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Objectives: No detailed country-specific cross-sectional studies have been reported on endoscopic plastic surgery. For the first time, the Japan Society of Plastic and Reconstructive Surgery conducted a nationwide survey to ascertain the status of endoscopic procedures in plastic surgery in Japan. This article discusses the current situation based on this survey findings. Methods: A questionnaire survey was conducted among 566 Japan Society of Plastic and Reconstructive Surgery-certified training facilities regarding the status of endoscopic plastic surgery procedures completed between January 2020 and December 2021. Results: Of the 143 institutions, 33 conducted endoscopic plastic surgery operations during the period, for a total of 753 procedures. Two hundred sixty-two procedures were conducted in the craniomaxillofacial region at 19 institutions and 491 in the extremities and trunk region at 19 institutions. Five intraoperative accidents were recorded, but no cases were moved to traditional surgery based on intraoperative choices. Sixteen postoperative problems were reported, but there were no reports of fatalities. Conclusions: The number of endoscopic plastic surgery cases is anticipated to rise, and this nationwide survey will contribute to this by offering useful data and insights.

Abstract Background Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population. Methods This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs. Discussion This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction. Trial registration UMIN-CTR Clinical Trial Registry (UMIN000040678).

Spinal cord injury (SCI) has limited treatment options for regaining function. Adipose-derived stem cells (ADSCs) show promise owing to their ability to differentiate into multiple cell types, promote nerve cell survival, and modulate inflammation. This review explores ADSC therapy for SCI, focusing on its potential for improving function, preclinical and early clinical trial progress, challenges, and future directions.Preclinical studies have demonstrated ADSC transplantation's effectiveness in promoting functional recovery, reducing cavity formation, and enhancing nerve regrowth and myelin repair. To improve ADSC efficacy, strategies including genetic modification and combination with rehabilitation are being explored. Early clinical trials have shown safety and feasibility, with some suggesting motor and sensory function improvements.Challenges remain for clinical translation, including optimizing cell survival and delivery, determining dosing, addressing tumor formation risks, and establishing standardized protocols. Future research should focus on overcoming these challenges and exploring the potential for combining ADSC therapy with other treatments, including rehabilitation and medication.

Chronic wounds represent a significant global burden, afflicting millions with debilitating complications. Despite standard care, impaired healing persists due to factors like persistent inflammation and impaired tissue regeneration. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) offer an innovative regenerative medicine approach, delivering stem cell-derived therapeutic cargo in engineered nanoscale delivery systems. This review examines pioneering bioengineering strategies to engineer MSC-EVs into precision nanotherapeutics for chronic wounds. Emerging technologies like CRISPR gene editing, microfluidic manufacturing, and biomimetic delivery systems are highlighted for their potential to enhance MSC-EV targeting, optimize therapeutic cargo enrichment, and ensure consistent clinical-grade production. However, key hurdles remain, including batch variability, rigorous safety assessment for potential tumorigenicity, immunogenicity, and biodistribution profiling. Crucially, collaborative frameworks harmonizing regulatory science with bioengineering and patient advocacy hold the key to expediting global clinical translation. By overcoming these challenges, engineered MSC-EVs could catalyze a new era of off-the-shelf regenerative therapies, restoring hope and healing for millions afflicted by non-healing wounds.

Abstract This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Summary:. Superior orbital fissure syndrome (SOFS) is a rare complication of craniofacial fracture, caused by damage to cranial nerves Ⅲ, Ⅳ, Ⅴ, and Ⅵ, which typically is associated with ophthalmoplegia, blepharoptosis, pupil dilatation and fixation, and upper eyelid and forehead hypesthesia. However, we here describe a very unusual case of craniofacial fracture with SOFS in the absence of pupil symptoms, involving a patient who was injured when he fell while riding his bicycle. Upon medical examination, we observed mild blepharoptosis and ophthalmoplegia of the right eye without pupillary symptoms. Computed tomography (CT) revealed basal skull and zygomatic fractures. After the patient had been treated conservatively for his skull base fracture, facial bone reduction was performed at our hospital. Because ophthalmoplegia and blepharoptosis remained after the surgery, we checked the preoperative CT images again and discovered stenosis of the superior orbital fissure. Postoperative CT revealed a widening of the superior orbital fissure after the facial bone reduction, and therefore, the patient was given steroid treatment without additional surgery. At 6 months postoperatively, the cranial nerves had completely recovered. Our finding emphasizes that, in contrast to common theory, trauma-induced SOFS can result in pupil-sparing oculomotor nerve palsy.

The shortcomings of qualitative visual assessment have led to the development of computer-based tools to characterise and quantify disease on high-resolution computed tomography (HRCT) in patients with interstitial lung diseases (ILDs). Quantitative CT (QCT) software enables quantification of patterns on HRCT with results that are objective, reproducible, sensitive to change and predictive of disease progression. Applications developed to provide a diagnosis or pattern classification are mainly based on artificial intelligence. Deep learning, which identifies patterns in high-dimensional data and maps them to segmentations or outcomes, can be used to identify the imaging patterns that most accurately predict disease progression. Optimisation of QCT software will require the implementation of protocol standards to generate data of sufficient quality for use in computerised applications and the identification of diagnostic, imaging and physiological features that are robustly associated with mortality for use as anchors in the development of algorithms. Consortia such as the Open Source Imaging Consortium have a key role to play in the collation of imaging and clinical data that can be used to identify digital imaging biomarkers that inform diagnosis, prognosis and response to therapy.

