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Cutaneous dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor characterized by a high risk of local recurrence but a low risk of metastasis. Wide local excision (WLE) has been an important treatment option, but its clinical outcomes and safety have not been thoroughly evaluated in previous reports. The aim of this study was to determine appropriate surgical margins (deep and lateral) and prognostic factors associated with recurrence‐free survival (RFS) of DFSP. A database collected by two dermatology departments in Japan was retrospectively reviewed to identify 116 patients with DFSP who underwent complete resection with WLE between 1994 and 2021. Sixty‐one men (53%) and 55 women (47%) were included in our cohort. The primary sites of DFSP were as follows: 11 head and neck (9%); seven face (7%); 12 upper extremities (10%); 20 lower extremities (17%); and 66 trunk (57%). There were 103 cases (89%) of primary DFSP and 13 cases (11%) of recurrent DFSP. Total 10‐year RFS was 96.6%. There were significant differences in RFS by tumor size (median size: 3 cm), disease status (primary versus recurrent DFSP), and fibrosarcomatous change (positive versus negative) (all p < 0.05). Two patients (1.7%) with buccal or head lesions had positive deep margins. In all cases, the lateral margin was negative at the postoperative evaluation. Tumor size, disease status, and fibrosarcomatous change are important risk factors for recurrence. Both face and head–neck lesions were more likely to have positive deep margins than other anatomic areas in DFSP. Although this study was limited by its retrospective design, a narrow 2‐cm lateral margin is especially considered for low‐risk patients. [ABSTRACT FROM AUTHOR]

Most clinical trials investigating targeted therapies for patients harboring BRAF V600 mutations have included mostly White patients, and data for Asian patients are scarce. Although there are several retrospective studies in Japanese patients, they have investigated only the dabrafenib + trametinib regimen, and have had a short follow‐up period. We conducted a single‐center retrospective study to update previous studies and compare the outcomes with those in White patients. We analyzed 89 patients who received dabrafenib + trametinib or encorafenib + binimetinib, including 11 who received both treatment regimens. The overall response rate was 79.8%, with complete response in 25 patients (28.1%) and partial response in 45 patients (51.7%). The median progression‐free survival was 13.7 months, and the median overall survival was 32.9 months. The 3‐year progression‐free and overall survival rates were 31.8% and 47.9%, respectively. Although the two regimens showed no significant differences in efficacy, their safety profiles differed, as reported in clinical trials. Therefore, the most frequent adverse event associated with the dabrafenib + trametinib regimen was pyrexia (61.3%) and that of encorafenib + binimetinib was blurred vision (32.0%). Switching directly to another targeted therapy after progressive disease showed no clinical response; however, rechallenge followed by immune checkpoint inhibitor therapy showed a certain response. As a prognostic factor, performance status was associated with progression‐free survival, and performance status, serum lactate dehydrogenase level, and dose interruption were associated with overall survival in the multivariate analysis. Real‐world data on targeted therapy for patients with melanoma in Japan suggest that both dabrafenib + trametinib and encorafenib + binimetinib show similar efficacy and safety in Asian and White patients. [ABSTRACT FROM AUTHOR]

The efficacy and safety of nivolumab and ipilimumab (N + I) combination therapy for Japanese patients with advanced unresectable melanoma was re‐evaluated in clinical practice. One hundred Japanese patients with advanced melanoma were included. The overall response rate was 24%; complete response (CR), 6%; partial response, 18%. The response rates were 33.3% in the systemic therapy‐naïve and 15.4% in the prior‐treatment groups, and 16.1% for patients who were treated with first‐line anti‐programmed death 1 antibody monotherapy followed by second‐line N + I therapy after progression of the disease. The response rate for cutaneous melanoma was 32.7%, and 47.8% in the naïve group. Response rates for non‐acral, acral, and mucosal melanoma were 34.9%, 25%, and 16.7%, respectively. The median progression‐free survival (PFS) for all patients was 3.25 months (6.5 and 2.5 months in the naïve and prior‐treatment groups, respectively). Median overall survival (OS) was 14.5 months (25.25 and 7.5 months in the naïve and prior‐treatment groups, respectively). There were no significant differences in PFS or OS for patients with non‐acral, acral, or mucosal melanoma. The 3‐year PFS and OS were both 100% in patients who achieved CR with combination therapy. Adverse events occurred in 89% and were grade three or higher in 56% of cases. Although direct comparisons cannot be made due to different patient backgrounds, N + I combination therapy in Japanese patients in clinical practice tended to be inferior when compared to global study and non‐Asian patients in clinical practice. The highest response rate was in the cutaneous melanoma therapy‐naïve group. The best tumor response was associated with survival outcome, and the PFS and OS were good in cases where CR was obtained. The proportion of grade three and four adverse events was as high as that in the global study. [ABSTRACT FROM AUTHOR]

