Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part).

BACKGROUND: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE). PATIENTS AND METHODS: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period. RESULTS: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks. CONCLUSION: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000024113).

Emaciation, Congestive Heart Failure, and Systemic Amyloidosis in Severe Recessive Dystrophic Epidermolysis Bullosa: Possible Internal Complications Due to Skin-Derived Inflammatory Cytokines Derived from the Injured Skin.

Inherited epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by epithelial tissue fragility. Recessive dystrophic epidermolysis bullosa (RDEB) is the most severe form, characterized by the presence of blisters, erosion, and ulcer formation, leading to scarring and contraction of the limbs. RDEB is also associated with extra-cutaneous complications, including emaciation, congestive heart failure, and systemic amyloidosis. The main cause of these clinical complications is unknown; however, we hypothesized that they are caused by elevated circulating inflammatory cytokines overproduced by injured keratinocytes. We addressed this phenomenon using keratin-14 driven, caspase-1 overexpressing, transgenic (KCASP1Tg) mice in which injured keratinocytes release high levels of IL-1α and ß. KCASP1Tg showed severe spontaneous dermatitis, as well as systemic complications, including aberrant weight loss, cardiovascular disease, and extensive amyloid deposition with organ dysfunction, resembling the complications observed in severe EB. These morbid conditions were partially ameliorated by simultaneous administration of anti-IL-1α and ß antibodies. The skin not only constitutes a physical barrier, but also functions as the largest immune organ. We suggest a novel role for IL-1 in the pathogenesis of EB and the use of anti-IL-1 antibodies as a potential therapy for EB complications.

Non-invasive quantitative measures of qualitative grading effectiveness as the indices of acute radiation dermatitis in breast cancer patients.

BACKGROUND: Recent improvement of machinery evaluation for the skin changes in various therapies enabled us to evaluate fine changes quantitatively. In this study, we performed evaluation of the changes in radiation dermatitis (RD) using quantitative and qualitative methods, and verified the validity of the conventional qualitative assessment for clinical use. METHODS: Forty-three breast cancer patients received conventional fractionated radiotherapy to whole breast after breast-conserving surgery. Erythema, pigmentation and skin dryness were evaluated qualitatively, and biophysical parameters of RD were measured using a Multi-Display Device MDD4 with a Corneometer for capacitance, a Tewameter for transepidermal water loss (TEWL), a Mexameter for erythema index and melanin index. Measurements were performed periodically until 1 year. RESULTS: The quantitative manifestations developed serially from skin erythema followed by dryness and pigmentation. Quantitative measurements detected the effects of irradiation earlier than that of qualitative indices. However, the grades of the domains in RD by qualitative and quantitative assessment showed similar time courses and peak periods. However, no significant correlation was observed between the skin dryness grade and skin barrier function. In contrast to serial increase in pigmentation grades, melanin index showed initial decrease followed by marked increase with significant correlation with pigmentation grades. CONCLUSION: Subjectively and objectively measured results of RD were almost similar course and peak points through the study. Therefore, validity of the conventional qualitative scoring for RD is confirmed by the present quantitative assessments. Instrumental evaluations revealed the presence of modest inflammatory changes before radiotherapy and long-lasting skin dryness, suggesting indication of intervention for RD.

Elevated plasma D-dimer levels in dermatomyositis patients with cutaneous manifestations.

To explore the influence of dermatomyositis (DM)-specific cutaneous manifestations (scm) on systemic coagulation and fibrinolysis, we retrospectively studied plasma D-dimer levels with/without venous thromboembolism (VTE), malignancy, infection or other connective tissue diseases (CTDs) and scm. One hundred fifty patients with DM were retrospectively investigated using medical records regarding scm, VTE, malignancy, infection, other CTDs, laboratory data and systemic corticosteroid therapy. All DM patients were categorized as follows: group 1, without scm, VTE, infection, malignancy or other accompanying CTDs; group 2, with scm only; and group 3, with VTE, infection, malignancy and other accompanying CTDs but without scm. The D-dimer plasma levels were significantly increased in group 3 compared with healthy subjects and those in groups 1 and 2 (p < 0.001). The D-dimer plasma level in group 2 was significantly increased compared with healthy subjects and those in group 1 (p < 0.001). Increased D-dimer plasma levels were detected in DM patients with scm without detectable VTE, malignancy, infection or accompanying CTDs. In addition to the known risk factors for increased plasma D-dimer levels in DM patients, including VTE, malignancy, infection and other accompanying autoimmune diseases, the presence of cutaneous manifestations should be considered as a new clinical risk factor.

Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption.

Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR-TKI afatinib/erlotinib-treated patients and for 8 weeks in 20 anti-EGFR antibody cetuximab-treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE ≥ Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE ≤ Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE ≥ Gr2 patients significantly decreased compared with that of AfE ≤ Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE ≥ Gr2 were significantly higher than those with AfE ≤ Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE.

Transfer of cyanobacterial carbon to a higher trophic-level fish community in a eutrophic lake food web: fatty acid and stable isotope analyses.

The dietary utilization of cyanobacterial carbon by fish communities is poorly understood. We examined the transfer of cyanobacterial carbon to fish in a eutrophic lake using fatty acid biomarkers and measuring the stable carbon isotope ratios of fatty acid and bulk nitrogen. We collected five species of fish (Hypomesus nipponensis, Carassius sp., Cyprinus carpio, Tridentiger brevispinis, and Gymnogobius castaneus) as well as the seston from June to November 2016 from Lake Hachiro, Japan. Cyanobacterial blooms were observed from August to October. From June to August, cyanobacterial fatty acid biomarkers (18:2ω6 and 18:3ω3) accounted for only 1.4-4.3% of total fatty acids in these fish species, indicating a low contribution of cyanobacteria to fish diets during this period. However, the contribution of the cyanobacterial fatty acid biomarkers in these fish species increased sharply in September (10.5-17.1%), except in second-year H. nipponensis. In September, the stable carbon isotope ratios of 18:3ω3 in these fish species were almost equivalent to those in the seston, which was primarily composed of cyanobacteria. The trophic positions of the collected fish species ranged from 1.6 to 3.4, based on their stable nitrogen isotope values, indicating that some fish ingested cyanobacteria directly, while others acquired cyanobacteria indirectly, through the food chain. These findings indicate that cyanobacterial carbon is transferred up the food chain in eutrophic lake ecosystems with cyanobacterial blooms.

The efficacy of a lip balm containing pseudo-ceramide on the dry lips of sensitive skin-conscious subjects.

BACKGROUND: Many people use lip care products daily to prevent dry lips. However, some people, especially those with sensitive skin-consciousness, complain of various skin problems on their lips including contact dermatitis caused by lip care products. Dry lips have decreased water holding capacity and cutaneous barrier function as well as reduced stratum corneum ceramide levels. In this study, we investigated the usefulness of a newly formulated lip balm containing pseudo-ceramide for the dry lips of subjects with sensitive skin. METHOD: Thirty subjects with dry lips and sensitive skin-consciousness used the test lip balm more than twice a day for 4 weeks. Lip conditions were evaluated before and after 2 and 4 weeks. RESULT: Visual evaluation by a dermatologist showed that overall improvements were observed in all subjects as early as week 2. After 4 weeks of usage, 27% of the subjects were objectively judged as "markedly improved" and 60% of the subjects were judged as "improved". No adverse event developed throughout the test period, and all subjects were able to use the lip balm safely for 4 weeks. Usefulness was judged based on all evaluation items, and 27%, 70%, and 3% of the subjects were judged as "very useful," "useful," and "slightly useful," respectively. Ninety percentage of the subjects expressed improvement and acceptance of the lip balm. CONCLUSION: Based on these results, the newly formulated lip balm containing pseudo-ceramide is very useful for the lip care of sensitive skin-conscious subjects as well as for daily use by healthy subjects.

The Plasma Levels of ADAMTS-13, von Willebrand Factor, VWFpp, and Fibrin-Related Markers in Patients With Systemic Sclerosis Having Thrombosis.

