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Papers by Yasuhiro Fujisawa

British Journal of Dermatology

In Japanese patients with melanoma, the response rate of nivolumab plus ipilimumab (N/I) was lowe... more In Japanese patients with melanoma, the response rate of nivolumab plus ipilimumab (N/I) was lower than (35.1%) and the rate of adverse events was similar to (60.4%) those reported in previous clinical trials. No survival difference was observed with the use of N/I between clinical types. Patients who achieved a good response had better outcomes. Elevated lactate dehydrogenase level and having three or more metastatic sites were poor prognostic factors.

European Journal of Cancer, 2021

BACKGROUND As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Min... more BACKGROUND As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations. MATERIAL AND METHODS Data from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed. RESULTS We analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia. CONCLUSION B + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.

Journal of Clinical Oncology, 2020

e22106 Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique sub... more e22106 Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique subgroup of malignant melanomas with important differences in biological properties and treatment. In Japan adequate surveys have not been performed.The objective of this study was to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. Methods: Women with invasive VuM or VaM were identified from a medical records. Data on clinician (Gynecologist or Dermatologist), age, location, node status, ulceration, mitotic count, histologic subtype, American Joint Committee on Cancer (AJCC) stage, primary surgery, and surgical margin were collected. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. Results: A total of 217 patients (pts) were identified; 109 (50.2%) had VuM and 108 (49.8%) had VaM. The median ...

The Journal of Dermatology, 2019

Dear Editor, A 23-year-old man was referred to our hospital after a black nodule on his left abdo... more Dear Editor, A 23-year-old man was referred to our hospital after a black nodule on his left abdomen had been resected and diagnosed as BRAF-mutated malignant melanoma. Two years after wide resection and left inguinal lymph node dissection, a small nodule appeared in his right lung, which was diagnosed as metastatic malignant melanoma (Fig. 1a). He was initiated on dabrafenib (300 mg/day) plus trametinib (2 mg/day) therapy (combi-DT). Seven days after initiation, he developed a fever of 39°C. Although celecoxib was started with combi-DT being held, an intermittent fever of 37-38°C persisted. On day 28, a blood coagulation test revealed a remarkable increase of fibrin Figure 1. (a) A small nodule of 4 mm in diameter in the right lung (red arrow). (b) The nodule diminished (red arrow) after combination therapy with dabrafenib plus trametinib (combi-DT). (c) The time course of plasma fibrin degradation product (FDP; lg/mL), D-dimer (lg/mL), C-reactive protein (CRP; mg/mL) and procalcitonin (ng/mL) after the cessation of combi-DT.

Cancer Science, 2019

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses... more The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression‐free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (TRAE), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all pa...

Journal of Dermatological Science, 2018

Background: Both lymph nodes (LNs) and lymphatic channels from primary sites to regional LNs are ... more Background: Both lymph nodes (LNs) and lymphatic channels from primary sites to regional LNs are critical for initiation of adaptive immunity. However, as LNs are common metastatic sites in skin cancers, LN biopsies or dissections are frequently performed. In addition, reconstructive skin flaps after tumor resection may damage lymphatic flow from primary sites to regional LNs. Objective: This study was designed to investigate the effect on tumor progression by such surgeries. Methods: We developed a mouse model that simulates LNs dissection or skin flap that blocks lymphatic flow from primary sites to regional LNs and monitored tumor progression. Results: As a poor immunogenic tumor line, the growth of inoculated B16F10 melanoma into syngeneic C57BL/6 mice was not affected by these surgeries. However, the growth of the same cell line in allogenic Balb/c mice was accelerated while immune cell infiltration (CD4 + and CD8 + T cells) into the tumor was reduced by these surgeries. In addition, both cytotoxicity against B16F10 melanoma and numbers of apoptotic tumor cells were diminished by these surgeries. Similarly, tumor growth of the immunogenic MC38 cell line in syngeneic C57BL/6 mice was accelerated and immune cell infiltration and apoptotic tumor cells were reduced by these surgeries. Conclusion: These results strongly indicate that surgical damage of the lymphatic system may promote tumor progression via impaired adaptive immune response.

