxel was achieved in 4 (50.0%) patients with ≧ 75 years (n = 8) and 16 (41.0%) patients with less than 75 years (n = 39). There was no significant correlation between the PSA response and patients’ age (p = 0.707). A 30% PSA response to cabazitaxel was achieved in 13 (46.4%) and 7 (36.8%) patients with and without that to docetaxel, respectively. A 30% PSA response to cabazitaxel was achieved in 5 (16.6%) and 7 (41.2%) patients who had treated with less than 10 cycles docetaxel or 10 ≦ cycles, respectively. Univariate and multivariate analyses revealed that there were no significant correlation of patient age (p = 0.537), the response to prior docetaxel therapy (p = 0.339) or cycles of docetaxel therapy (p = 0.379) with shorter OS. Conclusion: These results indicate that the introduction of cabazitaxel for Japanese mCRPC patients could result in oncological outcomes without any association with patient’s age and the profiles of previous docetaxel therapy.

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Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

Tanaka N., Katayama S., Reddy A., Nishimura K., Niwa N., Hongo H., Ogihara K., Kosaka T., Mizuno R., Kikuchi E., Mikami S., Miyakawa A., Arenas E., Kere J., Oya M., Uhlén P.

Cancer Medicine (Cancer Medicine) 7 ( 12 ) 6193 - 6204 2018.12

© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

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Aldosterone and 18-oxocortisol coaccumulation in aldosterone-producing lesions

Sugiura Y., Takeo E., Shimma S., Yokota M., Higashi T., Seki T., Mizuno Y., Oya M., Kosaka T., Omura M., Nishikawa T., Suematsu M., Nishimoto K.

Hypertension (Hypertension) 72 ( 6 ) 1345 - 1354 2018.12

ISSN 0194911X

© 2018 American Heart Association, Inc. Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1-4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6-8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value (m/z). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.

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Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer

Hongo H., Kosaka T., Oya M.

Cancer Science (Cancer Science) 109 ( 9 ) 2937 - 2945 2018.09

ISSN 13479032

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ-resistant CRPC. In order to investigate the CBZ-resistant mechanism, the establishment of a CBZ-resistant cell line is urgently needed. We established CBZ-resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G2/M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP-BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel -resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G2/M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ-resistant CRPC.

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Incidence and timing of inadvertent nephrostomy catheter displacement in patients with ureteral obstruction

Niwa Naoya, Matsumoto Kazuhiro, Kikuchi Eiji, Yazawa Satoshi, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Shinoda Kazunobu, Mizuno Ryuichi, Shinojima Toshiaki, Asanuma Hiroshi, Oya Mototsugu

Clinical Nephrology (Clinical Nephrology) 90 ( 2 ) 112 - 116 2018.08

ISSN 0301-0430

Introduction: To evaluate nephrostomy catheter displacement, we assessed the cumulative nephrostomy catheter displacement rate in patients with percutaneous nephrostomy and compared the nephrostomy displacement rates between pigtail and balloon catheters. Materials and methods: Between 2003 and 2011, 87 patients who underwent percutaneous nephrostomy catheter placement and more than one subsequent catheter replacement were retrospectively identified. We evaluated their inadvertent nephrostomy catheter displacement. Results: 20 patients (23.0%) experienced incidental nephrostomy catheter displacement during the follow-up period. Kaplan-Meier analysis revealed that the 1-year nephrostomy catheter displacement-free survival rate was 62 ± 9%. No significant independent risk factors for predicting nephrostomy catheter displacement were identified, including the type of catheter. The median time from initial placement to displacement of pigtail catheters was shorter than that of balloon catheters. Conclusion: There were no significant differences in the nephrostomy catheter displacement-free survival rates between the two types of catheters. Regardless of the type of catheter, our results indicated that careful handling and guiding during catheter placement are important for all patients because of the high risk of inadvertent events.

