Near-Infrared Photoimmunotherapy Using a Protein Mimetic for EGFR-Positive Salivary Gland Cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on a monoclonal antibody (mAb) conjugated to a photosensitizer (IR700Dye). The conjugate can be activated by near-infrared light irradiation, causing necrotic cell death with high selectivity. In this study, we investigated NIR-PIT using a small protein mimetic (6-7 kDa, Affibody) which has more rapid clearance and better tissue penetration than mAbs for epidermal growth factor receptor (EGFR)-positive salivary gland cancer (SGC). The level of EGFR expression was examined in vitro using immunocytochemistry and Western blotting. Cell viability was analyzed using the alamarBlue assay. In vivo, the volume of EGFR-positive tumors treated with NIR-PIT using the EGFR Affibody-IR700Dye conjugate was followed for 43 days. It was found that NIR-PIT using the EGFR Affibody-IR700Dye conjugate induced the selective destruction of EGFR-positive SGC cells and restricted the progression of EGFR-positive tumors. We expect that NIR-PIT using the EGFR Affibody-IR700Dye conjugate can efficiently treat EGFR-positive SGC and preserve normal salivary function.

A case of radicular cyst on deciduous tooth in a 7-year-old child.

Radicular cysts are the most common cystic lesions in the oral cavity, and have a rare occurrence in the primary dentition. We report a case of radicular cyst of mandible in child by multimodal imaging including panoramic radiography, CT, and MR imaging. A 7-year-old girl presented with swelling and without pain, and hypoesthesia on the right side of the mandible. On clinical examination, an expansive lesion with undulation was found to the buccal cortex of the right side of the mandible. Panoramic radiograph showed a unilocular radiolucency with well-defined margin, displaced tooth, and root resorption in the right mandible. Regarding CT imaging, axial soft tissue algorithm CT and bone tissue algorithm CT showed a low-attenuation internal structure and expansion of the buccal cortex of the right side of the mandible. Three-dimensional-CT showed expansion of the buccal cortex of the right side of the mandible. Multiplanar reformation imaging showed displaced tooth, root resorption, and expansion of the buccal cortex of the right side of the mandible. On T1-weighted image, the expansive lesion showed low signal intensity, and T2-weighted and STIR images revealed high signal intensity. A partial biopsy of the mandibular region was performed. Histopathological diagnosis was radicular cyst caused by apical periodontitis with abscess. This case suggests that multimodal imaging, especially CT and MR imaging, could be effective for evaluating mandibular lesions in child.

The effect of the formalin-fixed paraffin-embedded process on salivary microbiota profiling.

In recent years, bacterial DNA in formalin-fixed paraffin-embedded (FFPE) samples has been recognized as a valuable bioresource for microbiota studies. This study aimed to examine the effect of the FFPE process on microbiota profiling to evaluate whether FFPE samples could serve as an alternative bioresource to fresh samples in oral microbiota studies. Fresh saliva was collected from nine subjects. The pellets obtained by centrifuging the collected saliva were fixed in formalin, then dehydrated and embedded in paraffin to prepare FFPE samples. The abundance of the hypervariable regions V1-9, V1-2, and V3-4 of the 16S rRNA gene in fresh and FFPE samples was relatively compared. In addition, microbiota profiling was performed to compare the results between the two sample types. The results showed that the FFPE process resulted in a certain degree of fragmentation of the 16S rRNA gene. However, the V1-2 region was relatively well-preserved compared to the V1-9 and V3-4 regions, suggesting that short regions are suitable targets for oral microbiota analysis. Importantly, there were no significant differences in alpha and beta diversity of microbiota between fresh and FFPE samples, and microbiota profiles were similar between the two sample types, suggesting that FFPE samples could be a valuable bioresource for oral microbiota studies.

A novel assay for improved detection of sputum periostin in patients with asthma.