European journal of dermatology : EJD, 2018

387 [2-4]. One of these cases arose on the right index finger of a middle-aged woman. The others ... more 387 [2-4]. One of these cases arose on the right index finger of a middle-aged woman. The others arose on the big toe of middle-aged women. Regarding differential diagnosis, it is important to differentiate FOPD from subungual fibrokeratoma, subungual exostosis, and subungual osteoma cutis. Fibrokeratoma does not contain bone tissue [5]. Subungual exostosis is connected to the underlying phalangeal bone and is easily identified by X-ray examination [6]. Although it is sometimes difficult to distinguish subungual osteoma cutis histopathologically [7], FOPD clearly differs from osteoma cutis due to the presence of osteoclasts [8]. We diagnosed the patient with FOPD based on the presence of bone, abundant hyalinized collagen bundles and osteoid tissue, and the transition of fibroblasts to osteoblasts and osteocytes, all of which are common features of FOPD. Of note, however, our case showed much more abundant bony tissue and much less osteoid tissue compared with previous FOPD cases. Although the reason for the abundant bony tissue formation is not clear, it is possible that the osteoid tissue matured into bony tissue over the course of the disease. It is well known that transformation of fibroblasts to osteoblasts can occur [9, 10]. Therefore, FOPD could be a disease with various stages depending on the relative contribution of fibrous and osseous tissue. Dermatologists should be aware of the occurrence of various histopathological types of FOPD in a subungual region, as well as the importance of differential diagnosis in relation to subungual exostosis.

European journal of dermatology : EJD, 2018

371 pathogenesis of PG is not clear, and the association between EBV and PG may be coincidental. ... more 371 pathogenesis of PG is not clear, and the association between EBV and PG may be coincidental. On the one hand, patients may have EBV infection before PG develops, and the virusinfectious condition of the body leads to the exacerbation of PG and the emergence of haematological abnormality. On the other hand, high-dose corticosteroid therapy generates an immunosuppressive condition in patients and they become susceptible to pathogenic microorganisms in the surrounding environment, such as EBV. Many researches have demonstrated that EBV infection can result in haematological alteration, such as infectious mononucleosis, malignancies, and hemophagocytic syndrome [3, 4]. Therefore, bullous PG combined with EBV infection may develop a more severe haematological abnormality, as in our patients, and give rise to a worse clinical outcome. Consequently, we tentatively put forward that EBV infection may serve as a marker for poor prognosis in patients with bullous PG, and for each bullous PG patient, EBV in the blood should be examined. This is a new finding, however, we were unable to demonstrate further evidence in our patients. More clinical research will be necessary to better define the association between bullous PG and EBV.

European journal of dermatology : EJD, Jan 5, 2018

531 negative six months later, but MPO-ANCA remained elevated (figure 1D). Based on the clinical ... more 531 negative six months later, but MPO-ANCA remained elevated (figure 1D). Based on the clinical course and laboratory findings, PTU-induced AAV was diagnosed. Hyperthyroidism recurred eight months after withdrawal of PTU and was treated with methimazole. After 36 months of follow-up, the patient had no recurrence of vasculitis. A unique feature of this clinical course was that PR3-ANCA correlated well with disease activity. PR3-ANCA decreased soon after cessation of PTU, whereas MPO-ANCA titres remained high. Our patient was positive for both MPO-ANCA and PR3ANCA. It has been reported that 22.2-37.5% of patients with anti-thyroid drug-induced AAV show double positivity for MPO-ANCA and PR3-ANCA [7, 8]. The pathomechanism of PTU-induced AAV is not fully understood. One possible explanation for MPO-ANCA production is that PTU could alter the structure of MPO, which acts as a neoantigen [6, 9]. However, the mechanism of PR3-ANCA production remains unknown. PTU-induced MPO-ANCA seropositivity is usually asymptomatic. In a cohort study, 21 of 56 patients (37.5%) receiving long-term treatment with PTU developed MPOANCA seropositivity; PR3-ANCA was not detected in any patients. Among them, 12 (57.1%) had no symptoms [10]. MPO-ANCA seropositivity without vasculitis suggests that MPO-ANCA alone is insufficient to induce PTU-induced AAV. In this study, we focused on the chronological changes in ANCA titres. Several reports have indicated that MPOANCA titres correlate with disease activity, however, others have reported that MPO-ANCA became negative in only four of 15 patients (26.7%) during follow-up after discontinuation of PTU [4]. A recent review of PTU-induced AAV showed that five of six (83.3%) patients who were positive for both MPO-ANCA and PR3-ANCA at diagnosis were negative for PR3-ANCA at the last follow-up visit, however, only 33.3% (2/6) of patients showed negativity for MPO-ANCA at the last follow-up visit [8]. Detailed time course observations for PR3-ANCA titres in our case led us to hypothesize that PR3-ANCA may be a useful marker for disease activity in PTU-induced double ANCA-positive vasculitis. In summary, we report a case of PTU-induced double ANCA-positive vasculitis in which PR3-ANCA titres correlated with disease activity. However, it remains uncertain whether PR3-ANCA is a pathogenic antibody in PTUinduced double ANCA-positive vasculitis. Further reports are necessary to understand the pathomechanism of PTUinduced double ANCA-positive vasculitis.

