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Supplementary Tables 1-3 from Silencing of Peroxiredoxin 2 and Aberrant Methylation of 33 CpG Islands in Putative Promoter Regions in Human Malignant Melanomas

Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2′-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in ≥9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers. (Cancer Res 2006; 66(12): 6080-6)

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.

Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events.Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study.Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan-Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight.A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.

A 67-year-old Japanese man was referred to us with numerous papules and nodules. Examination revealed i) IgM-monoclonal proteinemia, ii) amyloid protein deposition around vessels in the dermis and subcutis, and iii) lymphoplasma cells into bone marrow. This report shows that Waldenström’s macroglobulinemia causes papules/nodules through the development of amyloidosis.

Voriconazole is commonly administered for a long period to patients receiving immunosuppressive therapy. Although voriconazole potentially induces skin cancers in association with sun exposure, this has not yet been examined in detail in a single ethnic patient group. Therefore, the present study investigated the risk of developing squamous cell carcinoma (SCC) in Japanese patients with voriconazole-related actinic keratosis (AK) and the prognosis of Japanese patients with voriconazole-related SCC. We retrospectively examined 37 Japanese patients with AK, including five voriconazole-treated patients (mean age, 57.9 ± 16.3 years) and 32 non-treated patients (74.9 ± 9.2 years), and 18 Japanese patients with SCC, including four voriconazole-treated patients (55.4 ± 16.7 years) and 14 non-treated patients (74.1 ± 10.7 years). Among the 37 patients with AK, SCC developed in five, including four with a history of treatment with both voriconazole and immunosuppressive agents, independent of AK progression. In these four patients, the mean period from the diagnosis of AK to that of SCC was 13.8 ± 11.6 months. Kaplan--Meier analyses showed that the risk of developing SCC was significantly higher in patients with both voriconazole and immunosuppressants/corticosteroid-treated patients with AK than in non-voriconazole-treated patients with AK (the Log-rank test, p 0.001). The analyses also showed that the mortality rate was significantly higher in patients with both voriconazole and immunosuppressants/corticosteroid-treated patients with SCC than in non-voriconazole-treated patients with SCC (p = 0.018). The present results suggest that voriconazole-related AK precedes the development of cutaneous SCC and voriconazole-related SCC leads to a poor prognosis under the immunosuppressive condition.

Psoriasis patients have been reported to have a higher prevalence of nonalcoholic fatty liver disease (NAFLD), therefore detection at an early stage is important since it may progress to hepatic cirrhosis or hepatocellular carcinoma. We evaluated liver fat accumulation in patients with moderate to severe psoriasis by chest computed tomography (CT). The images were taken for screening purposes prior to the start of any biologics. The prevalence of NAFLD in patients with psoriasis vulgaris, psoriatic arthritis, and control subjects was 19.4%, 33.3% and 9.8%, respectively (P = 0.004). The mean CT score in psoriasis patients was significantly lower (51.684 ± 12.778) than that in control subjects (61.204 ± 9.498, P 0.001). Multivariate logistic regression analysis showed that only CT scores were associated with the presence of psoriasis (P = 0.001). No significant relationship was observed between the Psoriasis Activity and Severity Index scores and CT scores of psoriasis patients (P = 0.055), suggesting that the presence of psoriasis may contribute to the pathogenesis of NAFLD. By analysis of chest CT imaging, our study successfully assessed liver fat accumulation. Chest CT is a useful diagnostic tool for the quantitative measurement of fat accumulated in the liver, enabling the early noninvasive detection of NAFLD and early therapeutic intervention.

Solitary angiokeratoma is reported to be distinguishable from intracorneal hemorrhage. Dermoscopy shows a whitish veil in solitary angiokeratoma and a homogeneous or globular lesion in intracorneal hemorrhage. However, we encountered a case of solitary angiokeratoma that was indistinguishable from intracorneal hemorrhage by dermoscopy. Dermatologists need to recognize this dermoscopic pitfall.

