| 1. |
Taku Fujimura, Takeo Maekawa, Hiroshi Kato, Takamichi Ito, Shigeto Matsushita, Koji Yoshino, Yasuhiro Fujisawa, Shoichiro Ishizuki, Kojiro Segawa, Jun Yamamoto, Akira Hashimoto, Yumi Kambayashi, Yoshihide Asano, Treatment for taxane-resistant cutaneous angiosarcoma: A multicenter study of 50 Japanese cases., The Journal of Dermatology, 10.1111/1346-8138.16786, 2023.03, Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane-switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second-line chemotherapy were evaluated retrospectively in 50 Japanese taxane-resistant CAS patients. Although there was no significant difference in progression-free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane-switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane-resistant CAS in second-line therapy based on the safety profiles.. |
| 2. |
Gaku Tsuji, Akiko Hashimoto-Hachiya, Ayako Yumine, Masaki Takemura, Makiko Kido-Nakahara, Takamichi Ito, Kazuhiko Yamamura, Takeshi Nakahara, PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes., Journal of Dermatological Science, 10.1016/j.jdermsci.2023.04.007, 2023.04, BACKGROUND: Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. OBJECTIVE: To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. METHODS: We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. RESULTS: We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. CONCLUSION: These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.. |
| 3. |
Takamichi Ito, Hiroki Hashimoto, Yumiko Kaku-Ito, Yuka Tanaka, Takeshi Nakahara, Nail Apparatus Melanoma: Current Management and Future Perspectives. [Review], Journal of Clinical Medicine, 10.3390/jcm12062203, 12, 6, 2023.03, Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.. |
| 4. |
Yuka Tanaka, Takamichi Ito, Yumiko Kaku-Ito, Keiko Tanegashima, Gaku Tsuji, Makiko Kido-Nakahara, Yoshinao Oda, Takeshi Nakahara, Human epidermal growth factor receptor 3 serves as a novel therapeutic target for acral melanoma., Cell Death Discovery, 10.1038/s41420-023-01358-5, 9, 1, 54-54, 2023.02, Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients' AM tissues with various intensities and HER3 expression was significantly correlated with patient's disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.. |
| 5. |
Taku Fujimura, Sadanori Furudate, Takeo Maekawa, Hiroshi Kato, Takamichi Ito, Shigeto Matsushita, Koji Yoshino, Akira Hashimoto, Yusuke Muto, Kentaro Ohuchi, Ryo Amagai, Yumi Kambayashi, Yasuhiro Fujisawa, Cutaneous angiosarcoma treated with taxane-based chemoradiotherapy: A multicenter study of 90 Japanese cases., Skin Health and Disease, 10.1002/ski2.180, 3, 1, e180, 2023.02, Cutaneous angiosarcoma (CAS) is rare and most previous studies of CAS have been small case series, and randomized, phase II studies of CAS are limited. Since treatment options for CAS are controversial, and because only paclitaxel should be recommended based on high-level evidence, it is important to evaluate the efficacy of another taxane-derived agents, docetaxel, in real-world practice. The efficacy and safety profiles of chemoradiotherapy using taxane-based agents, docetaxel and paclitaxel, were retrospectively examined in the maintenance setting in 90 Japanese CAS patients, including 35 docetaxel-treated cases and 55 paclitaxel-treated cases. Overall survival and dose duration time of the patient group treated with docetaxel was equivalent to that with paclitaxel, even in the cohorts with metastasis. Adverse events due to docetaxel and paclitaxel were observed in 77.1% and 69.1% of cases, respectively. The incidence ratio of total severe adverse events tended to be higher in the docetaxel-treated group (40.0%) than in the paclitaxel-treated group (23.6%). Peripheral neuropathy occurred only in the paclitaxel-treated group, whereas high-grade interstitial pneumonia developed only in the docetaxel-treated group. In addition, we also evaluate 19 patients selected other taxanes, 17 patients selected eribulin methylate, 11 patients pazopanib, and 2 patients selected nivolumab as second-line chemotherapy. The efficacy of a monthly docetaxel regimen is equivalent to a three-weekly paclitaxel regimen evaluated by Overall survival and DDT, even in the cohorts with metastasis, and it is a tolerable protocol for CAS as a maintenance therapy in the Japanese population.. |
