Ikuko Hirai

Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population

Although immune checkpoint inhibitors (ICI) significantly improve the survival of advanced melanoma, more than half of the patients received no benefit. To predict outcomes, efforts to associate baseline peripheral blood biomarkers were started in patients given treatment with ipilimumab. Among the most critical markers is an increased neutrophil-to-lymphocyte ratio (NLR), which negatively correlates with outcome. Although several baseline factors have been reported to correlate with outcome in patients treated with nivolumab/pembrolizumab (eosinophil count, lymphocyte count, lactate dehydrogenase [LDH], and c-reactive protein [CRP]), a positive link between NLR and outcome has yet to be shown. This article is protected by copyright. All rights reserved.

Modified weekly regimen of cisplatin, epirubicin and paclitaxel induced a durable response in two cases of metastatic extramammary Paget's disease

Metastatic extramammary Pagets disease (EMPD) is a rare cancer with no standardized treatment. We report two cases of metastatic EMPD treated with a modified weekly PET (cisplatin, epirubicin and paclitaxel) regimen given biweekly (i.e. 2 weeks on/2 weeks off) that had durable responses. Case 1 was a 74‐year‐old man with EMPD metastatic to lymph nodes, lung, and bone who presented with a hemorrhagic tumor on the scrotum. We tried the PET regimen weekly, but adjusted the interval to biweekly after two doses because of hematological side‐effects. After five doses, he showed a partial response (PR) on imaging, including the bone lesions. The lesions have remained the same size for 1 year. Case 2 was a 65‐year‐old man with EMPD metastatic to a right inguinal lymph node who presented with an erosive tumor on the scrotum. He was started on weekly docetaxel. However, the lymph node grew and iliac lymph node metastasis developed. Therefore, we tried the PET regimen with a 2 weeks on/2 weeks off schedule. After five doses, he showed a PR. In both cases, all adverse effects were manageable and this modified regimen could be administrated on an outpatient basis. With no current validated chemotherapy regimen, clinicians may consider a modified weekly PET regimen in future treatment of metastatic EMPD.

Interstitial‐type granuloma annulare associated with Sjögren syndrome

The association of granuloma annulare (GA) with autoimmune disease – especially autoimmune thyroid disease – have been reported; however, to the best of our knowledge, only one case of GA associated with Sjögren syndrome (SS) has been described [1]. Here we report a case of interstitial type GA associated with SS. A 53-year-old woman presented with a one-year history of annular skin lesions on the hands. She also had a three-year history of polyarthralgia of the knees and fingers, and had been treated with low-dose oral corticosteroids (prednisolone 1 mg/day). The rest of her history was unremarkable. Physical examination revealed annular red-brown skin lesions on the hands (Figure 1), which were neither painful nor pruritic. Laboratory tests revealed elevated values for erythrocyte sedimentation rate (26 mm/hr, normal 3–11); C-reactive protein (1.72 mg/ dl, normal ≤ 0.30); IgG (1 984 mg/dl, normal 870–1 700); IgA (475 mg/dl, normal 110–410); and IgM (252 mg/dl, normal 35–220). Serum was positive for antinuclear antibody (x320, speckled pattern), anti-Ro/SS-A antibodies (120.3, normal < 10), and anti-La/SS-B antibodies (102.3, normal < 10). The level of glycosylated hemoglobin A was normal, and other autoantibodies, including rheumatoid factor, anti-cyclic citrullinated peptide, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-Jo-1, anti-Scl-70, and anti-cardiolipin, were absent. Schirmer test (right, 4 mm; left, 4 mm) and the tear break-up time (right, 3 sec; left, 3 sec) were positive. Sialography was also positive. Based on these findings, the patient was diagnosed with SS. The absence of bony erosions in radiographs, and the absence of rheumatoid factor and anti-cyclic citrullinated peptide suggested that her polyarthralgia was caused by SS. Skin biopsy revealed dermal interstitial CD68-positive histiocytes and lymphocytes infiltrated around deposits of alcian bluepositive mucin in the reticular dermis (Figure 2). Interstitial histiocytic infiltration was present throughout dermis; however, eosinophils and neutrophils were absent. These histopathological findings were consistent with interstitial-type GA. Topical corticosteroids (0.05 % Clinical letter difluprednate cream) produced improvement but complete resolution was not achieved. A differential diagnosis in the present case is interstitial granulomatous dermatitis (IGD), a disorder described by Ackerman et al. in 1993 [2]. IGD is associated with rheumatoid arthritis and other autoimmune diseases and characterized by papules and plaques located on the trunk and extremities. Histopathological findings show an interstitial histiocytic infiltration that is localized primarily in the lower dermis. Eosinophils and neutrophils are often present, while mucin is typically absent. In contrast, interstitial GA is characterized by mucin associated with histiocytes. Although the presence of polyarthralgia initially suggested IGD in the present case, both the clinical appearance of the skin lesions and the histopathological findings were consistent with the diagnosis of GA. The pathomechanism of GA associated with autoimmune disease remains unknown. However, several reports support the possible association of GA and autoimmunity, including the hypothesis of the existence of a common immunological pathway for both conditions [3]. In addition, Paola et al. reported a case of GA, autoimmune thyroiditis, and lichen sclerosus in a woman. They suggested that GA, with lymphocytemediated hypersensitivity type IV mechanism and a cell-mediated immune process, could help trigger an organ-specific autoimmune response [4]. The pathomechanism of IGD is also still unknown, but the association with rheumatoid arthritis and other autoimmune diseases suggests an immune complex-mediated mechanism [5]. As GA associated with autoimmune disease and IGD share some similarities, the two disorders may belong to the same disease spectrum.