Introduction Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by eczema and pruritus, and frequently impairs sleep quality. Although cyclosporine improves symptoms of AD, objective evaluation of sleep in patients with AD treated with cyclosporine has not been reported. This study was conducted to elucidate the effects of cyclosporine on sleep quality for patients with AD. Methods Twelve patients with moderate-to-severe AD were recruited. Nocturnal sleep quality was evaluated for 7 days using a sleep analyzer, which patients wore at the waist before and after cyclosporine was administered at 2.0–4.0 mg/kg per day. Seven parameters of sleep quality were measured before and after cyclosporine administration for a period of 7 days for each patient. Results The administration of cyclosporine significantly improved total sleep time in four cases, sleep latency in two cases, wake after sleep onset in six cases, number of awakenings in two cases, sleep efficiency in seven cases, number of awakenings for more than 8 min in three cases, and number of position changes recorded every 2 min in three cases. The mean values of sleep latency significantly decreased after cyclosporine administration (P = 0.023). The mean value of sleep efficiency significantly increased after the administration (P = 0.002). Conclusion Cyclosporine improves sleep quality in patients with moderate-to-severe AD. Electronic supplementary material The online version of this article (10.1007/s13555-020-00451-2) contains supplementary material, which is available to authorized users.

CD30‐positive large cell transformation that occurs in early mycosis fungoides potentially possesses characteristics of spontaneous regression as with CD30‐positive lymphoproliferative disorders. Such transformation may not relate to poor prognosis.

Imatinib mesylate seemed to inhibit development of cutaneous neurofibromas (c‐NFs) and promote growth of pre‐existing c‐NFs in our neurofibromatosis type 1 case. This report potentially provides new findings in the effects of imatinib mesylate.

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.

Introduction: The present study aimed to obtain fundamental data, including climate conditions and Demodex mites, on rosacea and similar diseases in the situation where the wearing of face masks is mandatory due to the coronavirus disease 2019 pandemic. Methods: We enrolled 86 Japanese patients habitually wearing face masks with rosacea and similar diseases. Disease severity was assessed using the Investigator Global Assessment. The presence of Demodex mites was examined microscopically. Treatment involved acaricidal and antibiotic agents. Results: The numbers of male and female patients enrolled were 11 and 75, respectively. Among these patients, 85 (98.8%), 57 (66.3%), and 76 (88.4%) had rosacea, rosacea-like dermatitis (RLD), and demodicosis, respectively. The monthly number of patients with rosacea and demodicosis showed two peaks from May to June and in October, during which monthly mean temperature was approximately 20°C (68°F). Improvement rates in rosacea, RLD, and demodicosis were significantly higher when Demodex mites were no longer detected after treatment. Conclusion: The present results suggest that a season with a mean temperature of approximately 20°C is a risk factor for rosacea and similar diseases in individuals wearing face masks in Japan, and a decrease in Demodex mites is associated with the attenuation of symptoms.

Ultrasonography and magnetic resonance imaging (MRI) are useful for diagnosing psoriatic arthritis (PsA). However, ultrasonography depends on the skill of the operator and MRI is often disturbed by artifacts when distal interphalangeal joints are examined. Although iodine-enhanced dual-energy computed tomography (DECT) has the potential to diagnose PsA without these disadvantages, its usefulness over ultrasonography has not yet been examined in detail; therefore, the present study was conducted to address this issue. The acral joint of 13 PsA patients, which was the most severely affected, was scanned with imaging devices. Ultrasonography was performed with a high-frequency linear 18-MHz probe. Iodine-enhanced DECT was conducted in the DE mode with iohexol as a contrast material. Psoriatic Arthritis Screening and Evaluation (PASE) scores were recorded. Synovitis and periarticular inflammation delineated with iodine-enhanced DECT correlated with the loss of the fibrillar pattern delineated with ultrasonography (p = 0.033 and 0.002, respectively). Peritendinitis delineated with iodine-enhanced DECT also correlated with tendon thickening delineated with ultrasonography (p = 0.011). Iodine uptake did not correlate with Doppler signal or PASE scores. In conclusion, the present results demonstrated that the qualitative findings of iodine-enhanced DECT correlated with those of ultrasonography in PsA patients, whereas quantitative findings did not. Iodine-enhanced DECT may be an alternative imaging modality for the diagnosis of PsA.

Antigenic competition in the skin is a phenomenon in which the current dermatitis is distributed away from the area of previously existing dermatitis. Bullous pemphigoid may present such phenomenon, even if the responsible antigen was the same.

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.