| 6. |
Yasuhiro Fujisawa, Kenjiro Namikawa, Koji Yoshino, Yukiko Kiniwa, Takamichi Ito, Hiroshi Kato, Shigeto Matsushita, Toshihiko Hoashi, Yasuhiro Nakamura, Shusuke Yoshikawa, Takuya Miyagawa, Jun Asai, Taisuke Matsuya, Satoshi Fukushima, Jyunji Kato, Tatsuya Takenouchi, Hiroshi Uchi, Mamiko Masuzawa, Teruki Yanagi, Takeo Maekawa, Combined use of nivolumab and ipilimumab among Japanese melanoma patients: Multi-center, retrospective study of 111 cases., The British Journal of Dermatology, 10.1093/bjd/ljad114, 2023.04. |
| 7. |
Takashi Inozume, Kenjiro Namikawa, Hiroshi Kato, Shusuke Yoshikawa, Yukiko Kiniwa, Koji Yoshino, Satoru Mizuhashi, Takamichi Ito, Tatsuya Takenouchi, Shigeto Matsushita, Yasuhiro Fujisawa, Takamitsu Matsuzawa, Satoru Sugihara, Jun Asai, Hiroshi Kitagawa, Takeo Maekawa, Taiki Isei, Masahito Yasuda, Naoya Yamazaki, Hisashi Uhara, Yasuhiro Nakamura, Analyzing the relationship between the efficacy of first-line immune checkpoint inhibitors and cumulative sun damage in Japanese patients with advanced BRAF wild-type nonacral cutaneous melanoma: A retrospective real-world, multicenter study., Journal of Dermatological Science, 10.1016/j.jdermsci.2023.03.008, 2023.03, BACKGROUND: Efficacy of anti-PD-1 antibody monotherapy (PD1) or anti-PD-1 plus anti-CTLA-4 combination therapy (PD1 +CTLA4) for melanoma is affected by its clinical subtype. The amount of tumor mutation burden (TMB) caused by cumulative sun damage (CSD) is occasionally used to explain this; however, their relationship in Japanese nonacral cutaneous melanoma (NACM) is still unclear. OBJECTIVE: To analyze the ICI efficacy and its relationship with CSD of the primary lesion in Japanese patients with NACM. METHODS: Japanese patients with advanced BRAF wild-type NACM who received first-line ICIs were recruited. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), and the degree of solar elastosis (SE) were evaluated. RESULTS: A total of 146 patients (PD1 group 113 and PD1 +CTLA4 group 33) were included. No significant differences in ORR were observed between the PD1 and PD1 +CTLA4 groups (35 % vs. 36 %; P = 0.67) or PFS and OS (median PFS 6.1 months vs. 8.5 months; P = 0.46, median OS 28.1 months vs. not reached; P = 0.59). Multivariate survival analysis revealed that PD1 +CTLA4 did not prolong the PFS and OS. The SE score had no effect on either PFS or OS. CONCLUSIONS: ICI efficacy was not as high as those reported in Western countries, and PD1 +CTLA4 did not present better clinical efficacy compared to PD1. Indicators of CSD did not serve as a predictor for clinical advantage. These findings may partially support the theory that ICI efficacy is affected by CSD; however, other unrecognized factors may also exist.. |
| 8. |
Yuka Tanaka, Maho Murata, Keiko Tanegashima, Yoshinao Oda, Takamichi Ito, Nectin cell adhesion molecule 4 regulates angiogenesis through Src signaling and serves as a novel therapeutic target in angiosarcoma, Scientific Reports, 10.1038/s41598-022-07727-x, 12, 1, 2022.12, Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody–drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.. |
| 9. |