Assessment of the methods used to detect HER2-positive advanced extramammary Paget’s disease

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 of these methods, the degree of HER2 expression detected by each method was correlated with the staining profiles of activated downstream signaling pathways involving phosphorylated p44/42 MAPK (Thr202/Tyr204) (p-ERK1/2) and phosphorylated AKT (Ser473) (p-AKT). Among 16 lymph node metastasis samples, all HER2-positive samples as determined by the testing algorithm stained positively for both p-ERK1/2 and p-AKT. On the other hand, 10-14.3% of the samples determined by FISH or IHC showed negative staining for p-ERK1/2 and p-AKT. The results showed that combining the results of IHC and FISH according to the HER2 testing algorithm is a useful method for accurately evaluating HER2-positive EMPD.

Evaluation of the appropriate surgical margin for pigmented basal cell carcinoma according to the risk factors for recurrence: a single-institute retrospective study in Japan

Basal cell carcinoma (BCC) is the most common skin cancer and tends to appear on the face and neck.1 For the complete removal of BCC, a surgical margin of at least 4mm is recommended by the guidelines of various dermatological and oncologic associations.2-4 However, 4mm is not always feasible because of anatomic and cosmetic restrictions. Moreover, these recommendations are based on studies of Caucasian non-pigmented BCCs. In contrast, most Asian BCCs are pigmented and relatively demarcated. This article is protected by copyright. All rights reserved.

Carboplatin and epirubicin combination therapy for advanced malignant epithelial skin tumors: Retrospective study of six patients

