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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.

Atopic dermatitis (AD), a chronic relapsing inflammatory skin disease with a high disease burden, is one of the most common dermatological conditions in Japan. Herein, we report the disease profiles and current AD treatment during 2-year management of Japanese adults with moderate-to-severe AD. ADDRESS-J was a prospective, longitudinal, observational study that evaluated real-world effectiveness and safety of current AD treatments of adult patients with moderate-to-severe AD (Investigator's Global Assessment score 3 or 4) in Japan. The maximum follow-up period was 2 years. Among 300 patients enrolled, 288 had ≥1 post-baseline evaluation and were analyzed (mean age, 35.5 years; 60.1% male). Almost all patients (99.7%) received topical therapy; the most commonly used therapy was topical corticosteroids of the second-highest potency (86.5%) (e.g., 0.1% mometasone furoate) followed by medium-potency topical corticosteroids (50.3%) (e.g., 0.05% clobetasol butyrate). At month 12 of the study, 10.4% of patients had Investigator's Global Assessment 0/1, similarly at month 24 (10.8%). A total of 132 patients (45.8%) had ≥1 AD flare-up during the observation period, with the majority of first flares occurring within the first year of the study. Various physician- and patient-reported outcomes improved considerably during the first 3 months of the study, with only minor changes after this time. In this cohort, 16.7% of patients had skin infections requiring treatment; 7.3% had adverse events (AE) potentially related to treatment; 1.7% had serious AE; and 1.0% had treatment discontinuations due to AE. Limitations include missing data at later timepoints and the inclusion criteria limiting generalizability. In summary, this analysis of the ADDRESS-J study showed that some patients with moderate or severe AD respond to conventional therapies, while others do not. For those with inadequately controlled moderate-to-severe AD, the newly emerged systemic agents, such as biologics, may provide a potential strategy for long-term disease management.

Mucinous lung tumors often develop locoregional recurrence after surgery because tumor cells spread with mucus through the bronchus, worsening the patient prognosis. We suspect that tumor spread is encouraged by intraoperative procedures, such as grasping, pressing, or manipulating the lobes of the lung wherein the tumor is located. When surgeons perform pulmonary resection, they typically avoid these procedures until the bronchus is separated from the healthy lung. We have tried to modify an earlier era technique [5, 6] of posterior bronchus first lung resections for infective conditions and use it for VATS lobectomy for metastatic mucinous carcinoma of the lung in a patient. Our aim was to see if it can reduce loco-regional spread through the airspaces and improve recurrence-free survival. We present the technique in images and a video. A 73-year-old woman was referred to our hospital to treat lung metastasis of the pseudomyxoma peritonei in the left lower lobe. This mucinous tumor was resected by Bronchus-first video-assisted left lower lobectomy, and the patient had no evidence of recurrence at 2 years and 9 months after surgery. There is no evidence yet that bronchus first lobectomy prevents locoregional recurrence by avoiding intraoperative procedures like grasping, pressing, or manipulating of lung which may push the tumor edge forward. We hope that this surgical concept is recognized and that future observational studies will investigate its effect on locoregional recurrence.

A 76-year-old woman presented with dyspnea. Computed tomography showed massive pericardial effusion, so percutaneous catheter drainage was performed. The usual causes of exudate were ruled out, and no diagnosis was reached. Thoracoscopic pericardial fenestration was performed for the purpose of pericardial biopsy and to create a passage allowing longer-term drainage. We observed the pericardial cavity after removing effusion, and incidentally revealed a tumor measuring 2 cm in diameter located between the left atrial appendage and left pulmonary artery. Surgical resection of the tumor attached to the left atrial appendage was performed. The pathological diagnosis was hemangioma.

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.