Medical oncology (Northwood, London, England), Jan 9, 2018

The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a the... more The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget's disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy ...

The Journal of dermatology, Jan 6, 2018

Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2017

Behandlung eines kutanen Plattenepithelkarzinoms mit intraarterieller Radiochemotherapie Cutaneou... more Behandlung eines kutanen Plattenepithelkarzinoms mit intraarterieller Radiochemotherapie Cutaneous squamous cell carcinoma treated with preoperative intraarterial chemoradiation therapy

International journal of dermatology, 2017

The number of very elderly patients who require surgery for cutaneous tumors is increasing. Howev... more The number of very elderly patients who require surgery for cutaneous tumors is increasing. However, there is limited information on the safety of cutaneous surgery in such patients. To evaluate the safety of cutaneous surgery in patients 90 years of age and older, we retrospectively reviewed the elderly patients who underwent surgery for cutaneous tumors under local anesthesia. Consecutive patients 90 years of age and older and 75-80 years old were included in the elderly group and the control group. The elderly and control groups included 104 and 106 patients, respectively. The mean age of the patients was 93.4 years (range, 90-101 years) in the elderly group and 77.4 years (range, 75-80 years) in the control group. The preoperative performance status was significantly worse in the elderly group than in the control group (P < 0.001). The surgical time was not significantly different between the two groups (P = 0.09). The occurrences of intraoperative and postoperative complicat...

Journal of dermatological science, Jan 29, 2016

Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tum... more Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-a is a biomarker of nivolumab recativity Nivolumab is a standard recombinant antibody treatment for patients with malignant melanoma (MM), which functions as an immune checkpoint inhibitor by blocking the programmed cell death-1 (PD-1) pathway in T cells. However, it leads to various immune-related adverse events (irAEs), and also exacerbates underlying autoimmune diseases [1]. Herein reported a new case of MM with no prior dermatological histories who developed a rare manifestation of psoriasiform dermatitis after treatment with nivolumab (case 1, Supplementary materials and methods) together with a case of nivolumab-associated psoriasiform dermatitis in MM that we have previously reported (case 2) [2]. Psoriasis is a common inflammatory skin disease, characterized by circumscribed, scaling and erythematous plaques. Type 1 and 17 helper T cells (Th1/Th17) are considered to mediate psoriasis [3], and serum levels of some Th1/Th17-related pro-inflammatory cytokines, such as interferon (IFN)-g, tumor necrosis factor (TNF)

Indian journal of dermatology

Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignan... more Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignant skin tumors including basal cell carcinoma (BCC) rarely arise within SKs. We report a rare case of an 82-year-old man with nodulocystic BCC that appeared at the center of a scaly hyperpigmented SK that had been presented for more than 10 years. It was histologically confirmed that CK19-positive BCC arose directly from the wall of the pseudohorn cyst, a part of the SK. Nodular and/or cystic BCC also rarely arise within SKs while the most common histologic type of BCC within SKs is the superficial type. Careful observation of SKs is important even though it is rarely a background condition for malignant transformation.

Clinical & experimental metastasis, Oct 11, 2016

Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2... more Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2) in primary extramammary Paget disease (EMPD). These results indicate that therapies that target HER2 may be useful in treating metastatic EMPD, for which the prognosis is poor. However, there is limited information on the expression and gene amplification of HER2 in metastatic EMPD. Twenty-six corresponding lymph node metastatic sites of primary EMPD underwent immunohistochemical evaluation of HER2 protein overexpression. In cases of HER2 protein overexpression, further analysis into the amplification of the HER2 gene was undertaken using dual colored in situ hybridization. In the corresponding lymph node metastasis of EMPD, HER2 protein overexpression and gene amplification were detected in 38 % and 19 % of cases, respectively. In 22 out of 26 cases (85 %), there were no differences in HER2 protein overexpression between the primary tumors and the corresponding lymph node metastasis (...

The Journal of dermatology, Jan 25, 2015

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condi... more In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58...

