Recent treatment and prognosis in 643 patients with extramammary Paget's disease.

Information about extramammary Paget's (EMPD) treatment is limited because of the rarity of the disease. The prognosis differs between in situ EMPD and invasive EMPD; therefore, therapy should be planned according to the disease stage. We collected data on 643 EMPD cases treated between 2015 and 2019 in Japan and assessed recent trends in EMPD treatment and prognosis based on the EMPD-oriented TNM staging. Among the 643 patients, 317 had stage 0 (49.3%), 185 had stage I (28.8%), 51 had stage II (7.9%), 18 had stage IIIA (2.8%), 48 had stage IIIB (7.5%) and 24 had stage IV (3.7%) disease. Each stage showed a distinct survival curve, with the exception of stages II and IIIA. Curative surgery was most common in patients with stage 0-III disease. Chemotherapy was the first-line therapy, mainly in patients with stage IIIB and IV disease, most commonly with docetaxel (DTX), followed by DTX + tegafur gimeracil oteracil potassium (TS-1) and TS-1. Patients with local disease exhibited a 4.4% recurrence rate. Univariate analysis revealed no prognostic differences according to age, sex or primary tumour site. SLNB was not related to disease-specific survival. In multivariate analysis, female sex significantly predicted local relapse in stage 0-I (HR 3.09; 95% CI, 1.13-8.43), and initial treatment with curative surgery was significantly protective in terms of disease-specific survival in stage II-IIIA (HR, 0.17; 95% CI, 0.04-0.71) and stage IIIB-IV (HR 0.16; 95% CI, 0.05-0.51). Further clinical studies are needed to improve the prognosis of patients with stage II-IV EMPD.

Epidemiology of skin cancer based on Japan's National Cancer Registry 2016-2017.

Skin cancer is most frequently diagnosed in the White population. However, its subtypes and epidemiology in Japan are understudied. We aimed to elucidate skin cancer incidence in Japan based on the National Cancer Registry, a new nationwide integrated population-based registry. Data from patients diagnosed with skin cancer in 2016 and 2017 were extracted and classified by cancer subtypes. Data were analyzed using the World Health Organization and General Rules tumor classifications. Tumor incidence was calculated as the number of new cases divided by the corresponding total person-years. Overall, 67,867 patients with skin cancer were included. The percentage of each subtype was as follows: basal cell carcinoma, 37.2%; squamous cell carcinoma, 43.9% (18.3% of which, in situ); malignant melanoma, 7.2% (22.1% of which, in situ); extramammary Paget's disease, 3.1% (24.9% of which, in situ); adnexal carcinoma, 2.9%; dermatofibrosarcoma protuberans, 0.9%; Merkel cell carcinoma, 0.6%; angiosarcoma, 0.5%; and hematologic malignancies, 3.8%. The overall age-adjusted incidence of skin cancer was 27.89 for the Japanese population model and 9.28 for the World Health Organization (WHO) model. The incidences of basal cell carcinoma and squamous cell carcinoma were the highest (3.63 and 3.40 per 100,000 persons, respectively, in the WHO model) among skin cancers, whereas the incidences of angiosarcoma and Merkel cell carcinoma were the lowest (0.026 and 0.038 per 100,000 persons, respectively, in the WHO model). This is the first report to provide comprehensive information on the epidemiological status of skin cancers in Japan using population-based NCR data.

Functional preservation benefits of minimal surgery for extramammary Paget's disease.

As extramammary Paget's disease (EMPD) sometimes invades and metastasizes from the skin to the mucosa, radical surgical resection of these lesions is often difficult. The purpose of this study was to analyse the association between surgical margins and survival as well as the benefit of functional preservation over complete resection, in patients with EMPD. We retrospectively analysed 230 patients diagnosed with EMPD between 1969 and 2020. Patient and treatment characteristics were recorded. Since our centre is a specialized hospital and almost all patients were referred from other hospitals, we reviewed their referral letters. Prognostic factors and survival time were also analysed. Among 230 patients, 78 (33.9%) had positive margins. The presence of margin positive lesions increased the local recurrence rate but was not significantly correlated with survival. Of all the patients who had received a thorough explanation about the surgical procedure in the referring hospital, 43.8% were scheduled for surgeries that would result in functional impairment, and all of them had function-preserving surgeries at our hospital with a 10-year survival rate of 100%. Our result suggest that less invasive surgery preserves anogenital and urethral function may be an acceptable option for EMPD treatment.