We aimed to develop a reliable identification algorithm combining diagnostic codes with several treatment factors for inpatients with acute ischemic stroke (AIS) to conduct pharmacoepidemiological studies using the administrative database MID-NET® in Japan.We validated 11 identification algorithms based on 56 different diagnostic codes (International Classification of Diseases, Tenth Revision; ICD-10) using Diagnosis Procedure Combination (DPC) data combined with information on AIS therapeutic procedures added as "AND" condition or "OR" condition. The target population for this study was 366 randomly selected hospitalized patients with possible cases of AIS, defined as relevant ICD-10 codes and diagnostic imaging and prescription or surgical procedure, in three institutions between April 1, 2015 and March 31, 2017. We determined the positive predictive values (PPVs) of these identification algorithms based on comparisons with a gold standard consisting of chart reviews by experienced specialist physicians. Additionally, the sensitivities of them among 166 patients with the possible cases of AIS at a single institution were evaluated.The PPVs were 0.618 (95% confidence interval [CI]: 0.566-0.667) to 0.909 (95% CI: 0.708-0.989) and progressively increased with adding or limiting information on AIS therapeutic procedures as "AND" condition in the identification algorithms. The PPVs for identification algorithms based on diagnostic codes I63.x were 0.8. However, the sensitivities progressively decreased to a maximum of ~0.2 after adding information on AIS therapeutic procedures as "AND" condition.The identification algorithms based on the combination of appropriate ICD-10 diagnostic codes in DPC data and other AIS treatment factors may be useful to studies for AIS at a national level using MID-NET®.

Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the signs and symptoms of AD. However, these treatments are not always enough to provide relief. A new medicine called abrocitinib, which is taken every day as a tablet, reduces part of the body’s immune response that happens in AD. The clinical study described in this plain language summary, called JADE COMPARE, investigated how well and how safely 16 weeks of treatment with abrocitinib worked in adults with AD compared to placebo (‘dummy treatment’) and a medicine that is already approved for AD, called dupilumab. The study showed that abrocitinib was better than placebo in improving the signs and symptoms of AD after 16 weeks. In addition, patients who were taking abrocitinib 200 mg for 2 weeks experienced greater relief from itch than patients who were taking abrocitinib 100 mg, placebo, or dupilumab. More people who took abrocitinib 200 mg reported side effects than those taking abrocitinib 100 mg, placebo, or dupilumab, but most of these side effects were mild or moderate. ClinicalTrials.gov NCT number: NCT03720470 .

Introduction Previous drug survival studies of dupilumab in atopic dermatitis (AD) show that many patients continue treatment through 1 year, suggesting that patients experience clinically relevant benefits with long-term treatment. Methods This post hoc analysis included data through week 100 from 391 adult patients from the dupilumab open-label extension (OLE) study who had not achieved the endpoints of at least 75% improvement from baseline in the Eczema Area and Severity Index (EASI-75) or an Investigator’s Global Assessment (IGA) score of 0 or 1 with short-term (16 weeks, 300 mg qw or q2w) dupilumab treatment in the parent SOLO 1 or 2 studies. All patients received dupilumab 300 mg qw in the OLE study, irrespective of whether they received qw or 2qw dosing in the parent study. Results Among those who had not achieved EASI-75 or IGA 0/1 during the 16-week parent study, the proportion of patients achieving EASI-75 by week 100 was 91%. The proportion achieving IGA 0 or 1 at week 100 was 45% for patients initially on q2w week dosing and 49% for those on initial qw dosing. Conclusion Long-term dupilumab treatment may be associated with improvement in AD in patients with suboptimal responses during the initial 16 weeks of treatment. Clinical Trial Registration LIBERTY AD SOLO 1: ClinicalTrials.gov identifier NCT02277743; EudraCT 2014-001198-15. LIBERTY AD SOLO 2: ClinicalTrials.gov identifier NCT02277769; EudraCT 2014-002619-40. LIBERTY AD OLE: ClinicalTrials.gov Identifier NCT01949311; EudraCT 2013-001449-15. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00643-4.

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. 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. 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