Abstract While high-level evidence is lacking, numerous retrospective studies have depicted the value of supplemental oxygen in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, and its use should be encouraged where necessary. The clinical course and survival of patients with IPF who have been introduced to oxygen therapy is still not fully understood. The objective of this study was to clarify overall survival, factors associated with prognosis, and causes of death in IPF patients after the start of oxygen therapy. This is a prospective cohort multicenter study, enrolling patients with IPF who started oxygen therapy at 19 hospitals with expertise in interstitial lung disease. Baseline clinical data at the start of oxygen therapy and 3-year follow-up data including death and cause of death were assessed. Factors associated with prognosis were analyzed using univariable and multivariable analyses. One hundred forty-seven eligible patients, of whom 86 (59%) were prescribed ambulatory oxygen therapy and 61 (41%) were prescribed long-term oxygen therapy, were recruited. Of them, 111 died (76%) during a median follow-up of 479 days. The median survival from the start of oxygen therapy was 537 ± 74 days. In the univariable analysis, low body mass index (BMI), low forced vital capacity (FVC), low diffusion capacity (DLCO), resting hypoxemia, short 6 min-walk distance, and high COPD assessment test (CAT) score were significantly associated with poor prognosis. Multivariable analysis revealed low BMI, low FVC, low DLCO, low minimum SpO2 on 6MWT, and high CAT score were independent factors for poor prognosis. The overall survival of IPF patients after starting oxygen therapy is about 1.5 years. In addition to pulmonary function tests, 6MWT and patient reported outcomes can be used to predict prognosis more accurately. Clinical Trial Registration: UMIN000009322.

Objectives: Until 1999 at our hospital, primary cleft lip repair was performed by the straight-line method and external rhinoplasty was performed by the inverted trapezoidal suture method with bilateral reverse-U incisions for children with cleft lip and palate. Subsequently, repeated surgical corrections of the external nasal morphology became necessary during the growth period, often with unsatisfactory results because repeated external rhinoplasty results in a stronger scar contracture. From 2000 to 2004, we performed external rhinoplasty after patients had stopped growing; however, delaying surgery created a psychological burden for patients. Therefore, since 2005, we have focused on improving alar base ptosis and forming the nostril sill during the primary surgery. This study was performed to subjectively and objectively evaluate whether the current surgical method or the earlier technique produces a better treatment outcome. Methods: We subjectively and objectively evaluated alar base asymmetry after primary cleft lip repair but before bone grafting for alveolar cleft repair. For the objective evaluation, we measured the angle of alar base ptosis in frontal view photographs taken at the age of 6 or 7 years in patients who underwent repair before 1999 (Group A) and after 2005 (Group B). Results: The median angle was 2.75° in Group A and 1.50° in Group B, demonstrating a significant difference (P=0.04). Conclusions: The current surgical method, which reflects our focus on improving alar base ptosis and forming the nostril sill, subjectively and objectively improved the external nasal morphology.

Osteoclasts are derived from circulating myeloid cells to mediate bone repair, maintenance and remodeling. Here, the authors show that the lung also recruits and reprograms monocytes and alveolar macrophages into osteoclast-like cells to clear pathogenic particles from the airspace.

Plain language summary Patients with worsening fibrosis (scarring) of the lungs may lose weight. This study suggests that the course of disease may be worse in patients who lose weight. Measures to prevent weight loss may be needed in these patients.

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. Methods: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1–3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal–Wallis, and chi-square tests were used to compare cluster differences. Results: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. Conclusions: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)

Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as “stem cell,” “alopecia,” “hair loss,” “Androgenetic alopecia,” “male-pattern hair loss,” “female-pattern hair loss,” “regenerative hair growth,” “cell therapy,” “mesenchymal stem cells,” “MSC-derived extracellular vesicles,” “MSC-derived exosomes,” and “platelet-rich plasma” and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.

Abstract Background Acute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). AE-IPF patients require optimal palliative care; however, the real-world clinical situations are poorly understood. We aimed to survey the palliative care received by AE-IPF patients, especially with respect to opioid use for dyspnea and the end-of-life discussions (EOLd). Methods Self-administered questionnaires were dispatched to 3423 of the certified pulmonary physicians in Japan. They were asked to report a care report form of one patient each with AE-IPF who died very recently about opioid use for dyspnea and EOLd. We further explored the factors associated with the early use of opioids for dyspnea. Results Among the 3423 physicians, 1226 (35.8%) returned the questionnaire with the report forms of 539 AE-IPF patients. Of 539 AE-IPF patients, 361 (67.0%) received opioids for dyspnea. Of the 361 patients, 72 (20.0%) received opioids during the initial treatment with an intention of recovery (early use), while 289 (80.0%) did when the recovery was deemed impossible. EOLd was held before the onset of AE in 124 patients (23.0%); however, the majority of patients had EOLd after the admission for AE-IPF. EOLd before the onset of AE was significantly associated with the early use of opioids. Conclusion In terminally ill AE-IPF patients, opioids are usually administered when the recovery is deemed impossible, and EOLd are rarely held before the onset of AE. Further studies are warranted on the efficacy of opioids for dyspnea and the appropriate timing of EOLd.