BACKGROUND: Serum periostin associates with type-2 inflammation in asthmatic airways, but also reflects whole body periostin levels originating from multiple sources. Less is known about sputum periostin as a biomarker in asthma as detection levels are low using currently available periostin assays. We aimed to investigate detection of sputum periostin using ELISA assays targeting different periostin epitopes and relate levels to clinical characteristics. METHODS: Two ELISA systems were developed using antibodies detecting whole periostin or cleavage products, the molecular weight and amino acid sequences of which were confirmed. The ELISA assays were applied to sputum from 80 patients with mild-to-moderate and severe asthma enrolled in the European, multi-center study BIOAIR. Results were related to clinical characteristics. RESULTS: Sputum was found to contain smaller periostin fragments, possibly due to proteolytic cleavage at a C-terminal site. Comparing ELISA methodology using antibodies against cleaved versus whole periostin revealed detectable levels in 90% versus 44% of sputum samples respectively. Sputum periostin showed associations with blood and sputum eosinophils. Furthermore, sputum, but not serum, periostin correlated with reduced lung function and sputum IL-13 and was reduced by oral corticosteroid treatment. CONCLUSIONS: We present an ELISA method for improved analysis of sputum periostin by detecting cleavage products of the periostin protein. Using this assay, sputum periostin was detectable and associated with more disease-relevant parameters in asthma than serum periostin. Sputum periostin is worth considering as a phenotype-specific biomarker in asthma as its proximity to the airways may eliminate some of the confounding factors known to affect serum periostin.

Study of clinical factors, focus score, lymphocyte type and NF-κB pathway in Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease that occurs predominantly in middle-aged and older women. Although focus score (FS) and lesion grade are determined at pathological diagnosis, few reports have examined whether these results reflect clinical symptoms. In this study, we examined and compared the results of comprehensive immunohistochemical staining of lymphocytes and NF-κB pathway in labial gland biopsies, clinical test data, and radionuclide imaging findings. One hundred labial gland biopsy specimens obtained from 20 female patients with primary SS (5 specimens per patient) were studied. Hematoxylin-eosin-stained specimens were reviewed and FS were calculated. Immunohistochemical staining of CD4, CD8, CD20, CD25, Foxp3, NF-κB, TNFAIP3 and IκBα was performed, and the results were compared with anti-SS-A/Ro (SS-A), anti-SS-B/La (SS-B) and antinuclear antibodies (ANA), and salivary gland scintigraphy findings. FS were significantly higher in the SS-A-, SS-B- and ANA-positive groups than in the respective -negative groups (p < 0.05). Of eight SS-A-positive and SS-B-negative cases, mean FS was 1.9 (seven cases: FS ≥ 1.0) and six cases were ANA-positive. In four SS-A-positive and SS-B-positive cases, mean FS was 3.2 (all cases: FS ≥ 1.0) and all cases were ANA-positive. In immunohistochemical staining, CD4-positive T cells tended to be more abundant than CD8-positive T cells. Small numbers of Foxp3-positive cells were found in all cases. NF-κB, TNFAIP3 and IκBα were positive in the acini, ductal epithelium, and lymphocytes in all cases. The above findings indicated a relationship between FS and clinical test data, and the association of NF-κB pathway with the pathophysiology of primary SS.

Expression of Periostin in Vocal Fold Polyps.

Long-term voice abuse or sudden vocal fold microvascular disruption may lead to injury and subsequent repair/remodeling in the vocal fold mucosa. Periostin is known to be involved in airway remodeling and also in various otolaryngological diseases. The aim of this article was to investigate the expression and the role of periostin in the formation of vocal fold polyps. The expression patterns of periostin in 59 surgical specimens of vocal fold polyps from 54 patients were investigated immunohistochemically. Normal vocal fold mucosa specimens from 5 patients who had undergone total laryngectomy were used as the control group. Retrospective study with planned data collection was conducted at Tohoku Medical and Pharmaceutical University. Expression of periostin was detected in 43 (72.9%) samples and four patterns of periostin expression were observed in vocal fold polyps: negative type, superficial type, infiltrative type, and diffuse type. An association was observed between periostin expression patterns and the histological subtypes of vocal fold polyps. The infiltrative pattern of periostin expression was significantly dominant in vascular-hyaline types. Expression of transforming growth factor-ß (TGF-ß) was also detected in the vocal fold polyps. Our results confirmed that periostin might be involved in certain pathological changes in vocal fold polyps, such as extracellular matrix accumulation, local fibrosis, and formation and development of vocal fold polyps.