Malignant melanoma (MM) is usually resistant to radiotherapy. Brachytherapy may be an option in patients with bleeding or pain, and those in whom surgery is difficult. Brachytherapy has few side effects and can be used in combination with external beam radiotherapy or chemotherapy. We summarize the demographic and clinical characteristics of 15 patients who received brachytherapy for MM at our hospital and describe two of these representative cases. Patient 1 had an approximately 10‐mm, dark‐red nodule near the external urethral meatus. Excision was not performed to preserve urethral function. A gradual improvement was observed after 48 Gy of remote afterloading system (RALS) brachytherapy and nivolumab therapy. Patient 2 had a 38‐mm, black tumor on the vagina. Post‐resection, RALS brachytherapy was administered to treat the residual black macule and a lesion quickly disappeared. In all 15 cases, nine patients received radiotherapy for local control and six patients received palliative radiotherapy to reduce symptoms such as bleeding and pain. The irradiation site was the vagina in six patients, lymph node metastasis in five, head and neck in two, skin or subcutaneous metastases in two, and the anus in one. Treatment effect for local control and palliative care was 75% and 83% of patients, respectively. In particular, disappearance of the tumor or disappearance of symptoms was observed in half of the cases of brachytherapy to the vagina. On the other hand, brachytherapy was not very effective for lymph node metastases. Immediately after radiotherapy, eight (53%) patients experienced dermatitis or mucositis. Due to the histological and structural characteristics of mucosal melanoma of the luminal organs, brachytherapy may be an effective therapy. Hence, widespread use of brachytherapy with an appropriate irradiation technique aiming for local control and palliative care in case of unresectable MM should be considered. [ABSTRACT FROM AUTHOR]

Invasive extramammary Paget's disease may cause lymph node and distant metastases. Complete lymph node dissection is generally performed for extramammary Paget's disease presenting with lymph node metastases. Patients with extramammary Paget's disease and multiple lymph node metastases typically have poor prognoses, and there is no effective postoperative treatment to prevent recurrence or further metastases in such patients to date. This study aimed to evaluate the efficacy of postoperative radiotherapy in patients with extramammary Paget's disease and multiple lymph node metastases. We enrolled 26 patients with extramammary Paget's disease with ≥3 lymph node metastases who were treated at the National Cancer Center Hospital in Japan between January 2000 and June 2021. The patients were divided into those who underwent complete lymph node dissection only or with postoperative radiotherapy. We evaluated recurrence‐free survival, distant metastasis‐free survival, and overall survival outcomes with Kaplan–Meier curves. Among the 26 enrolled patients, 16 underwent complete lymph node dissection only and 10 underwent complete lymph node dissection with postoperative radiotherapy. The median follow‐up period was 16 months. The 5‐year recurrence‐free, distant metastasis‐free, and overall survival values were 47.3%, 63.0%, and 90% in those with complete lymph node dissection and postoperative radiotherapy, while these outcomes were all 0% (p = 0.001, 0.004, and 0.009, respectively) in those with only complete lymph node dissection. Thus, survival was significantly prolonged with postoperative radiotherapy. Additional postoperative radiotherapy may substantially improve the prognoses of patients with extramammary Paget's disease and ≥3 lymph node metastases, and undergoing curative surgery. [ABSTRACT FROM AUTHOR]

