Yasuhiro Fujisawa

Indocyanine green fluorescence-navigated sentinel node biopsy showed higher sensitivity than the radioisotope or blue dye method, which may help to reduce false-negative cases in skin cancer.

Although sentinel lymph node (SLN) biopsy using radioisotope (RI) and blue dye (BD) achieved a high detection rate, approximately 5% of melanomas with negative SLNs develop nodal metastasis. We tested a new lymphatic navigation method using indocyanine green fluorescence imaging (ICG‐FI) to detect such “occult” SLNs.

Metastatic extramammary Paget's disease successfully controlled with tumour dormancy therapy using docetaxel

SIR, Extramammary Paget’s disease (EMPD) is fatal once the tumour invades the dermis and metastasizes to the visceral organs. As no significantly effective treatment has yet been established, it is still extremely difficult to treat patients in the advanced stages of this disease. We report a patient with multiple bone and lung metastases of EMPD who was treated with weekly docetaxel. The patient was a 69-year-old man who had developed a large papillomatous tumour in the inguinal region and scrotum which was treated by wide local excision and bilateral groin lymph node dissection in April 2000. Histopathological examination showed the tumour cells to be those of EMPD. There was no recurrence or metastasis for about 4 years, but the patient began to suffer from lower back pain in January 2004. Computed tomography (CT) revealed multiple osteolytic lesions in the vertebrae and ilium with multiple nodules in the lungs, and the patient was admitted to Tsukuba University Hospital the following month for treatment. On admission, the symptoms were found to be derived from nerve root disturbance: severe lumbago, dysaesthesia in the toes, and lower limb paralysis. Magnetic resonance imaging (MRI) indicated not only multiple metastases in the vertebrae and ilium but also severe destruction of the 9th)11th thoracic vertebrae; the vertebral canal was almost completely surrounded by the tumour. Laboratory examination indicated elevated serum alkaline phosphatase and carcinoembryonic antigen (CEA, 65 ng dL). It is well known that CEA level correlates with tumour progression in advanced EMPD; nevertheless, as the patient had been surgically treated for EMPD 4 years earlier, the possibility that the metastatic disease arose from another primary site had to be excluded. Therefore, CT and MRI of the colon, rectum, stomach, pancreas and prostate, as well as tests for occult blood in the stool and prostate-specific antigen were performed. Based on the negative results of the examinations, we eventually diagnosed this case as metastatic EMPD. Radiotherapy of the lower thoracic vertebrae was administered at a dose of 3 Gy per day in five fractions per week (total dose 39 Gy). In addition, the patient received intravenous docetaxel therapy at a dose of 25 mg m weekly for 2 weeks, followed by a 1-week rest. To avoid allergic reaction, the patient was given dexamethasone 8 mg prior to docetaxel administration. The course of treatment is shown in Figure 1. A gradual improvement in the patient’s condition was accompanied by a decrease in the serum CEA level. Sclerotic changes were observed in metastatic lesions in the vertebrae, suggesting tumour regression and regeneration of the bone. Moreover, some of the metastatic lesions in the lung disappeared on CT scan (Fig. 2). Other than mild general fatigue, no toxicity due to chemotherapy was observed. The patient was discharged after the 10th course of therapy and is still receiving chemotherapy on an outpatient basis without serious side-effects. His clinical progress has been satisfactory, and currently, 6 months after discharge, he has little limitation in daily life at home. The prognosis of EMPD is extremely poor once the tumour metastasizes. As metastatic EMPD is relatively rare, there has been little progress in the development of systemic chemotherapy regimens for this disease. Some authors have reported tumour response with combination chemotherapy, e.g. 5fluorouracil (5-FU) + mitomycin C, carboplatin + 5-FU + leucovorin, and low-dose 5-FU + cisplatin therapy. However, these chemotherapy regimens require daily intravenous drips and may require a week’s hospitalization in some cases. In contrast, weekly docetaxel administration can be applied on an outpatient basis with a reduction of acute toxicity and only mild myelosuppression. Based on the recent results of clinical trials, doses of 36–42 mg m were recommended for the weekly schedule, and the objective response rate was reported to be up to 53% in metastatic breast cancer, 46% in prostate cancer, and 23% in nonsmall cell lung cancer. In this range Fig 1. Treatment and clinical outcome. CEA, carcinoembryonic antigen.

