Low-Dose MST-16/VP-16 Combination Chemotherapy in 9 Patients with Tumor Stage Mycosis Fungoides.

BACKGROUND/AIM: MST-16 and VP-16, both of which are topoisomerase II inhibitors, are antitumor agents regularly used to treat malignant lymphoma and small cell lung carcinoma. New therapeutic agents for tumor stage mycosis fungoides (MF) have recently been developed, but their efficacy is limited. We herein retrospectively reported the use of MST-16/VP-16 combination therapy for tumor stage MF at multiple treatment centers and examined their antitumor effect. METHODS: Five male and four female patients with tumor stage MF were enrolled. Age at the start of therapy ranged from 33 to 80 years (average: 54.5 years), and the previous treatment consisted of R-CHOP, CAVOP-IFN, etc. The protocol for low-dose MST-16/VP-16 combination chemotherapy consisted of 800 mg MST-16 and 25 mg VP-16 administered 5 days per month. RESULTS: Three of the 9 patients died, but two of the three fatalities were unrelated to MF. A treatment effect was seen in three and 6 patients who showed a complete response and a partial response, respectively. The 5-year and 10-year overall survival rate was 85.7% and 57.1%, respectively. Adverse reactions consisted of 4 cases of nausea and 1 case of leukopenia. CONCLUSION: The present study demonstrated that the response rate to MST-16/VP-16 combination therapy was 100% and that the treatment effect was relatively long, suggesting that this therapy may be a viable option for treating tumor stage MF.

Long-term efficacy and safety of bexarotene for Japanese patients with cutaneous T-cell lymphoma: The results of a phase 2 study (B-1201).

The present study (B-1201 clinical trial) was conducted as a multicenter, open-label, single-arm phase II study to evaluate the long-term safety, tolerability and efficacy of bexarotene. This study enrolled 10 Japanese adults aged more than 20 years with cutaneous T-cell lymphoma (CTCL) who completed the 24-week study period of the B-1101 trial. The objective response rate (ORR) was 53.8% (95% confidence interval, 25.1-80.8). In the early stage (IB), the ORR was 60% (3/5 cases). In the advanced stage (IIB and IIIA), the ORR was 57.1% (4/7 cases). The median time to response was 58 days (range, 27-168). The median treatment duration was 380 days (range, 33-1674). The median duration of response (DOR) could not be reached during the study period. The longest DOR reached 1618 days at the end of the B-1201 trial. Nine patients (56.3%) in the full analysis set (FAS) population experienced dose reduction of bexarotene. Common drug-related adverse events in the FAS population included hypothyroidism (93.8%), hypertriglyceridemia (81.3%), hypercholesterolemia (81.3%), leukopenia (68.8%) and neutropenia (56.3%). Dose-limiting toxicity (DLT) was present in five (38.5%) of the 13 patients in the 300 mg/m2 cohort. Of the five patients, four developed grade 3 neutropenia and one developed grade 4 hypertriglyceridemia. All DLT cases recovered after the discontinuation of bexarotene. None of the five patients discontinued this trial because of DLT. The B-1201 trial shows the long-term safety of oral bexarotene for Japanese patients with CTCL, despite frequent dose reduction.

Comparative analysis of methicillin-resistant Staphylococcus aureus isolated from outpatients of dermatology unit in hospitals and clinics.

Community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) is a causative agent of intractable skin infections. In general, clinical symptoms of hospital outpatients with skin infections are severer than those of clinic patients. Hence, molecular epidemiological features of the CO-MRSA strains from hospital outpatients are predicted to be different from those of clinic patients. Here, we conducted a comparative analysis for CO-MRSA isolates from outpatients with impetigo in hospitals and clinics located in the same district of Tokyo, Japan. Incidence of MRSA infection was higher in hospital outpatients (21.5%, 20/93 isolates) than in clinic patients (14.5%, 121/845 isolates). The resistance rate to clindamycin, which is a common topical antimicrobial agent in dermatology, in the isolates from hospital outpatients (60.0%) was higher than those from clinic patients (31.4%). Proportion of the staphylococcal cassette chromosome (SCC) mec type II, which is a representative type of hospital-acquired MRSA in Japan, in the isolates from hospital outpatients (65.0%) was significantly higher than those from clinic patients (30.6%) (P < 0.01). Multilocus sequence typing showed that the clonal complex 89-SCCmec type II (CC89-II) clone, which exhibits clindamycin resistance, was the most predominant (55.0%) in the isolates from hospital outpatients. On the other hand, all CC8-IV, CC121-V, and CC89-V clones accounted for 60% in clinic patients were susceptible to clindamycin. Our findings suggested that the clindamycin-resistant CC89-II CO-MRSA clone might be more related to skin infections in hospital outpatients than clinic patients.

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas.

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)-selective retinoid, were evaluated in Japanese patients with stage IIB-IVB and relapsed/refractory stage IB-IIA cutaneous T-cell lymphomas (CTCL). This study was conducted as a multicenter, open-label, historically controlled, single-arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity-weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose-limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2 : two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2 , common drug-related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment-related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.

Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia.