Objectives: Breast reconstruction using synthetic materials has increased rapidly in Japan since July 2013, when national health insurance began covering the procedure. Although synthetic material-based reconstruction of other body parts has not resulted in wounds with complications, this significant advantage is overshadowed by a risk of complications, including infection, following breast reconstruction. We therefore reviewed breast-reconstruction patients who experienced infection after implantation of synthetic materials and the countermeasures we used to address the problem. Methods: From July 2013 through December 2019, our department performed primary breast reconstructions using tissue expanders (TEs) in 106 patients and secondary breast reconstructions in 39 patients. We retrospectively reviewed these 145 patients in terms of their age, body mass index, timing of the reconstruction, presence/absence of both chemotherapy and radiation therapy before and after surgery, presence/absence of postoperative wound complications, and presence/absence of atopic dermatitis. We then evaluated whether these factors put patients at risk for postoperative TE infection. Results: Among the 145 patients who underwent reconstruction with TE, 3 (2.0%) were diagnosed with a postoperative TE infection. Our review revealed that necrosis of the skin around the surgical wound (P=0.004) and atopic dermatitis (P=0.041) were risk factors for TE infection. Conclusions: Infection following breast reconstruction with synthetic materials is a serious complication. Thus, patients requiring this surgery deserve optimal perioperative management. For those with known risk factors, a more appropriate surgical approach—e.g., using autologous tissue instead of a synthetic material—could be considered.

Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.

Background. Pulmonary sarcoidosis predominantly affects the upper lung zones but sometimes affects the lower lung zones. We hypothesised that patients with lower lung zone-dominant sarcoidosis had lower baseline forced vital capacity, progressive restrictive lung function decline, and higher long-term mortality. Methods. We retrospectively reviewed clinical data including the pulmonary function tests of 108 consecutive patients with pulmonary sarcoidosis pathologically confirmed by lung and/or mediastinal lymph node biopsy from 2004 to 2014 from our database. Results. Eleven patients (10.2%) with lower lung zone-dominant sarcoidosis were compared with 97 patients with nonlower lung zone-dominant sarcoidosis. The median age of the patients with lower dominance was significantly older (71 vs. 56, p=0.0005). The patient with lower dominance had a significantly lower baseline percent forced vital capacity (FVC) (96.0% vs. 103%, p=0.022). The annual change in FVC was −112 mL in those with lower dominance vs. 0 mL in nonlower dominance (p=0.0033). Fatal acute deterioration was observed in three patients (27%) in the lower dominant group. Overall survival in the lower dominant group was significantly worse. Conclusions. Patients with lower lung zone-dominant sarcoidosis had an older age and lower baseline FVC with disease progression and acute deterioration associated with higher long-term mortality.

Abstract Background Patients with lymphangioleiomyomatosis (LAM) frequently experience pneumothorax. Although sirolimus is the standard therapy for LAM, its effect on pneumothorax is controversial. Recently, total pleural covering (TPC) and modified TPC (mTPC) were introduced as surgical treatment options for pneumothorax for patients with LAM. However, the effect of sirolimus on the recurrence of pneumothorax in patients who underwent the treatments is still uncertain. We hypothesized that some clinical factors including sirolimus treatment could predict postoperative recurrence of pneumothorax. In order to clarify this hypothesis, we retrospectively analyzed the clinical data from 18 consecutive patients with LAM who underwent 24 surgical pleural covering of entire lung (SPC) as 17 TPC and 7 mTPC against pneumothoraces from surgical database between January 2005 and January 2019, and we determined the predictors of postoperative recurrence. Results Of the 24 surgeries of SPC, 14 surgeries (58.3%) had a history of two or more ipsilateral pneumothoraces, and 11 surgeries (45.8%) had a history of ipsilateral pleural procedures before SPC. Sixteen surgeries (66.6%) in 12 patients received treatment of sirolimus after SPC (sirolimus group). With a median follow-up time of 69.0 months after SPC, four surgeries (16.6%) in three patients had a postoperative recurrence, and the 5-year recurrence-free survival (RFS) after SPC was 82.9%. In patients with postoperative recurrence, serum level of vascular endothelial growth factors D was significantly higher than that in those with non-recurrence (3260.5 vs. 892.7 pg/mL, p = 0.02), and the rate of sirolimus treatment in the recurrence group was significantly lower than that in the no-recurrence group (0 vs. 80%, p = 0.006). The log-rank test showed that the RFS of the sirolimus group (sirolimus use after SPC) was significantly better than that of the non-sirolimus group (p = 0.001), and no significant difference was observed for other factors. Conclusion We first reported sirolimus might effectively suppress the recurrence of pneumothoraces in LAM patients who received SPC. Sirolimus induction after SPC (TPC or mTPC) might be a feasible option for frequent pneumothorax in LAM.

Background Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO.Methods We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO.Results Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22–56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted 20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.