Eccrine syringofibroadenoma in a patient with a burn scar ulcer

A 72‐year‐old woman with a burn scar on the calves of both legs developed an ulcer on her right heel, surrounded by multiple verrucous nodules and plaques. She had experienced similar verrucous lesions on both legs in the burn scar areas. Although the clinical diagnosis was Marjolins ulcer, histologically the ulcer region showed thick fibrous tissue without any atypical epithelial cells. The verrucous lesions were consistent with the diagnosis of eccrine syringofibroadenoma (ESFA). Moreover, an ESFA‐like growth pattern was seen in the elevated margin of the ulcer. Our findings suggest that these lesions developed as a result of reactive eccrine duct hyperplasia followed by skin tissue remodelling.

Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma.

ABSTRACT Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 (p = 0.03), expression levels of PD-1 ligand-2 (PD-L2), granzyme A (GZMA) and human leukocyte antigen-A (HLA-A) in the pre-treatment tumors were significantly higher (p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 (PRF1) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor β (TCR-β) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands (PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.

Chemoradiotherapy with taxane is superior to conventional surgery and radiotherapy in the management of cutaneous angiosarcoma: a multicentre, retrospective study.

The prognosis of cutaneous angiosarcoma (CAS), especially for patients with tumours > 5 cm has been reported to be dismal, even after conventional surgery and radiotherapy (S + RT).

Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2–9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression‐free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11–0.55 and 0.03–0.79; P = 0.005, and 0.047, respectively). At the 20‐week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.

A Custom-Made, Low-Cost Intraoperative Fluorescence Navigation System with Indocyanine Green for Sentinel Lymph Node Biopsy in Skin Cancer

Background: Recently, indocyanine green (ICG) fluorescence imaging has been reported as new method to detect sentinel lymph nodes (SLNs). However, high introduction costs limit its use. Objective: The purpose of this study was to test an ICG fluorescence detection system constructed with parts commonly available on the market and to compare the SLN detection rate with that of the conventional combined dye and RI methods. Methods: We constructed this system using a charge-coupled device camera and light-emitting diodes. Results: We could construct our system at a cost of less than USD 1,600. This system could trace lymphatic channels through the skin and detect SLNs in 16 patients with skin cancer. However, SLNs in the neck were difficult to detect through the skin. Conclusion: Our system could be assembled at a reasonable cost and allowed us to detect SLNs efficiently. It may be used as an alternative to radiotracer for detecting SLNs located in the groin and axillary regions.

The benefit of a sentinel lymph node biopsy and adjuvant therapy in thick (>4 mm) melanoma: multicenter, retrospective study of 291 Japanese patients

The benefit of a sentinel lymph node (SLN) biopsy and adjuvant therapy for patients with thick (>4 mm) melanoma has not been well studied in the Asian population. We examined the benefit of an SLN biopsy and adjuvant therapy on prognosis in Japanese patients with thick melanoma. A review of the melanoma database collected from 26 institutions in Japan identified 291 patients with thick melanoma between 2005 and 2010. Univariate and multivariate analyses were performed to evaluate the factors predictive of the overall survival (OS) and the disease-free survival (DFS). Of the 242 patients with thick melanoma who underwent an SLN biopsy, the results for 96 (40%) were positive. On multivariate analysis, increased Breslow thickness (relative risk, 1.11; 95% confidence interval, 1.05–1.17; P=0.0002) and SLN metastasis (2.14; 1.04–4.43; P=0.040) were associated with a poor OS. Increased Breslow thickness (1.11; 1.04–1.18; P =0.0018), ulceration (3.11; 1.25–7.72; P=0.014), satellitosis (3.89; 1.62–9.31; P=0.0023), and SLN metastasis (2.24; 1.16–4.36; P=0.017) were associated with DFS. Adjuvant chemotherapy had no impact on either OS or DFS. Adjuvant use of a monthly dermal injection of interferon-&bgr; (IFN-&bgr;) was associated with a improvement in both OS (0.34; 0.17–0.67; P=0.0022) and DFS (0.42; 0.20–0.86; P=0.018). An SLN biopsy provided useful prognostic information and the adjuvant use of IFN-&bgr; improved both OS and DFS in Japanese patients with thick melanoma. These results were consistent with those of previous studies carried out on a white population. Therefore, we suggest that an SLN biopsy and adjuvantIFN should be considered for patients with thick melanoma irrespective of the Breslow thickness or ethnicity.

Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients

BACKGROUND The importance of the genetic background of melanoma cells to the individual susceptibility to treatment has become apparent. In Caucasians, BRAF mutations are frequently detected in lesions on the skin of younger patients compared to NRAS and KIT mutations. However, clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations have not been fully evaluated in East Asians. OBJECTIVE To clarify clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. METHODS Clinical data were retrospectively collected from 11 hospitals in Japan. BRAF, NRAS and KIT mutations were evaluated with polymerase chain reaction and Sanger sequencing. The relationships between these gene mutations and pathological and clinical findings were analyzed. RESULTS The number of cases examined was 171 (primary: 135, metastases: 11, paired: 25), and all were Japanese patients. The detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively. Compared with the wild type, the presence of BRAF mutations was significantly associated with younger age (median, 50.0 years vs. 70.0 years, p<0.001). BRAF mutation was frequently detected in the lesions of the scalp (80%; 4/5), trunk (72.0%; 18/25), extremities (56.7%; 17/30) and neck (44.4%; 4/9), and the least prevalent were the face (22.2%; 2/9), nail (12.5%; 3/24), palm or sole (8.9%; 4/45) and mucosa (0%). NRAS mutations were prevalent in the face (33.3%) and palm or sole (20.0%), and the median age of these patients was 70.5 years. A KIT mutation was observed in the nail apparatus (25%), palm or sole (15.6%) and mucosa (18.2%). The median age of the patients with a KIT mutation was 63.0 years. Heterogeneity of mutations between primary and metastatic lesions was detected in six of 25 cases (24%). Solar elastosis was identified in 12 of 71 cases (15.3%), among which four cases harbored BRAF(V600E) (2 cases), BRAF(V600K), NRAS(Q61K) or NRAS(Q61L), respectively. CONCLUSION Some clinical characteristics associated with BRAF, NRAS and KIT mutations were observed in Japanese patients, and we observed both similarities to and differences from those of Caucasians. Our findings could provide useful information in efforts to clarify the tumor genesis of malignant melanomas.

Improvement of the sentinel lymph node detection rate of cervical sentinel lymph node biopsy using real‐time fluorescence navigation with indocyanine green in head and neck skin cancer

The standard technique using lymphoscintigraphy, blue dye and a gamma probe has established a reliable method for sentinel node biopsy for skin cancer. However, the detection rate of cervical sentinel lymph nodes (SLN) is generally lower than that of inguinal or axillary SLN because of the complexity of lymphatic drainage in the head and neck region and the “shine‐through” phenomenon. Recently, indocyanine green fluorescence imaging has been reported as a new method to detect SLN. We hypothesized that fluorescence navigation with indocyanine green in combination with the standard technique would improve the detection rate of cervical sentinel nodes. We performed cervical sentinel node biopsies using the standard technique in 20 basins of 18 patients (group A) and using fluorescence navigation in combination with the standard technique in 12 basins of 16 patients (group B). The mean number of sentinel nodes was two per basin (range, 1–4) in group A and three per basin (range, 1–5) in group B. The detection rate of sentinel nodes was 83% (29/35) in group A and 95% (36/38) in group B. The false‐negative rate was 6% (1/18 patients) in group A and 0% in group B. Fluorescence navigation with indocyanine green may improve the cervical sentinel node detection rate. However, greater collection of data regarding the usefulness of cervical sentinel node biopsy using indocyanine green is necessary.