Establishment of a novel ELISA system for measuring periostin independently of formation of the IgA complex.

BACKGROUND: Periostin, a matricellular protein that modulates cell functions having various pathophysiological roles, has the potential to be a useful biomarker for various diseases. We recently found that periostin forms a complex with IgA in human serum, which may affect the periostin measurement. METHODS: We investigated (1) whether the formation of the periostin-IgA complex affects the original periostin ELISA system, decreasing the values of serum periostin? (2) bow each domain of periostin affects periostin measurement by the original periostin ELISA system? (3) whether we can establish a novel ELISA system that is not affected by formation of the IgA complex? RESULTS: The periostin value at the reducing condition was significantly higher than that of the non-reducing condition, demonstrating that formation of the IgA complex affects periostin measurement. The monoclonal antibodies (mAbs) for periostin recognizing the EMI and R1 domains immunoprecipitated serum periostin in the reducing condition more than in the non-reducing condition, whereas the mAbs recognizing the R2 or R3 domain immunoprecipitated comparable amounts of serum periostin in the reducing and non-reducing conditions, suggesting the EMI and R1 domains contribute to formation of the complex with IgA. Using SS16A recognizing the R3 domain combined with SS17B recognizing the R4 domain, we established an ELISA system that was able to measure periostin independently of the IgA complex. CONCLUSIONS: We have established a novel ELISA system that measures periostin independently of the IgA complex. This system is promising in identifying periostin as a biomarker for various diseases.

Further evidence for association of YKL-40 with severe asthma airway remodeling.

BACKGROUND: The chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. OBJECTIVE: To evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. METHODS: The patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography-derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). RESULTS: Circulating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = -0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was -33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (ß = -0.24, P = .02), even after controlling for exponent D (ß = -0.26, P = .01). CONCLUSION: These results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Can serum periostin predict bronchopulmonary dysplasia in premature infants?

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. The objectives of this study were to establish whether serum periostin at birth, day of life (DOL) 28, and corrected 36 weeks' gestational age could be potential biomarkers for BPD. METHODS: A total of 98 preterm Japanese infants born at <32 weeks and comparing 41 healthy controls born at term, were divided into BPD (n = 44) and non-BPD (n = 54) cohorts. Serum periostin levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Among 98 preterm infants, the median serum periostin levels at birth were higher with BPD (338.0 ng/mL) than without (275.0 ng/mL, P < 0.001). Multivariate analysis revealed that serum periostin levels at birth were significantly associated with BPD (P = 0.013). Serum periostin levels at birth with moderate/severe BPD (345.0 ng/mL) were significantly higher than those with non-BPD/mild BPD (283.0 ng/mL, P = 0.006). CONCLUSIONS: Serum periostin levels were significantly correlated with birth weight and gestational age, and serum periostin levels at birth in BPD infants were significantly higher than that in non-BPD infants. IMPACT: This study found higher serum periostin levels at birth in preterm infants subsequently diagnosed with bronchopulmonary dysplasia. It also emerged that serum periostin levels at birth significantly correlated with gestational age and birth weight. The mechanism by which serum periostin is upregulated in BPD infants needs further investigation.

Nasal polyp eosinophilia and FeNO may predict asthma symptoms development after endoscopic sinus surgery in CRS patients without asthma.