Rheumatoid arthritis (RA) is a highly prevalent, chronic, and progressive autoimmune disorder primarily affecting joints and muscles. The associated inflammation, pain, and motor restriction negatively impact patient quality of life (QOL) and can even contribute to premature mortality. Further, conventional treatments such as antiinflammatory drugs are only symptomatic. Substantial progress has been made on elucidating the etiopathology of overt RA, in particular the contributions of innate and adaptive immune system dysfunction to chronic inflammation. Although the precise mechanisms underlying onset and progression remain elusive, the discovery of new drug targets, early diagnosis, and new targeted treatments have greatly improved the prognosis and QOL of patients with RA. However, a sizable proportion of patients develop severe adverse effects, exhibit poor responses, or cannot tolerate long-term use of these drugs, necessitating more effective and safer therapeutic alternatives. Mounting preclinical and clinical evidence suggests that the transplantation of multipotent adult stem cells such as mesenchymal stromal/stem cells is a safe and effective treatment strategy for controlling chronic inflammation and promoting tissue regeneration in patients with intractable diseases, including RA. This review describes the current status of MSC-based therapies for RA as well as the opportunities and challenges to broader clinical application.

Abstract Background Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP. Subjects and methods BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles. Results In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p

Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Objective: This study aimed to explore the predictors of morphine efficacy in the alleviation of dyspnea in COPD. Background: Dyspnea is prevalent in patients with chronic obstructive pulmonary disease (COPD) and often persists despite conventional treatment. Methods: A secondary analysis of a multi-institutional prospective before?after study was conducted focusing on morphine use for alleviating dyspnea in COPD patients. Subjects included COPD patients with dyspnea at seven hospitals in Japan. Patients received 12 mg/day of oral morphine (or 8 mg/day if they had low body weight or renal impairment). Univariate and multivariate logistic regression analyses were performed with numerical rating scale (NRS) score of the current dyspnea intensity in the evening of day 0, Eastern Cooperative Oncology Group Performance Status (ECOG PS; ?2 or ?3), age, and partial arterial pressure of carbon dioxide (PaCO2) as independent factors; an improvement of ?1 in the evening NRS score of dyspnea from day 0 to 2 was the dependent factor. Results: Thirty-five patients were enrolled in this study between October 2014 and January 2018. Excluding one patient who did not receive the treatment, data from 34 patients were analyzed. In the multivariate analysis, lower PaCO2 was significantly associated with morphine efficacy for alleviating dyspnea (odds ratio [OR] 0.862, 95% confidence interval [CI] 0.747?0.994), whereas the NRS of dyspnea intensity on day 0 (OR 1.426, 95% CI 0.836?2.433), ECOG PS (OR 4.561, 95% CI 0.477?43.565), and patients' age (OR 0.986, 95% CI 0.874?1.114) were not. Discussion: Morphine can potentially alleviate dyspnea in COPD patients with lower PaCO2. Trial registration: UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm)

We report 2 case-patients in Japan with Mycobacterium shigaense pulmonary infections. One patient was given aggressive treatment and the other conservative treatment, according to distinctive radiologic evidence. A close phylogenetic relationship based on whole-genome sequencing was found between strain from the conservatively treated patient and a reference strain of cutaneous origin.

Abstract Background Anti-granulocyte–macrophage colony-stimulating factor autoantibody (GMAb) has been recognized as a diagnostic biomarker for autoimmune pulmonary alveolar proteinosis (aPAP). The aims of this study were to know the incidence of increased level of serum GMAb in granulomatous lung diseases (sarcoidosis and hypersensitivity pneumonitis [HP]) and to clarify the role of GMAb. Consecutive individuals diagnosed with sarcoidosis (n = 92) and HP (n = 45) at National Hospital Organization Kinki-Chuo Chest Medical Center were retrospectively analyzed. We measured serum GMAb levels at the diagnosis. Cut-off values of GMAb discriminating aPAP (n = 110) from healthy controls (n = 31) were determined by receiver operating characteristic (ROC) curve analysis. We compared the clinical features of sarcoidosis and HP patients with GMAb levels above the cut-off value (“Elevated-GMAb”) with those of patients whose GMAb levels below the cut-off value (“Low-GMAb”). Radiological and pathological findings in elevated-GMAb patients were re-evaluated to elucidate the role of GMAb in granulomatous lung diseases. Results Analysis of ROC indicated a sensitivity and specificity of 100% at GMAb level of 3.33 μg/mL for discriminating aPAP from healthy controls (area under curve = 1.000, p

Background: Mycobacteroides abscessus complex (MABC) exhibits smooth morphotypes, expressing glycopeptidolipid (GPL), and rough morphotypes, expressing diminished GPL, on the MABC cell wall. Few reports have focused on the relationship between anti-GPL-core immunoglobulin A (IgA) antibody and colony morphology in MABC lung disease. Methods: This study aimed to test GPL core antigen in patients with MABC lung disease to investigate the relationship between coinfection/contamination in other nontuberculous mycobacteria species and colony morphology variant in MABC isolates. Patients with MABC lung disease and contamination diagnosed between 2012 and 2017 at our hospital were enrolled retrospectively. Results: Of the assessed patients, 43 patients with MABC lung disease and 13 with MABC contamination were included. There was a significant difference in anti-GPL-core IgA antibody levels between them (P = 0.02). Forty-three patients with MABC lung disease were divided into two groups as positive and negative antibodies groups. A significant increase in the positive anti-GPL-core IgA antibody was observed in coexistence with both Mycobacterium avium complex (MAC) (P = 0.02) and the isolate of the smooth variant (P = 0.03) in MABC.Conclusions: Anti-GPL-core IgA antibodies in patients with MABC are greatly influenced by MAC coexistence, and colony morphology variant of the MABC isolate.