Cutaneous Rosai-Dorfman disease (CRDD) is a rare skin-limited form of Rosai-Dorfman disease, a benign histiocytic proliferative disorder commonly affecting lymph nodes. Here, we report a case of CRDD characterized by pruritic reddish-brown macules, which we initially misdiagnosed as post-inflammatory pigmentation due to uremic dermatitis. A 64-year-old Japanese man was referred to us with an 8-month history of pruritic eruption located in the trunk and limbs. He had been receiving dialysis for chronic renal failure for 24 years. Physical examination revealed multiple reddish-brown macules measuring 1–10 cm in diameter with scratch marks irregularly distributed on the trunk and limbs. Pruritic score on the Numeric Rating Scale (NRS) was 9 out of 10. The patient displayed no extracutaneous involvements such as lymphadenopathy, fever or weight loss. Histopathological examination of the reddish-brown macules showed dense infiltration of histiocytes with lymphocytes and plasma cells in the dermis covered by epidermis with a faintly pigmented basal layer. Some histiocytes had taken in red blood cells, representing so-called emperipolesis. Immunohistochemical analyses of histiocytes showed reactivity to anti-S-100 protein antibodies and anti-CD68 antibodies, but not to anti-CD1a antibodies. Based on these findings, CRDD was diagnosed. This case suggests that CRDD may present with: i) macular lesions in the active phase; and ii) severe pruritus.

Background Malignant peripheral nerve sheath tumors (MPNSTs) occur in several percent of neurofibromatosis type 1 (NF-1) patients. When a CpG island (CGI) in the 5' region of a gene is methylated, transcription of that gene may be suppressed. Although cancer-testis antigens, including MAGEB2, are potential therapeutic targets for cancer in medical practice, information on MAGEB2 in MPNST is scarce. Objective The purpose is to clarify the methylation status and expression of MAGEB2 in MPNSTs derived from patients with NF-1. Methods Quantitative real-time methylation-specific PCR (RT-MSP) and quantitative real-time reverse transcription-PCR (RT-PCR) were performed to measure methylation and mRNA expression, respectively, in MPNST cell lines and in MPNST and neurofibroma samples from patients with NF-1. Immunohistochemical analysis was also performed to assess MAGEB2 protein expression. Results RT-MSP and RT-PCR data showed low methylation levels and detectable mRNA expression of MAGEB2 , respectively, in one MPNST cell line, but high methylation level and absence of expression in each other cell line and in normal cells. Based on RT-MSP data, 3 of 18 MPNST clinical samples exhibited low methylation levels; in contrast, all cutaneous and plexiform neurofibroma samples and normal cells exhibited high methylation levels. Methylation levels were not significantly associated with any clinical parameters. Immunohistochemical analysis revealed expression of MAGEB2 protein in MPNST clinical samples with the low methylation level. Conclusions MAGEB2 can be aberrantly demethylated and expressed in MPNSTs. Conversely, the gene may not be demethylated in any types of neurofibroma, suggesting that the demethylation does not occur before malignant transformation.

Background Type 1 interferons (IFNs), including IFN-β, 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-β on melanoma are not yet completely understood. Objective The purpose was to reveal the mechanisms underlying the tumor-suppressive effects of IFN-β 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-β 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-β-sensitive cells after treatment with IFN-β. 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-β. IFN-β treatment induced extracellular IL-24 protein in IFN-β-sensitive cells, but did not induce intracellular IL-24 protein. Knock-down of IL-24 changed melanoma cells into IFN-β-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-β. Treatment with recombinant human IL-24 did not have any effects on all the melanoma cell lines. Conclusion Our data suggest that IFN-β suppresses the proliferation of melanoma cells through extracellular IL-24 protein derived from melanoma cells.

Background Retiform hemangioendothelioma (RH) is a locally aggressive vascular tumor. Wide surgical excision with tumor-free margins is the standard treatment strategy. However, surgical excision is not an option for lesions near critical anatomical structures, such as those on the face. We report the case of a patient with retiform hemangioendothelioma that responded to non-surgical treatments. Methods We describe the case of a 72-year-old male patient with a retiform hemangioendothelioma on the face that responded to a combination of pulsed dye laser, local corticosteroid injection, and application of imiquimod cream. In addition, we reviewed past case reports of patients with retiform hemangioendothelioma. Results Thirty-five cases that describe the management of RH, including the present case, have been reported. Review of the cases indicate a relatively low disease-free survival rate in cases that underwent surgical excision as the initial therapy for retiform hemangioendothelioma. Conclusion Surgical excision might not be the best therapeutic option. Local control with conservative therapy is an acceptable strategy for lesions in anatomical regions including the face.