Malignant epithelial skin tumors are cutaneous malignancies arising from epidermal or adnexal structures, including squamous cell carcinoma (SCC), basal cell carcinoma and skin appendage carcinomas. While the majority of them can be cured by surgical excision, advanced cases with unresectable or metastatic lesions have poor prognosis. Furthermore, tolerable chemotherapy regimens with high efficacy for advanced SCC and skin appendage carcinomas have not been established to date. Several published works have reported the efficacy of chemotherapy regimens including those based on cisplatin (CDDP), peplomycin and irinotecan. Among them, the combination therapy of CDDP 75 mg/m and adriamycin (ADM) 50 mg/m every 3 weeks (CA regimen) had high efficacy for advanced SCC showing a response rate of 57.1% (n = 7; complete response [CR], 28.6%; partial response [PR], 28.6%). However, there are safety concerns regarding CDDP and ADM combination therapy. According to a previously published work reporting the safety profile of CDDP 50 mg/m and ADM 60 mg/m every 3 weeks in 194 cases of endometrial carcinoma, 88% grade 3 or 4 hematological toxicities, 20% grade 3 gastrointestinal, 15% cardiac and 7% neurological toxicities were observed. Furthermore, CDDP frequently shows renal insufficiency. To solve these concerns of toxicity in CDDP and ADM combination therapy, combination of carboplatin (CBDCA) 200–400 mg/m and epirubicin (Epi-ADM) 30–60 mg/m every 3 weeks (C’A’ regimen) was proposed as an alternative regimen. The safety profile of the combination of CBDCA and EpiADM was also reported in endometrial cancer showing 16% grade 3 or 4 hematological toxicity, 2% grade 3 gastrointestinal toxicity and neither cardiac nor neurological toxicities. In this study, we retrospectively analyzed the efficacy and safety of C’A’ therapy in unresectable stage III and IV malignant epithelial skin tumor patients at Keio University Hospital from 2010 to 2017. This study was approved by the ethics committee in Keio University Hospital. Patients who were histopathologically diagnosed with SCC or adnexal carcinomas and had unresectable metastatic lesions were included. Subsequently, two stage III SCC, three stage IV SCC and one stage IV eccrine porocarcinoma (EPC) patients who were treated with i.v. administration of an area under the curve (AUC)5 dose of CBDCA and 60 mg/m of Epi-ADM every 3 weeks were analyzed (Table 1). The dose of CBDCA and Epi-ADM was decreased to AUC4 and 48 mg/m, respectively, as necessary, according to the severity of toxicity. Treatment response was evaluated according to Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events (AE) were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03.

Rapidly developed BRAF inhibitor-induced verrucous keratosis

Dear Editor, BRAF inhibitors (BRAFi) are utilized for the treatment of various malignancies, including melanoma. These agents are associated with the development of squamoproliferative lesions such as squamous cell carcinomas (SCC), keratoacanthomas and BRAFi-induced verrucous keratosis (BIVK). Compared with Caucasians, these lesions rarely occur in Asian subjects. Here, we report the first case of BIVK in an Asian subject, which developed rapidly with unique initial lesion, HRAS mutation and cyclin-dependent kinase inhibitor 2A (CDKN2A) amplification. A 74-year-old Japanese woman presented with melanoma that had originated in the sacral region skin, with BRAF V600E mutation and multiple in-transit metastases; her disease progressed through treatment with a clinical trial of combination BRAFi and mitogen-activated protein kinase kinase inhibitor (MEKi). Six months after the clinical trial started, a new in-transit metastasis occurred and she was withdrawn. The lesion was surgically removed and 1 month after discontinuation of the drug, vemurafenib monotherapy was started. After 4 days, she developed a 25 mm 9 10 mm pearly reddish plaque on the outside of the lower lip (Fig. 1a) with skin rash and milia. Prednisolone 10 mg/day was administrated for rash, the plaque did not shrink but changed like a verruca (Fig. 1b). Histopathologically, the lesion showed acanthosis with papillomatosis and hypergranulosis without koilocytes or keratinocyte atypia (Fig. 1c,d). The immunohistochemical (IHC) staining pattern of p53 showed so-called wild-type pattern, interestingly activated Notch 1 (Fig. 1e) and Ki-67 (Fig. 1f) positive from the epidermal basal cell layer. A negative finding of p16 IHC staining and human papillomavirus (HPV) in situ hybridization denied the involvement of HPV infection. By using an original gene panel, “NCC oncopanel v3”, the targeted gene sequencing analysis revealed that our case had HRAS mutation (G12C) and CDKN2A amplification. As for the development of squamoproliferative lesions associated with BRAF inhibitors, paradoxical mitogenactivated protein kinase activation was thought to be mediated. Among them, HRAS mutations were reported as a most predominant in BIVK (90% of lesions). In our case, BIVK occurred only after use of BRAFi monotherapy, but not after MEKi combination. The process supported the hypothesis. On the other hand, CDKN2A gene amplification has not been reported in BIVK but has nevertheless been reported in SCC. In our case, the amplification of CDKN2A could be associated with rapid occurrence and unique initial appearance. Physicians need to pay attention for the development of BIVK even when the patients are Asian.