Yusuke Muto, Yumi Kambayashi, Hiroshi Kato, Satoshi Fukushima, Takamichi Ito, Takeo Maekawa, Yasuhiro Fujisawa, Koji Yoshino, Hiroshi Uchi, Shigeto Matsushita, Yuki Yamamoto, Ryo Amagai, Kentaro Ohuchi, Akira Hashimoto, Taku Fujimura, Adjuvant Anti-PD-1 Antibody Therapy for Advanced Melanoma: A Multicentre Study of 78 Japanese Cases., Acta Dermato-Venereologica, 10.2340/actadv.v102.678, 102, adv00756, 2022.08, Anti-PD-1 antibodies (Abs) are among the optimal adjuvant therapies for melanoma at high risk of recurrence, especially BRAF wild-type melanoma, but the anti-tumour effects of anti-PD-1 Abs in the adjuvant setting for acral melanoma have not been evaluated previously. The aim of this study was to analyse the efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting in an Asian population including a high ratio of acral melanoma. The efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting were retrospectively analysed in 78 Japanese patients with advanced melanoma, including 31 cases (40%) of acral melanoma. Overall relapse-free survival was 60.3% (47 of 78 cases, 95% confidence interval (CI) 49.2–70.4%), and 39.7% of patients (31 of 78 patients, 95% CI 29.6–50.8%) relapsed during the adjuvant PD-1 Ab treatment. Six cases (7.9%) discontinued the protocol due to serious adverse events. One case (1.3%) discontinued the protocol due to trauma. The relapse-free survival of acral melanoma was 25.8%, whereas that of high cumulative sun damage was 60.0%, and that of low cumulative sun damage was 57.1%. The acral type had a significantly lower 12-month relapse-free survival than other cutaneous types (p = 0.029). The acral type appeared to be an independent prognostic factor on multivariate analysis (p = 0.015). Adverse events due to anti-PD-1 antibody were observed in 37.1% overall. The results of this study suggest that anti-PD-1 Ab therapy in the adjuvant setting is less effective for acral melanoma than for other cutaneous types.. |
| 10. |
Hiroki Hashimoto, Takamichi Ito, Current Management and Treatment of Extramammary Paget's Disease. [review], Current Treatment Options in Oncology, 10.1007/s11864-021-00923-3, 23, 6, 818-830, 2022.06, OPINION STATEMENT: Extramammary Paget's disease (EMPD) is a rare neoplastic disease affecting areas rich in apocrine glands in the elderly. EMPD clinically resembles a benign inflammatory skin disease, and ill-defined tumor borders can lead to misdiagnosis and incomplete excision. Several prognostic factors have been reported, including nodule formation, tumor thickness, tumor invasion, lymphovascular invasion, and a perianal location, which are characteristic of primary tumors. EMPD typically presents as an in situ tumor spreading horizontally within the epidermis and then invading into the dermis as it transitions to a vertical growth phase. For this reason, tumor thickness, rather than tumor size, is correlated with patient prognosis. The best treatment for resectable EMPD is complete surgical removal of the tumor. EMPD sometimes has unclear tumor borders, and it can unexpectedly spread beyond its clinical boundaries. Surgical resection in such cases is often associated with tumor-positive margins, which can result in recurrence. However, surgical excision with wide margins may deteriorate patients' organ functions and quality of life. Mohs micrographic surgery may be ideal for controlling the surgical margins and minimizing the sacrifice of normal tissue, but this technique is not always feasible because of constraints associated with the medical environment. No standard treatment for unresectable or metastatic EMPD has been established. Although conventional chemotherapy has been used as the first-line treatment, it frequently causes adverse events, and consequently, targeted therapy will become more valuable in the near future.. |
| 11. |
Hiroki Hashimoto, Yuka Tanaka, Maho Murata, Takamichi Ito, Nectin-4: a Novel Therapeutic Target for Skin Cancers. [review], Current Treatment Options in Oncology, 10.1007/s11864-022-00940-w, 23, 4, 578-593, 2022.04, OPINION STATEMENT: Nectin-4 is a tumor-associated antigen that is highly expressed on various cancer cells, and it has been further proposed to have roles in tumor development and propagation ranging from cellular proliferation to motility and invasion. Nectin-4 blockade reduces tumor proliferation and induces apoptosis in several malignancies. Nectin-4 has been used as a potential target in antibody-drug conjugate (ADC) development. Enfortumab vedotin, an ADC against