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.

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.

The detection of Propionibacterium acnes signatures in granulomas of lupus miliaris disseminatus faciei.

Lupus miliaris disseminatus faciei (LMDF) is a papular eruption that occurs on adults' faces, predominantly on the lower eyelids. Histologically, the granulomatous lesions are primarily situated around the hair follicles, particularly the superficial region/infundibula. Its etiology remains to be elucidated. Recently, Propionibacterium acnes (P. acnes) has been suspected as a cause of sarcoidosis. In light of the sarcoid-like reactions that are present in LMDF, we hypothesized that P. acnes may also be implicated in granulomas associated with the disease. We evaluated nine DNA samples from granulomatous lesions from the skin of patients with LMDF. We used laser capture microdissection to extract DNA from these regions. Polymerase chain reaction was performed to amplify segments of the 16S ribosomal RNA of P. acnes, and the P. acnes gene was clearly detectable in all nine DNA samples. The gene was also detected in samples from normal-appearing skin, but these bands were faint in all samples. The results of the present study suggest that P. acnes plays a pathogenetic roles in LMDF.

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.

Angioadnexocentric nevus.

An association of melanocytic nevus with eccrine glands has been well-documented and well-known as eccrine-centered nevus. Non-giant congenital nevi sometimes contain angiocentric and/or adnexocentric growth of nevus cells. Blood vessels are the most prominent site of nevus cell infiltration and propagation. In our specimen, the second was eccrine ducts. These selective sites of infiltration gave rise to a linear pattern of nevus cell distribution. Upon cursory examination at low magnification, vascular pathologies such as lymphocytic perivasculitis and particularly "coat-sleeve-like" pattern of erythema annulare centrifugum were suggested. S-100 immunostained perivascular and periductal lymphocytoid cells while CD3, 4 and 8 for T cells, and CD20 and 79a for B cells, were all negative. S-100 detected some invasive behavior of nevus cells penetrating into the vascular and ductal walls. However, Ki-67 was negative in all cells, suggesting a benign nature of this lesion. It is postulated that intradermal nevus cells of fetal skin freely migrate through mesenchymal tissue and stop when they hit barriers such as blood vessels and eccrine ducts and propagate in situ. How does this random migration theory explain the blood vessels and eccrine ducts getting the largest share of nevus cells? It is because they are the largest barriers of fetal dermis.

Human T-lymphotropic virus 1 (HTLV-1) infection--dermatological implications.

Human T-lymphotropic virus type 1 (HTLV-1) is a type C retrovirus primarily endemic to Japan, Central and South America, the Middle East, regions of Africa, and the Caribbean. Currently, an estimated 10-20 million people worldwide are infected with this virus. Although the majority of infected individuals remain asymptomatic, HTLV-1 is the causative agent of a number of disorders, notably adult T-cell leukemia/lymphoma (ATLL) and a progressive demyelinating neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to ATLL and HAM/TSP, HTLV-1 has been associated with a spectrum of skin disorders, such as infective dermatitis associated with HTLV-1, crusted scabies, and leprosy. The understanding of the interaction between virus and host response has improved markedly, but there are still few treatment options.

Epstein-Barr virus-associated primary central nervous system lymphoma in a patient with adult T-cell leukemia / lymphoma.

We present a case of Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma (PCNSL) arising from a patient with cutaneous-type adult T-cell leukemia/lymphoma (ATLL). Extranodal sites affected by ATLL include the skin, lung, liver, gastrointestinal tract and central nervous system (CNS). CNS involvement usually occurs as an acute and lymphoma-type ATLL. PCNSL is a rare type of tumor and the vast majority of PCNSL are of B-cell lineage. Individuals with acquired, iatrogenic or congenital immunodeficiency are at increased risk of PCNSL, which is commonly associated with EBV. In our patient, the expression of latent infection membrane protein 1 (LMP1), EBV nuclear antigen 2 (EBNA2), and EBV-encoded small RNA (EBER) in tumor cells confirmed a type III latency of EBV infection. Human T-cell lymphotropic virus type I (HTLV-I) can induce immunodeficiency before the overt development of ATLL. The HTLV-I infection led to suppression of the immune system and the development of EBV-associated PCNSL. This is the first reported case of the clinicopathological features of EBV-associated PCNSL arising from a patient with ATLL.

An autopsy case of chemical burns by hydrochloric acid.

A 34-year-old man was discovered by his coworkers in a tank filled with 35% (w/w) hydrochloric acid. Despite undergoing intensive treatment, he died one and a half days later. An autopsy revealed generalized high tensity, overall grayish brown skin color, heavy gastric submucosal hemorrhage and heavy pulmonary edema. We concluded that death was caused by burn shock due to wide, generalized chemical burn. Microscopic investigation of the burn in the area with grayish brown skin considered coagulation necrosis of full-thickness of the skin (third-degree or deep burn), revealed that the burn was judged to cover the partial thickness of the skin (second-degree or dermal burn). These findings suggest that chemical burn by hydrochloric acid results in a change of skin color due to chemical reaction so that the appearance of the chemical burn is more severe than the degree assigned by histological examination.

