Japanese Dermatological Association guidelines: Outlines of Japanese clinical guidelines for basal cell carcinoma 2021.

To summarize the current therapies for skin cancers, the Japanese Skin Cancer Society issued the first guidelines for skin cancers, including melanoma, squamous cell carcinoma, basal cell carcinoma (BCC), and extramammary Paget's disease, in 2007. These guidelines were revised in 2015. Herein, we present the English version of the 2021 edition of the Japanese clinical guidelines for BCC. In the latest edition, all procedures were performed according to the Grading of Recommendations, Assessment, Development and Evaluation systems. The clinical questions that could not be answered were selected for further analysis. A comprehensive literature search, systematic review, and recommendations for each clinical question were determined by a multidisciplinary expert panel comprising dermatologists, a plastic and reconstructive surgeon, and a pathologist. Surgical resection is the gold-standard therapy of BCC. Radiotherapy or topical treatments, other than surgical resection, have been used in some cases. Patients with unresectable or metastatic BCC require systemic therapy. Novel agents, such as immune response modifiers or hedgehog pathway inhibitors, are emerging worldwide for the treatment of BCC. Based on these viewpoints, four relevant clinical questions regarding, surgical resection, radiotherapy, topical treatment, and systemic therapy, were raised in this report that aims to help clinicians select suitable therapies for their patients.

Systemic therapy for Asian patients with advanced BRAF V600-mutant melanoma in a real-world setting: A multi-center retrospective study in Japan (B-CHECK-RWD study).

BACKGROUND: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. METHODS: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. RESULTS: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. CONCLUSIONS: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

Concordance in judgment of clinical borders of basal cell carcinomas in Japanese patients: A preliminary study of JCOG2005 (J-BASE-MARGIN).

Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use.

A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma: Japan Clinical Oncology Group study (JCOG1605, JCOG-PCAS protocol).

BACKGROUND: Paclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial. METHODS: In February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute. DISCUSSION: If the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established. TRIALS REGISTRATION: Registry number: UMIN000031438 [ http://www.umin.ac.jp/ctr/index.htm ]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.

Surgery with curative intent is associated with prolonged survival in patients with cutaneous angiosarcoma of the scalp and face -a retrospective study of 38 untreated cases in the Japanese population.

BACKGROUND: In patients with cutaneous angiosarcoma of the scalp and face, the validity of surgery remains controversial, because of the potentially diffuse nature of involvement and difficulty in obtaining negative margins. OBJECTIVE: To evaluate the survival benefit of surgery as a primary treatment. PATIENTS AND METHODS: Fifty-one patients with primary cutaneous angiosarcoma of the scalp and face presenting with locoregional involvement were referred to National Cancer Center Hospital, Tokyo, Japan, between May 1982 and March 2013. Data of those patients in whom the diagnosis had been confirmed histologically and the primary treatments had been initiated at our center were analysed retrospectively. Only untreated cases were selected with aim to evaluate actual survival benefit of surgery as a primary treatment. RESULTS: Of the 51 patients, 38 were found to be eligible for inclusion in this analysis; of these 38 patients, 29 (29/38 = 76.3%) patients had tumour diameter > 5 cm, and 29 underwent surgery with curative intent (curative-intent surgery) as the initial treatment. Histologically positive margins were found in 10 patients. Multivariate analysis identified curative-intent surgery as being significantly associated with improved overall survival (OS; HR = 0.26; 95% CI, 0.10-0.63). In the Surgery group, neither negative margins nor combined-modality treatment had any significant influence on the OS. CONCLUSION: Removal of primary tumour with curative-intent surgery may be a valid treatment option even for patients with primary cutaneous angiosarcoma of the scalp and face larger than 5 cm in size, regardless of the histological surgical margin status.

Pazopanib treatment slows progression and stabilizes disease in patients with taxane-resistant cutaneous angiosarcoma.

Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS.

BRAF V600 mutations and pathological features in Japanese melanoma patients.

Ultraviolet radiation is a risk factor for BRAF V600 mutations frequently found in melanomas that cause constitutive BRAF activation. Primary sites of melanoma and the frequency of BRAF mutations might differ between races. Melanoma is rare in Japan (1500-2000 cases/year compared with 132 000/year worldwide) and the frequency and distribution of BRAF V600 mutations are unknown. We aimed to investigate the frequency of BRAF V600 mutations in a cohort of Japanese patients with melanoma and determine the relationship between mutations and clinical/pathologic features. DNA was extracted from 80 formalin-fixed, paraffin-embedded tumours from individuals diagnosed with melanoma. BRAF V600 mutations were detected using the Cobas 4800 System with z480 Analyzer and Cobas 4800 BRAF V600 Mutation Test reagents. BRAF V600 mutations were detected in 41.8% of tested tumours, with an invalid rate of 1.3%. The mutation rate was more than 60% in patients aged less than 60 years and more than 36% in patients with stage III/IV disease. No sex difference in the mutation rate was observed. BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas (ALMs), 64.7% of superficial spreading melanomas, 50.0% of lentigo maligna melanomas and 20.0% of nodular melanomas. Although the mutation rate was low in ALMs, 36.4% were mutation positive at stage III/IV compared with 9.5% at stage I/II. This study confirmed associations among BRAF V600 mutations, pathological features and subtypes of melanoma. BRAF V600 mutations were more frequent in late-stage ALMs than in early-stage ALMs. Superficial spreading melanomas had similar mutation rates at all stages. These insights suggest improved treatment predictions for stage III/IV melanoma patients.