OBJECTIVE: Autoimmune cerebellar ataxias were recently reported to be treatable. However, the proportion of patients with cortical cerebellar atrophy of unknown etiology with autoimmune-associated cerebellar ataxia and the actual effectiveness of immunotherapy in these diseases remain unknown. METHODS: We measured the level of autoantibodies (including anti-gliadin antibody, anti-glutamic acid decarboxylase (GAD) antibody, and anti-thyroid antibody) in 58 Japanese patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, cancer, or those who were receiving phenytoin, and the efficacy of immunotherapy was assessed. RESULTS: Thirty-one of 58 (53%) patients were positive for anti-GAD antibody, anti-gliadin antibody, or anti-thyroid antibody. Seven of the 12 anti-gliadin antibody-positive patients, three of the four anti-GAD antibody-positive patients, and three of the six anti-thyroid antibody-positive patients responded well to immunotherapy, indicating that 59% of patients with ataxia-associated antibody-positive cerebellar ataxia undergoing immunotherapy responded well. CONCLUSION: Some patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity.

Hidradenoma papilliferum of the vulva in association with an anogenital mammary-like gland.

Hidradenoma papilliferum (HP) is a benign adnexal neoplasm which preferentially develops in the anogenital region of women. Although the origin of HP was previously thought to be an apocrine sweat gland, recent studies have suggested that it may derive from the anogenital mammary-like gland (MLG). In this paper, we present a 43-year-old Japanese woman with hidradenoma papilliferum of the vulva. The lesion developed 7 years prior to her visit, and clinically appeared as a skin-colored cystic nodule. Histopathological examination revealed that the neoplasm was formed by the tubular structures consisting of two types of pleomorphic cells, columnar cells in the luminal layer and cuboidal cells in the basal layer. Further, the surgical specimen contained a wide, divergent, lobular ductal structure located in the vicinity of the neoplastic lesion, which was consistent with MLG.

Three cases of sacral pressure ulcers presenting primary dermatoporosis on the forearms.

The relatively new term dermatoporosis refers to chronic deficiencies in the skin's functions in the elderly population due to aging. This syndrome is marked by chronic cutaneous fragility clinically represented by skin atrophy, senile purpura, stellate pseudoscars, skin laceration, and dissecting hematoma of the skin. In this paper, we report three cases of sacral pressure ulcers presenting primary dermatoporosis on the forearms. Case 1 was a 74-year-old male who presented with a stage IV sacral pressure ulcer. The signs of dermatoporosis appeared on the forearms. Histopathology of the lesions revealed epidermal thinning with loss of rete ridges. Azan and Elastica van Gieson staining demonstrated the degeneration of the dermal collagen fibers and elastic fibers, respectively. In spite of 6 months of treatment, the ulcer failed to heal sufficiently. Case 2 was a 74-year-old male and Case 3 was a 97-year-old female. Both cases presented with a stage II sacral pressure ulcer and dermatoporosis on the forearms. Histopathological examinations and the clinical course of the wound could not be ascertained in Cases 2 and 3. None of the patients had previously used corticosteroids. The presence of a primary dermatoporosis on the forearms in these cases may be associated with the increased risk of pressure ulcer development.

Guidelines for the management of cutaneous lymphomas (2011): a consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group.

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) - Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T-cell leukemia/lymphoma and extranodal natural killer/T-cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS - Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.

Eccrine porocarcinoma: clinical and pathological report of eight cases.

BACKGROUND: Eccrine porocarcinoma (EPC), a slow-growing carcinoma of the sweat gland, is a rare condition documented only in a small number of case series. Due to its rarity, guidelines and specific recommendations are not widely available. Accordingly, many dermatologists encounter difficulty in diagnosing and treating EPC. The aim of this study is to report the clinical and pathological features of EPC in order to contribute to the body of information currently available on the subject. PATIENTS AND METHODS: From 2003 to 2013, 8 Japanese patients were diagnosed with EPC at the Department of Dermatology in the Hachioji Medical Center of Tokyo Medical University. Patient data, including clinical manifestations, histopathological findings, immunohistochemical results, treatment method, and clinical course were collected and documented. RESULTS: The mean age of the patients (6 males and 2 females) was 72.6 years. The duration of the lesions ranged from 4 months to 5 years (mean: 3.5 years). All of the lesions clinically presented with erosive reddish nodules (mean size: 39.0 mm). Initial CT imaging revealed that 1 case had multiple distant metastases. Surgical resection was performed for all primary lesions and follow-up observations were available in all cases (mean: 10.9 months). One case with distal metastases underwent both radiation therapy and chemotherapy, but nevertheless succumbed to the disease. CONCLUSION: The EPC cases in our department presented a versatile clinical appearance and characteristic histopathological features.

A case of cutaneous T cell pseudolymphoma in a patient with Helicobacter pylori infection.

Cutaneous pseudolymphomas (CPL) are benign cutaneous lymphoproliferative infiltrations of various origin, including among others bacterial infections, viral infections and drugs . Helicobacter pylori has been frequently founded in the stomach of patients with MALT lymphoma. In January 2001, a 43-year-old man was referred to our department because of a 1-month history of itchy erythematous patches, plaques and flat tumors on his body. Histological examination revealed nodular infiltrations composed of lymphocytes, plasma cells and histiocytes with exocytosis of lymphocytes within the epidermis. Molecular analysis of rearrangement of T cell receptor and immunoglobulin heavy-chain genes did not reveal monoclonality. Based on these clinical, laboratory and histopathological data, a diagnosis of cutaneous T cell pseudolymphoma (CTPL) was made. The patient was anti-H. pylori antibody-positive, and was treated with anti-H. pylori combination with the result that all of the tumors had disappeared by January 2002. The patient has maintained complete response up to the last follow-up visit in December 2005.

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.