Defect of hepatocyte growth factor activator inhibitor type 1/serine protease inhibitor, Kunitz type 1 (Hai-1/Spint1) leads to ichthyosis-like condition and abnormal hair development in mice.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1(+/+) blastocysts with Hai-1/Spint1(-/-) embryonic stem cells successfully generated high-chimeric Hai-1/Spint1(-/-) embryos (B6Hai-1(-/-High)) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1(-/-) mice was caused by placental dysfunction. However, newborn B6Hai-1(-/-High) mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development.

New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma: human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types.

Adult T-cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T-lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. We propose an entity of cutaneous ATLL, which has less than 5% abnormal T lymphocyte in peripheral blood, a normal lymphocyte count (i.e. <4 x 10(9)/L), no hypercalcemia and lactate dehydrogenase values of up to 1.5 times the normal upper limit. At least one of the histologically proven skin lesions should be present accompanying monoclonal integration of human T-cell lymphotropic virus type 1 (HTLV-1) proviral DNA in the skin lesion. Blood samples were collected from 41 HTLV-1-infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV-1 proviral loads, soluble interleukin-2 receptors and other parameters were examined in each case. HTLV-1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.

Two Japanese cases of lichen planus pigmentosus-inversus.

Case 1 was a 51-year-old Japanese woman. She presented with an asymptomatic brown macule located on the right axilla of 2 months' duration. The smooth macule was 2 cm in diameter with a sharp demarcation (Fig. 1A). Case 2 was a 62-year-old Japanese man. He presented with asymptomatic, symmetric, gray-brown macules located on the groin, axillae, and popliteal region of 6 months' duration. The smooth macules were several millimeters to centimeters in diameter and sharply demarcated (Fig. 1B). Oral or nail lesions, previous inflammatory processes in affected areas, and internal malignancies were absent. A causal relationship with drugs, recent sun exposure, or trauma could not be identified. Findings for work-up, including blood cell count, fasting blood sugar levels, liver function, serum electrolyte levels, serum electrophoresis, urinalysis, antinuclear antibodies, and serological examinations for human hepatitis viruses and syphilis, were within normal limits or negative. The lesions gradually disappeared without medication within 6 months. Biopsy specimens showed a lymphocytic infiltrate with basal vacuolar changes and prominent melanin incontinence in the upper dermis (Fig. 2A). The band-like lymphocytic infiltrate was moderate in Case 1 and mild in Case 2. Immunohistochemistry showed infiltrative CD8(+) T lymphocytes with keratinocytic damage, indicating cytotoxic injury of the keratinocytes (Fig. 2B). Both the epidermis and the upper dermis contained CD1a(+) cells (Fig. 2C). The keratinocytes focally and weakly expressed HLA-DR (Fig. 2D). These findings were identical in samples from both patients.

A case of pemphigus vulgaris accompanied by multiple myeloma.

Pemphigus is a mucocutaneous intraepithelial blistering disease caused by autoantibodies to epithelial cell adhesion molecules (desmoglein). The association between pemphigus and malignant neoplasm is well recognized. We present the case of a 62-year-old woman with pemphigus vulgaris accompanied by multiple myeloma. To the best of our knowledge, this is the first report of a case of pemphigus vulgaris concomitant with multiple myeloma. From the results of immunoblotting using normal human epidermal extracts and indirect immunofluorescence using rat bladder sections, and her clinical manifestations, our case does not seem to be one of paraneoplastic pemphigus.

A case of cytomegalovirus colitis following immunosuppressive treatment for pyoderma gangrenosum.

We report a case of pyoderma gangrenosum (PG) complicated by cytomegalovirus (CMV)-induced colitis. A 79-year-old woman with PG was treated with corticosteroid and cyclosporin. She had blood in her stool and advancing anemia during the treatment. A colonoscopic biopsy specimen from the colon revealed typical CMV-infected cells with CMV inclusions confirmed by immunohistochemistry. Furthermore, there were many CMV-antigen-positive leukocytes, suggesting an active CMV infection, which is serious in compromised hosts. Although ulcerative colitis and Crohn's disease are well known as complications of PG, CMV enterocolitis should be considered in the differential diagnosis of enterocolitis in immunocompromised patients.

Bilateral lichen striatus.

