Glucose-6-phosphate dehydrogenase correlates with tumor immune activity and programmed death ligand-1 expression in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer. Some cases have a good prognosis and spontaneous regression can occur. Reported prognostic markers, such as Merkel cell polyoma virus infection or programmed death ligand-1 (PD-L1) expression, remain insufficient for precisely estimating the vastly different patient outcomes. We performed RNA sequencing to evaluate the immune response and comprehensively estimate prognostic values of immunogenic factors in patients with MCC. METHODS: We collected 90 specimens from 71 patients and 53 blood serum samples from 21 patients with MCC at 10 facilities. The mRNA was extracted from formalin-fixed paraffin-embedded tissues. Next-generation sequencing, immunohistochemical staining and blood serum tests were performed. RESULTS: Next-generation sequencing results classified MCC samples into two types: the 'immune active type' was associated with better clinical outcomes than the 'cell division type'. Expression of the glucose-6-phosphate dehydrogenase (G6PD) gene was highly significantly upregulated in the 'cell division type'. Among 395 genes, G6PD expression correlated with the presence of lymph node or distant metastases during the disease course and significantly negatively correlated with PD-L1 expression. Immunohistochemical staining of G6PD also correlated with disease-specific survival and exhibited less heterogeneity compared with PD-L1 expression. G6PD activity could be measured by a blood serum test. The detection values significantly increased as the cancer stage progressed and significantly decreased after treatment. CONCLUSIONS: G6PD expression was an immunohistochemically and serum-detectable prognostic marker that negatively correlated with immune activity and PD-L1 levels, and could be used to predict the immunotherapy response.

Primary amelanotic malignant melanoma of the male urethra with inguinal lymph node metastasis successfully controlled by nivolumab: A case report.

We report a rare case of primary amelanotic malignant melanoma of the male urethra. A 65-year-old man with a urethral mass was referred to our hospital. A pathological diagnosis of a biopsy specimen revealed malignant melanoma. Thereafter, the patient underwent partial penectomy. The histopathological diagnosis was amelanotic malignant melanoma of the urethra. The patient had received DAV-Feron in an adjuvant setting; however, PET-CT revealed multiple metastasis. After receiving more than 10 cycles of nivolumab, the accumulation of FDG was no longer observed on PET-CT. The patient is currently free from recurrence at 20 months after nivolumab treatment.

Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041).

PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma.

In the adjuvant setting for malignant melanoma, interferon (IFN)-α-2b and pegylated (PEG) IFN-α-2b were approved in several countries including the USA before these were approved in Japan. To resolve the "drug-lag" issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN-α-2b. As with a previously reported phase III study, patients were to receive PEG IFN-α-2b 6 µg/kg per week s.c. during an 8-week induction phase, followed by a maintenance phase at a dose of 3 µg/kg per week up to 5 years. Dose-limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose-limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug-related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration-time curve and maximum observed serum concentration were observed between Japanese and historical non-Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN-α-2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

Radiation therapy for angiosarcoma of the scalp: treatment outcomes of total scalp irradiation with X-rays and electrons.

BACKGROUND AND PURPOSE: Wide surgical excision is the standard treatment for angiosarcoma of the scalp, but many patients are inoperable. Therefore, we investigated the outcome of radiation therapy for angiosarcoma of the scalp. PATIENTS AND METHODS: Seventeen patients with angiosarcoma of the scalp underwent radiation therapy with total scalp irradiation. Four patients had cervical lymph node metastases, but none had distant metastases. A median initial dose of 50 Gy in 25 fractions was delivered to the entire scalp. Subsequently, local radiation boost to the tumor sites achieved a median total dose of 70 Gy in 35 fractions. RESULTS: Fourteen of the 17 patients developed recurrences during the median follow-up period of 14 months after radiation therapy; 7 had recurrences in the scalp, including primary tumor progression in 2 patients and new disease in 5, and 12 patients developed distant metastases. The primary progression-free, scalp relapse-free, and distant metastasis-free rates were 86, 67, and 38 % at 1 year and 86, 38, and 16 % at 3 years, respectively. Thirteen patients died; the overall and cause-specific survival rates were both 73 % at 1 year and 23 and 44 % at 3 years, respectively. The median survival time was 16 months. There were no therapy-related toxicities ≥ grade 3. CONCLUSION: Total scalp irradiation is safe and effective for local tumor control, but a dose of ≤ 50 Gy in conventional fractions may be insufficient to eradicate microscopic tumors. For gross tumors, a total dose of 70 Gy, and > 70 Gy for tumors with deep invasion, is recommended.

Recurrent endocrine mucin-producing sweat gland carcinoma in the eyelid.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) has recently been recognised as a low-grade carcinoma that almost always occurs on the eyelid. This carcinoma is very rare, with only 20 cases (including the present one) having been reported in the literature. EMPSGC is frequently found in association with invasive mucinous carcinoma. While EMPSGC treatments consist of a complete surgical removal, there has been no consensus regarding the surgical margin. Therefore, reports on surgical management of EMPSGC may potentially provide important therapeutic information. Here, we present a case of a 74-year-old man with EMPSGC of the eyelid that repeatedly recurred despite surgical treatments at another institution. After referral to our department, the patient underwent tumour excision. However, the specimen revealed a positive surgical margin and thus, he subsequently underwent a wider excision. There has been no sign of tumour recurrence or metastasis 6 months after his last operation. This article reviews the current literature and discusses the surgical management of EMPSGC.