Merkel cell carcinoma: a review of clinical management with focus on Asian patients.

Merkel cell carcinoma is a highly aggressive skin cancer characterized by neuroendocrine differentiation. This review aimed to present updates on the knowledge and current trends of clinical management of Merkel cell carcinoma. Additionally, we focused on Asian reports of Merkel cell carcinoma because most skin cancers differ substantially between Caucasians and Asians, and researchers have reported differences in Merkel cell carcinoma in racial and ethnic groups. Owing to its rarity, there is limited evidence for the epidemiology, pathogenesis, diagnosis and Merkel cell carcinoma treatment. The development of a nationwide survey or cancer registry, the identification of Merkel cell polyomavirus and the use of immune checkpoint inhibitors allowed a better understanding of its characteristics and biology and have revolutionized the clinical management of patients with Merkel cell carcinoma. Its incidence has gradually increased worldwide; however, it depends on the geographic location, race and ethnicity. No randomized prospective studies have evaluated the significance of sentinel lymph node biopsy, complete lymph node dissection and adjuvant radiation therapy; however, most patients with localized Merkel cell carcinoma are treated surgically or with post-operative radiation. Patients with distant Merkel cell carcinoma are administered immune checkpoint inhibitors as the first-line therapy; however, there is no established second-line therapy for refractory Merkel cell carcinoma. Furthermore, it is necessary to validate the favorable results of clinical studies performed in Western countries in the patients in Asia.

Clinical outcomes of head and neck mucosal melanoma treated with surgery: a single-center study in Japan.

BACKGROUND: Head and neck mucosal melanomas are rare malignancies. Although the prognosis is poor owing to the high incidence of distant metastases, locoregional control remains important. It is difficult to obtain results in a large cohort because of its rarity. This study aimed to elucidate the survival outcomes of patients with head and neck mucosal melanoma treated with surgery in Japan. METHODS: Patients with head and neck mucosal melanoma who were surgically treated between 2007 and 2021 at the National Cancer Center Hospital were retrospectively analyzed. RESULTS: A total of 47 patients were included in this study. The 5-year overall survival, disease-specific survival, locoregional control and relapse-free survival rates were 42%, 50%, 79% and 13%, respectively. The disease-specific survival of the oral mucosal melanoma group was significantly better than that of the sinonasal mucosal melanoma group (5-year disease-specific survival rate: 70% versus 37%, respectively; P = 0.04). Multivariate analyses revealed that sinonasal mucosal melanoma were independently significant adverse prognostic factor, for overall survival and disease-specific survival. Patients with oral mucosal melanoma patients had a higher incidence of lymph node metastasis than those with sinonasal mucosal melanoma patients (P < 0.0001). CONCLUSION: This study demonstrated the survival outcomes of the largest cohort of patients with head and neck mucosal melanomas treated surgically at a single institution within the past 20 years in Japan. We found that survival outcomes and incidence of nodal metastases varied by site.

Efficacy of chemotherapies for unresectable extramammary Paget disease: a single-centre retrospective study.