Background. We have previously analysed serum autoantibody levels in patients with idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), and healthy controls and identified the autoantibody against anti-myxovirus resistance protein-1 (MX1) to be a specific autoantibody in iNSIP. We found that a higher anti-MX1 autoantibody level was a significant predictor of a good prognosis in patients with non-IPF idiopathic interstitial pneumonias. In this retrospective study, we sought to clarify the prognostic significance of the anti-MX1 autoantibody in IPF. Methods. We measured anti-MX1 immunoglobulin (Ig) G, IgA, and IgM autoantibody levels by enzyme-linked immunosorbent assay in serum collected at the time of diagnosis from 71 patients with IPF diagnosed according to the 2018 IPF guideline. The gender-age-physiology (GAP) index was calculated in each case. Results. The study population (59 men and 12 women) had a median age of 67 years. Serum anti-MX1 IgG and IgA autoantibody levels correlated positively with GAP stage (p

The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis.

Background Acute exacerbation (AE) has been reported to herald a poor prognosis in idiopathic pulmonary fibrosis and is now thought to do so in idiopathic interstitial pneumonias (IIPs). However, the pathophysiology of AE-IIPs is not sufficiently understood. In our previously reported SETUP trial, we found better survival in patients with AE-IIPs treated with corticosteroids and thrombomodulin than in those treated with corticosteroids alone. In that study, we collected serum samples to evaluate changes in cytokine levels and retrospectively examined the prognostic significance and pathophysiological role of serum cytokines in patients with AE-IIPs.Methods This study included 28 patients from the SETUP trial for whom serial serum samples had been prospectively obtained. AE-IIPs were diagnosed using the Japanese Respiratory Society criteria. All patients were treated with intravenous thrombomodulin and corticosteroids from 2014 to 2016. Serum levels of 27 cytokines were measured using Bio-Plex. The high-resolution CT pattern at the time of diagnosis of AE was classified as diffuse or non-diffuse.Results Univariate analysis revealed that higher serum levels of interleukin (IL)-2, IL-7, IL-9, IL-12, IL13, basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor, interferon-γ inducible protein-10, platelet-derived growth factor and regulated on activation, normal T cell expressed and secreted (RANTES) at AE were significant predictors of 90-day survival. The HRCT pattern was also a significant clinical predictor of 90-day survival. Multivariate analysis with stepwise selection identified a higher serum RANTES level at AE to be a significant predictor of 90-day survival, including after adjustment for HRCT pattern. Multivariate analysis with stepwise selection suggested that a marked increase in the serum IL-10 level on day 8 could predict 90-day mortality.Conclusions A higher serum RANTES level at AE the time of diagnosis predicted a good survival outcome, and an elevated serum IL-10 level on day 8 predicted a poor survival outcome.Trial registration number UMIN000014969.

Novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. In particular, the hypersensitivity pneumonitis (HP) pattern of DRP has been increasingly recognized due to development of new therapeutic strategies, such as immunotherapy. However, literature describing detailed clinical cases is still lacking.Herein, we report three cases of DRP with typical HP radiographic pattern. These patients were treated with different drugs, namely nano albumin-bound (nab)-paclitaxel, everolimus, or nivolumab, but had common clinical features, including a good prognosis.

Background. Hemosiderin-laden macrophages (HLMs) have been identified in the bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF). This retrospective study examined the ability of HLMs in BALF to predict the acute exacerbation (AE) of chronic idiopathic interstitial pneumonias (IIPs). Methods. Two hundred and twenty-one patients with IIP diagnosed by bronchoscopy were enrolled in the study (IPF, n = 87; IIPs other than IPF, n = 134). Giemsa stain was used to detect HLMs in BALF specimens. Prussian blue stain was used to quantify HLMs in BALF, and a hemosiderin score (HS) was given to the specimens containing HLMs. Results. Twenty-four patients had a positive HS (range: 7‒132). The receiver-operating characteristic curve analysis identified the cutoff HS value for predicting the AE of IIPs to be 61.5. Seven cases had a higher HS (≥61.5) and 214 had a lower HS. AE occurred significantly earlier in the higher HS group (4/7 cases) than in the lower HS group (41/214 cases) during a median observation period of 1239 days (log-rank test, p = 0.026). Multivariate Cox proportional hazard regression analysis showed that a higher HS was a significant predictor of AE in addition to IPF, percent predicted forced vital capacity, and modified Medical Research Council score. The C-statistics for the prediction of AE did not significantly improve by all the above parameters with HS as compared without HS. Conclusions. A higher HS was a significant predictor of AE in IIPs but did not significantly improve the predictive ability of other parameters.