Nectin-4, has demonstrated efficacy against solid tumor malignancies. Enfortumab vedotin has received US Food and Drug Administration approval for treating urothelial cancer. Furthermore, the efficacy of ADCs against Nectin-4 against solid tumors other than urothelial cancer has been demonstrated in preclinical studies, and clinical trials examining the effects of enfortumab vedotin are ongoing. Recently, Nectin-4 was reported to be highly expressed in several skin cancers, including malignant melanoma, cutaneous squamous cell carcinoma, and extramammary Paget's disease, and involved in tumor progression and survival in retrospective studies. Nectin-4-targeted therapies and ADCs against Nectin-4 could therefore be novel therapeutic options for skin cancers. This review highlights current knowledge on Nectin-4 in malignant tumors, the efficacy of enfortumab vedotin in clinical trials, and the prospects of Nectin-4-targeted agents against skin cancers.. |
| 12. |
Ito T, Hashimoto H, Tanaka Y, Tanegashima K, Murata M, Ichiki T, Iwasaki T, Oda Y, Kaku-Ito Y., TROP2 Expression in Sebaceous and Sweat Gland Carcinoma., J Clin Med. 2022 Jan 25;11(3):607., 2022.01. |
| 13. |
Chi-Che Hsieh, Yue-Chiu Su, Kuan-Ying Jiang, Takamichi Ito, Ting-Wei Li, Yumiko Kaku-Ito, Shih-Tsung Cheng, Li-Tzong Chen, Daw-Yang Hwang, Che-Hung Shen, TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway., Journal of Advanced Research, 10.1016/j.jare.2022.03.005, 43, 45-57, 2023.01, Introduction: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. Objectives: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. Methods: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. Results: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. Conclusions: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.. |
| 14. |
Ito T, Tanegashima K, Tanaka Y, Hashimoto H, Murata M, Oda Y, Kaku-Ito Y., Trop2 Expression in Extramammary Paget's Disease and Normal Skin., Int J Mol Sci. 2021 Jul 19;22(14):7706., 2021.06. |
| 15. |
Hashimoto H, Kaku-Ito Y, Oda Y, Ito T., CDK4: A Novel Therapeutic Target for Extramammary Paget's Disease., Front Oncol. 2021 Jul 29;11:710378., 10.3389/fonc.2021.710378, 11, 710378-710378, 2021.06, BACKGROUND: The outcome of extramammary Paget's disease (EMPD) is poor when it progresses to metastasis because of the lack of effective systemic therapies. Recently, CDK4-targeted therapy has attracted attention as a potential therapeutic target for some cancers. The aim of this study was to analyze the impact of CDK4 expression on the survival of patients with EMPD. METHODS: We retrospectively reviewed 110 patients with EMPD. We conducted immunohistochemical analysis of CDK4 and cyclin D1 expression, and assessed the association between their expression and survival. RESULTS: Most EMPD lesions (108/110, 98.2%) were positive for CDK4 staining and there was a positive correlation between CDK4 expression and cyclin D1 expression (r = 0.54, p |
| 16. |
Fujisawa Y, Ito T, Kato H, Irie H, Kaji T, Maekawa T, Asai J, Yamamoto Y, Fujimura T, Nakai Y, Yasuda M, Matsuyama K, Muto I, Matsushita S, Uchi H, Nakamura Y, Uehara J, Yoshino K., Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases., Eur J Cancer 145: 210-220, 2021, 2021.04. |
| 17. |
Matsukane R, Watanabe H, Minami H, Hata K, Suetsugu K, Tsuji T, Masuda S, Okamoto I, Nakagawa T, Ito T, Eto M, Mori M, Nakanishi Y, Egashira N., Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events., Sci Rep 11: 1324., 2021, 2021.04. |
| 18. |
Hashimoto H, Ito T, Yamada Y, Oda Y, Furue M., Eosinophilic infiltration discriminates lichen-planus-like eruption caused by an immune checkpoint inhibitor from ordinary lichen planus., J Dermatol 48: e102-103, 2021., 2021.04. |
| 19. |
Tanaka Y, Murata M, Shen CH, Furue M, Ito T*., NECTIN4: A novel therapeutic target for melanoma., Int J Mol Sci 22: 976., 2021., 2021.04. |
| 20. |
Ide T, Ito T, Wada-Ohno M, Furue M., Preoperative screening CT/PET(-CT) scans for acral melanoma: Is it necessary?, J Clin Med 10: 811., 2021, 2021.04. |
