Role of Eosinophil Relative Count and Neutrophil-to-Lymphocyte Ratio in the Assessment of Severity of Atopic Dermatitis.

The aim of this study is to elucidate the relationship between 2 different types of severity-indicating parameters (i.e. between subjective and objective severity-indicating parametersin patients with atopic dermatitis. The disease severity of 55 patients with atopic dermatitis was assessed using 7 subjective parameters indicating severity, including visual analogue scale for itch, Patient-Oriented Eczema Measure, 5-D itch scale, Dermatology Life Quality Index, Eczema Area and Severity Index, body surface area, and Investigator Global Assessment, and 8 objective parameters indicating severity, including eosinophil relative count, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and thymus and activation-regulated chemokine. Five subjective parameters reflecting itch correlated significantly with eosinophil relative count, but not with neutrophil-to-lymphocyte ratio. In contrast, 2 subjective parameters, mainly reflecting the degree of inflammation and area of affected regions, correlated significantly with neutrophil-to-lymphocyte ratio. The eosinophil relative count may correlate with the degree of itch, while the neutrophil-to-lymphocyte ratio may correlate with the degree of inflammation and the area of the affected region. The eosinophil relative count and neutrophil-to-lymphocyte ratio may thus be stand-alone parameters from each other in the assessment of the severity of atopic dermatitis.

Role of interleukin-24 in the tumor-suppressive effects of interferon-ß on melanoma.

BACKGROUND: Type 1 interferons (IFNs), including IFN-ß, are widely used in adjuvant therapy for patients who undergo surgery for malignant melanoma to inhibit recurrence and in-transit metastasis. The precise mechanisms underlying the tumor-suppressive effects of IFN-ß on melanoma are not yet completely understood. OBJECTIVE: The purpose was to reveal the mechanisms underlying the tumor-suppressive effects of IFN-ß via interleukin (IL)-24. METHODS: Genome-wide oligonucleotide microarray, quantitative real-time reverse transcription-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay and western blotting assay were performed using four melanoma cell lines (A375, RPMI-7951, SK-MEL-5 and SK-MEL-1) treated with natural-type IFN-ß to assess the expression of IL-24. Proliferation assay was performed using these melanoma cells and IL-24 knock-down melanoma cells. RESULTS: Genome-wide microarray analysis detected candidate genes upregulated in IFN-ß-sensitive cells after treatment with IFN-ß. We focused on IL-24 among the candidate genes encoding secretory proteins. Peak IL-24 mRNA expression completely correlated with the order of sensitivity of melanoma cells to IFN-ß. IFN-ß treatment induced extracellular IL-24 protein in IFN-ß-sensitive cells, but did not induce intracellular IL-24 protein. Knock-down of IL-24 changed melanoma cells into IFN-ß-resistant cells. The expression ratio of IL-22R1, one of the IL-24 receptors, correlated with the order of sensitivity of melanoma cells to IFN-ß. Treatment with recombinant human IL-24 did not have any effects on all the melanoma cell lines. CONCLUSION: Our data suggest that IFN-ß suppresses the proliferation of melanoma cells through extracellular IL-24 protein derived from melanoma cells.

Silencing of homeobox A5 gene in the stratum corneum of psoriasis.

Analysis of psoriatic parakeratotic cells is helpful for understanding the pathogenesis of psoriasis. Methylation analysis can be performed on psoriatic scales, but it is unclear whether genes can be silenced by DNA methylation in psoriatic stratum corneum. The present study was conducted to detect genes silenced in psoriatic stratum corneum. Methylation array analysis with 485 577 probes, quantitative real-time methylation-specific PCR (RT-MSP) and bisulphite sequencing were performed for 30 psoriatic scale samples, 6 fully developed psoriatic skin samples and 12 normal skin samples. Immunohistochemical staining of HOXA5 was performed for 29 psoriatic epidermal samples and 13 normal epidermal samples. The genome-wide methylation array detected two CpG sites within CpG islands (CGIs) located in promoter regions of HOXA5 and LIAS that had methylation levels of >0.6 in at least one of the three psoriatic scale samples and of <0.2 in all three normal skin tissue samples (methylation rate range, 0.0-1.0). RT-MSP for HOXA5CGI, in which the primers were successfully developed, revealed that the average methylation level of 27 psoriasis scales (60.2%) is significantly higher than that of 9 normal skin samples (34.6%) (P=.013). Immunohistochemical staining revealed that HOXA5 protein was not expressed in the stratum corneum of fully developed psoriatic epidermis, but the protein was expressed in the stratum corneum of incompletely developed epidermis and normal epidermis. In conclusion, HOXA5 can be silenced in the stratum corneum of psoriasis. The silenced gene was identified by non-invasive methylation analysis of psoriatic scales.