BACKGROUND: Extramammary Paget disease (EMPD) is a cutaneous neoplasm that can metastasize to the lymph nodes and distant organs, resulting in a poor prognosis. For unresectable distant metastases of EMPD, no consensus has been reached regarding optimal chemotherapy owing to a lack of data. OBJECTIVES: To evaluate the efficacy of three regimens: docetaxel (DTX) monotherapy; combination therapy with 5-fluorouracil, epirubicin, carboplatin, vincristine and mitomycin C (FECOM); and tegafur (S-1) monotherapy. METHODS: This single-centre retrospective study included 32 patients diagnosed with unresectable EMPD and treated with chemotherapy between 2002 and 2022 at the National Cancer Center Hospital in Japan. Patient characteristics, responses to treatment and survival data were evaluated for each of the first-line therapies. RESULTS: Among the 17 patients who received DTX monotherapy, the response rate (RR) and disease control rate (DCR) were 47% and 77%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 12.3 months [95% confidence interval (CI) 6.1-26.6] and 19.2 months (95% CI 8.5-not reached), respectively. Among the 11 patients who received combination FECOM chemotherapy, the RR and DCR were 55% and 64%, respectively. The median PFS and OS were 6.8 months (95% CI 3.5-not reached) and 13.4 months (95% CI 8.6-21.3), respectively. Among the four patients who received S-1 monotherapy, the RR and DCR were 0% and 25%, respectively. The median PFS and OS were 5.4 months (95% CI 2.3-not reached) and 12.5 (95% CI 2.3-not reached) months, respectively. CONCLUSIONS: Further investigations with prospective analysis are required to confirm these findings.

Prognostic factors in cutaneous apocrine carcinoma: a single-institution retrospective study of 32 patients.

BACKGROUND: Cutaneous apocrine carcinoma (CAC) is a rare adnexal carcinoma. Limited data exists on the demographics and overall survival (OS) of patients with CAC; thus, there is no consensus on surgical management. This study aimed to examine demographic and survival data of patients with CAC to determine optimal surgical management. METHODS: A single-center retrospective cohort study was conducted at the National Cancer Center Hospital in Tokyo between 2005 and 2022. Patients with a histologically-confirmed CAC diagnosis were identified and data on patient demographics, OS, and lymph node (LN) status were gathered. RESULTS: Thirty-two patients were included (median age, 65.5 years; male-female ratio, 15:1). The most common involvement site was the axilla (87.5%). Of the nine patients in the clinical local stage, pathological LN metastases were found in five patients. Either pathological LN or distant metastases were present in 75% of the patients at initial diagnosis. The most common initial surgical treatments included wide local excision and complete LN dissection. Across cohorts, the median OS was 39 months. Patients with ≥ 4 LN metastases had reduced recurrence-free survival and OS compared to those with ≤ 3 LN metastases (p = 0.042, p = 0.041, respectively). The OS was not remarkably different between patients who did and did not receive postoperative radiation therapy. CONCLUSIONS: Since CAC has a high rate of LN metastasis-and the number of LN metastases is a significant prognostic factor-LN evaluation should be considered for patients with CAC as initial treatment. Nonetheless, ≥ 4 LN metastases can be a poor prognostic factor for CAC.

Clinical significance of local control of primary tumour in definitive radiotherapy for scalp angiosarcomas.

INTRODUCTION: Scalp angiosarcoma is a rare and aggressive cancer. Definitive radiotherapy is a treatment option for localised scalp angiosarcoma patients. Although definitive surgical resection reportedly prolongs overall survival (OS), whether initial local treatment effect affects OS when definitive radiotherapy is administered is unclear. Therefore, this study analysed whether local recurrence within 6 months of irradiation correlates with OS and cancer-specific survival (CSS). Furthermore, how local control affects patients' quality of life was investigated. MATERIALS AND METHODS: Thirty-one localised scalp angiosarcoma patients who had received definitive radiotherapy at our institution between October 2010 and July 2021 were analysed retrospectively. The most commonly used dose fractionation was 70 Gy in 35 fractions (83.9%). Local recurrence within 6 months of radiotherapy and other clinical factors were examined in univariate and subsequent multivariate analyses for correlation with OS and CSS. RESULTS: The median follow-up period was 16 months (range, 6-45 months). Local recurrence was detected in 16 patients (51.6%), 12 of whom had recurrence within 6 months. In multivariate analyses, the presence of local recurrence within 6 months of radiotherapy was significantly associated with OS and CSS (p = 0.003, 0.0001, respectively). Ten of the 16 patients with local recurrence had severe symptoms such as bleeding, pain, difficulty opening the eye and malodour. CONCLUSIONS: The initial local treatment effect was significantly associated with OS and CSS after definitive radiotherapy. Furthermore, local recurrence after radiotherapy resulted in a variety of symptoms, including bleeding and pain, which reduced the patient's quality of life.