| 21. |
Fujimura T, Yoshino K, Kato H, Fujisawa Y, Nakamura Y, Yamamoto Y, Kurimoto K, Ito T, Matsushita S, Maekawa T, Ohuchi K, Amagai R, Muto Y, Kambayashi Y, Hashimoto A, Aiba S., Case series of BRAF mutated advanced melanoma treated with encorafenib plus binimetinib combined therapy., J Dermatol 48: 397-400, 2021., 2021.04. |
| 22. |
Hashimoto H, Ito T, Ichiki T, Yamada Y, Oda Y, Furue M., The clinical and histopathological features of cutaneous immune-related adverse events and their outcomes., J Clin Med 10: 728., 2021, 2021.04. |
| 23. |
Hashimoto H, Kaku-Ito Y, Furue M, Ito T., The outcome of chemotherapy for metastatic extramammary Paget’s disease., J Clin Med 10: 739., 2021, 2021.04. |
| 24. |
Yuka Tanaka, Maho Murata, Yoshinao Oda, Masutaka Furue, Takamichi Ito, Nectin cell adhesion molecule 4 (Nectin4) expression in cutaneous squamous cell carcinoma: A new therapeutic target?, Biomedicines, 10.3390/biomedicines9040355, 9, 4, 2021.04, Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is rising because of the aging population. Nectin cell adhesion molecule 4 (NECTIN4) is involved in the progression of tumors and has attracted interest as a potential therapeutic target. However, little is known about the expression and significance of NECTIN4 in cSCC. The aim of this study was to determine the expression and function of NECTIN4 in cSCC. Immunohistological NECTIN4 expression was investigated in tissues from 34 cSCC patients. Using an A431 human SCC cell line, the role of NECTIN4 in the regulation of cell–cell attachment and migration and proliferation was assessed. NECTIN4 was expressed in most cSCC tissues and on the plasma membrane of A431 cells. Silencing of NECTIN4 prevented cell–cell attachment and induced the expression migration-related molecules, leading to an increase in cell migration. Knockdown of NECTIN4 downregulated extracellular signal-regulated kinase signaling, decreased cyclin D1 expression, and inhibited cell proliferation. These results show that NECTIN4 is expressed in cSCC and functions in the regulation of cell–cell interactions, as well as in the migration and proliferation of SCC cells. NECTIN4-targeted therapy may serve as a novel and promising treatment for cSCC.. |
| 25. |
Hiroki Hashimoto, Yumiko Kaku-Ito, Masutaka Furue, Takamichi Ito, Mucosal Invasion, but Not Incomplete Excision, Has Negative Impact on Long-Term Survival in Patients With Extramammary Paget’s Disease, Frontiers in Oncology, 10.3389/fonc.2021.642919, 11, 2021.04, Background: Extramammary Paget’s disease (EMPD) sometimes spreads from the skin to mucosal areas, and curative surgical excision of these areas is challenging. The aim of this study is to analyze the impact of mucosal involvement and surgical treatment on the survival of patients with EMPD. Methods: We conducted a retrospective review of 217 patients with EMPD. We also assessed the associations between tumor involvement in boundary areas (anal canal, external urethral meatus, vaginal introitus), prognostic factors, and survival in 198 patients treated with curative surgery. Results: Of 217 patients, 75 (34.6%) had mucosal boundary area involvement. Lesions in these areas were associated with frequent lymphovascular invasion (p = 0.042), lymph node metastasis (p = 0.0002), incomplete excision (p |
| 26. |
Takamichi Ito, Yuka Tanaka, Maho Murata, Yumiko Kaku-Ito, Kazuhisa Furue, Masutaka Furue, BRAF Heterogeneity in Melanoma. [review], Current treatment options in oncology, 10.1007/s11864-021-00818-3, 22, 3, 20-20, 2021.02, OPINION STATEMENT: In the era of molecular targeted therapy, the accurate detection of BRAF mutation in melanoma has become increasingly important. With the advances of molecular analyses and immunohistochemistry, the presence of BRAF mutational heterogeneity in melanoma has been widely recognized. Although most patients with melanoma have a homogeneous BRAF mutation status because the BRAF mutation occurs at an early stage