British Journal of Dermatology

In Japanese patients with melanoma, the response rate of nivolumab plus ipilimumab (N/I) was lowe... more In Japanese patients with melanoma, the response rate of nivolumab plus ipilimumab (N/I) was lower than (35.1%) and the rate of adverse events was similar to (60.4%) those reported in previous clinical trials. No survival difference was observed with the use of N/I between clinical types. Patients who achieved a good response had better outcomes. Elevated lactate dehydrogenase level and having three or more metastatic sites were poor prognostic factors.

European Journal of Cancer, 2021

BACKGROUND As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Min... more BACKGROUND As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations. MATERIAL AND METHODS Data from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed. RESULTS We analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia. CONCLUSION B + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.

Journal of Clinical Oncology, 2020

e22106 Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique sub... more e22106 Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique subgroup of malignant melanomas with important differences in biological properties and treatment. In Japan adequate surveys have not been performed.The objective of this study was to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. Methods: Women with invasive VuM or VaM were identified from a medical records. Data on clinician (Gynecologist or Dermatologist), age, location, node status, ulceration, mitotic count, histologic subtype, American Joint Committee on Cancer (AJCC) stage, primary surgery, and surgical margin were collected. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. Results: A total of 217 patients (pts) were identified; 109 (50.2%) had VuM and 108 (49.8%) had VaM. The median ...

The Journal of Dermatology, 2019

Dear Editor, A 23-year-old man was referred to our hospital after a black nodule on his left abdo... more Dear Editor, A 23-year-old man was referred to our hospital after a black nodule on his left abdomen had been resected and diagnosed as BRAF-mutated malignant melanoma. Two years after wide resection and left inguinal lymph node dissection, a small nodule appeared in his right lung, which was diagnosed as metastatic malignant melanoma (Fig. 1a). He was initiated on dabrafenib (300 mg/day) plus trametinib (2 mg/day) therapy (combi-DT). Seven days after initiation, he developed a fever of 39°C. Although celecoxib was started with combi-DT being held, an intermittent fever of 37-38°C persisted. On day 28, a blood coagulation test revealed a remarkable increase of fibrin Figure 1. (a) A small nodule of 4 mm in diameter in the right lung (red arrow). (b) The nodule diminished (red arrow) after combination therapy with dabrafenib plus trametinib (combi-DT). (c) The time course of plasma fibrin degradation product (FDP; lg/mL), D-dimer (lg/mL), C-reactive protein (CRP; mg/mL) and procalcitonin (ng/mL) after the cessation of combi-DT.

Cancer Science, 2019

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses... more The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression‐free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (TRAE), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all pa...

Journal of Dermatological Science, 2018

Background: Both lymph nodes (LNs) and lymphatic channels from primary sites to regional LNs are ... more Background: Both lymph nodes (LNs) and lymphatic channels from primary sites to regional LNs are critical for initiation of adaptive immunity. However, as LNs are common metastatic sites in skin cancers, LN biopsies or dissections are frequently performed. In addition, reconstructive skin flaps after tumor resection may damage lymphatic flow from primary sites to regional LNs. Objective: This study was designed to investigate the effect on tumor progression by such surgeries. Methods: We developed a mouse model that simulates LNs dissection or skin flap that blocks lymphatic flow from primary sites to regional LNs and monitored tumor progression. Results: As a poor immunogenic tumor line, the growth of inoculated B16F10 melanoma into syngeneic C57BL/6 mice was not affected by these surgeries. However, the growth of the same cell line in allogenic Balb/c mice was accelerated while immune cell infiltration (CD4 + and CD8 + T cells) into the tumor was reduced by these surgeries. In addition, both cytotoxicity against B16F10 melanoma and numbers of apoptotic tumor cells were diminished by these surgeries. Similarly, tumor growth of the immunogenic MC38 cell line in syngeneic C57BL/6 mice was accelerated and immune cell infiltration and apoptotic tumor cells were reduced by these surgeries. Conclusion: These results strongly indicate that surgical damage of the lymphatic system may promote tumor progression via impaired adaptive immune response.