Moderate to severe atopic dermatitis (AD) has a high disease burden and a significant effect on quality of life. Observational studies are necessary to determine the patient disease burden and long‐term disease control in the Japanese population. ADDRESS‐J is a non‐interventional, observational registry of adult Japanese patients with moderate to severe AD. Herein, we report baseline data from the ADDRESS‐J study describing disease characteristics and current treatment practices. At baseline, 300 adult AD patients with Investigator's Global Assessment (IGA) scores (range, 0–4) of 3 (moderate) or 4 (severe) whose treatments for AD were intensified, were assessed for clinical and patient‐reported outcomes and current AD treatments. The registry patients’ median age was 34.0 years; 60.7% were male and 71.7% had had AD for more than 20 years. At baseline, 220 study patients had an IGA score of 3 and 80 had an IGA score of 4. The median Eczema Area and Severity Index score was 21.7 (range, 0–72), the median body surface area involvement was 46.25%, and the median pruritus numerical rating scale score was 7.0 (range, 0–10); for each of these measures, higher scores represent greater severity. Most registry patients (86.7%) had recently used topical corticosteroids or topical calcineurin inhibitors as treatment for AD. This registry cohort represents a population of Japanese patients with moderate to severe AD and provides an important resource for characterizing the disease burden and evaluating the safety and effectiveness of various AD treatments.

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 (P0.001 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 (P0.001 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, an anti-IL (Interleukin) -4 receptorα mAb, inhibits IL-4/IL-13 signaling and is indicated for the treatment of inadequately controlled AD, asthma and CRSwNP because IL-4/IL-13 signaling is a key driver of type2/Th2 immune diseases (atopic/allergic diseases). As well as the above diseases, a therapeutic effect of dupilumab on PAR can be expected. We investigated the effect of dupilumab on PAR in severe AD patients with comorbid PAR.Prospective observational study. 21 severe AD patients with PAR who started dupilumab were enrolled and we devided them into 2 groups: more than moderate group and less than moderate group. We investigated subjective symptoms, QOL scores, face scale, findings of nasal cavity and laboratory findings before start of therapy and 12 months later.In more than moderate group, significant improvements were observed in subjective symptoms (except a part), QOL scores (except a part), face scale and findings of nasal cavity. On the other hand, in less than moderate group, no improvement was observed in all items. Subjective symptom assessments were estimated lowlier than objective finding assessments.Dupilumab has a therapeutic effect on severe PAR in severe AD patients.

Background: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. Methods: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients’ sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between “baseline levels of 18 biomarkers” and “% change from baseline of EASI at 16 weeks of dupilumab treatment.” Discussion: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

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.

A 53-year-old man underwent surgical repair and drainage of a spontaneous esophageal rupture through a left anterolateral intercostal thoracotomy. Thereafter, wound infection persisted for 3 years with formation of cutaneous fistulae and granulation tissue. Chest computed tomography revealed osteolysis, swollen ribs and costal cartilage, and cutaneous fistulous tracts. Bone scintigraphy with 99mTechnetium revealed abnormal accumulation in the ribs and costal cartilage, indicating costochondritis and osteomyelitis of ribs with cutaneous fistulae. Surgical resection of the skin including the cutaneous fistulae, infected ribs and costal cartilage were performed successfully.

In elderly patients with lung cancer, the presumed fear of postoperative complications has resulted in the delivery of limited resection. Surgical decision-making for such patients would become easier if clinicians could predict who is at high risk of postoperative complications. The purpose of this study is to propose a scoring system to predict the risk of postoperative complications for elderly patients with lung cancer. We reviewed patients aged 75 years or older who underwent lobectomy for lung cancer at a single hospital (n = 199). A multivariable logistic regression model was utilized to determine risk factors for postoperative complications. Six risk factors for postoperative complications were identified, and we derived a risk score by assigning weights to these factors based on their odds ratios, as follows: Risk score = 7 × (performance status of 2) + 6 × (coronary artery disease) + 3 × (a history of cerebrovascular accident) + 2 × (restrictive ventilatory impairment) + 1 × (male sex) + 1 × (interstitial pneumonia). The postoperative complication rates in patients with risk scores of 0, 1–2, 3–5, 6–8, and 9–14 were 19, 29, 56, 68, and 90%, respectively. The proposed risk score was able to predict the incidence of postoperative complications. The risk score can be used to identify high-risk patients and to select proper treatment strategies.

Optimal management of atopic dermatitis requires a comprehensive assessment of response to treatment in order to inform therapeutic decisions. In a real-world setting, successful response to atopic dermatitis treatment is measured by sustained improvements in signs, symptoms, and quality of life. Post-hoc analyses of a 1-year, randomized, double-blinded, placebo- controlled trial (NCT02260986) of dupilumab with concomitant topical corticosteroids in 421 adults with moderate-to-severe atopic dermatitis (of whom 315/106 received placebo/dupilumab (of whom 315 received placebo and 106 received dupilumab) was performed to assess the proportion of responders to dupilumab through a multidimensional composite endpoint. At 6-months, 80.2% of dupilumab-treated vs 40.0% placebo patients (p

BACKGROUND\ud Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits\ud signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important\ud drivers of atopic or allergic diseases such as atopic dermatitis.\ud METHODS\ud In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1\ud and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose\ud disease was inadequately controlled by topical treatment. Patients were randomly\ud assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg)\ud or placebo weekly or the same dose of dupilumab every other week alternating\ud with placebo. The primary outcome was the proportion of patients who had both\ud a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment\ud and a reduction of 2 points or more in that score from baseline at week 16.\ud RESULTS\ud We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary\ud outcome occurred in 85 patients (38%) who received dupilumab every other week and\ud in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received\ud placebo (P

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Objectives 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). Materials and methods 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. Results 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). Conclusion 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.

What is known and objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is new and conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

A 16-year-old male high-school student experienced generalized itchy wheal and dyspnea during physical exercise after lunch. Each food material of his lunch was examined using a prick-prick test, allergen-specific IgE test (ImmunoCAP

Background: 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). Objectives: 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. Methods: 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. Results: 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–

Purpose The purpose of this study is to evaluate the accuracy of gastrointestinal (GI) perforation ICD-10 coding in the Diagnosis Procedure Combination (DPC) database and to examine drug exposure risk factors for GI perforation. Methods A total of 100 patients with GI perforation ICD-10 codes were selected randomly from Kagawa University Hospital's DPC database between April 2011 and December 2016. Two experienced specialist physicians independently reviewed the medical records and classified cases as "definite A," "definite B," "probable," or "no GI perforation." The positive predictive values (PPVs) of "definite A/B" cases were calculated after stratification by sex, age, ICD-10 code, and diagnostic information in the DPC data. The number of prescribed drugs with side effects of GI perforation according to historical data was compared between "definite A/B" and "no GI perforation" cases. Results The overall PPV was 47.0% (95% confidence interval [CI], 36.9-57.2). However, the PPVs for the three categories of diagnostic information in the DPC data ("main diagnosis," "diagnosis causing admission," and "most resource-intensive diagnosis") were each more than 70% after excluding inappropriate patients. Additionally, the PPV focused on these three categories was 76.3% (95% CI, 59.8-88.6). Prescribed drugs with side effects of GI perforation were more frequently detected in "definite A/B" cases (P = .028). Conclusions Although the overall PPV for GI perforation based on ICD-10 code was low, our results suggest that the PPV could be improved by appropriate selection of DPC diagnosis category and that use of multiple medications enhances the risk of GI perforation.

Galectin‑3 plays crucial roles in tumor progression. However, in non‑small cell lung cancer (NSCLC), it remains unclear whether the hypoxic tumor microenvironment enhances galectin‑3‑induced cell motility. We investigated galectin‑3 expression in NSCLC cells under hypoxia, and the possible molecular mechanisms by which galectin‑3 influences tumor aggressiveness. Galectin‑3 levels in NSCLC cell lines under hypoxia were assessed using reverse transcription PCR and western blotting. To clarify the role of endogenous galectin‑3, the effect of galectin‑3 knockdown in NSCLC cells was investigated using scratch and invasion assays. The expression and clinicopathological significance of galectin‑3 in 57 patients with pN0M0 invasive pulmonary adenocarcinoma were investigated by immunohistochemistry. Both mRNA and protein levels of galectin‑3 in the NSCLC cell lines A549 and LK‑2 were upregulated by hypoxia. As revealed by scratch and invasion assays, the cell migratory and invasive activities were significantly increased under hypoxia, but were reduced by galectin‑3 knockdown. Notably, addition of galectin‑3 to the media did not improve the cell motility impaired by galectin‑3 knockdown. To clarify the role of endogenous galectin‑3 in the enhancement of tumor cell motility under hypoxia, we focused on the function of RhoA. RhoA level in the plasma membrane, but not in the cytoplasm, was increased under hypoxia and decreased by galectin‑3 knockdown. RhoA activity was significantly enhanced under hypoxia and effectively inhibited by galectin‑3 knockdown. In patients with pN0M0 invasive pulmonary adenocarcinoma, higher galectin‑3 expression on tumor cells was significantly associated with tumor cell invasion into microvessels and tumor recurrence after surgery. These data demonstrate that in NSCLC cells under hypoxia, upregulated galectin‑3 levels increase the localization of RhoA to the plasma membrane, thus enhancing RhoA activity, which is associated with aggressive cell motility. In pN0M0 invasive pulmonary adenocarcinoma, galectin‑3 is a potential biomarker for predicting tumor recurrence after radical surgery.

Surgery remains the best treatment for obtaining cure in patients with resectable lung cancer, regardless of age. In elderly patients, however, the presumed fear of decreased performance status (PS) after lobectomy has resulted in the delivery of sub-optimal cancer surgery. Surgical decision making for such patients would become easier if post-lobectomy survival benefits and changes in PS were well defined.We reviewed patients aged 75 years or older who received lobectomy for non-small cell lung cancer (NSCLC) at our hospital between January 2004 and December 2014. Eastern Cooperative Oncology Group PS was preoperatively and postoperatively assessed in 137 patients. Patients were classified into 2 groups based on the change in PS: in Group 1, postoperative and preoperative PS were the same; in group 2, postoperative PS was less than preoperative PS. We compared the characteristics of patients in groups 1 and 2.Overall 5-year survival was 47.4% in group 1 and 0% in group 2 (P0.001). History of cardiac ischemia (P=0.001) and squamous cell carcinoma (P=0.015) were identified as significant predictors of reduced postoperative PS.Our results show that maintenance of PS after lobectomy is expected to be associated with a good prognosis. However, reduction of PS after lobectomy indicates an extremely poor prognosis in elderly patients with lung cancer. History of cardiac ischemia and squamous cell carcinoma are possible risk factors for decreasing PS. Thus, careful patient evaluation and selection are needed when deciding whether to use lobectomy in clinical practice.

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.

We examined phototactic responses of dipteran insects, including Neoempheria ferruginea (Brunetti), Sciaridae, and Drosophila, using ultraviolet (365nm), green (525nm), and white wavelengths of a LED (light emitting diode) using a water-pan trap. The number of N. ferruginea captured (trap catches) were highest in the trap with ultraviolet LED. Then, we examined the effects of ultraviolet LED and surfactant (1% Tween 80) in the water-pan trap on the trap catches using generalized linear mixed model. Both ultraviolet LED and surfactant were shown to affect positively on the trap catches. Nevertheless, the LED variable had the highest effect on N. ferruginea trap catches. On the other hand, trap catches of Sciaridae and Drosophila were affected most by the surfactant.

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmo, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [ including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

症例は乳癌・胃癌・腎癌の既往のある75歳女性．胸部CTで右肺下葉に異常陰影を認めるとのことで当科に紹介となった．胸部CTで右S8に8mm大の小結節影を認めた．retrospectiveにみると3年前の胸部CTで同部に3mm大の結節影を，2年前の胸部CTで4mm大の結節影を認めていた．増大傾向を認めており転移性肺腫瘍を疑われたため手術を行った．術中迅速組織診で腎癌肺転移と診断された．術後永久標本において豊富な淡明細胞質を有する細胞が薄壁性の類洞様血管を伴ってシート状に配列しており，免疫染色ではPAS・MelanA陽性，CD10・HMB45陰性であり淡明細胞腫と診断された．肺原発淡明細胞腫は比較的稀な腫瘍である．腎細胞癌肺転移との鑑別を要するが実際に腎細胞癌の既往を有する症例の報告は我々が検索した限り認められなかった．本症例の経過を若干の文献的考察を加えて報告する．

Case: 72-yr-old manChief complaint: Breathing difficulty with wheezingwhen cutting Falcata.Personal medical history: Eczema since infancy.Tubercular pleurisy at the age of 28.Family medical history: Nothing of special note.Occupational history: Worker in wood furnitureproduction. Had been working with wood sincegraduation from junior high school.Working inpresent position since the age of 18.Smoking status: Nonsmoker, both present and past.Alcohol consumption: One bottle of beer and twoglasses of brandy every day.Pets: None.History of present illness: The patient had bronchialasthma at the age of 17. The main symptom was coughingwith slight breathing difficulty. At 30 yr of age, he wasstruck by a severe asthma attack, and was unconsciousovernight. From that time, his asthma attacks appearedonly at the turn of the season. Control by drug therapywas excellent for about ten years from when he was 60yr old, and there were no asthma attacks. The patientbecame conscious of breathing difficulty with wheezingafter entering the factory at the age of 70 yr. He began toregularly visit a local doctor’s office once a week. Hedid not have the complaint of itchy eyes. Theophyllinetablets were prescribed three times a day after each meal.Becromesazon inhalation medicine and Predonizorontablets were prescribed for use during an attack. Recently,he noticed that the symptoms appeared when cuttingFalcata with a circular saw. He could not enter the factorywhen Falcata was being cut. His symptoms appearedeven if he entered the factory without knowing thatFalcata had been cut. The severity of his symptomsgradually decreased when he left the factory and did notappear with wood other than Falcata. His symptomsdisappeared after the processing of Falcata wasdiscontinued.Two other employees also complained of sneezing,runny nose and voice change after cutting Falcata.However, they did not suffer from breathing difficultywith wheezing. Employees at other factories have alsocomplained of sneezing and runny nose after handlingFalcata.To confirm the diagnosis of occupational asthma (OA)induced by Falcata, the patient was hospitalized at theOsaka Prefectural Medical Center for Respiratory andAllergic Diseases on September 12, 2005. Signedinformed consent was obtained from the patient for thisstudy and the bronchial provocation test. This study andthe bronchial provocation test were approved by theHospital Ethics Committee. Findings on admission: Height 160.8 cm, weight 60Kg, temperature 36.5 °C, pulse 76 beats per minute, bloodpressure 140/75 mmHg, SpO

We reported a case of surgically resected double bronchogenic cysts within the anterior mediastinum. An anterior mediastinal tumor had been found at medical examination 6 years ago in a 66-year-old man, but has been followed up without treatment. After the treatment of another disease, he was referred to our hospital for evaluation of the mediastinal tumor. A chest computed tomography showed 2 anterior mediastinal nodules. Nodules in the thymus were resected with video-assisted thoracic surgery. The tumors were both pathologically diagnosed as bronchogenic cysts.

A population survey of phytoseiid mites and spider mites was conducted on peach leaves and wild plants in Japanese peach orchards having different pesticide practices. The phytoseiid mite species composition on peach leaves and wild plants, as estimated using quantitative sequencing, changed during the survey period. Moreover, it varied among study sites. The phytoseiid mite species compositions were similar between peach leaves and some wild plants, such as Veronica persica, Paederia foetida, Persicaria longiseta, and Oxalis corniculata with larger quantities of phytoseiid mites, especially after mid-summer. A PCR-based method to detect the ribosomal ITS sequences of Tetranychus kanzawai and Panonychus mori from phytoseiid mites was developed. Results showed that Euseius sojaensis (specialized pollen feeder/generalist predator) uses both spider mites as prey in the field.

Genes of the IL-1 family encode three different peptides, IL-1alpha, IL-1beta, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-1. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63-19. 8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with A1 homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1beta and IL-1Ra, these findings suggest that dysregulation of IL-1beta/IL-1Ra, probably due to interaction between epithelium and immuno-competent cells in the airway, is important in asthma inflammation.

We examined the genomic organization of the sodium channel α-subunit gene in two strains of melon thrips, Thrips palmi, having differing sensitivity to cypermethrin. The nucleotide sequences of the strains included 18 or 16 putative exons which covered the entire coding region of the gene producing 2039 amino acid residues. Deduced amino acid sequences of both strains showed 80% homology with those of Periplaneta americana and Cimex lectularius. Comparison of deduced amino acid sequences of both strains showed no consistent amino acid difference. In addition to the previously reported resistant amino acid (Ile) at the T929I site, both strains encoded another resistant amino acids at two positions which are involved in pyrethroid resistance in other arthropods. These amino acids might also involve in the basal levels of resistance to pyrethroids of both strains.