BACKGROUND: Asthma is a significant comorbidity of eosinophilic chronic rhinosinusitis (CRS). Type2-driven biomarkers such as sinus tissue eosinophilia and fractional nitric oxide (FeNO) may be utilized to detect high risk patients who develop asthma symptoms after endoscopic sinus surgery (ESS) in CRS patients. METHODS: Thirty-six CRS patients without asthma who agreed to undergo ESS between October 2015 and December 2017 were prospectively observed for 12 months following ESS. They were monitored for the development of typical asthma symptoms including dyspnea, wheezes, and cough which responded to anti-asthma medication. Biomarkers were compared between patients who developed asthma symptoms after ESS (asthma symptoms group) and those who did not (non-asthma group). Biomarker changes following ESS intervention were also evaluated. RESULTS: Six patients were lost to follow after ESS. Thus, 30 CRS patients [16 with nasal polyps (NPs) proved by surgery] were followed. Seven (23%) newly complained of asthma symptoms during follow-up. Levels of FeNO and the prevalence of eosinophilic NPs (eosinophils ≥ 70/high power fields) were significantly higher in the asthma symptom group than in non-asthma group [50.7 ppb vs 22.4 ppb for FeNO levels, and 100% (n = 3) vs 23% (n = 3) for eosinophilic NP prevalence, both p < 0.05]. Levels of sputum periostin decreased significantly by ESS in the non-asthma group. However, changes of biomarkers after ESS were comparable between the two groups. CONCLUSIONS: Eosinophils in NPs (≥70/high power fields) and preoperative FeNO may be significant biomarkers for predicting the development of asthma symptoms after ESS.

Medication-related osteonecrosis of the jaw in a patient with multiple myeloma: an unusual case with tumor in the surgical specimen.

Multiple myeloma is characterized by a neoplastic proliferation of plasma cells primarily in the bone marrow. Neoplastic plasma cells stimulated osteoclasts, and destroy bone tissue, causing bone pain, pathological fractures, paralysis due to spinal cord compression, and hypercalcemia. Bisphosphonates are used as supportive therapy in the management of multiple myeloma. Medication-related osteonecrosis of the jaw (MRONJ) is a well-known complication of treatment with bisphosphonates, denosumab, and other drugs, such as anti-angiogenic agents and novel anti-cancer drugs. We report MRONJ in a patient with multiple myeloma, especially an unusual case with tumor in the surgical specimen. A 73-year-old woman presented with pain on the left side of the mandible within 3 months. On clinical examination, an exposed bone without purulent drainage presented on the left side of the mandible. Before 2 years, she received chemotherapy of zoledronate for multiple myeloma at another hospital. Panoramic imaging showed radiopacities of bone in the left side of the mandibular molar area. Multidetector computed tomography (MDCT) with axial, multiplanar reformation (MPR) and three-dimensional (3D) images showed the sequestrum without periosteal reaction. She was diagnosed as MRONJ, and underwent surgery. Finally, the surgical specimen was diagnosed as multiple myeloma in the sequestrum. This case suggests that the evaluation of the surgical specimen of MRONJ could be essential for detection of primary tumor.

Squamous cell carcinoma antigens are sensitive biomarkers for atopic dermatitis in children and adolescents: a cross-sectional study.

BACKGROUND: We recently reported that squamous cell carcinoma antigen 2 (SCCA2) is a reliable biomarker for atopic dermatitis (AD). OBJECTIVE: To further clarify its utility, we investigated for effects of comorbid allergies and AD treatment on serum SCCA levels. METHODS: Volunteers <18 years old were recruited through our website. Their allergic status was elucidated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We also recruited pediatric patients who were hospitalized because of severe AD. The serum levels of SCCA1 and SCCA2 were measured by enzyme-linked immunosorbent assays. In the severe AD patients, the levels of thymus and activation-regulated chemokine (TARC), SCCA1, and SCCA2 were measured before and after hospitalization. The severity of AD was assessed using the severity scoring of atopic dermatitis (SCORAD). RESULTS: A total of 576 participants (547 volunteers and 29 patients) were enrolled in the study. The levels of SCCA1 and SCCA2 were significantly higher in volunteers with mild AD and patients with severe AD than in healthy volunteers without allergic diseases. The levels were not elevated in those who had mild bronchial asthma or allergic rhinitis without AD. TARC, SCCA1, and SCCA2 were decreased during the treatment in severe AD patients, reflecting clinical improvement in response to treatment. Linear regression analysis for predicting a decrease in the SCORAD index showed R2 values of 0.16, 0.38, and 0.48 for TARC, SCCA1, and SCCA2, respectively. CONCLUSION: SCCAs, especially SCCA2, are sensitive biomarkers for detecting AD in children and adolescents and for assessing the severity and response to treatment of severe AD.