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Fatal Intracranial Hemorrhage Due to Thrombocytopenia in a Patient with Castration-Resistant Prostate Cancer Showing Extensive Bone Uptake of Injected 223Ra Dichloride

Nakahara Tadaki, Owaki Yoshiki, Kosaka Takeo, Fukada Junichi, Ichimura Akira, Jinzaki Masahiro

Clinical Nuclear Medicine (Clinical Nuclear Medicine) 43 ( 7 ) 546 - 547 2018.07

ISSN 0363-9762

A 64-year-old man with castration-resistant prostate cancer received ²²³Ra injection to treat bone metastases. The patient underwent a ²²³Ra SPECT scan after the first ²²³Ra injection in which there was increased uptake all over the spine. Spine-to-background activity ratio in the patient was approximately three times greater than normal spine-to-background activity ratios in ²²³Ra SPECT obtained from the other patients. Eight days after the fifth injection, the patient exhibited a very poor neurologic examination and died of intracranial hemorrhage due to severe thrombocytopenia (platelet counts, 23,000/mm³). The extensive radiation to the spine may have enhanced myelophthisic process in this case.

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PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer

Yasumizu Yota, Hongo Hiroshi, Kosaka Takeo, Mikami Shuji, Nishimoto Koshiro, Kikuchi Eiji, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 45 ) 27698 - 27707 2018.06

ISSN 1949-2553

The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/ Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC.

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Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non–muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

Niwa N., Kikuchi E., Matsumoto K., Kosaka T., Mizuno R., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 6 ) 306.e1 - 306.e8 2018.06

ISSN 10781439

© 2018 Elsevier Inc. Purpose: It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). Materials and methods: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). Result: The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. Conclusions: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.

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New targeted approach to CRPC

Kosaka T., Oya M.

Hormone Therapy and Castration Resistance of Prostate Cancer (Hormone Therapy and Castration Resistance of Prostate Cancer) 375 - 385 2018.05

ISSN 9789811070129

© Springer Nature Singapore Pte Ltd. 2018. All rights reserved. Our understanding of the heterogeneity and genetic characteristics of CRPC demonstrates underlying their complexity, which has been thought to be associated with their intractability. Recent advance of integrative next generation sequencing unveiled the extensive mutational landscape of metastatic CRPC, many of which can be a targetable mutation and been linked to ongoing clinical trials. Molecular stratification of patient groups will clearly be critical to successful drug development and clinical trials from the view point of precision medicine. In this review, we discuss the potential of new targeted approach to impact the clinical management of CRPC.

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Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer

Hagiwara Masayuki, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

BMC Cancer (BMC Cancer) 18 ( 1 ) 2018.01

ISSN 1471-2407

Background: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. Methods: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. Results: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. Conclusions: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.

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Vasohibin-1 as a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer

Kobayashi Hiroaki, Kosaka Takeo, Mikami Shuji, Miyazaki Yasumasa, Matsumoto Kazuhiro, Kikuchi Eiji, Miyajima Akira, Kameyama Kaori, Sato Yasufumi, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 12 ) 10203 - 10210 2018.01

ISSN 1949-2553

Background: We previously reported high expression of vasohibin-1 (VASH1), which is specifically expressed in activated vascular endothelial cells, was a prognostic indicator of disease progression in prostate cancer. The aim of this study was to assess whether VASH1 expression at the area of normal prostatic tissue as well as that of intratumoral tissue could reflect the grade of malignancy of prostate cancer. Results: Pathological upgrade of Gleason Score ≥7 by radical prostatectomy was observed in 48 patients (upgraded group). The median VASH1 densities of the intratumoral and normal areas were 9.7 ± 9.5 and 13.3 ± 11.8, respectively, and the median MVDs were 58.6 ± 20.3 and 64.1 ± 23.5, respectively. We detected a strong positive correlation with each other for both VASH1 density (ρ = 0.589, p < 0.001) and MVD (ρ = 0.342, p < 0.001). VASH1 density was significantly higher in the upgreaded group than in the non-upgraded group regardless of prostatic location (intratumoral area: p < 0.001, normal area: p < 0.001). Conclusions: Even if the tumor volume was low in biopsy samples, VASH1 density reflected the grade of malignancy throughout the prostate. These results suggested that VASH1 expression could be a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer. Materials and Methods: Among the 1177 patients who underwent radical prostatectomy, 104 patients diagnosed with Gleason Score ≤6 and positive cores ≤3 were included. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD), and those with activated endothelial cells as VASH1 density using prostatic biopsy samples, and evaluated the association between their expressions and clinicopathological findings.

