Cutavirus Infection in Large Plaque Parapsoriasis, a Premalignant Condition of Mycosis Fungoides.

BACKGROUND: Cutavirus (CuV) is associated with mycosis fungoides; however, the CuV status in parapsoriasis en plaques (PP), a premalignant inflammatory condition of mycosis fungoides, has not been fully delineated. METHODS: Fifty-five Japanese patients with chronic inflammatory skin diseases, including 13 patients with PP, were studied. RESULTS: CuV DNA was detected significantly more frequently in biopsies of the lesional skin from patients with PP (38% [4/13]) than in those from patients with other inflammatory skin diseases (2% [1/42]; P = 0.009). All CuV-positive PP cases were of the large plaque parapsoriasis (LPP) subtype. The viral loads ranged from 83,450 to 2,164,170 copies/103 cells. We recovered near-full-length CuV sequences from the CuV-positive LPP biopsies, all of which were of the Japanese/Asian genotype. The CuV genome appeared to be present within lymphoid cells infiltrating the epidermis and dermis. CuV NS1 and VP1 gene transcripts were also detected in the affected tissues. CONCLUSIONS: The preferential detection of high levels of CuV DNA with the expression of viral mRNA suggests a potential role for CuV in the pathogenesis of LPP, making it necessary to study further the impact of CuV, especially regarding the viral genotype, on the outcomes of patients with CuV-positive LPP.

Involvement of cutavirus in a subset of patients with cutaneous T-cell lymphoma with an unfavorable outcome.

BACKGROUND: European studies suggest an association between cutavirus (CuV) and cutaneous T-cell lymphoma (CTCL); however, the worldwide prevalence of CuV in patients with CTCL and its prognostic impact remain unknown. METHODS: We investigated the prevalence and viral loads of CuV DNA using biopsy specimens from the lesional skins of 141 Japanese patients with cutaneous malignancies, including 55 patients with various types of CTCL. RESULTS: CuV DNA was detected significantly more frequently in biopsies from patients with mycosis fungoides (MF) (38% [13/34]; the most common subtype of CTCL) than in those from patients with other cutaneous malignancies (6% [6/107]; P<0.001). The viral-load range in patients with CuV DNA-positive MF was 23-3922 copies/103 cells and 8-65 copies/µg of DNA. A phylogenetic analysis using the partial sequences of the CuV viral capsid protein 1 (VP1)/VP2 genes revealed that the CuV sequences identified here were clustered in a Japanese-specific clade distinct from that comprising CuV sequences from European patients with MF. Kaplan-Meier curves and a log-rank test showed that CuV positivity was associated with a shorter disease-specific survival in patients with MF (P = 0.031), whereas no significant difference in overall survival was observed (P = 0.275). No significant correlation was observed between CuV DNA load and survival in patients with CuV-positive MF. CONCLUSIONS: Our results suggest that CuV is associated with MF in a subset of Japanese patients. Large-scale prospective studies are warranted to clarify the role of CuV status, especially regarding the viral genotype, on adverse outcomes in patients with CuV-positive MF.

Primary Cutaneous Gamma-Delta T-Cell Lymphoma Initially Diagnosed as Subcutaneous Panniculitis-like T-Cell Lymphoma with Dermatomyositis.

Primary cutaneous gamma-delta T-cell lymphoma (CGD-TCL) is a rare cutaneous lymphoma. Panniculitis-like T-cell lymphoma (SPTCL) has a better prognosis than CGD-TCL. SPTCL is sometimes associated with autoimmune disease. A 64-year-old Japanese female with a history of dermatomyositis presented with subcutaneous nodules on the upper extremities and exacerbated dermatomyositis. A skin biopsy showed lobular panniculitis, a vacuolar interface change, and a dermal mucin deposit. Fat cells rimmed by neoplastic cells, fat necrosis, and karyorrhexis were observed. The atypical lymphoid cells showed CD3+, CD4-, CD8+, granzyme B+, CD20-, and CD56-. Polymerase chain reaction analysis demonstrated a T-cell receptor rearrangement. The patient was initially diagnosed with SPTCL, so the dose of prednisone was raised from 7.5 to 50 mg daily (1 mg/kg). After one month, erythematous nodules regressed, and muscle symptoms improved. Subsequently, prednisone was tapered, and cyclosporin A was added. After one year, the patient remained symptom-free and continued taking 7.5 mg prednisone and 100 mg cyclosporin A daily. Afterward, we immunostained skin samples with antibodies against TCR-ß and δ and found positive TCR-δ and negative TCR-ß. Therefore, we corrected the diagnosis to CGD-TCL, although the clinical course and the presence of dermatomyositis were reminiscent of SPTCL.