of melanoma development and acts as a driver gene mutation, BRAF mutational heterogeneity does exist, among different tumor sites of a single patient (intertumor heterogeneity) and/or even within a single tumor (intratumor heterogeneity). To summarize the published reports, about 10% of melanoma patients may show intertumorally discordant BRAF status and about 15% of BRAF-mutated melanomas may have intratumor BRAF heterogeneity, although the reported results vary strikingly among the studies and methods used. Considering the BRAF heterogeneity of melanoma, a single biopsy from a single tumor may not be sufficient to uncover the entire BRAF status of a patient. Multiple samples from different sites may be preferable to assess the indication of BRAF/MEK inhibitors, as recommended by the current clinical guidelines. The impact of BRAF heterogeneity on patient survival or the response to treatment with BRAF/MEK inhibitors is an interesting issue, but requires further investigation.. |
| 27. |
Tanaka Y, Ito T, Tsuji G, Furue M., Baicalein inhibits benzo[a]pyrene-induced toxic response by downregulating Src phosphorylation and by upregulating NRF2-HMOX1 system., Antioxidants (Basel) 9: 507., 2020, 2020.04. |
| 28. |
Ito T*, Kaku-Ito Y, Wada-Ohno M, Furue M., Narrow margin excision for acral melanoma: Is it acceptable?, J Clin Med 9: 2266., 2020, 2020.04. |
| 29. |
Furue K, Ito T, Tsuji G, Nakahara T, Furue M., Scratch wound-induced CXCL8 upregulation is EGFR-dependent in keratinocytes., J Dermatol Sci 99: 209-212, 2020, 2020.04. |
| 30. |
Murata M, Ito T*, Tanaka Y, Kaku-Ito Y, Furue M., NECTIN4 Expression in Extramammary Paget's Disease: Implication of a New Therapeutic Target., Int J Mol Sci 21:5891., 2020, 2020.04. |
| 31. |
Furue K, Ulzii D, Tanaka Y, Ito T, Tsuji G, Kido-Nakahara M, Nakahara T, Furue M., Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis.[Review], 2020.04. |
| 32. |
Furue K, Ito T, Tsuji G, Nakahara T, Furue M., The CCL20 and CCR6 axis in psoriasis.[Review], 2020.04. |
| 33. |
Ito T*, Kaku-Ito Y, Murata M, Furue K, Shen CH, Oda Y, Furue M., Immunohistochemical BRAF V600E expression and intratumor BRAF V600E heterogeneity in acral melanoma: Implication in melanoma-specific survival., J Clin Med., 10.3390/jcm9030690, 9, 3, 2020.03, Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan-Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.. |
| 34. |
Tsuji G, Hashimoto-Hachiya A, Yen V, Miake S, Takemura M, Mitamura Y, Ito T, Murata M, Furue M, Nakahara T., Aryl hydrocarbon receptor activation downregulates IL-33 expression in keratinocytes via ovo-like 1., J Clin Med., 2020.03. |
| 35. |
Furue K, Ito T, Tanaka Y, Hashimoto-Hachiya A, Takemura M, Murata M, KIdo-Nakahara M, Tsuji G, Nakahara T, Furue M., The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients., Int J Mol Sci, 2020.02. |
| 36. |
Murata M, Ito T*, Yamamura K, Hashimoto-Hachiya A, Furue K, Furue M., OVOL2-mediated ZEB1 downregulation may prevent promotion of actinic keratosis to squamous cell carcinoma., J Clin Med, 2020.02. |
| 37. |
Ito T*, Kaku-Ito Y, Murata M, Ichiki T, Kuma Y, Tanaka Y, Ide T, Ohno F, Wada-Ohno M, Yamada Y, Oda Y, Furue M., Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis., Int J Mol Sci., 10.3390/ijms20246191, 20, 24, 2019.12, The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma. As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important. However, the genetic heterogeneity of acral melanoma-a distinct type of melanoma with a unique genetic background-has not fully been investigated. We conducted a retrospective review of our acral melanoma patients. Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas. We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody. Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method. A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1. In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions. Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma. Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.. |
