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.

A review of cutaneous apocrine carcinoma: epidemiology, diagnosis, prognosis, and treatment options.

Cutaneous apocrine carcinoma is a rare skin cancer arising from apocrine sweat glands. Disease-specific treatments are required for cutaneous adnexal carcinomas due to their heterogeneous treatment responsiveness. This review reports on the epidemiology, diagnosis, pathological features, surgical management, and use of systemic therapies for cutaneous apocrine carcinoma. Diagnosing cutaneous apocrine carcinoma requires presenting with distinctive pathological features and excluding metastatic adenocarcinomas, particularly breast cancer. Clinical findings are essential to exclude metastatic adenocarcinomas, and immunohistochemistry can be used as an adjunctive tool to rule out other diseases. Wide local excision is the standard treatment for resectable cutaneous apocrine carcinomas. Prophylactic lymphadenectomy should be considered as a treatment option given the high incidence of lymph node metastasis. Generally, cutaneous apocrine carcinomas are resistant to chemotherapy and radiation therapy; however, adjuvant radiotherapy is recommended for high-risk patients. Radiation or systemic therapy is administered to patients with distant metastases or recurrence. The systemic therapeutic options include cytotoxic chemotherapy, hormonal therapy, targeted therapy, and immune checkpoint inhibitors. Given the lack of data on clinical prognosis and standardized treatments, further studies are needed to improve our understanding of cutaneous apocrine carcinomas.

Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

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.

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.

Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome.

Mutations of OCRL cause Lowe syndrome, which is characterised by congenital cataracts, infantile hypotonia with mental retardation, and renal tubular dysfunction and Dent-2 disease, which only affects the kidney. While few patients with an intermediate phenotype between these diseases have been reported, the mechanism underlying variability in the phenotype is unclear. We identified an intronic mutation, c.2257-5G>A, in intron 20 of OCRL in an older brother with atypical Lowe syndrome without eye involvement and a younger brother with renal phenotype alone. This mutation created a splice acceptor motif that was accompanied by a cryptic premature termination codon at the junction of exons 20 and 21. The mutation caused incomplete alternative splicing, which created a small amount of wild-type transcript and a relatively large amount of alternatively spliced transcript with a premature termination codon. In the patients' cells, the alternatively spliced transcript was degraded by nonsense-mediated decay and the wild-type transcript was significantly decreased, but not completely depleted. These findings imply that an intronic mutation creating an incomplete alternative splicing acceptor site results in a relatively low level of wild-type OCRL mRNA expression, leading to partial phenotypes of Lowe syndrome.

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.

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.

The present status of xeroderma pigmentosum in Japan and a tentative severity classification scale.

Xeroderma pigmentosum (XP) is a rare autosomal recessive hereditary disease. Patients with XP have severe hypersensitivity to sunlight, resulting in skin cancers, and some patients have neurological symptoms. In Japan, XP complementation group A (XP-A) is the most common form, and it is associated with severe neurological symptoms. We performed a nationwide survey on XP to determine the present status of XP in Japan. The distribution of complementation groups in Japan was considerably different from that in other countries, but there was a higher frequency in group A and the variant type, which is similar to previous reports in Japan. Basal cell carcinoma was the most frequent skin cancer that patients with XP developed, followed by squamous cell carcinoma and malignant melanoma. The frequency of these skin cancers in patients with XP-A has decreased, and these skin cancers have been occurring in much older people than those previously observed. Diagnosing XP in patients at younger ages seems to encourage patients and their parents to use sun protection, which helps prevent skin cancer. We also created a tentative scale for classifying the severity of XP, and we evaluated the neurological symptoms of XP-A using this severity scale. Our classification correlated well with patients' age, suggesting that it may be useful and feasible in clinical practice to assess the progression of symptoms of each patient with XP and evaluate the effects of treatment in the future.

A 10-year follow-up of a child with mild case of xeroderma pigmentosum complementation group D diagnosed by whole-genome sequencing.

