Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia.

Although the anti-CCR4 antibody mogamulizumab (moga) shows striking antitumor activity against adult T cell leukemia (ATL), it can also cause fatal immunological pathology such as severe skin rash and graft-versus-host disease, which might be attributed to depletion of CCR4+ regulatory T cells. We previously showed that next generation sequencing enables precise analysis of the T cell receptor (TCR) repertoire, and we here used the technique to reveal the immunological dynamics in moga-treated ATL patients. Treatment with moga resulted in remarkable reduction or elimination of clonal cells, and enhanced reconstitution of non-tumor polyclonal CD4+ T cells and oligoclonal CD8+ T cells. Interestingly, cutaneous T cells infiltrating moga-related skin rashes did not share the same major clones in peripheral blood, which minimizes the possibility of cross-reaction. Thus, deep sequencing of the TCR can reveal the immune reconstitution of moga-treated ATL and provides powerful insights into its mode of action.

Overexpression of p16(INK4a) in Mastocytosis (Urticarial Pigmentosa).

The expression of p16(INK4a) has been reported to induce cell-cycle arrest and cellular senescence. The p16(INK4a) expression has never been examined in human mast cells and mastocytosis. We immunohistologically examined the expression of p16(INK4a) and tryptase in 5 normal human skin and 4 mastocytosis. In normal mast cells, only 5.9 ± 3.4 (mean ± standard deviation) % of tryptase-positive mast cells coexpressed p16(INK4a). However, significantly higher percentage (86.0 ± 14.1%) of tryptase-positive tumor cells was immunoreactive to p16(INK4a) in all of 4 mastocytosis. The p16(INK4a) overexpression may induce the senescence of neoplastic mast cells to undergo spontaneous regression of mastocytosis.

Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.

The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644-9. ©2016 AACR.

Rituximab-containing Chemotherapy (R-CHOP)-induced Kaposi's Sarcoma in an HIV-negative Patient with Diffuse Large B Cell Lymphoma.

Rituximab treatment may cause or exacerbate Kaposi's sarcoma (KS) in patients with human immunodeficiency virus (HIV)-associated multicentric Castleman's disease. Despite the widespread use of rituximab, rituximab-induced KS has not yet been reported in HIV-negative patients with diffuse large B cell lymphoma (DLBCL). We herein report a case of KS that developed after undergoing rituximab-containing chemotherapy in an HIV-negative patient with DLBCL. An 84-year-old man who received rituximab-containing chemotherapy for the treatment of DLBCL developed severe infection, and subsequently KS. Our observations indicate that serious infections under rituximab treatment may trigger KS. KS should therefore be considered when skin tumors appear in lymphoma patients receiving rituximab-containing chemotherapy.

The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV), a novel bunyavirus reported to be endemic in central and northeastern China. This article describes the first identified patient with SFTS and a retrospective study on SFTS in Japan. METHODS: Virologic and pathologic examinations were performed on the patient's samples. Laboratory diagnosis of SFTS was made by isolation/genome amplification and/or the detection of anti-SFTSV immunoglobulin G antibody in sera. Physicians were alerted to the initial diagnosis and asked whether they had previously treated patients with symptoms similar to those of SFTS. RESULTS: A female patient who died in 2012 received a diagnosis of SFTS. Ten additional patients with SFTS were then retrospectively identified. All patients were aged ≥50 years and lived in western Japan. Six cases were fatal. The ratio of males to females was 8:3. SFTSV was isolated from 8 patients. Phylogenetic analyses indicated that all of the Japanese SFTSV isolates formed a genotype independent to those from China. Most patients showed symptoms due to hemorrhage, possibly because of disseminated intravascular coagulation and/or hemophagocytosis. CONCLUSIONS: SFTS has been endemic to Japan, and SFTSV has been circulating naturally within the country.

Antioxidant Houttuynia cordata extract upregulates filaggrin expression in an aryl hydrocarbon-dependent manner.

The plant Houttuynia cordata, which is called "dokudami" in Japanese, is known as a potent antioxidant herb that has been traditionally consumed as a folk medicine for various ailments, such as diabetes, obesity, cough, fever and skin diseases, in Asia. However, its antioxidant mechanism remains largely unknown. In the present study, we investigated the effects of Houttuynia cordata extract (HCE) on human keratinocytes. HCE activated aryl hydrocarbon receptor (AHR) and nuclear factor E2-related factor 2, with subsequent induction of the antioxidative enzyme NAD (P)H: quinone oxidoreductase 1 gene. HCE inhibited the generation of reactive oxygen species (ROS) in keratinocytes stimulated with tumor necrosis factor α or benzo(α)pyrene. Moreover, HCE upregulated the gene expression of filaggrin, an essential skin barrier protein, in an AHR-dependent manner. HCE may be beneficial for treating ROS-related photoaging and barrier-disrupted skin conditions.

Combination cryosurgery with hyperthermia in the management of skin metastasis from breast cancer: A case report.

INTRODUCTION: Skin metastases may impair the quality of life due to physical appearance, odour, and bleeding. PRESENTATION OF CASE: A 70-year-old woman presented with two enlarging nodules (measuring 12 cm and 3 cm in diameter) consistent with metastatic breast cancer in the left subclavicular area. The larger tumour did not respond to initial cryosurgery. Therefore we added hyperthermia using a disposable body warmer. In addition, the cryosurgery technique was modified to freeze deeper tissue. The entire tumour was covered with dry cotton, to which liquid nitrogen was applied. Twenty weeks later, the tumour became nearly flat and the patient noted improved activity in her daily life. DISCUSSION: Combination treatment with sufficient freezing is important for controlling the tumour, while hyperthermia may accelerate the antitumor effects of cryosurgery. CONCLUSION: [corrected] This treatment provides an alternative for unresectable breast cancer skin metastases resistant to chemotherapy and radiotherapy.

Successful treatment of epidermal growth factor receptor inhibitor-induced periungual inflammation with adapalene.

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used for cancer treatment, but commonly carry dermatologic side effects. Periungual inflammation is a particularly painful condition that additionally worsens quality of life. In this paper, we report 3 cases of successful treatment of periungual inflammation induced by 3 different EGFR inhibitors (gefitinib, erlotinib, and cetuximab) with topically applied adapalene.