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Purified Protein Derivative Skin test prior to bacillus Calmette-Guérin Therapy May have Therapeutic Impact in Patients with Nonmuscle Invasive Bladder Cancer

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Journal of Urology (Journal of Urology) 199 ( 6 ) 1446 - 1451 2018.01

ISSN 0022-5347

Purpose: We investigated the clinical impact of the purified protein derivative skin test prior to bacillus Calmette-Guérin therapy in patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin therapy. Materials and Methods: A total of 498 patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin were included in study, of whom 320 underwent the purified protein derivative skin test 1 to 2 weeks prior to therapy. Oncologic outcomes and the rate of bacillus Calmette-Guérin related side effects were statistically evaluated. Results: The mean ± SD 5-year recurrence-free survival rate in patients who did vs did not undergo the purified protein derivative skin test was 66.6% ± 2.8% and 59.1% ± 4.1%, respectively, which was significantly different (p = 0.048). No significant difference was observed in the progression-free survival rate between patients who did vs did not undergo the test. Multivariate Cox regression analysis revealed that a history of recurrence (HR 1.59, p = 0.02), multiple tumors (HR 1.95, p <0.01), the bacillus Calmette-Guérin Connaught strain (HR 0.71, p = 0.04), 7 or more bacillus Calmette-Guérin instillations (HR 0.70, p = 0.04) and undergoing the purified protein derivative skin test (HR 0.72, p = 0.04) were independently associated with tumor recurrence. Major bacillus Calmette-Guérin related side effects were noted in 77 of the 320 patients (24.1%) who did vs 27 of the 178 (15.2%) who did not undergo the test, which was significantly different (p = 0.02). Conclusions: The purified protein derivative skin test prior to bacillus Calmette-Guérin treatment enhances the therapeutic effects of this treatment and potentially results in a higher incidence of major bacillus Calmette-Guérin related side effects. Combination therapy with bacillus Calmette-Guérin using the purified protein derivative skin test may improve the oncologic outcomes of that therapy.

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Change of the 5α/5β ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Homma Keiko, Yasumizu Yota, Hattori Seiya, Kosaka Takeo, Shinoda Kazunobu, Miyajima Akira, Oya Mototsugu

Clinical Biochemistry (Clinical Biochemistry) 55 36 - 41 2018.01

ISSN 0009-9120

Background: The effects of the administration of dutasteride (DUT) on steroid metabolite pathways in BPH patients have not been examined. Methods: Urine and blood samples as well as clinical parameters were prospectively collected after the administration of DUT to 60 BPH patients, and after its withdrawal in another set of 25 BPH patients. Urine samples were assessed using gas chromatography/mass spectrometry for the urinary steroid profile (USP), which simultaneously measures 63 steroid metabolites. We examined pharmacological changes in the 5α/5β ratio of urinary metabolites and their relationships with clinical parameters in patients treated with DUT. Results: The mean urinary androsterone/etiocholanolone (An/Et) ratio in sex-steroid pathways significantly decreased from 1.39 to 0.02 (p < 0.01). Urinary metabolites in other steroid pathways such as 5αTHF/5βTHF in the glucocorticoid pathway and 5αTHB/5βTHB in the mineralocorticoid pathway also significant decreased after the DUT treatment. As compared to baseline level, the mean An/Et ratios in patients with the withdrawal of DUT were 0.7%, 1.4%, 12.6%, and 82.4% at just before, one month, 3 months, and 6 months after the withdrawal of DUT, respectively. All other steroid pathways changed in a similar manner without the aggravation of urinary symptoms. The recovery ratio of An/Et in USP before and 3 months after the withdrawal of DUT correlated with the recovery ratio of serum PSA levels (ρ = 0.61, p < 0.01). Conclusion: Urinary 5α/5β metabolites in all pathways were strongly suppressed after the administration of DUT for one month and the pharmacological effect of DUT prolonged even after withdrawal of DUT.

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Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2018.01

ISSN 1078-1439

Purpose: It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). Materials and methods: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). Result: The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. Conclusions: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.

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