BACKGROUND: Most patients with xeroderma pigmentosum complementation group D (XP-D) from Western countries suffer from neurological symptoms, whereas Japanese patients display only skin manifestations without neurological symptoms. We have previously suggested that these differences in clinical manifestations in XP-D patients are attributed partly to a predominant mutation in ERCC2, and the allele frequency of S541R is highest in Japan. METHODS: We diagnosed a child with mild case of XP-D by the evaluation of DNA repair activity and whole-genome sequencing, and followed her ten years. RESULTS: Skin cancer, mental retardation, and neurological symptoms were not observed. Her minimal erythema dose was 41 mJ/cm(2) , which was slightly lower than that of healthy Japanese volunteers. The patient's cells showed sixfold hypersensitivity to UV in comparison with normal cells. Post-UV unscheduled DNA synthesis was 20.4%, and post-UV recovery of RNA synthesis was 58% of non-irradiated samples, which was lower than that of normal fibroblasts. Genome sequence analysis indicated that the patient harbored a compound heterozygous mutation of c.1621A>C and c.591_594del, resulting in p.S541R and p.Y197* in ERCC2: then, patient was diagnosed with XP-D. Y197* has not been described before. CONCLUSION: Her mild skin manifestations might be attributed to the mutational site on her genome and daily strict sun protection. c.1621A>C might be a founder mutation of ERCC2 among Japanese XP-D patients, as it was identified most frequently in Japanese XP-D patients and it has not been found elsewhere outside Japan.

Autoimmune-type atypical hemolytic uremic syndrome treated with eculizumab as first-line therapy.

We report a case of atypical hemolytic uremic syndrome (aHUS) in a 4-year-old boy. Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality. He was given eculizumab as first-line therapy, which led to significant clinical improvement, thus avoiding any risk of complications associated with plasma exchange and central venous catheterization. Retrograde functional analysis of the patient's plasma using sheep erythrocytes indicated an increase in hemolysis, suggesting impairment of host cell protection by complement factor H. The use of eculizumab as first-line therapy in place of plasma exchange might be reasonable for pediatric patients with aHUS.

Long-term survival with systemic therapy in the last decade: Can melanoma be cured?

Immune checkpoint inhibitors have been shown to prolong survival of patients with several types of cancer, and the finding was first established in melanoma. Previously, systemic therapy for advanced melanoma aimed only at tumor control and palliation of symptoms. However, in recent years, some patients who received systemic therapy have achieved a complete response and survived without continuous treatment for more than several years. This review discusses the long-term survival rates achieved with currently used systemic therapies and their future perspectives. Long-term survival is currently most likely to be achieved with the use of the standard-dose combination of nivolumab plus ipilimumab, however, this regimen is associated with a high frequency of serious or persistent immune-related adverse events. Several new anti-PD-1-based combination therapies with a better risk-benefit balance are currently under development. Although the acral and mucosal subtypes tend to be less responsive to immune checkpoint inhibitors, anti-PD-1-based combination therapy should continue to be investigated for these subtypes owing to its potential for better long-term survival. With the development of efficacious immunotherapy and targeted therapy, it is important to determine the optimal duration of systemic therapy to avoid unnecessary health and financial burdens as well as to improve efforts to support long-term cancer survivors. As the goal of systemic therapy shifts from tumor control to long-term survival, in future clinical trials, long-term clinical outcomes should be evaluated to assess the benefits of novel agents.

Real-world efficacy and safety of BRAF-targeted therapy for patients with advanced melanoma: A single-center retrospective study in Japan.

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.

Analysis of surgical margins and prognostic factors in dermatofibrosarcoma protuberans after wide local excision: A multicenter study of 116 Japanese patients.

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.

Updated analysis of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma.

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.

A case of Cockayne syndrome with unusually mild clinical manifestations.

We present a mild case of Cockayne syndrome that was referred to us with an extreme sunburn at the age of 3. In early teens, although her cutaneous symptoms alleviated without any medications, she developed tremor and dysarthria. Neurological examination and brain imaging suggested demyelination disorders. The patient's cells indicated a reduced recovery of RNA synthesis, which was partially restored by the introduction of CSB (Cockayne Syndrome B)-cDNA. In addition, her cells indicated a substantially reduced level of CSB protein. Despite the insidious progression of neurological symptoms, she gave birth to a child. Such mild cases of Cockayne syndrome may be misdiagnosed.