Predictive factors and scoring system for intravascular large B-cell lymphoma among suspected cases: a single-center retrospective analysis.

BACKGROUND: Although the utility of random skin biopsies in the diagnosis of intravascular large B-cell lymphoma (IVLBCL) has been confirmed, the patients who should undergo random skin biopsies remain unclear. OBJECTIVES: To assess predictive factors for IVLBCL and establish a scoring system for the applicability of random skin biopsies. METHODS: We conducted a retrospective case-control study of IVLBCL-suspected patients who underwent random skin biopsies between April 2010 and March 2022. We compared the general symptoms, imaging findings, and laboratory findings between IVLBCL and non-IVLBCL cases. RESULTS: Fifty-three patients were enrolled in this study. Eight patients were diagnosed with IVLBCL, and 35 patients were diagnosed with other diseases. The final diagnosis was unclear in 10 patients. There were no significant differences in the frequency of general symptoms and imaging findings between IVLBCL and non-IVLBCL cases. Among laboratory findings, IVLBCL cases showed significantly higher serum lactate dehydrogenase (LDH) and soluble IL-2 receptor (sIL-2R) levels and lower platelet counts than non-IVLBCL cases. We established a scoring system to predict IVLBCL by using these three parameters. The cut-off values were as follows: serum LDH level, 256 IU/l; serum sIL-2R level, 2011 U/ml; and platelet count, 107 × 109 /l. IVLBCL was not included in patients with scores of <2. The probabilities of IVLBCL in patients with scores 2 and 3 were 18% and 86%, respectively. CONCLUSIONS: Our simple scoring system can help clinicians determine the applicability of random skin biopsies in IVLBCL-suspected cases.

Increased Interleukin-36ß Expression Promotes Angiogenesis in Japanese Atopic Dermatitis.

While atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, an increase in other types of inflammatory cytokines is also noted in AD and they may also contribute to the development of the disease. Recently, the efficacy of an anti-IL-36 receptor antibody in AD was demonstrated in a clinical trial. Although there have been several reports on IL-36α and IL-36γ expression and function in AD, IL-36ß has been barely studied. In this report, we examined IL-36ß expression and function using clinical samples of AD and the epidermal keratinocyte cell line, HaCaT cells. We demonstrated that IL-36ß expression in epidermal keratinocytes was increased in AD lesional skin compared to healthy skin. IL-36ß promoted vascular endothelial growth factor A production in HaCaT keratinocytes through phosphorylation of extracellular signal-regulated kinases 1 and 2. In addition, IL-36ß up-regulated placental growth factor mRNA expression in HaCaT keratinocytes. IL-36ß expression levels in epidermal keratinocytes were correlated with the number of dermal vessels in AD skin. These results suggest that IL-36ß may play an important role for angiogenesis in lesional skin of AD and that IL-36ß can be a therapeutic target in AD.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Elevated Myeloperoxidase-DNA Complex Levels in Sera of Patients with IgA Vasculitis.

INTRODUCTION: IgA vasculitis is a systemic disease that results from the entrapment of circulating IgA-containing immune complexes in small-vessel walls in the skin, kidneys, and gastrointestinal tract. An excessive formation of neutrophil extracellular traps (NETs) is involved in the pathogenesis of vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This study aimed to clarify whether NETs are implicated in IgA vasculitis. METHODS: Twenty-two patients with IgA vasculitis and 4 healthy volunteers were enrolled in this study. Serum levels of myeloperoxidase (MPO)-DNA complex, a fragment derived from NETs, were determined by enzyme-linked immunosorbent assay (ELISA), and the association between MPO-DNA complex levels and clinical parameters was examined. The presence of the ANCA was also assessed by ELISA specific for MPO and proteinase 3 (PR3) and indirect immunofluorescence (IIF), followed by assessing the differences in clinical parameters with and without the ANCA. RESULTS: Serum MPO-DNA complex levels were significantly higher in patients with IgA vasculitis than those in healthy controls. A significant positive correlation between the serum MPO-DNA complex and IgA levels was noted. Interestingly, 63.6% of IgA vasculitis patients were ANCA-positive in IIF with an atypical pattern, whereas neither MPO-ANCA nor PR3-ANCA was detected by ELISA. These findings indicated that some IgA vasculitis patients possessed the so called minor ANCA. Serum IgA and MPO-DNA complex levels and the frequency of hematuria in the minor ANCA-positive group were significantly higher than in the minor ANCA-negative group. CONCLUSION: The collective findings suggested that NETs are certainly involved in the pathogenesis of IgA vasculitis.

Increase of lymphocytes and eosinophils, and decrease of neutrophils at an early stage of anti-PD-1 antibody treatment is a favorable sign for advanced malignant melanoma.

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.

Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells.

Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders.