Thymus and activation‐regulated chemokine (TARC/CCL17) is a member of the T‐helper 2 chemokine family. In Japan, serum TARC level has been commercially measured since 2008. After years of experience, ...we realized that TARC is an extremely useful clinical biomarker for atopic dermatitis (AD) treatment. Usually, physicians conduct a visual examination to determine whether their treatment has been successful; however, the visual examination results may not always be accurate; in such cases, serum TARC levels should be measured to eliminate any ambiguity regarding the treatment outcome. When the waning and waxing of eczema and fluctuations in the serum TARC levels were considered, we frequently found that AD does not follow a natural course but follows non‐regulated inflammatory floating caused by insufficient intermittent topical treatment. Serum TARC is a promising biomarker for remission and can be used for accurately monitoring proactive treatment for long‐term control. Abnormally high serum TARC levels indicate accelerated pathogenesis of cutaneous inflammation. Rapid normalization and maintaining normal serum TARC levels using appropriate topical treatment is a reasonable strategy for alleviating inflammation without upregulating cytokine expression. Observing serum TARC levels during early intervention for severe infantile AD is worthwhile to determine initial disease activity and evaluate treatment efficacy. Appropriate control of severe early‐onset infantile AD is important for improving prognosis of eczema and for preventing food allergies. Additionally, this biomarker is useful for improving patient adherence. Dermatologists will be able to make great progress in treating AD by adopting biomarkers such as TARC for accurately assessing non‐visible subclinical disorders.
The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials ...comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.
In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 clear or 1 almost clear on the IGA scores range from 0 to 4, with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI scores range from 0 to 72) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale scores range from 0 to 10) at week 2 and IGA and EASI-75 responses at week 16.
A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.
In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).
Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or ...allergic diseases such as atopic dermatitis.
In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.
We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.
In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).
•In this pooled analysis dupilumab significantly improved signs and symptoms of AD.•Dupilumab treatment alleviated pain/discomfort on the EuroQoL-5D.•Patient distribution within responder categories ...improved over time with dupilumab.•No new safety signals were observed with dupilumab.•Dupilumab had an overall favorable benefit-risk profile.
Two phase 3 trials with identical design, LIBERTY AD SOLO 1 (NCT02277743) and LIBERTY AD SOLO 2 (NCT02277769), confirmed dupilumab efficacy and safety versus placebo in adults with moderate-to-severe atopic dermatitis (AD).
To report a pooled analysis of these trials to further explore dupilumab’s effects on AD clinical parameters, patient-reported outcomes (PROs), symptoms of anxiety/depression, health-related quality of life (HRQoL), and safety.
A pooled analysis of two 16-week phase 3 studies in adults with moderate-to-severe AD (N = 1379) inadequately controlled with/inadvisable for topical medications, randomized to dupilumab 300 mg once weekly (qw), every 2 weeks (q2w), or placebo.
Dupilumab significantly improved all pre-specified efficacy endpoints versus placebo (P < 0.0001), including clinical severity outcomes and PROs, symptoms of anxiety/depression, and HRQoL, consistent with previously published results. In post-hoc analyses, among patients reporting at least some baseline pain/discomfort on the EuroQoL-5D, no pain/discomfort at Week 16 was reported by 43%/46%/14% of dupilumab qw/q2w/placebo-treated patients (P < 0.0001). The distribution of dupilumab-treated patients within pre-defined score categories on the Investigator’s Global Assessment (0–1/2/3/4) and Eczema Area and Severity Index (≥90%/≥75–<90%/≥50–<75%/<50%) steadily and consistently improved over time versus marginal changes with placebo. Dupilumab significantly improved pruritus within 1–3 days of treatment initiation. No new safety signals were observed. Injection-site reactions and conjunctivitis were more common with dupilumab; AD exacerbation and non-herpetic skin infections more frequent with placebo.
Dupilumab versus placebo significantly improved objective AD signs, subjective PROs, symptoms of anxiety/depression, and HRQoL, with a favorable benefit-risk profile in adults with moderate-to-severe AD.
•Cancer-associated fibroblasts (CAFs) play critical pro-tumorigenic roles in tumor stroma.•PD-L1 expression on CAFs is reversibly regulated by IFN-γ released from activated lymphocytes.•In pN0M0 ...NSCLC, postoperative RFS is significantly longer in patients with PD-L1+ CAFs.•PD-L1 expression on CAFs is an independent prognostic factor of higher 5-y RFP in pN0M0 NSCLC.
Cancer-associated fibroblasts (CAFs) are a dominant cell type in tumor stroma and support the generation of pro-tumorigenic microenvironment. CAFs have frequent opportunities to interact with immune cells infiltrating the tumor stroma, but the process remains to be determined. In this study, we focused on immune checkpoint mechanism. We also examined the induction of programmed cell death-ligand 1 (PD-L1) on CAFs by immune cell, and the clinical significance of PD-L1-expressed CAFs in non-small cell lung cancer (NSCLC).
CAFs were isolated from human NSCLC tissues, and PD-L1 expression levels in CAFs were analyzed by real-time polymerase chain reaction and flow-cytometry. Following immunohistochemical analysis of PD-L1 in surgically resected pN0M0 NSCLC (n = 125, including 88 invasive adenocarcinomas and 37 squamous cell carcinomas), the correlation of PD-L1-positive CAFs with clinicopathological features was investigated.