Background Acute exacerbation (AE) in idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias (IIPs) are poor prognostic events although they are usually treated with conventional therapy with corticosteroids and immunosuppressants. Previously, we demonstrated the safety and efficacy of recombinant human soluble thrombomodulin (rhTM) for AE-IIP in the SETUP trial. Here, we aimed to clarify the efficacy of rhTM for poor-prognosis cases of AE-IIP.Methods In this study, we included 85 patients, in whom fibrin degradation product (FDP)/d-dimer was evaluated at AE, from the 100 patients in the SETUP trial. The AE-IIP patients in the rhTM arm (n=39) were diagnosed using the Japanese criteria from 2014 to 2016 and treated with intravenous rhTM for 6 days in addition to the conventional therapy. The AE-IIP patients in the control arm (n=46) were treated with the conventional therapy without rhTM between 2011 and 2013. The subjects were classified into higher and lower FDP/d-dimer groups based on the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation scoring system. A multivariate Cox proportional hazard regression analysis with stepwise selection was performed to reveal the prognostic factors of AE-IIP.Results We developed a prognostic scoring system using two significant prognostic factors, higher FDP/d-dimer at AE and prednisolone therapy before AE, with 3 and 2 points assigned for each parameter, respectively. The prognostic scores ranged from 0 to 5. Survival of AE-IIP patients with a prognostic score=0 was significantly better than that of patients with score ≥2. Survival was improved with the rhTM therapy (p

Abstract Benralizumab is an interleukin‐5 (IL‐5) receptor α‐directed cytolytic monoclonal antibody that reduces rapid and nearly complete depletion of eosinophils by enhancing antibody‐dependent cell‐mediated cytotoxicity. The depletion of eosinophilic inflammation is expected to reduce mucus hypersecretion and mucoid impaction. A 75‐year‐old non‐smoking female had been treated for uncontrolled bronchial asthma with multiple drugs. Treatment with benralizumab was initiated after the asthma attack; however, four months later, she developed massive atelectasis in the left lung leading to the tracheal deviation, to the extent that nasal high‐flow therapy was required. The laboratory data showed elevated neutrophil count, whereas blood eosinophils were almost completely depleted. The thick mucus was removed by bronchofiberscopy and the atelectasis was completely resolved. No exacerbation has been observed for nine months after discontinuation of benralizumab and initiation of erythromycin. This is the first documented case that developed atelectasis by mucoid impaction during treatment with anti‐IL‐5 receptor antibody.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort.Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ

Background Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

Abstract Drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of hypersensitivity drug reaction. Here, we report the case of a 78‐year‐old man who presented with a rash, fever, dry cough, and swollen parotid glands who had been prescribed clopidogrel for one year. Computed tomography showed consolidation and interlobular septal thickening with enlarged mediastinal lymph nodes. As oxygen therapy was ineffective, the patient was intubated and bronchoalveolar lavage cellular analysis showed an increase in eosinophils. Clopidogrel was discontinued and the parotid biopsy revealed periductal lymphocytic infiltration. High doses of corticosteroids were administered, and his symptoms improved. However, his symptoms recurred when clopidogrel was restarted. Skin biopsy showed mild lymphocytic infiltration in the upper dermis with vasculitis, and Epstein–Barr virus (EBV) DNA was detected in his blood and lymph node tissue. On the basis of the pathology and disease manifestations, the patient was diagnosed with DRESS. Once clopidogrel treatment ceased, his symptoms never recurred.

A 60-year-old man was admitted for ground glass opacity in the lower lung field and mediastinal lymphadenopathy. Blood tests revealed elevated serum IgM levels, and the urine test detected Bence-Jones protein. Surgical biopsy from the mediastinal lymph node and lung showed small lymphocytes and plasma cells between follicles, and AL kappa amyloid deposition. Genetic examination detected MYD88 L265P mutation. Our diagnosis was lymphoplasmacytic lymphoma (LPL), involving the mediastinum and the lung, followed by amyloidosis. Mutation analysis, in addition to conventional histological evaluation, was useful for a precise diagnosis.

Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

Abstract Background Lymphangioleiomyomatosis (LAM) and connective tissue diseases (CTDs) occur more frequently among women than men. We investigated the frequency of comorbid CTD and positive serum autoantibody findings in patients with LAM. Methods A total of 152 patients with LAM were prospectively and consecutively registered in the National Hospital Organization Kinki-Chuo Chest Medical Centre cohort. The clinical data were retrospectively analysed, and patients were categorised into the following three groups: a CTD group, a non-CTD-autoantibody-positive group, and a non-CTD-autoantibody-negative group. Results All patients were women. We identified five patients with comorbid CTDs (3.3%): Sjögren’s syndrome (SjS) (n = 3), systemic lupus erythematosus (n = 1), and rheumatoid arthritis (n = 1). One patient with SjS was also diagnosed with antiphospholipid antibody syndrome. The positive rate for anti nuclear antibody was 31.5% and 6.9% at dilution of 1:40 or higher, and those of 1:160 or higher, respectively. It tended to be lower in patients with LAM than in healthy women. The positive rate for anti-SS-A and anti-SS-B antibody was 7.9% and 1.8%, respectively. No significant differences in age, type of LAM, smoking status, serum vascular endothelial growth factor D level, respiratory function, treatment, or prognosis were observed among the three groups. Conclusions Comorbid CTDs, especially SjS, in LAM patients should be considered.