We describe a very rare case of bilateral lichen striatus on the lower extremities with a history of more than ten years. Histopathologically, the lesions demonstrated a lichenoid tissue reaction with foci of spongiosis and perivascular inflammatory cell infiltration. In addition, the finding of lymphocytic infiltrations around the eccrine duct was observed. They were treated successfully with topical application of corticosteroid ointment. To the best of our knowledge, no other lichen striatus case has been reported with bilateral distribution and such long-term persistence.

Two cases of angiosarcoma of the face.

Angiosarcoma is a rare vascular malignant tumor most commonly seen on the scalp of elderly people. We report here two cases of angiosarcoma of the face in 74- and 75-year-old males. It is very unusual to find the development of an angiosarcoma with a rosacea on the face. To the best of our knowledge, only three such cases have been reported.

Syringocystadenoma papilliferum: report of the first case on the lower leg.

Syringocystadenoma Papilliferum (SCAP) is a benign adnexal tumor which most frequently arises from an organoid nevus on the head and neck. Although they are rarely found on the trunk and limbs, we treated a case of this disorder on the lower leg. A 26-year-old man had an asymptomatic tumor on his lower leg. Histopathological examination showed it to be a typical SCAP on organoid nevus. This is the first report of SCAP on the lower leg.

Three cases of malignant melanoma arising on burn scars.

It is well known that up to 2% of chronic burn scar lesions can transform into malignant tumors. Most of them are squamous cell carcinoma (SCC) and, more occasionally, basal cell carcinoma (BCC). The incidence of malignant melanoma (MM) is extremely low. To the best of our knowledge, there are only 23 such cases reported in the literature. We report here three cases of MM arising on burn scars and analyze the 23 cases reported previously. Case 1: a 74-year-old Japanese man sustained a burn injury on about 54% of his whole body surface when he was accidentally bathed in boiling oil at the age of 37 years old. Some small tumors developed on the burn scar on his right lumbar region. A wide excision of the tumor was performed. Case 2: a 51-year-old Japanese woman was injured on her right forearm and face by deep burns from a flame when she was 7 months old. She presented with a rapidly growing, painless black nodule on the dark skin lesion on her right forearm. She was treated with a wide excision followed by a full-thickness skin graft. Intravenous administration of one unit of OK-432 every week has been continued. Case 3: a 73-year-old Japanese woman was burned on her left leg and hand from a flame when she was 6 years old. A nodular lesion appeared within the ulcer two months previously and it was growing rapidly. This lesion was ulcerated on the top of its central area and was slightly reddish without any pigmentation. The patient was treated with a wide excision and a split-thickness skin graft. The 5-year survival rate of MM in an old burn scar is 53.6%. It is suggested that the prognosis of burn scar carcinoma is not worse than that of non-burn scar carcinoma.

A pediatric case of sclerodermatous chronic graft-versus-host disease.

We report a rare case of sclerodermatous chronic graft-versus-host disease (GVHD) in a 6-year-old boy that occurred after bone marrow transplantation for his aplastic anemia. The clinical manifestation and histopathologic findings were typical of scleroderma. Although various kinds of treatment have been tried for scleroderma, no established therapy exists. Furthermore, treating this disease is even more difficult in children. In the future, clarification of the pathogenesis of chronic GVHD and establishment of therapy will be necessary.

Analysis of hepatitis C virus (HCV) RNA in the lesions of lichen planus in patients with chronic hepatitis C: detection of anti-genomic- as well as genomic-strand HCV RNAs in lichen planus lesions.

BACKGROUND: Hepatitis C virus (HCV) is a single-strand RNA virus. The association of lichen planus with chronic HCV infection has been reported, as has been cryoglobulinemic purpura, psoriasis, urticaria, and porphyria cutanea tarda. However, the cause of lichen planus is unclear. OBJECTIVES: To investigate whether genomic- and/or anti-genomic-strand HCV RNAs are present in the lichen planus lesions of chronic hepatitis C patients and to elucidate the pathogenesis of lichen planus. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) followed by nested-PCR was carried out to detect HCV RNA using RNA samples from lichen planus lesions of three patients with chronic hepatitis C. Since it is well known that commonly there is relatively dense inflammatory cell infiltration mainly in the upper dermis in lichen planus, the same RT-PCR procedure was performed using RNA from peripheral blood leukocytes from the same patients. In addition, in one patient, the same procedure was also performed using an RNA sample from normal skin. RESULTS: Bands of the appropriate size (161 base pairs corresponding to region 98-258 of HCV RNA) in the nested-PCR products for both genomic- and anti-genomic-strands were detected in lichen planus lesions as well as in peripheral blood leukocytes in all the cases. CONCLUSION: To the best of our knowledge, this is the first report showing the presence of anti-genomic- as well as genomic-strand HCV RNAs in lichen planus lesions in patients with chronic hepatitis C; suggesting that HCV-associated lichen planus lesions may be sites of HCV replication.