Combination of Near-Infrared Photoimmunotherapy Using Trastuzumab and Small Protein Mimetic for HER2-Positive Breast Cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy based on a monoclonal antibody conjugated to a photosensitizer (IR700Dye) that is activated by near-infrared light irradiation. We previously reported on the use of NIR-PIT with a small protein mimetic, the Affibody molecule (6-7 kDa), instead of a monoclonal antibody. In this study, we investigated a combination of NIR-PIT for HER2-positive breast cancer cells (SK-BR3, MDA-MB361, and JIMT1) with HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate. HER2 Affibody and trastuzumab target different epitopes of the HER2 protein and do not compete. In vitro, the combination of NIR-PIT using both HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate induced necrotic cell death of HER2-positive breast cancer cells without damage to HER2-negative breast cancer cells (MCF7). It was more efficient than NIR-PIT using either the HER2 Affibody-IR700Dye conjugate alone or the trastuzumab-IR700Dye conjugate alone. Additionally, this combination of NIR-PIT was significantly effective against HER2 low-expressing cancer cells, trastuzumab-resistant cells (JIMT1), and brain metastatic cells of breast cancer (MDA-MB361). Furthermore, in vivo imaging exhibited the strong fluorescence intensity of both HER2 Affibody-IR700Dye conjugates and trastuzumab-Alexa488 conjugates in HER2-positive tumor, indicating that both HER2 Affibody and trastuzumab specifically bind to HER2-positive tumors without competing with each other. In conclusion, the combination of NIR-PIT using both HER2 Affibody and trastuzumab expands the targeting scope of NIR-PIT for HER2-positive breast cancer.

Pathological Roles and Clinical Usefulness of Periostin in Type 2 Inflammation and Pulmonary Fibrosis.

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-ß, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.

Association of serum monomeric periostin level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

BACKGROUND: The associations of serum monomeric periostin (M-PN) level and serial change in M-PN with acute exacerbation of chronic fibrosing interstitial pneumonia (AE-FIP) are unclear. METHODS: We prospectively measured serum M-PN level from onset of AE to day 14 in 37 patients with AE-FIP and evaluated its association with outcome. To determine localization of periostin expression, immunohistochemical staining of pathological lung tissue from autopsy cases of AE-IPF was evaluated. RESULTS: Data from 37 AE-FIP patients (28 men; age 73.9±7.8 years) were analyzed. With healthy controls as reference, serum M-PN level was significantly higher in patients with AE-FIP (P=0.02) but not in those with stable idiopathic pulmonary fibrosis (P=1.00). M-PN was significantly lower on day 7 than at AE-FIP onset in survivors [14.6±5.8 vs. 9.3±2.8 ng/mL (onset to day 7: P<0.001)] but not in non-survivors [14.6±5.1 vs. 13.2±5.1 ng/mL (onset to day 7: P=0.07)]. In analysis using a cut-off value for serial change in M-PN (ΔM-PN), 3-month survival was 92.3% in the ΔM-PN decrease group and 36% in the ΔM-PN increase group (P=0.002). In multivariate analysis, 3-month survival tended to be associated with high ΔM-PN (OR: 12.4, 95% CI: 0.82-187.9, P=0.069). CONCLUSIONS: Serial change in serum M-PN level may be a prognostic indicator of AE-FIP.