What Are Reactive Oxygen Species, Free Radicals, and Oxidative Stress in Skin Diseases?

Oxygen in the atmosphere is a crucial component for life-sustaining aerobic respiration in humans. Approximately 95% of oxygen is consumed as energy and ultimately becomes water; however, the remaining 5% produces metabolites called activated oxygen or reactive oxygen species (ROS), which are extremely reactive. Skin, the largest organ in the human body, is exposed to air pollutants, including diesel exhaust fumes, ultraviolet rays, food, xenobiotics, drugs, and cosmetics, which promote the production of ROS. ROS exacerbate skin aging and inflammation, but also function as regulators of homeostasis in the human body, including epidermal keratinocyte proliferation. Although ROS have been implicated in various skin diseases, the underlying mechanisms have not yet been elucidated. Current knowledge on ROS-related and oxidative stress-related skin diseases from basic research to clinical treatment strategies are discussed herein. This information may be applied to the future treatment of skin diseases through the individual targeting of the ROS generated in each case via their inhibition, capture, or regulation.

Multiple roles of macrophage in skin.

More than 100 years have passed since Elie Metchnikoff discovered macrophage. Over the recent decade, attracting information about macrophage polarization have been reported. This is because many molecules have been identified as markers of macrophage polarization. Additionally, mechanistic insights have been demonstrated by experiments with various stimuli-induced macrophage polarization. Historically and simply, macrophages are divided into M1 (classically activated) and M2 (alternatively activated). However, some of them are not specific yet. Studies in the field of cardiology revealed the plasticity of macrophages and their subsets are divided into details: Mhem, MHb, Mox and M4 macrophages. M2 macrophages were further divided in M2a, M2b, M2c and M2d. There appears to be more phenotypes of macrophages. However, there still lack studies in dermatological field. This review summarizes the spectrum of macrophage activation and finding about various roles of macrophages in the dermatological field.

Durable response after discontinuation of pembrolizumab therapy for intrahepatic cholangiocarcinoma: a case report.

Although it has recently been reported that immune checkpoint inhibitors (ICIs) constitute effective treatment for solid tumors, the success rate in patients with intrahepatic cholangiocarcinoma is limited. We administered pembrolizumab to a patient as treatment for liver and lymph node metastases of intrahepatic cholangiocarcinoma. The patient had abundant infiltration of programmed death ligand 1-positive macrophages, cytotoxic T cells (CD8-positive lymphocytes), and programmed death 1-positive lymphocytes as well as a high combined positive score of 33.1, high-frequency microsatellite instability, and mismatch repair deficiency. These characteristics are predictive biomarkers of the efficacy of ICIs. After pembrolizumab was administered four times (triweekly administration), the carbohydrate antigen 19-9 serum level fell within the normal range, and computed tomography revealed that the size of the metastatic liver tumors and enlarged hilar lymph node had markedly decreased. However, the patient developed pruritus and exanthema on the trunk and limbs after 14 administrations and was diagnosed with bullous pemphigoid. We discontinued pembrolizumab therapy and started treatment for bullous pemphigoid. Nine months after discontinuation of pembrolizumab therapy, the patient remains alive without tumor relapse. This patient had durable response even after discontinuation of pembrolizumab therapy for multiple metastases of intrahepatic cholangiocarcinoma.