A phase I study of the safety and efficacy of talimogene laherparepvec in Japanese patients with advanced melanoma.

Talimogene laherparepvec (T-VEC) is approved for the treatment of unresectable melanoma in the USA, Europe, and Australia. This phase I, multicenter, open-label, dose de-escalation study evaluated the safety and efficacy of T-VEC in Japanese patients with unresectable stage IIIB-IV melanoma. Eligible adult patients had histologically confirmed stage IIIB-IVM1c cutaneous melanoma, may have received prior systemic anticancer therapy, must have had ≥1 injectable lesion, serum lactate dehydrogenase ≤1.5x upper limit of normal, ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. T-VEC was injected intralesionally (first dose, ≤4.0 ml of 106  PFU/ml; after 3 weeks and then every 2 weeks thereafter, ≤4.0 ml of 108  PFU/ml). Primary endpoints were dose-limiting toxicities (DLTs) and durable response rate (DRR). Of 18 enrolled patients (72.2% female), 16 had received ≥1 prior line of therapy. Ten patients discontinued T-VEC due to disease progression. Median (range) follow-up was 20.0 (4-37) months. No DLTs were observed; 17 (94.4%) patients had treatment-emergent adverse events (AEs). Fourteen (77.8%) patients had treatment-related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T-VEC in non-Asian patients. The safety profile was consistent with the patients' underlying disease and the known safety profile of T-VEC.

IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation.

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. METHODS: Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. EXPECTED OUTCOME: Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. TRIAL REGISTRATION: The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma.

Assessment of treatment efficacy of immune checkpoint inhibitors in melanoma patients is difficult as the response to these therapies varies among patients or lesions. The clonal evolution of cancer during immune checkpoint blockade therapy could cause treatment resistance. We investigated the potential of liquid biopsy in monitoring the mutational profiles of metastatic melanoma during immunotherapy. Plasma samples collected from 21 Japanese metastatic melanoma patients before immune checkpoint blockade therapy were subjected to whole-exome sequencing (WES). Furthermore, 14 Japanese patients with melanoma were enrolled for longitudinal analysis of circulating tumor DNA (ctDNA). Plasma samples were collected prospectively before and during therapy and sequenced. WES of the pretreatment plasma from Japanese melanoma patients showed detectable ctDNA levels with wide ranges of variant allele frequencies within a sample, suggesting clonal and subclonal mutations in ctDNA. In targeted sequencing using longitudinal samples, ctDNA levels correlated with increased tumor size, while ctDNA content immediately decreased after a surge in a patient exhibiting pseudo-progression, suggesting the potential of ctDNA analysis in discriminating between pseudo- and true progression. Mutant ctDNA levels showed different patterns within the clinical course of specific patients, suggesting that these mutations were derived from different tumor clones with distinct therapeutic responses. During further investigation, WES of plasma samples from 1 patient showed marked differences in the mutational profiles of ctDNA, including expansive tumor evolution during an acute exacerbation. Immunotherapy may induce characteristic clonal evolutions of tumors; longitudinal analysis of ctDNA has the potential of determining these tumor evolution patterns and therapeutic responses.

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.

A review of the AJCC melanoma staging system in the TNM classification (eighth edition).

In the eighth edition of the American Joint Committee on Cancer Staging Manual, several modifications were made for melanoma. These modifications were aimed at improving the prognosis prediction accuracy of the staging system. The main modifications are as follows: the cutoff value of the T1 category has been changed, and there are new classifications of stage IIID and of M1d (metastasis of the central nervous system). These changes will allow for more accurate stratification of melanoma prognosis. However, it is necessary to validate the new modifications through future clinical research.

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

BACKGROUND: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma. METHODS: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours. RESULT: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events. CONCLUSION: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.

RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)-associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV- (10%); CK20-, and MCPyV- (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation-positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation-negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.

Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.

BACKGROUND: Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients. METHODS: Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed. RESULTS: The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047). CONCLUSION: Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.

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.

Association between prognosis and complete resection in primary cutaneous myoepithelial carcinoma: two case presentations and literature review.

Myoepithelial carcinoma is a rare tumor that occurs in the salivary glands. Therefore, primary cutaneous myoepithelial carcinoma is extremely rare. The malignancy of this tumor is due to its aggressive nature and high metastatic potential. Despite the general consideration that primary cutaneous myoepithelial carcinoma has a poor prognosis, there are few available prognostic data. Herein, we report two cases of primary cutaneous myoepithelial carcinoma to expand the literature on the clinical and pathological characteristics of this disease. In case 1, the tumor was completely resected and sentinel lymph node biopsy was performed, resulting in long-term survival. In contrast, case 2 progressed aggressively with multiple bone metastases despite treatment with docetaxel chemotherapy, and the patient ultimately died of the disease. Only 14 cases, including the present two cases, of primary cutaneous myoepithelial carcinoma have been reported to date. Overall, patients with clinical regional or distant metastases show a severe clinical course. Nevertheless, even in cases of inappropriate resection or local recurrence, if complete resection is ultimately achieved prior to clinical metastasis, the prognosis is good and survival is prolonged. Therefore, obtaining complete resection appears to be the most important treatment strategy for primary cutaneous myoepithelial carcinoma.

Hemophagocytic lymphohistiocytosis with advanced malignant melanoma accompanied by ipilimumab and nivolumab: A case report and literature review.

Combination therapy with nivolumab + ipilimumab was recently approved for treating unresectable cases of malignant melanoma. In spite of the high response rate, it is associated with a high incidence of serious adverse events, including immune-related hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (irHPS/HLH), a difficult to diagnose rare disease. This is the first report of this disease in an Asian malignant melanoma patient treated with nivolumab + ipilimumab. A 69-year-old Japanese woman with unresectable malignant melanoma was treated with nivolumab + ipilimumab. Following the combined therapy, her fever and symptoms of malaise occurred, and she visited to our hospital's emergency department. Blood tests revealed significant liver dysfunction, anemia, and thrombocytopenia. We suspected irHPS/HLH, based on tests revealing decreased fibrinogen and significantly increased ferritin. Bone marrow biopsy revealed numerous macrophages and high hemophagocytosis levels. After 50 mg prednisolone (1 mg/kg per day) was administered, fever and cytopenia markedly improved. irHPS/HLH has a high rate of coagulation abnormalities accompanied by hypertriglyceridemia and hypofibrinogenemia, which are unlikely to occur in adult HPS/HLHs. Because irHPS/HLH responds better to steroids than other secondary HPS/HLHs, we expect a complete cure with steroids. Quick diagnosis and appropriate treatment based on clinical symptoms and laboratory tests are needed in suspected cases.

Efficacy of oral retinoids for keratoacanthoma centrifugum marginatum.

Keratoacanthoma centrifugum marginatum (KCM) is a rare variant of keratoacanthoma. This condition is difficult to diagnose because of its large size and expansive nature and may be diagnosed as a malignant tumor. There are various treatments such as surgery and oral retinoids; however, limited studies have verified their effectiveness. Here, we report a case of KCM on the anterior chest of a 50-year-old woman and evaluate the efficacy of oral retinoids. In this case, oral retinoids were highly effective for KCM treatment. A total of 55 cases of KCM, including 54 previously reported cases, were reviewed, and their clinical characteristics and treatment were examined. In this report, 14 of 16 patients were effectively treated with oral retinoids, resulting in a treatment rate of 87.5%. Furthermore, even low-to-medium doses were sufficient for treatment and prevention. KCM can be misdiagnosed as a malignant disease based on its clinical features. Due to its large size and expansive nature, a wide excision may be performed; however, because oral retinoids have a very high response rate, an accurate diagnosis will help avoid an unnecessary wide excision.