CBCT imaging and histopathological characteristics of osteoradionecrosis and medication-related osteonecrosis of the jaw.

PURPOSE: The purpose of this study was to evaluate the cone-beam computed tomographic (CBCT) imaging and histopathological characteristics of osteoradionecrosis (ORN) and medication-related osteonecrosis of the jaw (MRONJ). MATERIALS AND METHODS: Ten surgical specimens from segmental mandibulectomy (3 ORN and 7 MRONJ) were analyzed using CBCT. The CBCT parameters were as follows: high-resolution mode (tube voltage, 90.0 kV; tube current, 4.00 mA; rotation time, 16.8 s; field of view, 56 mm×56 mm; thickness, 0.099 mm). Histopathological characteristics were evaluated using histological slides of the surgical specimens. The Pearson chi-square test was used to compare ORN and MRONJ in terms of CBCT findings (internal texture, sequestrum, periosteal reaction and cortical perforation) and histopathological characteristics (necrotic bone, inflammatory cells, reactive bone formation, bacteria, Actinomyces, and osteoclasts). A P value less than 0.05 was considered to indicate statistical significance. RESULTS: MRONJ showed periosteal reaction on CBCT more frequently than ORN (7 of 7 [100%] vs. 0 of 3 [0%], P<0.05). Regarding histopathological characteristics, MRONJ showed osteoclasts more frequently than ORN (6 of 7 [85.7%] vs. 0 of 3 [0%], P<0.05). CONCLUSION: This study evaluated the CBCT imaging and histopathological characteristics of ORN and MRONJ, and the findings suggest that CBCT could be useful for the evaluation of ORN and MRONJ.

Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation.

BACKGROUND: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. OBJECTIVE: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. METHODS: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. RESULTS: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). CONCLUSION: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring.

High serum free IL-18 is associated with decreased omalizumab efficacy: findings from a 2-year omalizumab treatment study.

OBJECTIVE: Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment. METHODS: Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined. RESULTS: Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios. CONCLUSIONS: High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

Expert artificial intelligence-based natural language processing characterises childhood asthma.

INTRODUCTION: The lack of effective, consistent, reproducible and efficient asthma ascertainment methods results in inconsistent asthma cohorts and study results for clinical trials or other studies. We aimed to assess whether application of expert artificial intelligence (AI)-based natural language processing (NLP) algorithms for two existing asthma criteria to electronic health records of a paediatric population systematically identifies childhood asthma and its subgroups with distinctive characteristics. METHODS: Using the 1997-2007 Olmsted County Birth Cohort, we applied validated NLP algorithms for Predetermined Asthma Criteria (NLP-PAC) as well as Asthma Predictive Index (NLP-API). We categorised subjects into four groups (both criteria positive (NLP-PAC+/NLP-API+); PAC positive only (NLP-PAC+ only); API positive only (NLP-API+ only); and both criteria negative (NLP-PAC-/NLP-API-)) and characterised them. Results were replicated in unsupervised cluster analysis for asthmatics and a random sample of 300 children using laboratory and pulmonary function tests (PFTs). RESULTS: Of the 8196 subjects (51% male, 80% white), we identified 1614 (20%), NLP-PAC+/NLP-API+; 954 (12%), NLP-PAC+ only; 105 (1%), NLP-API+ only; and 5523 (67%), NLP-PAC-/NLP-API-. Asthmatic children classified as NLP-PAC+/NLP-API+ showed earlier onset asthma, more Th2-high profile, poorer lung function, higher asthma exacerbation and higher risk of asthma-associated comorbidities compared with other groups. These results were consistent with those based on unsupervised cluster analysis and lab and PFT data of a random sample of study subjects. CONCLUSION: Expert AI-based NLP algorithms for two asthma criteria systematically identify childhood asthma with distinctive characteristics. This approach may improve precision, reproducibility, consistency and efficiency of large-scale clinical studies for asthma and enable population management.