Pathophysiological characteristics of melanoma in-transit metastasis in a lymphedema mouse model.

In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system.

A new aspect of metastasis in cutaneous cancer: two cases of presacral squamous cell carcinoma with metastases to internal iliac nodes.

We report 2 cases of presacral squamous cell carcinoma. In these cases, it was suspicious that the tumor disseminated to the internal iliac nodes through the direct pathway called the neurovascular lymphatic space (NVLS) around the superior/inferior gluteal vessels or sciatic nerve bypassing external iliac nodes. NVLS was initially reported as accessory pathway which follows the major vessels forming a sheath like structure with an actual or potential space between the vessel wall and the enveloping membrane. NVLS has been reported to be observed as a tubular shadow within the neurovascular sheath by lymphangiographies of lymphedema patients using oil-based contrast material. These cases provide insights into the potential pathway through which a cutaneous tumor disseminates.

Vascularised fat flaps lose 44% of their weight 24 weeks after transplantation.

BACKGROUND: Microsurgical transfer of the vascularised fat flaps has become a well-established method for soft-tissue augmentation because it has been believed to provide the restoration of symmetry without atrophy. Yet little has been reported on the long-term fate of the vascularised fat flaps. The purpose of this study was to evaluate the postoperative changes that occur in the vascularised fat flaps after transplantation. METHODS: The superficial epigastric fat flaps based on the superficial inferior epigastric vessels in rats were used for this study. Postoperative changes were analysed by comparing pre- and postoperative weight, histological examination and fluorescent angiography. RESULTS: The weight of vascularised fat flaps was 56±18% of the original weight (corrected for body weight gain) 24 weeks after transplantation. In histological examinations, the vascularised fat flaps had almost normal appearances throughout the experimental period. Apoptosis of adipocytes was detected in the vascularised fat flaps using terminal deoxynucleotidyl transferase (TdT)-mediated deoxy-uridine triphosphate (dUTP)-biotin nick end-labelling (TUNEL) method during the first 4 weeks after transplantation. CONCLUSIONS: The vascularised fat flaps reduced in weight by about 44% over a period of 24 weeks after transplantation. Apoptosis may partly explain the weight loss.

A new model of acquired lymphedema in the mouse hind limb: a preliminary report.

Lymphedema is known to be caused by many pathologic conditions; however, its correct diagnosis and optimal therapeutic strategies remain to be established. In this report, we describe an experimental model for acquired lymphedema in the lower extremity of the mouse that creates a lymphatic block in the groin induced by both radiation treatment and surgical division of the superficial and deep lymphatics. To evaluate the lymphatic system in this model, an indocyanine green fluorescence-sensitive camera system was used. This model has the advantages of relative technical simplicity and cost-effective use of a rodent animal model. Furthermore, a greater range of research tools such as antibodies and various databases are available for mice. This mouse model may be useful to anyone modeling lymphedema mechanisms, by providing a defined molecular context.

Merkel cell carcinoma of the face: an analysis of 16 cases in the Japanese.

BACKGROUND: There is no agreement regarding a staging system and optimal treatment of Merkel cell carcinoma. Some centres have reported results from larger series of patients, but these do not include Asian or Japanese centres. OBJECTIVE: The purpose of this study was to retrospectively review our experience with the surgical treatment of MCC of the face in the Japanese and to study its management and outcome using the staging system described by Clark et al. METHODS: We report our experiences with 16 cases between 1991 and 2004. Patients and tumour characteristics, treatment variables and outcome were analysed. RESULTS: The follow-up periods ranged from 1 to 180 months. The average was 32.6 months and the median was 17.5 months. The relapse-free survival for all patients was 51% at 2 years. The relapse-free survival was 80% for the patients with Stage I and 33% with Stage II at 2 years. CONCLUSION: This staging system was suggested to reflect prognosis although the number of patients in this series was small. Sentinel lymph node biopsy should be considered to determine the accurate nodal staging, and patients with MCC of the head and neck may be treated according to the revised staging system by Clark et al.