European journal of dermatology : EJD, 2018

387 [2-4]. One of these cases arose on the right index finger of a middle-aged woman. The others ... more 387 [2-4]. One of these cases arose on the right index finger of a middle-aged woman. The others arose on the big toe of middle-aged women. Regarding differential diagnosis, it is important to differentiate FOPD from subungual fibrokeratoma, subungual exostosis, and subungual osteoma cutis. Fibrokeratoma does not contain bone tissue [5]. Subungual exostosis is connected to the underlying phalangeal bone and is easily identified by X-ray examination [6]. Although it is sometimes difficult to distinguish subungual osteoma cutis histopathologically [7], FOPD clearly differs from osteoma cutis due to the presence of osteoclasts [8]. We diagnosed the patient with FOPD based on the presence of bone, abundant hyalinized collagen bundles and osteoid tissue, and the transition of fibroblasts to osteoblasts and osteocytes, all of which are common features of FOPD. Of note, however, our case showed much more abundant bony tissue and much less osteoid tissue compared with previous FOPD cases. Although the reason for the abundant bony tissue formation is not clear, it is possible that the osteoid tissue matured into bony tissue over the course of the disease. It is well known that transformation of fibroblasts to osteoblasts can occur [9, 10]. Therefore, FOPD could be a disease with various stages depending on the relative contribution of fibrous and osseous tissue. Dermatologists should be aware of the occurrence of various histopathological types of FOPD in a subungual region, as well as the importance of differential diagnosis in relation to subungual exostosis.

European journal of dermatology : EJD, 2018

371 pathogenesis of PG is not clear, and the association between EBV and PG may be coincidental. ... more 371 pathogenesis of PG is not clear, and the association between EBV and PG may be coincidental. On the one hand, patients may have EBV infection before PG develops, and the virusinfectious condition of the body leads to the exacerbation of PG and the emergence of haematological abnormality. On the other hand, high-dose corticosteroid therapy generates an immunosuppressive condition in patients and they become susceptible to pathogenic microorganisms in the surrounding environment, such as EBV. Many researches have demonstrated that EBV infection can result in haematological alteration, such as infectious mononucleosis, malignancies, and hemophagocytic syndrome [3, 4]. Therefore, bullous PG combined with EBV infection may develop a more severe haematological abnormality, as in our patients, and give rise to a worse clinical outcome. Consequently, we tentatively put forward that EBV infection may serve as a marker for poor prognosis in patients with bullous PG, and for each bullous PG patient, EBV in the blood should be examined. This is a new finding, however, we were unable to demonstrate further evidence in our patients. More clinical research will be necessary to better define the association between bullous PG and EBV.

European journal of dermatology : EJD, Jan 5, 2018

531 negative six months later, but MPO-ANCA remained elevated (figure 1D). Based on the clinical ... more 531 negative six months later, but MPO-ANCA remained elevated (figure 1D). Based on the clinical course and laboratory findings, PTU-induced AAV was diagnosed. Hyperthyroidism recurred eight months after withdrawal of PTU and was treated with methimazole. After 36 months of follow-up, the patient had no recurrence of vasculitis. A unique feature of this clinical course was that PR3-ANCA correlated well with disease activity. PR3-ANCA decreased soon after cessation of PTU, whereas MPO-ANCA titres remained high. Our patient was positive for both MPO-ANCA and PR3ANCA. It has been reported that 22.2-37.5% of patients with anti-thyroid drug-induced AAV show double positivity for MPO-ANCA and PR3-ANCA [7, 8]. The pathomechanism of PTU-induced AAV is not fully understood. One possible explanation for MPO-ANCA production is that PTU could alter the structure of MPO, which acts as a neoantigen [6, 9]. However, the mechanism of PR3-ANCA production remains unknown. PTU-induced MPO-ANCA seropositivity is usually asymptomatic. In a cohort study, 21 of 56 patients (37.5%) receiving long-term treatment with PTU developed MPOANCA seropositivity; PR3-ANCA was not detected in any patients. Among them, 12 (57.1%) had no symptoms [10]. MPO-ANCA seropositivity without vasculitis suggests that MPO-ANCA alone is insufficient to induce PTU-induced AAV. In this study, we focused on the chronological changes in ANCA titres. Several reports have indicated that MPOANCA titres correlate with disease activity, however, others have reported that MPO-ANCA became negative in only four of 15 patients (26.7%) during follow-up after discontinuation of PTU [4]. A recent review of PTU-induced AAV showed that five of six (83.3%) patients who were positive for both MPO-ANCA and PR3-ANCA at diagnosis were negative for PR3-ANCA at the last follow-up visit, however, only 33.3% (2/6) of patients showed negativity for MPO-ANCA at the last follow-up visit [8]. Detailed time course observations for PR3-ANCA titres in our case led us to hypothesize that PR3-ANCA may be a useful marker for disease activity in PTU-induced double ANCA-positive vasculitis. In summary, we report a case of PTU-induced double ANCA-positive vasculitis in which PR3-ANCA titres correlated with disease activity. However, it remains uncertain whether PR3-ANCA is a pathogenic antibody in PTUinduced double ANCA-positive vasculitis. Further reports are necessary to understand the pathomechanism of PTUinduced double ANCA-positive vasculitis.