| 38. |
Furue K, Ito T, Tsuji G, Ulzii D, Vu YH, Kido-Nakahara M, Nakahara T, Furue M., The IL-13-OVOL1-FLG axis in atopic dermatitis.[Review], 2019.11. |
| 39. |
Tanaka Y, Uchi H, Ito T, Furue M., Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing., Sci Rep., 2019.10. |
| 40. |
Furue K, Ito T, Tsuji G, Esaki H, Kido-Nakahara M, Nakahara T, Furue M., Does mechanical scratching cause the recruitment of T-helper 17 cells in atopic dermatitis?[Review], 2019.10. |
| 41. |
Furue K, Ito T, Tanaka Y, Yumine A, Hashimoto-Hachiya A, Takemura M, Murata M, Yamamura K, Tsuji G, Furue M., Cyto/chemokine profile of in vitro scratched keratinocyte model: Implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon., J Dermatol Sci, 2019.09. |
| 42. |
Wada-Ohno M, Ito T, Furue M., Adjuvant Therapy for Melanoma.[Review], 2019.09. |
| 43. |
Kaku-Ito Y, Ito T (co-first), Tsuji G, Nakahara T, Uchi H, Hagihara A, Furue M., Evaluation of mapping biopsies for extramammary Paget's disease: a retrospective study., J Am Acad Dermatol, 76: 1171-1177, 2018, 2018.06. |
| 44. |
Ito T*, Kaku-Ito Y, Furue M., The diagnosis and management of extramammary Paget's disease.[Review], 2018.06. |
| 45. |
Furue K, Ito T, Tsuji G, Kadono T, Furue M., Autoimmuity and autoimmune comorbidities in psoriasis.[Review], 2018.04. |
| 46. |
Furue M, Ito T, Wada M, Wada N, Kadono T, Uchi H., Melanoma and immune checkpoint inhibitors.[Review], 2018.04. |
| 47. |
Tsuji G, Ito T, Chiba T, Mitoma C, Nakahara T, Uchi H, Furue M., The role of the OVOL1-OVOL2 axis in normal and diseased human skin.[Review], 2018.04. |
| 48. |
Kuma Y, Yamada Y, Yamamoto H, Kohashi K, Ito T, Furue M, Oda Y., A Novel Fusion Gene CRTC3-MAML2 in Hidradenoma: Clinicopathological and Histopathological Significance., Hum Pathol, Hum Pathol 70: 55-61, 2017, 2017.12. |
| 49. |
Chang CH, Kuo CJ, Ito T, Su YY, Jiang ST, Chiou MH, Lin YH, Memberg M, Stiewe T, Ito S, Wakamatsu K, Alkalay I, Ben-Neriah Y., CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation., Proc Natl Acad Sci USA, 114: E8035-E8044, 2017, 2017.09. |
| 50. |
Hiraki-Hotokebuchi Y, Yamada Y, Kohashi K, Yamamoto H, Endo M, Setsu N, Yuki K, Ito T, Iwamoto Y, Furue M, Oda Y., Alteration of PDGFRβ-Akt-mTOR Pathway Signaling in Fibrosarcomatous Transformation of Dermatofibrosarcoma Protuberans., Hum Pathol, Hum Pathol 67: 60-68, 2017, 2017.09. |
| 51. |
Wada M, Ito T, Tsuji G, Nakahara T, Uchi H, Hagihara A, Furue M., Acral lentiginous melanoma versus other melanoma: a single-center analysis in Japan., J Dermatol, J Dermatol 44: 932-8, 2017, 2017.08. |
| 52. |
Tsuji G, Hashimoto-Hachiya A, Kiyomatsu-Oda M, Takemura M, Ohno F, Ito T, Morino-Koga S, Mitoma C, Nakahara T, Uchi H, Furue M., Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis., Cell Death Dis, Cell Death Dis 8: e2931, 2017, 2017.07. |
| 53. |
Yamada Y, Kuda M, Kohashi K, Yamamoto H, Takemoto J, Ishii T, Iura K, Maekawa A, Bekki H, Ito T, Otsuka H, Kuroda M, Honda Y, Sumiyoshi S, Inoue T, Kinoshita N, Nishida A, Yamashita K, Ito I, Komune S, Taguchi T, Iwamoto Y, Oda Y., Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes., Virchows Arch, Virchows Arch 470: 373-380, 2017, 2017.07. |
| 54. |
Yamada Y, Kinoshita I, Kohashi K, Yamamoto H, Kuma Y, Ito T, Koda K, Kisanuki A, Kurosawa M, Yoshimura M, Furue M, Oda Y., HIF-1α, MDM2, CDK4, and p16 expression in ischemic fasciitis, focusing on its ischemic condition., Virchows Arch, Virchows Arch 471: 117-122, 2017, 2017.07. |
| 55. |
Ito T*, Tsuji G, Ohno F, Nakahara T, Uchi H, Furue M., Potential role of the OVOL1-OVOL2 axis and c-Myc in the progression of cutaneous squamous cell carcinoma., Mod Pathol, 30: 919-927, 2017, 2017.06. |
| 56. |
Itoh E, Nakahara T, Murata M, Ito T, Onozuka D, Furumura M, Hagihara A, Furue M., Chronic spontaneous urticaria: implications of subcutaneous inflammatory cell infiltration in an intractable clinical course., J Allergy Clin Immunol, J Allergy Clin Immunol 139: 363-366, 2017, 2017.01. |