In 2016, disseminated tuberculosis caused by Mycobacterium caprae was diagnosed in a captive Borneo elephant in Japan. The bacterium was initially identified from clinical isolates. An isolate collected during a relapse showed isoniazid monoresistance and a codon 315 katG mutation.

Purpose: Never-smokers account for a large proportion of subjects in general population studies on nontuberculous mycobacteria lung disease (NTM-LD). However, the influence of NTM infection on the lung function of never-smokers has not yet been evaluated. The aim of this study was to determine how NTM-LD impairs the lung function in never-smokers, and whether there are an association between successful NTM-LD treatment in radiologic outcomes and improvement in lung function of never-smokers with NTM-LD or not. Methods: We performed a retrospective study of patients (1) who have never smoked during their lifetime; (2) with at least two respiratory specimens from sputum, one bronchial washing sample, or one lung tissue that were culture positive for the same NTM species; and (3) who underwent at least two pulmonary function tests. We enrolled healthy never-smokers as the control group. Results: In 22 never-smokers with NTM-LD, the median forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) at baseline was lower than those in 9 healthy never-smokers [1800 vs 2080 ml (p = 0.23) and 2230 vs 2620 ml (p = 0.06)], respectively. The median change in FEV1 in never-smokers with NTM-LD was lower than that in healthy never-smokers [−70 vs 20 ml per year (p = 0.07), respectively]. On univariate analysis, baseline %-predicted FEV1 in never-smokers with NTM-LD was associated with changes in FVC (p = 0.026) and FEV1 (p = 0.013). Anti-NTM treatment was administered for at least 1 year in 19 patients (86.4%). The relationship between worsening chest CT findings and rapid progressive decline in both FVC (p = 0.66) and FEV1 (p = 0.23) were not significant. Conclusion: Never-smokers with NTM-LD showed lung function decline. There was no association between successful NTM-LD treatment in radiologic outcomes and improvement in lung function of never-smokers. Keywords: Lung function, Never-smoker, Nontuberculous mycobacterial lung disease, Bronchiectasis

Background: Among Mycobacterium abscessus complex infections, patients with M. abscessus subsp. abscessus (MAA) lung disease are difficult to treat and no standard therapy has been established. Few reports have investigated the drug susceptibility of these strains. We retrospectively investigated how in vitro drug susceptibility testing (DST) of MAA affects the induction of sputum conversion using pharmacotherapy. Methods: Patients with MAA lung disease diagnosed and treated between 2010 and 2014 at our hospital were enrolled and divided into Group A (sputum conversion without relapse within 1 year) and Group B (persistent positive cultured or negative conversion with relapse). MAA was identified in M. abscessus using sequence with genotyping, and DST of MAA was performed. Results: We assessed 23 patients (9 males and 14 females). There were 8 patients in Group A and 15 in Group B. Higher prevalence of susceptible isolates for clarithromycin (CAM) susceptibility on day 14 was noted in Group A than in Group B (P = 0.03) and no significant difference observed in the two groups for other drugs. Conclusions: In vitro DST of MAA, especially CAM susceptibility on day 14, affected the results of negative conversion. No other drugs were found to affect sputum culture negative conversion.

Introduction Standard treatment for nodular/bronchiectatic Mycobacterium avium complex lung disease (NB MAC-LD), excluding severe-status cases, differs between Japan and other countries. Internationally, three-drug combination intermittent treatment (three times a week administration) with macrolide, ethambutol and rifampicin is recommended, but a daily treatment regimen is recommended in Japan. To date, no randomised controlled study directly comparing intermittent treatment with daily treatment has been performed. The purpose of this study is to investigate the usefulness of intermittent treatment.Methods and analysis A total of 140 patients diagnosed with NB MAC-LD in Japan will be randomly assigned, in a 1:1 ratio, to intermittent treatment group or daily treatment group, and three-drug combination therapy with clarithromycin, rifampicin and ethambutol will be continued for 1 year. The primary endpoint is the proportion of patients requiring modification of the initial treatment regimen. Secondary endpoints are adverse events, sputum culture conversion, time to sputum culture conversion, improvement of chest CT findings, change in health-related quality of life score and development of clarithromycin resistance.Ethics and dissemination This trial was approved by the National Hospital Organisation Review Board for Clinical Trials (Headquarters). The results of this study will be reported at a society meeting or published in a peer-review journal.