The efficacy and safety of nivolumab + ipilimumab combination therapy were retrospectively examined in Japanese patients with unresectable advanced melanoma in clinical practice. Fifty‐seven patients with advanced melanoma received the nivolumab + ipilimumab combination therapy. The primary site was cutaneous, mucosal, uveal and unknown in 35, 16, two and four patients, respectively. The overall response rate was 26.3%, with complete response observed in two (3.5%) patients, partial response in 13 (22.8%), stable disease in 12 (21.1%) and progressive disease in 30 (52.6%). The response rate in the treatment‐naive and prior systemic therapy group was 40.7% and 13.3%, respectively. For those treated with a single immune checkpoint inhibitor followed by the nivolumab + ipilimumab combination therapy as second‐line therapy after disease progression, the response rate was 18.8%. Median progression‐free survival (PFS) and overall survival (OS) in all patients was 3.3 and 14 months, respectively. Median PFS in the treatment‐naive and prior systemic therapy groups was 13 and 2 months, respectively. Median OS was unreached in the treatment‐naive group and was 6.3 months in prior systemic therapy groups. There was no significant difference in PFS and OS for non‐acral, acral and mucosal melanoma. Adverse events occurred in 86% of patients; 56.1% were grade 3 or worse. The response rate in an actual clinical setting, including the prior systemic therapy group, was lower than that in the global study and the Japanese phase II study. However, in the treatment‐naive group, the rate was equivalent to that in the Japanese phase II study. PFS and OS in the treatment‐naive group were comparable with those in the global study and Japanese phase II study, suggesting that the treatment was effective. The proportion of grade 3 and 4 immune‐related adverse events was as high as that in the global study and Japanese phase II study. [ABSTRACT FROM AUTHOR]

Treatment for patients with unresectable melanoma has been dramatically changed by the use of immunocheckpoint inhibitors (ICI). In this study, we reviewed patients with unresectable stage III/IV melanoma, who were treated with nivolumab between July 2014 and March 2017 at the Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, and retrospectively recorded cutaneous adverse events (cAE), development of vitiligo, clinical characteristics and clinical responses. We identified 128 patients, 61 (47.7%) of whom showed cAE, including 30 (23.4%) with development or exacerbation of vitiligo. The prognosis of patients with melanoma treated with ICI correlated with cAE, including development of vitiligo. Patients with cAE showed better objective responses (41.0% vs 6.0%, P < 0.001), progression‐free survival (PFS) (377 vs 61 days, P < 0.001) and overall survival (OS) (763 vs 209 days, P < 0.001) than did patients without cAE. Patients who developed vitiligo showed better objective responses (53.3% vs 29.0% vs 6.0%, P < 0.001), PFS (median, not reached vs 317 vs 65 days, P < 0.001) and OS (not reached vs 689 vs 209 days, P < 0.001) than did patients with other cAE and patients without cAE. Landmark analysis showed development of vitiligo starting 20 weeks after starting nivolumab correlated with better OS. In multivariate analysis, OS correlated with performance status, number of metastasized organs, cAE other than vitiligo and development of vitiligo. Despite the fact that the correlation between other cAE and OS was less than that of vitiligo, cAE may be a simple marker of favorable prognosis. [ABSTRACT FROM AUTHOR]

Extramammary Paget's disease (EMPD) often invades the dermis and metastasizes to the lymph nodes. Patients with EMPD associated with lymph node metastases have poor prognosis; to date, effective treatment has not yet been established. Lymph node dissection, aiming to control the local disease, is a standard form of management for EMPD patients with lymph node metastases (LNM). We investigated the clinical and pathological features, treatment strategies and prognostic factors of patients with metastatic EMPD who underwent lymph node dissection. We retrospectively evaluated 38 cases of extramammary Paget's disease with lymph node metastasis over 10 years. All patients underwent wide resection of the primary lesion and lymph node dissection. Univariate analysis revealed the number of metastatic nodes and lymphadenopathy as prognostic factors. In multivariate analysis, the number of metastatic lymph nodes retained statistical significance (hazard ratio, 35.3; 95% confidence interval, 3.23–387.0; P = 0.003). The 5‐year survival rate was 100% and 19.1% in patients with two or less LNM and with three or more LNM, respectively. In patients with three or more LNM, the 5‐year survival rate after adjuvant radiation therapy was better than that after surgery alone (75% vs 0%). In conclusion, patients with two or less LNM can be expected to have long‐term survival with lymph node dissection only, while patients with three or more LNM may require adjuvant radiation therapy to improve prognosis. These results suggest that lymph node dissection may be a strategy to treat EMPD with regional LNM. [ABSTRACT FROM AUTHOR]

We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma in real‐world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation‐positive advanced melanoma in our hospital (26 men and 24 women, aged 21–86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression‐free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long‐term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most serious form of skin cancer. Nowadays, ipilimumab is used for advanced melanoma refractory to first‐line anti‐programmed death 1 (PD‐1) antibodies. Thirty patients (male : female ratio, 18:12; median age, 60.5 years) sequentially treated with ipilimumab after anti‐PD‐1 antibody (nivolumab or pembrolizumab), while 58 (male : female ratio, 27:31; median age, 66.5 years) with anti‐PD‐1 antibody only. The kind of therapy and schedules were as follows: nivolumab, 2 mg/kg at 3‐week intervals or at 3 mg/kg every 2 week; pembrolizumab, 2 mg/kg every 3 weeks; ipilimumab, 3 mg/kg at 3‐week intervals for four doses. The sequential therapy was selected for the patients with disease progression and/or recovered from severe (immune‐related [ir]) adverse events (AE) after PD‐1 blockade monotherapy. We evaluated multiple parameters and analyzed their relevance to overall survival (OS). The best objective response rate was 6.7% in sequential ipilimumab treatment. Median OS was 163 days (range, 16–489). Baseline absolute lymphocyte count (ALC) and performance status (PS) before sequential ipilimumab were associated with OS in univariate analyses. Baseline PS and irAE within 6 weeks after ipilimumab administration showed significant differences on multivariate analysis. Prior to first‐line PD‐1 blockade, these parameters were not associated with OS. The other factors (i.e. age, sex, number of doses, absolute neutrophil counts, neutrophil : lymphocyte ratio, lactate dehydrogenase and C‐reactive protein) were not associated with OS. [Correction added on 17 April 2019, after first online publication: 'not related to OS' has been amended to 'not associated with OS'.] Ipilimumab as sequential therapy did not appear to improve OS and was associated with more severe irAE than PD‐1 blockade monotherapy. We need to carefully consider treating patients with poor PS and low ALC. [ABSTRACT FROM AUTHOR]

Abstract: The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinomas arise as secondary cancers in hematopoietic stem cell transplant survivors. They have been documented primarily in Western cohorts and relatively little is known about their occurrence in Asian hematopoietic stem cell transplant recipients, with no reports of squamous cell carcinomas with high-risk features in Asian patients. We describe a case of a cutaneous squamous cell carcinoma with high-risk features on the scalp of a Japanese bone marrow transplant recipient approximately 6.5 years post-transplant, who was on long-term voriconazole. The history of a photodistributed erythema followed by the appearance of multiple actinic keratoses and solar lentigines, together with the rarity of cutaneous squamous cell carcinomas in Asian hematopoietic stem cell transplant cohorts revealed in our literature review, suggest that voriconazole use contributed to the development of high-risk squamous cell carcinoma in our patient. [ABSTRACT FROM AUTHOR]

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., (© 2022 Japanese Dermatological Association.)

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies., (© 2018 The Authors The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

A solitary malignant peripheral nerve sheath tumor was resected, and a tumor cell line was obtained using an explant culture. The morphology of this cell line was quite similar to those of cell lines of dermal neurofibromas of neurofibromatosis 1, except for the fact that the malignant peripheral nerve sheath tumor cell line could be cultured for more than two months. When the tumor cell line was transfected with human gamma interferon gene, the growth rate was remarkably abolished, as previously observed in neurofibroma cell lines transfected with the gamma interferon gene. This new finding suggests the potential for treating either solitary or neurofibroma-related, inoperable, malignant peripheral nerve sheath tumors by local gamma interferon gene transfection in vivo.