Tumor-suppressive effects of natural-type interferon-ß through CXCL10 in melanoma.

INTRODUCTION: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-ß (IFN-ß) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-ß treatment of lymphatic endothelial cells. MATERIALS AND METHODS: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-ß, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-ß treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-ß and CXCL10 in melanoma cells. RESULTS: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-ß in lymphatic endothelial cells. IFN-ß treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-ß. CXCL10 reduced melanoma cell proliferation in IFN-ß-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-ß. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-ß and down-regulated in melanoma cells with medium to low sensitivity. CONCLUSIONS: Our data suggest that IFN-ß suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-ß may be associated with resistance to IFN-ß.

Real-world Settings for the Surgical Treatment of Neurofibroma in Patients with Neurofibromatosis Type 1.

Introduction: Even though an MEK inhibitor has been recently launched, neurofibroma still negatively affects the well-being of patients with neurofibromatosis type 1 (NF1). The coronavirus disease 2019 (COVID-19) pandemic resulted in restricted access to medical care. The present study was conducted to investigate the real-world settings of patients with NF1 who underwent surgery with or without restricted medical access during the COVID-19 pandemic. Methods: Based on data obtained from medical records, the present study examined 123 and 260 patients who underwent surgery for neurofibromas with and without restricted medical access, respectively. Results: The mean numbers of surgeries performed during the periods with and without restricted medical access were 5.8 and 9.8 per month, respectively, and there were 1.18- and 1.46-fold more female patients than male patients for each group, respectively. Regardless of whether medical access was restricted, the majority of patients who underwent surgery were middle-aged females with multiple or severe neurofibromas and mild extracutaneous symptoms. Tumor burden was the most common reason for surgery. However, cutaneous neurofibromas were more likely to be treated than plexiform neurofibromas under restricted medical access. Conclusions: Patients with NF1, particularly middle-aged females with severe cutaneous manifestations and mild extracutaneous manifestations, still underwent surgery for neurofibromas regardless of whether medical access was restricted.

Clinical course of psoriatic arthritis treated with biologics delineated with ultrasonography.

Psoriatic arthritis (PsA) is a chronic, inflammatory articular disease regarded as a specific subtype of psoriasis. Long-term assessment for PsA using ultrasonography has not yet been investigated. The present study was conducted to delineate the changes in articular lesions after the initiation of biologics using ultrasonography, and to provide the evidence of the utility of ultrasonography in long-term follow-up of PsA patients. We retrospectively recruited 17 Japanese PsA patients treated with biologics who met the classification criteria for psoriatic arthritis. Ultrasonographic images were recorded using a high-frequency linear 18 MHz probe through Doppler- and B-modes. Before the treatment with biologics, all examined patients (100%) had enthesitis and extensor tendinitis, while only six patients (35.3%) had loss of the fibrillar pattern of the tendon (LFP). There were significant changes over time in the numerical rating scale score for pain, and in the degree of ultrasonographic findings, including enthesitis, extensor tendinitis, and LFP. Also, there were significant changes over time between these ultrasonographic findings. The study identified the improvement course for a specific PsA lesion after the initiation of biologics. The improvement courses in enthesitis, extensor tendinitis, and LFP were found to differ from each other. These results may contribute to deeper understanding of the pathogenesis of PsA.

High prevalence of dermatophytosis of the feet in acral melanoma of the foot.

The clinical characteristics and pathogenesis of acral melanoma of the foot (AMF) have not been sufficiently elucidated. Clinical or subclinical persistent inflammation of the feet is caused by dermatophytosis of the feet (DPF). Persistent inflammation is potentially associated with oncogenesis. Moreover, diabetes has been reported to be associated with the development of dermatophytosis and cancer. The present study aimed to elucidate the clinical association between DPF and AMF, with consideration of diabetes. The medical records of 114 Japanese patients were retrospectively examined and divided into an AMF group (n = 30) and a control group consisting of patients with foot diseases other than melanoma (n = 84). Microscopic DPF screening was performed on all patients who reported symptoms in the foot, with or without AMF. Patients underwent a microscopic test to detect the presence of dermatophytes, and the diagnosis of DPF was made based on a positive result. In the AMF group, 18 (60.0%) and eight (26.7%) patients had DPF and diabetes, respectively. Four patients (13.3%) had both DPF and diabetes. In the control group, 25 (29.8%) and 11 (13.1%) patients had DPF and diabetes, respectively. Five patients (6.0%) had both DPF and diabetes. Univariate analyses showed a significantly higher prevalence of DPF in the AMF group than in the control group (odds ratio, 3.540; p = 0.003, Pearson χ2 test). Furthermore, multivariate analyses of sex, body mass index, DPF, and diabetes revealed DPF as a significant factor associated with AMF (odds ratio, 4.285; p = 0.002, logistic regression analysis). The hyperkeratotic type of DPF was more frequently observed in patients with AMF than in control patients (odds ratio, 11.083; p < 0.001, Pearson χ2 test). In conclusion, the present study found a significantly higher prevalence of DPF, especially its hyperkeratotic type, in patients with AMF. DPF may be associated with AMF pathogenesis.