This study aimed to examine the hemostatic abnormalities in patients with systemic sclerosis (SSc) and the relationship between these abnormalities and thrombotic events (THEs), focusing on the difference in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). The plasma levels of ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13), von Willebrand factor (VWF), VWF propeptide (VWFpp), d-dimer, and soluble fibrin (SF) were measured in 233 patients with SSc. The relationship between their levels and organ involvement, including THEs and interstitial lung disease (ILD), was evaluated. The plasma levels of VWF and VWFpp were significantly elevated and ADAMTS-13 activity was significantly decreased in patients with SSc compared to healthy participants. The VWFpp in dcSSc was significantly higher than in lcSSc. Twelve patients with SSc were complicated with acute THE, and 25 patients with SSc were complicated with past THE. The plasma levels of d-dimer and SF were significantly elevated in patients with SSc having THE. The plasma levels of VWF and VWFpp were significantly elevated in patients with SSc having ILD. The plasma levels of d-dimer were elevated in patients with SSc having other connective tissue diseases (CTDs). The plasma levels of ADAMTS-13 were significantly decreased and VWF, VWFpp, and SF were increased in patients with a d-dimer level of ≥1 µg/mL. Systemic sclerosis carries a high risk of THE, especially in patients with other CTDs. Plasma hemostasis-related markers are closely related to ILD and THE. These markers are important as markers of organ involvement as well as THE.

Cutaneous polyarteritis nodosa causing refractory skin deformation and pigmentation as sequel.

A 39-year-old woman presented with prominent and painful livedo reticularis lesions spreading on her upper and lower extremities. Histopathologically, the small-to medium-sized arteries in the deep dermis and subcutis showed necrotizing vasculitis with cellular infiltration, suggesting cutaneous polyarteritis nodosa. The serum levels of inflammatory markers normalized with aspirin 100mg/day and prednisolone 10mg/day within 2 months, and there was no other skin or organ involvement over 18 months of follow up. However, serious refractory skin depressions and pigmentation remained after two years of treatment. This suggests the importance of early and aggressive therapy for cutaneous polyarteritis nodosa to prevent unsightly skin sequel, as well as control of disease activity.

Successful combination therapy of propranolol and prednisolone for a case with congenital Kasabach-Merritt syndrome.

A male fetus was delivered by cesarean section with a large hemangioma on his right chest and thrombocytopenia. Clinically, Kasabach-Merritt syndrome (KMS) was suspected, and immediately he was treated with daily prednisolone (PSL) 1 mg/kg and recombinant thrombomodulin without response. Additional propranolol (1-3 mg/kg per day) and increased PSL 2 mg/kg per day therapy successfully controlled his disseminated intravascular coagulation and decreased the tumor size without serious side-effects. No relapse of KMS was observed after cease of PSL and propranolol. Combined use of propranolol and corticosteroid is expected as a candidate therapeutic tool for KMS.

Plasma ADAMTS13, von Willebrand Factor (VWF), and VWF Propeptide Profiles in Patients With Connective Tissue Diseases and Antiphospholipid Syndrome.

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

Hypofibrinogenemia and the α-Fibrinogen Thr312Ala Polymorphism may be Risk Factors for Early Pregnancy Loss.

We analyzed a cohort of 36 females with pregnancy loss. In addition to 11 patients with antiphospholipid antibody syndrome and 2 patients with congenital antithrombin (AT) or protein C deficiency, we identified 5 patients with low fibrinogen levels (median 110 mg/dL) prior to 10 weeks of gestation. Four of these 5 patients underwent a fibrinogen gene analysis, and all 4 were found to be heterozygotes for the α-fibrinogen (FGA) Thr321Ala polymorphism. One female without hypofibrinogenemia with a history of 8 pregnancy losses was found to be homozygous for the same polymorphism, and she also showed hypercoagulability without thrombosis. In conclusion, there was a relatively high frequency of pregnancy loss in the setting of hypofibrinogenemia and/or the FGA Thr312Ala polymorphism, and this may be an important risk factor for pregnancy loss and a hypercoagulable state in later pregnancy.