PD-L1 mRNA and protein expression on CAFs was upregulated by exogenously supplemented interferon-gamma (IFN-γ) and downregulated through the depletion of IFN-γ. PD-L1 expression on CAFs was upregulated by co-culture with activated lymphocytes releasing IFN-γ. Immunohistochemistry revealed that PD-L1-positive CAFs were observed in 31 cases (24.8%). Postoperative relapse-free survival was significantly prolonged in patients with PD-L1-positive CAFs as compared with those with PD-L1-negative CAFs, with 5-year relapse-free probabilities of 84.5% and 66.3%, respectively (P = 0.031). Multivariate analysis revealed that PD-L1 expression on CAFs was an independent prognostic factor of longer relapse-free survival after surgery (hazard ratio: 3.225, P = 0.027).
PD-L1 expression on CAFs is reversibly regulated by environmental stimuli including IFN-γ from activated lymphocytes. In the non-metastatic NSCLC, PD-L1 expression on CAFs suggests the induction of anti-tumor immune responses, contributing to better prognosis after surgery.
This study investigates the development of psoriasis‐like eruptions from dupilumab treatment. Our case suggests that psoriasis‐like eruptions might occur during dupilumab treatment, particularly in ...Asians, and requires careful follow‐up. We believe that our study makes a significant contribution to the literature as it highlights a potential adverse effect of this treatment for atopic dermatitis.
Programmed cell death-ligand 1 (PD-L1) expression on tumor cells is induced by interferon-gamma, suggesting the induction of an anti-tumor immune response. In turn, binding of PD-L1 to programmed ...cell death 1 (PD-1) triggers an immune checkpoint pathway that contributes to tumor growth. Though it remains to be elucidated, the clinical significance of PD-L1 expression might vary with tumor progression in non–small-cell lung cancer (NSCLC). Immunohistochemical analysis of PD-L1 was done in tumor specimens from patients who underwent radical surgery for stage I–IIIA NSCLC (
n
= 228). Tumor PD-L1 expression intensity was semi-quantitatively scored and its correlation with various clinicopathological features and postoperative relapse-free survival (RFS) was assessed relative to pathological stage. In stage I, postoperative RFS was significantly prolonged in patients with a high PD-L1 score compared with a low PD-L1 score, exhibiting 5-year relapse-free probabilities of 94.1% and 75.1%, respectively (
P
= 0.031). A multivariate analysis revealed that a high PD-L1 score was a prognostic factor of longer postoperative RFS (hazard ratio: 0.111,
P
= 0.033). Conversely, in stages II and IIIA, patients with a high PD-L1 score tended to suffer from postoperative tumor recurrence. In early-stage NSCLC, high tumor PD-L1 expression status represents a biomarker to predict good prognosis after radical surgery and may reflect the induction of an antitumor immune response. However, in locally advanced stage NSCLC, tumor PD-L1 expression status may reflect the execution of an immune checkpoint pathway and predicts the incidence of postoperative tumor recurrence.
Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled ...moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized.
Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL.
Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness.
Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001).
Limitations: Cultural differences of translated PROs.
Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.
In lung cancer, tumor‐associated macrophages (TAMs), especially M2‐like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2‐like TAMs may serve as ...a therapeutic target. The purpose of this study was to investigate the effect of M2‐like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP‐1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP‐1 and J774‐1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2‐like TAMs in transplanted lung cancer in mouse. We used the COX‐2 inhibitor nimesulide to inhibit the secretion of MCP‐1 and PGE2, which promotes macrophage migration and M2‐like differentiation. Nimesulide treatment decreased the secretion of MCP‐1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP‐1. Lung cancer supernatant induced the differentiation of macrophages toward the M2‐like phenotype, and nimesulide treatment inhibited M2‐like differentiation by blocking MCP‐1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2‐like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP‐1 and PGE2 from tumor cells depleted M2‐like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.
Nimesulide blocked the secretion of MCP‐1 and PGE2 from tumor cells, resulting in the depletion of M2 tumor‐associated macrophages (TAMs) in the tumor microenvironment (TME). Combination therapy of nimesulide with cisplatin considerably suppressed tumor growth in the LLC mouse model.
Objective
The predictive importance of galectin-3 in non-small cell lung cancer (NSCLC) has not been elucidated. We examined whether galectin-3 could serve as a predictor for tumor recurrence in ...NSCLC.
Methods
In 42 consecutive patients with NSCLC who underwent radical resection, galectin-3 expression in tumor cells was examined by immunohistochemistry. Galectin-3 levels in serum were assessed before surgery and 1 month after surgery by enzyme-linked immunosorbent assays.
Results
Higher expression of galectin-3 in tumor cells was associated significantly with lymphatic invasion (
p
= 0.049) and tumor recurrence (
p
= 0.001). The Kaplan–Meier curves for relapse-free survival after radical resection showed that patients with high expression of galectin-3 had significantly shorter relapse-free survival than those with low expression of galectin-3 (
p
< 0.001). The serum level of galectin-3 was not reduced after radical resection, and there was no significant correlation between the serum level of galectin-3 and recurrence.
Conclusions
Galectin-3 expression in tumor cells could serve as a predictive factor for recurrence, but serum level of galectin-3 is not useful for predicting NSCLC recurrence.
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