A case of primary malignant melanoma of the lung responded to anti-PD-1 antibody therapy

Primary malignant melanoma of the lung (PMML) is an exceedingly rare type of melanoma. Here, we report a case of an 86-year-old Japanese woman who was diagnosed as PMML with subcarinal lymph node metastasis. She was treated with intravenous administration of programmed cell death-1 (PD-1) inhibitor, nivolumab. After the treatment, lymph node lesion regressed. The size of primary lesion was also controlled in combination with radiotherapy. In this case, two histological features were noted in the biopsy specimen that supported a response to nivolumab: membranous expression of programmed death ligand-1 (PD-L1) in tumor cells and dense scattered infiltration of CD8+ TILs. The clinical course of this case suggests that certain PMML cases may also respond to anti-PD-1 therapy.

A case of neutrophilic dermatosis of the dorsal hand in acute leukemia - a distributional variant of Sweet's syndrome.

A 50-year-old Japanese woman presented with a two-week history of fatigue and shortness of breath. Workup revealed an elevated total white blood cell count with blast cells, and myeloperoxidase-positive blast cells in the bone marrow. The patient was diagnosed with acute myeloid leukemia (AML). Two days later, a painful rash appeared on the nail fold of the left middle finger. Over the following ten days, the lesion increased in size, subsequently showing bullous hemorrhagic changes with erythematous borders and spreading onto the back of the left hand, accompanied by fever (Figure 1a). The day after the cutaneous lesion had initially appeared, she had already undergone chemotherapy for AML. Because of progressive chemotherapy-induced pancytopenia and a high-grade fever, the lesion was suspected to be caused by an infection. However, after administration of various antibiotics, the lesion did not regress. Blood cultures were negative. Histologic examination of a biopsy taken ten days after the lesion had initially appeared showed a necrotic epidermis Clinical Letter with marked exocytosis of polymorphonuclear neutrophils and erythrocytes (Figure 2a). There was prominent papillary edema and a dense dermal neutrophilic infiltrate without any signs of leukocytoclastic vasculitis (Figure 2b). Immunohistochemical staining with myeloperoxidase and CD117 did not reveal a neoplastic myeloid infiltrate. Based on the characteristic distribution and pathologic findings, we diagnosed the condition as neutrophilic dermatosis of the dorsal hands (NDDH) without leukemic infiltration. Upon normalization of the white blood cell count, the lesion resolved without contracture of the finger after five weeks (Figure 1b). NDDH, a term proposed by Galaria et al. in 2000 [1], is an entity clinically and histologically similar to Sweets syndrome (SS). In 1995, Strutton et al. [2] had described this condition as “pustular vasculitis of the dorsal hands”, which

New Therapy Using Omega-3-Acid Ethyl Esters for Decubitus Ulcers and Stasis Dermatitis: A Case Report

Introduction: In daily practice, it is common to experience difficulty in treating decubitus ulcers (pressure ulcers, also known as decubitus ulcers) and stasis dermatitis of the lower limbs. We hereby report that omega-3-acid ethyl esters were remarkably effective when administered to cases of refractory pressure ulcers and stasis dermatitis for the purpose of improving the blood flow and promoting blood circulation. Case Presentation: Case 1: A 21-year-old Japanese female with lower-body paralysis. Pressure ulcers appeared on the heel and first toe of her left lower extremity. Although the patient had been treated with various ointments such as dimethyl isopropylazulene and 0.9% iodine-containing ointment, the course showed no improvement, so omega-3-acid ethyl esters was administered orally, completely healing the ulcer of the first toe in 10 weeks. Case 2: A 76-year-old Japanese male. The patient had been treated on an outpatient basis for 15 years due to hypertension, heart failure, type 2 diabetes mellitus, and hyperlipidemia. Two years prior to this presentation, stasis dermatitis occurred in the lower limbs and at the end of last year, erosive ulcers appeared on the front part of the lower-right thigh and shin. Although treatment with various topical ointment and dressings was performed, the course showed no improvement. Oral administration of omega-3-acid ethyl esters was initiated. At 12 weeks, his condition entered the white phase and healed almost completely. Conclusions: This report is the first to document other treatment possibilities for pressure ulcer and/or stasis dermatitis in cases where the use of topical applied ointments and medications is difficult. This new therapy may therefore help physicians to treat pressure ulcers and stasis dermatitis.