Medical oncology (Northwood, London, England), Jan 9, 2018

The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a the... more The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget's disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy ...

The Journal of dermatology, Jan 6, 2018

Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2017

Behandlung eines kutanen Plattenepithelkarzinoms mit intraarterieller Radiochemotherapie Cutaneou... more Behandlung eines kutanen Plattenepithelkarzinoms mit intraarterieller Radiochemotherapie Cutaneous squamous cell carcinoma treated with preoperative intraarterial chemoradiation therapy

International journal of dermatology, 2017

The number of very elderly patients who require surgery for cutaneous tumors is increasing. Howev... more The number of very elderly patients who require surgery for cutaneous tumors is increasing. However, there is limited information on the safety of cutaneous surgery in such patients. To evaluate the safety of cutaneous surgery in patients 90 years of age and older, we retrospectively reviewed the elderly patients who underwent surgery for cutaneous tumors under local anesthesia. Consecutive patients 90 years of age and older and 75-80 years old were included in the elderly group and the control group. The elderly and control groups included 104 and 106 patients, respectively. The mean age of the patients was 93.4 years (range, 90-101 years) in the elderly group and 77.4 years (range, 75-80 years) in the control group. The preoperative performance status was significantly worse in the elderly group than in the control group (P < 0.001). The surgical time was not significantly different between the two groups (P = 0.09). The occurrences of intraoperative and postoperative complicat...

Journal of dermatological science, Jan 29, 2016

Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tum... more Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-a is a biomarker of nivolumab recativity Nivolumab is a standard recombinant antibody treatment for patients with malignant melanoma (MM), which functions as an immune checkpoint inhibitor by blocking the programmed cell death-1 (PD-1) pathway in T cells. However, it leads to various immune-related adverse events (irAEs), and also exacerbates underlying autoimmune diseases [1]. Herein reported a new case of MM with no prior dermatological histories who developed a rare manifestation of psoriasiform dermatitis after treatment with nivolumab (case 1, Supplementary materials and methods) together with a case of nivolumab-associated psoriasiform dermatitis in MM that we have previously reported (case 2) [2]. Psoriasis is a common inflammatory skin disease, characterized by circumscribed, scaling and erythematous plaques. Type 1 and 17 helper T cells (Th1/Th17) are considered to mediate psoriasis [3], and serum levels of some Th1/Th17-related pro-inflammatory cytokines, such as interferon (IFN)-g, tumor necrosis factor (TNF)

Indian journal of dermatology

Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignan... more Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignant skin tumors including basal cell carcinoma (BCC) rarely arise within SKs. We report a rare case of an 82-year-old man with nodulocystic BCC that appeared at the center of a scaly hyperpigmented SK that had been presented for more than 10 years. It was histologically confirmed that CK19-positive BCC arose directly from the wall of the pseudohorn cyst, a part of the SK. Nodular and/or cystic BCC also rarely arise within SKs while the most common histologic type of BCC within SKs is the superficial type. Careful observation of SKs is important even though it is rarely a background condition for malignant transformation.

Clinical & experimental metastasis, Oct 11, 2016

Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2... more Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2) in primary extramammary Paget disease (EMPD). These results indicate that therapies that target HER2 may be useful in treating metastatic EMPD, for which the prognosis is poor. However, there is limited information on the expression and gene amplification of HER2 in metastatic EMPD. Twenty-six corresponding lymph node metastatic sites of primary EMPD underwent immunohistochemical evaluation of HER2 protein overexpression. In cases of HER2 protein overexpression, further analysis into the amplification of the HER2 gene was undertaken using dual colored in situ hybridization. In the corresponding lymph node metastasis of EMPD, HER2 protein overexpression and gene amplification were detected in 38 % and 19 % of cases, respectively. In 22 out of 26 cases (85 %), there were no differences in HER2 protein overexpression between the primary tumors and the corresponding lymph node metastasis (...

The Journal of dermatology, Jan 25, 2015

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condi... more In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58...