Introduction Nintedanib slows disease progression in patients with idiopathic pulmonary fibrosis (IPF) by reducing the rate of decline in forced vital capacity, with an adverse event profile that is manageable for most patients. We used data from six clinical trials to characterise the safety and tolerability profile of nintedanib and to investigate its effects on survival.Methods Data from patients treated with ≥1 dose of nintedanib 150 mg two times per day or placebo in the 52-week TOMORROW trial and/or its open-label extension; the two 52-week INPULSIS trials and/or their open-label extension, INPULSIS-ON; and a Phase IIIb trial with a placebo-controlled period of ≥6 months followed by open-label nintedanib were pooled. All adverse events, irrespective of causality, were included in descriptive analyses. Parametric survival distributions were fit to pooled Kaplan-Meier survival data from the trials and extrapolated to estimate long-term survival.Results There were 1126 patients in the pooled nintedanib group and 565 patients in the pooled placebo group. The mean duration of nintedanib treatment was 28 months. No new safety signals were observed. Incidence rates of bleeding, liver enzyme elevations and cardiovascular events were consistent with those observed in the INPULSIS trials. Diarrhoea was reported at a lower event rate in the pooled nintedanib group than in nintedanib-treated patients in the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years) and infrequently led to permanent treatment discontinuation (3.6 events per 100 patient exposure-years). Based on the Weibull distribution, mean (95% CI) survival was estimated as 11.6 (9.6, 14.1) years in nintedanib-treated patients and 3.7 (2.5, 5.4) years in placebo-treated patients.Conclusions Based on pooled data from six clinical trials, the adverse event profile of nintedanib was manageable for most patients. Exploratory analyses based on extrapolation of survival data suggest that nintedanib extends life expectancy in patients with IPF.

BackgroundIn lymphangioleiomyomatosis (LAM), tuberous sclerosis gene mutations activate the mechanistic target of the rapamycin pathway, resulting in vascular endothelial growth factor-D (VEGF-D) overproduction. While the utility of serum VEGF-D testing for the diagnosis of LAM is outlined in ATS/JRS LAM Guidelines, the assay has not been fully validated for Asian populations. Our aims were to validate serum VEGF-D testing in Japan, by directly comparing measurements in Japan and the U.S., determining the diagnostic cut-off for serum VEGF-D levels among the Japanese women with typical thin walled cystic change on CT, and determining the performance of VEGF-D as a prognostic biomarker.Subjects and methodsWe determined serum VEGF-D levels from 108 LAM patients, 14 disease controls, and 51 healthy volunteers from the Japanese population. Measurements of 61 LAM patients were compared to those from the principal VEGF-D laboratory in the U.S at Cincinnati Children's Hospital Medical Center. We correlated baseline serum VEGF-D levels with baseline and longitudinal clinical data to determine how pregnancy, sirolimus or gonadotrophin-releasing hormone (GnRH) agonists influence serum VEGF-D levels.ResultsSerum VEGF-D measurements in Japan and the U.S. were very similar. Baseline serum VEGF-D levels effectively distinguished LAM from other diseases and healthy volunteers at a cut-off level of 645 pg/ml and were diagnostically specific at 800 pg/ml, consistent with the recommendations of the ATS/JRS LAM Guidelines. Baseline serum VEGF-D correlated negatively with the DLco baseline % predicted and with the annual decrease in DLco % predicted. There was no significant association between baseline serum VEGF-D level and the outcomes of death or transplant. Serum VEGF-D levels markedly decreased during treatment with sirolimus, but not with GnRH analogues. Serum VEGF-D levels of most LAM patients did not increase over time, and neither pregnancy nor menopause significantly modulated serum VEGF-D levels.ConclusionsSerum VEGF-D is a useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support VEGF-D recommendations in the ATS/JRS LAM Guidelines for the Japanese population.

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be used to assess an array of constructs affected by a disease or the interventions implemented to treat it. Here, we review the impact of ILD that may present with a progressive-fibrosing phenotype on patients' lives and examine how PROs have been used to measure that impact and the effectiveness of therapeutic interventions.

Few studies have reported the diagnostic variability in patients with a possible usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) who underwent surgical lung biopsy (SLB), and the prognostic factors for these patients have not been fully evaluated. We retrospectively investigated the frequency of idiopathic pulmonary fibrosis (IPF) and prognostic factors in patients with possible UIP pattern on HRCT.Consecutive patients who had a possible UIP pattern on HRCT, underwent SLB, and had a diagnosis of IIPs before SLB were retrospectively recruited from 10 hospitals. Diagnoses were made based on multidisciplinary discussion using the criteria for current IPF guidelines and multidisciplinary classification for IIPs in each hospital.179 patients who underwent SLB were enrolled. The diagnoses were IPF in 91 patients (51%), unclassifiable IIPs in 47 (26%), idiopathic NSIP in 18 (10%), and chronic hypersensitivity pneumonia in 17 (9%). One-year FVC changes showed significant differences between IPF and non-IPF (-138.6 mL versus 18.2 mL, p = 0.014). Patients with IPF had a worse mortality than those with non-IPF (Logrank test, p = 0.025). Multivariable Cox regression analysis demonstrated that diagnoses of IPF (HR, 2.961; 95% CI, 1.183-7.410; p = 0.02), high modified MRC score (HR, 1.587; 95% CI, 1.003-2.510; p = 0.049), and low %FVC (HR, 0.972; 95% CI, 0.953-0.992; p = 0.005).About a half of patients with a possible UIP pattern on HRCT had diagnoses other than IPF, and patients with IPF had a worse mortality than those with an alternative diagnosis. We reaffirmed that multidisciplinary discussion is crucial in patients with possible UIP pattern on HRCT.

Preaxial prehallux is a rare clinical manifestation among patients with polydactyly. Few cases arising from tarsal bones have been reported. We present a case of a true prehallux occurring in a patient with a bilateral complete cleft lip, palate, and alveolus.