| 57. |
Ito T*, Uchi H, Nakahara T, Tsuji G, Oda Y, Hagihara A, Furue M., Cutaneous angiosarcoma of the head and face: a single-center analysis of treatment outcomes in 43 patients in Japan., J Cancer Res Clin Oncol, J Cancer Res Clin Oncol 142: 1387-1394, 2016, 2016.06. |
| 58. |
Ito T, Kohashi K, Yamada Y, Maekawa A, Kuda M, Furue M, Oda Y, Prognostic significance of forkhead box M1 (FoxM1) expression and antitumor effect of FoxM1 inhibition in melanoma., Histopathology, 69: 63–71, 2016, 2016.06. |
| 59. |
Ito T*, Tsuji G, Uchi H, Nakahara T, Hashimoto-Hachiya A, Yoshida Y, Yamamoto O, Oda Y, Furue M., Activation of the OVOL1-OVOL2 Axis in the Hair Bulb and in Pilomatricoma., Am J Pathol, 186: 1036-1043, 2016, 2016.04. |
| 60. |
Ito T, Kohashi K, Yamada Y, Iwasaki T, Maekawa A, Kuda M, Hoshina D, Abe R, Furue M, Oda Y., Prognostic Significance of Forkhead Box M1 (FOXM1) Expression and Antitumor Effect of FOXM1 Inhibition in Angiosarcoma., J Cancer, J Cancer 7: 823-830, 2016, 2016.04. |
| 61. |
Ito T*, Inatomi Y, Nagae K, Nakano-Nakamura M, Nakahara T, Furue M, Uchi H., Narrow-margin excision is a safe, reliable treatment for well-defined, primary pigmented basal cell carcinoma: an analysis of 288 lesions in Japan., J Eur Acad Dermatol Venereol, J Eur Acad Dermatol Venereol 29: 1828-31, 2015, 2015.09. |
| 62. |
Ito T*, Wada M, Nagae K, Nakano-Nakamura M, Nakahara T, Furue M, Uchi H., Triple-marker PCR assay of sentinel lymph node as a prognostic factor in melanoma., J Eur Acad Dermatol Venereol, J Eur Acad Dermatol Venereol 29: 912-918, 2015., 2015.05. |
| 63. |
Sakaizawa K, Ashida A, Uchiyama A, Ito T, Fujisawa Y, Ogata D, Matsushita S, Fujii K, Fukushima S, Shibayama Y, Hatta N, Takenouchi T, Uehara J, Okuyama R, Yamazaki N, Uhara H., Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melnoma patients., J Dermatol Sci, J Dermatol Sci 80: 33–7, 2015, 2015.04. |
| 64. |
Ito T*, Kaku Y, Nagae K, Nakano-Nakamura M, Nakahara T, Oda Y, Hagihara A, Furue M, Uchi H., Tumor thickness as a prognostic factor in extramammary Paget's disease., J Dermatol, J Dermatol 42: 269-75, 2015, 2015.03. |
| 65. |
Ito T*, Wada M, Nagae K, Nakano-Nakamura M, Nakahara T, Hagihara A, Furue M, Uchi H., Acral lentiginous melanoma: Who benefits from sentinel lymph node biopsy?, J Am Acad Dermatol, 72: 71-77, 2015, 2015.01. |
| 66. |
Mitoma C, Nakahara T, Uchi H, Ito T, Inatomi Y, Ide T, Jinnai S, Jinnai N, Iwasaki N, Sakamoto K, Kimura N, Maeda A, Kuma Y, Maehara E, Tsutsumi M, Kido-Nakahara M, Hirota T, Tamari M, Furue M., Preferential expression of OVOL1 in inner root sheath of hair, sebaceous gland, eccrine duct and their neoplasms in human skin., Fukuoka Acta Med, 105, 8, 166-173, Fukuoka Acta Med 105: 166-173, 2014, 2014.08, OVOL1は表皮細胞の増殖を抑制し角化を推進させる転写因子と考えられている。最近のgenome-wide association studyでは、アトピー性皮膚炎の疾患感受性遺伝子の一つとしても注目を浴びている。マウスではOvol1は皮膚及び毛嚢に発現していることが報告されているがヒトでの研究はこれまで報告されていない。本研究では、ヒト健常皮膚および皮膚疾患で、OVOL1の発現を免疫組織学的に明らかにした。健常皮膚では、OVOL1は基底層上層の表皮細胞、毛嚢の内毛根鞘、成熟した脂腺細胞、エクリン汗腺の導管部に優位に発現していた。炎症性皮膚疾患のOVOL1の発現は健常皮膚に比べ変化を認めなかった。OVOL1の発現はeccrine poromaとhidradenomaで亢進していた。ボーエン病と脂腺腫ではOVOL1の発現は亢進していたが、有棘細胞癌や脂腺癌ではむしろ減少していた。OVOL1はヒト皮膚の器官形成や腫瘍発生に重要な役割をになっているのではないかと考えた。(著者抄録). |
| 67. |
Zhu L, Kohda F, Nakahara T, Chiba T, Tsuji G, Hachisuka J, Ito T, Tu Y, Moroi Y, Uchi H, Furue M., Aberrant expression of S100A6 and matrix metalloproteinase 9, but not S100A2, S100A4, and S100A7, is associated with epidermal carcinogenesis., J Dermatol Sci, J Dermatol Sci 72:311-9, 2013, 2013.12. |
| 68. |
Zhu L, Ito T, Nakahara T, Nagae K, Fuyuno Y, Nakao M, Akahosi M, Nakagawa R, Tu Y, Uchi H, Furue M., Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma., J Dermatol, J Dermatol 40: 973-979, 2013, 2013.12. |
| 69. |
Ito T*, Moroi Y, Oba J, Nakahara T, Takeuchi S, Uchi H, Takahara M, Masuda T, Furue M., The prognostic value of RT-PCR assay of sentinel lymph node biopsy for patients with cutaneous melanoma: A single center analysis in Japan., Melanoma Res, Melanoma Res 22: 38-44, 2012, 2012.01. |