Definitive radiation therapy for extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is frequently inoperable because of old age and/or coexisting disease. We therefore reviewed the efficacy and toxicity of radiation therapy for EMPD. PATIENTS AND METHODS: Fourteen patients with EMPD underwent definitive radiation therapy. Three patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 52-80.2 Gy (median=60.6 Gy) were delivered to tumor sites in 26-43 fractions (median=33 fractions). RESULTS: Four patients had developed recurrence at a median follow-up period of 47 months. The 5-year local control and disease-free rates were 71% and 63%, respectively. Two patients died of old age and renal failure at 6 and 51 months, respectively, after irradiation. The 5-year disease-free, cause-specific and overall survival rates were 46%, 100% and 79%, respectively. No therapy-related toxicities of grade 3 or greater were observed. CONCLUSION: Radiation therapy is effective and safe, and appears to offer a curative treatment option for patients with EMPD.

Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma.

A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose-limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug-related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non-Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation.

Role of radiotherapy as curative treatment of extramammary Paget's disease.

PURPOSE: Extramammary Paget's disease (EMPD) is a relatively rare malignancy that usually arises in the genital areas. Wide surgical excision remains the standard and most reliable curative treatment of EMPD. However, surgery is sometimes not possible, because many patients are elderly, and complete excision can be difficult owing to the tumor location. We, therefore, performed a review to determine the role of radiotherapy (RT) for EMPD. METHODS AND MATERIALS: A total of 22 patients with EMPD in their external genitalia (4 men and 18 women, age 52-94 years at RT) underwent RT with curative intent. Nine patients had regional lymph node metastases. A total dose of 45-70.2 Gy (median, 60) was delivered to the pelvis, including the tumors, in 25-39 fractions (median, 33). RESULTS: In all but 3 patients, the irradiated tumors were controlled during a follow-up period of 8-133 months (median, 42). Of the 22 patients, 13 developed recurrences, including local progression within the radiation field in 3 and lymph node and/or distant metastases outside the radiation field in 10, at 3-43 months after treatment. The 2- and 5-year local progression-free rates were 91% and 84%, respectively. Of the 22 patients, 7 patients had died at 33-73 months after RT. The cause of death was tumor progression in 4, infectious pneumonia in 2, and renal failure in 1 patient. The overall and cause-specific survival rates were 100% for both at 2 years and 53% and 73% at 5 years, respectively. No therapy-related Grade 3 or greater toxicity was observed. CONCLUSIONS: RT is safe and effective for patients with EMPD. It appears to contribute to prolonged survival as a result of good tumor control.

Localized multiple glomangiomas on the foot.

We report a 15-year-old Japanese male with multiple, soft, blue and painless nodules on the left foot. The lesions had developed when the boy was 3 years old, and had enlarged gradually thereafter. None of his family members had any similar eruptions. All the lesions were resected under local anesthesia. Histological examination revealed cystically dilated spaces lined by endothelial cells and a few outer layers of glomus cells in the dermis and fat tissue. Immunohistochemistry demonstrated that the tumor cells were positive for alpha-smooth muscle actin. We diagnosed this case as localized multiple glomangioma. Multiple glomus tumors are much less common than solitary ones, and localized multiple glomus tumors are extremely rare. Because the clinical differential diagnosis of multiple glomangiomas includes common venous malformation, particularly blue rubber bleb nevus syndrome, histopathological studies should be performed.

Extramammary Paget's disease: analysis of growth signal pathway from the human epidermal growth factor receptor 2 protein.

Paget's disease is a skin cancer characterized by characteristic (Paget) cells scattered in the epidermis. Although its prognosis is generally favorable with surgical resection, the clinical outcome turns unfavorable in cases with recurrence and metastasis. Therefore, establishment of effective therapeutic regimens is required for advanced Paget's disease. The human epidermal growth factor receptor 2 (HER2) protein, a transmembrane growth factor receptor, is frequently overexpressed in malignancies, causing activation of the phosphatidylinositol 3 kinase (PI3K) and extracellular signal-regulated kinase (ERK) signal pathways. Recently, HER2-targeting molecular therapy using trastuzumab (Herceptin; Genentech, Inc, South San Francisco, Calif) was revealed to be effective in advanced breast cancers overexpressing HER2 protein. Here, we analyzed the correlation between activation of the HER2 signal pathways and clinicopathologic parameters of 36 extramammary Paget's disease samples from 34 Japanese patients, using immunohistochemical analyses for HER2, phosphorylated HER2, phosphorylated AKT, and phosphorylated ERK proteins. We found overexpression of the HER2 protein in 19.4% (7) of the lesions, 3 of which showed HER2 amplification by chromogenic in situ hybridization. Phosphorylated HER2 protein was detected in 12 lesions (33.3%), including 2 of the 7 HER2-overexpressing lesions. Phosphorylated AKT was detected in approximately 75.0% (27/36) and phosphorylated ERK in 38.9% (14/36). Both HER2 and AKT were simultaneously phosphorylated in 9 cases (25.0%) and HER2 and ERK in 9 cases (25.0%), but all 3 molecules were phosphorylated in only 1 sample. Phosphorylated ERK correlated with the maximum diameter of the tumors (P < .025), but other immunohistochemical parameters failed to show any correlation with clinicopathologic features. These results suggest the contribution of the HER2 signaling pathway to the pathogenesis and progression of some cases of extramammary Paget's disease, for which clinical use of molecular target therapy against the HER2 pathway is warranted.

[A case of Hansen's disease].

With the abolition of Leprosy Prevention Act of 1996, that opportunities examining the Hansen's disease patient with a general medical institution increase is expected. Because we experienced Hansen's disease of a staying in Japan foreigner then in such time, we present it. A case is a man of 50 years old, who is a Filipino of 3 years living in Japan. It recognized infiltrating deep erythema in a face and trunk. Furthermore, in dysesthesia, nerve hyperplasia, and Bl is positive in skin smear. Histopathology is a typical finding. Than the above, we diagnosed it as Hansen's disease of BL-LL type.