Sequential Combination Chemotherapy of Dacarbazine (DTIC) with Carboplatin and Paclitaxel for Patients with Metastatic Mucosal Melanoma of Nasal Cavity and Paranasal Sinuses.

By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis.

Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.

PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma.

PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01990859.

Combination chemotherapy for metastatic extramammary Paget disease.

BACKGROUND: It is difficult to treat patients in the advanced stages of extramammary Paget disease (EMPD) because no effective treatment has yet been established. OBJECTIVE: To describe the experience of using combination chemotherapy (FECOM) in patients with metastatic EMPD. METHODS: Since we reported a case of metastatic EMPD that responded to FECOM, we have treated further patients with metastatic EMPD using FECOM at the National Cancer Center Hospital in Japan. FECOM consists of epirubicin 40 mg m(-2) , mitomycin C 3·5 mg m(-2) and vincristine 0·7 mg m(-2) on day 1, carboplatin 300 mg m(-2) on day 2 and 5-fluorouracil 350 mg m(-2) on days 2-6. To evaluate the efficacy of this combination therapy in patients with metastatic EMPD, data regarding patients given FECOM for the first-line treatment of metastatic EMPD were extracted retrospectively. RESULTS: Seven patients were eligible for this study. A partial response was noted in four evaluable patients (100%). The other three patients were not evaluable for clinical response. One of the three unevaluable patients showed a decrease in tumour size by 100%, the other two by about 20%. The median overall survival and progression-free survival were 9·4 months (7·6-17·3) and 6·5 months (2·6-7·9), respectively. The 1-year survival rate was 43% (three of seven). Three of the seven patients (43%) had grade 3 haematological toxicities. All treatment-related toxicities were reversible and there was no febrile neutropenia or treatment-related deaths. CONCLUSION: This study suggests that the combination chemotherapy FECOM may be a treatment option for patients with metastatic EMPD.

Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease.

BACKGROUND: Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined. OBJECTIVES: To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD. METHODS: Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization. RESULTS: The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P=0·012) and were correlated with a larger number of lymph-node metastases (P=0·047). Log-rank tests for survival curves showed that lymph-node metastasis and ERBB2 amplification were significant prognostic factors (P=0·0001 and P=0·043, respectively). However, by a multivariate analysis, only lymph-node status was a significant indicator of Paget-disease-specific survival (P=0·0001). CONCLUSIONS: A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.

Reconstructive considerations in the treatment of soft tissue sarcomas of the cheek.

Soft tissue sarcomas of the head and neck region are rare, and very little has been described about the reconstructive methods used after sarcoma resection of cheek soft tissue sarcomas. Reconstructive methods for cheek defects after sarcoma resection are presented and the possibilities, advantages, disadvantages, and expected results are described. A series of 3 patients with cheek soft tissue sarcomas were examined. Reconstructive methods included; one skin graft, a free forearm flap and a cervicofacial flap. All patients had lesions < 5 cm and low-grade tumours, and no case presented local recurrence or metastases. The choice of reconstructive methods depends mostly on the complexity of the defect. In cases comprising comparatively small or minor defects, reconstructions using local flaps, such as the cervicofacial flap, provide better aesthetic and functional results than either free flaps or skin graft.

Surgical rehabilitation of reversible facial palsy: facial--hypoglossal network system based on neural signal augmentation/neural supercharge concept.

To obtain symmetric appearance in facial palsy patients, it is important to retain any remaining potential of the compromised facial mimetic muscles. The purpose of the present study was to introduce surgical rehabilitation based on neural signal augmentation/neural supercharge concept for the treatment of reversible facial palsy patients. With construction of facial-hypoglossal network system using end-to-side neurorrhaphy technique, both facial and hypoglossal motor signals are provided to the compromised facial mimetic muscles. It is hypothesised that the remaining potential of incompletely or completely paralysed muscles without atrophy is activated by a neural 'supercharge' effect. To date, nine patients presented with reversible facial palsy have been treated by surgical rehabilitation with facial-hypoglossal network system in our institutes. Facial mimetic muscle function evaluated by the House-Brackmann grading system was improved from grade IV-VI to II-III in this series. The postoperative ENMG findings showed double innervation of the mimetic muscles supplied by the facial and hypoglossal donor motor sources. Hemiglossal dysfunction and mimetic muscle synkinesis associated with tongue motion were never seen with an average follow-up period of 21 months after surgery. This reconstructive concept offers a significant advantage for the treatment of the facial palsy patients with persistent incomplete type and reversible complete type without distinct mimetic muscle atrophy.

Two innovations of the star-flap technique for nipple reconstruction.

Two innovations of the star-flap technique for nipple reconstruction are described. A combination of the star-flap technique and a contralateral nipple graft is indicated in patients with a large nipple and small areola on the contralateral side. It provides sufficient volume for the new nipple and improves the shape of the donor nipple. A combination of the star-flap technique and a banked costal-cartilage graft offers better nipple contour and projection than the conventional star-flap technique. Preparation of the cartilage graft is easy and does not result in additional scarring; the nipple projection can be expected to be maintained over a long period.

Long-term outcome of pressure sores treated with flap coverage.

This article provides our experience with 45 ischial sores and 24 sacral sores in 53 paraplegic patients between 1990 and 1995. Data were evaluated as to the sites of sores and types of the transferred flaps. Types of the transferred flaps were categorized into the fasciocutaneous flap and the myocutaneous or muscle flap. In the treatment of 45 ischial sores, 18 were reconstructed with the fasciocutaneous flaps and 27 with the myocutaneous or muscle flaps. In the treatment of 24 sacral sores, 23 were reconstructed with the fasciocutaneous flaps and 1 with the myocutaneous flap. The recurrence rate was analyzed by percent pressure sore free survival (%PSFS) by the Kaplan-Meier method. Overall, the ischial sores provided a higher recurrence rate than sacral sores; however, there was no significant difference in the %PSFS between the sites of sores. The group of the sores reconstructed with the fasciocutaneous flap demonstrated significant or marginally significant better results in the %PSFS (total of ischial and sacral, p = 0.0155; ischial, p = 0.0555) compared with the group of the sores reconstructed with the myocutaneous or muscle flap. These findings indicated that the use of the fasciocutaneous flap is expected to provide a better long-term result in surgical reconstruction of pressure sores than the myocutaneous or muscle flap.