A case of varicella due to primary varicella zoster virus infection followed by respiratory disease on the background of an immunocompromised condition.

We encountered an immunocompromised patient with severe respiratory disease immediately after the onset of varicella. Varicella zoster virus infection may be associated with more severe immunosuppressive condition.

Characteristics of mild and severe apalutamide-related cutaneous adverse events in patients with prostate cancer: A review of the literature.

Apalutamide is an antiandrogen used to treat prostate cancer. Although it sometimes induces mild cutaneous adverse events and occasionally severe ones, clinical differences between severe and mild cases remain unclear. To assess the risks in patients experiencing apalutamide-related cutaneous adverse events (ARCAEs), we aimed to characterize severe and mild ARCAEs in terms of onset time and lymphocyte transformation test (LTT) for apalutamide. We reviewed 41 ARCAE cases: 24 from our institute and 17 from the literature, comprising (i) eight severe cases including six with toxic epidermal necrolysis, one with acute generalized exanthematous pustulosis, and one with drug reaction with eosinophilia and systemic symptoms, and (ii) 33 mild cases. Patients with evere cases developed ARCAEs significantly earlier than patients with mild cases (5.2 vs 9.6 weeks). No severe cases appeared ≥8 weeks after initiation of apalutamide. LTTs showed positive results in two of seven mild cases (28.6%) and four of four severe cases (100.0%). In conclusion, we found that severe ARCAEs are characterized by earlier onset and LTT positivity. Dermatologists and urologists should pay special attention to patients who develop ARCAEs <8 weeks after initiating apalutamide and/or show positive LTT results.

A case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia.

We report a case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia. The annular appearance may be developed by immunomodulatory effects of blinatumomab.

Real-world Evidence for the Treatment of Rosacea with Sulfur or Metronidazole Preparation in Japanese Patients.

Introduction: There remains to be lacking real-world evidence for the treatment of rosacea with a topical sulfur preparation (TSP) or topical metronidazole preparation (TMP) among Japanese patients. Therefore, in this study, we examined the effects of TSP and TMP on rosacea in Japanese patients in real-world clinical settings. Methods: This retrospective observational analysis reviewed the medical records of 47 Japanese patients who were treated with TSP or TMP for more than 8 weeks in our clinic. Disease severity was evaluated using the Investigator Global Assessment (IGA) and the visual analog scale (VAS) for itching, burning sensation, flushing, and hypersensitivity before and 8 weeks after the initiation of the intervention. Results: In total, 10 erythematotelangiectatic rosacea (ETR) and 12 papulopustular rosacea (PPR) patients treated with TSP and 12 ETR and 13 PPR patients treated with TMP were analyzed. IGA and VAS scores for itching, burning sensation, flushing, and hypersensitivity were noted to significantly improve in the ETR and PPR patient groups treated with TSP and both groups treated with TMP, except for the VAS score for itching in the TSP-treated ETR group. No significant differences were observed in terms of the improvement rates of IGA, VAS scores, or the prevalence of adverse events between the TSP- and TMP-treated groups. Conclusions: As per our findings, TSP and TMP have similarly favorable effects on both ETR and PPR in Japanese patients in real-world settings.

A case of systemic amyloidosis showing papular/nodular lesions due to Waldenström's macroglobulinemia.

This case report provides evidence that Waldenström's macroglobulinemia may cause cutaneous manifestations represented as papules/nodules through the development of light chain amyloidosis. Here, we report a case of a 67-year-old man.

Case of follicular mucinosis showing brownish yellow and red dots via dermoscopy.

We herein describe a 68-year-old man with follicular mucinosis. A dermoscopic examination showed multiple, round, brownish yellow dots with a whitish rim in the follicular ostium and red dots in the interfollicular area. This case report is the first to suggest that follicular mucinosis shows these dermoscopic findings.

Improved renal function in neurofibromatosis type 1 patients.

Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is an autosomal dominant disease that presents with various symptoms, including café-au-lait spots and neurofibromas. NF1 patients occasionally suffer from renal artery vasculopathy, which impairs renal function, while results of a previous report suggested that male NF1 patients have a low creatinine level in peripheral blood. The assessment of renal function in NF1 patients remains inadequate. In this study, renal function in NF1 was assessed. We recruited 308 patients consisting of 149 NF1 patients (77 males and 72 females) and 159 control patients (102 males and 57 females). Creatinine, blood urea nitrogen and haemoglobin A1c in peripheral blood as well as protein, occult blood and sugar in urine were examined. In addition, the estimated glomerular filtration rate was calculated. The mean age and body mass index did not differ significantly between the NF1 patients and controls for both sexes. For both sexes, i) the mean creatinine value was significantly lower in the NF1 patients than in the controls; ii) the mean blood urea nitrogen value did not differ significantly between the NF1 patients and controls; iii) the mean blood urea nitrogen-to-creatinine ratio was significantly higher in the NF1 patients than in the controls; iv) the mean estimated glomerular filtration rate was significantly higher in the NF1 patients than in the controls; and v) the mean haemoglobin A1c value was significantly lower in the NF1 patients than in the controls. In conclusion, NF1 patients may have improved renal function. The clinical significances should be further examined.

Successful treatment with dacarbazine against a parathyroid hormone-related protein-producing melanoma causing hypercalcemia after immune checkpoint inhibitor failure.

Cancer-associated hypercalcemia commonly occurs through abnormal secretions of parathyroid hormone-related protein (PTHrP) from cancer cells. Several cases of PTHrP-producing melanoma causing hypercalcemia have been reported; however, effective management of PTHrP-producing BRAF wild-type melanoma causing hypercalcemia after immune checkpoint inhibitor (ICI) failure is unclear. We report a case of PTHrP-producing BRAF wild-type melanoma leading to oncological emergency by hypercalcemia that was successfully treated with dacarbazine after ICI failure. A 65-year-old Japanese woman had advanced BRAF wild-type melanoma that was refractory to ICI, and then led to hypoxia through exacerbated lung metastases and pleural effusion. Moreover, hypercalcemia appeared in parallel with increase of the serum PTHrP level. Dacarbazine was administered, and after the first administration, the pleural effusion was gradually decreased and hypoxia rapidly disappeared, and the serum calcium and PTHrP levels were improved within normal limits. Dacarbazine after ICI failure is potentially a useful option for oncological emergency due to progression of BRAF wild-type melanoma including PTHrP-producing types. Dacarbazine should be reevaluated as a therapeutic option for oncological emergency in patients with BRAF wild-type melanoma after ICI failure.

Multiple Phenotypic Conversion in Malignant Melanoma: Obtainment of Granulocyte Colony-Stimulating Factor-Producing Ability during the Intermission of Nivolumab Therapy.

Malignant melanoma (MM) is one of the most aggressive, recalcitrant, and recurrence-prone skin neoplasms. Its feature is likely to be associated with phenotypic conversion due to tumor heterogeneity. The multidisciplinary assessment, including surgery, drug therapy using anticancer agents and immune checkpoint inhibitors, and radiotherapy, is needed for the treatment of advanced MM. Herein, we report a long-term follow-up MM, in which multiple phenotypic conversion occurred during several treatments. In particular, our case obtained granulocyte colony-stimulating factor-producing ability during the intermission of nivolumab therapy and it was successfully controlled by re-administration of nivolumab. Sharing the case having a varied clinical course is meaningful to increase the knowledge and decision branches for the treatment of melanoma.

Precritical abnormalities in routine blood parameters in necrotizing fasciitis.

Necrotizing fasciitis is a rare and severe infectious disease that is often fatal and is characterized by the extensive necrosis of subcutaneous tissue and fascial planes. A number of clinical parameters have been intensively investigated to diagnose and assess the severity and prognosis of necrotizing fasciitis. Since it currently remains unclear whether these parameters are also abnormal before disease onset, the present study investigated this issue. We retrospectively recruited 38 patients, including 12 and 26 patients with necrotizing fasciitis and cellulitis, respectively. The results of routine blood examinations were collected at disease onset and also at baseline, which was defined as the time point before disease onset. No significant differences were observed in age or sex between the necrotizing fasciitis and cellulitis groups. However, significant differences were noted in the levels of hemoglobin, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio, sodium, creatinine, albumin, D-dimer, and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score at disease onset. Significant differences were also observed in the levels of hemoglobin, lymphocyte count, monocyte count, platelet count, creatinine, D-dimer, and LRINEC score at baseline. Hemoglobin, platelet count, C-reactive protein, creatinine, albumin, and D-dimer levels were already abnormal at baseline in the necrotizing fasciitis group. In conclusion, the present results revealed precritical abnormalities in routine blood parameters in patients with necrotizing fasciitis. Therefore, individuals predisposed to necrotizing soft tissue infection may be identified prior to disease onset.