Disease Lung Research Articles

Scoping review of post-TB pulmonary vascular disease: Proceedings from the 2nd International Post-Tuberculosis Symposium.

Tuberculosis (TB) may cause significant long-term cardiorespiratory complications, of which pulmonary vascular disease is most under-recognized. TB is rarely listed as a cause of pulmonary hypertension (PH) in most PH guidelines, yet PH may develop at various stages in the time course of TB, from active infection through to the post-TB period. Predisposing risk factors for the development of PH are likely multifactorial, involving active TB disease and post-TB lung disease (PTLD), host-related and environment-related factors. Moreover, post-TB PH should likely be classified in Group 3 PH, with the pathogenesis similarly complex and multifactorial as other Group 3 PH causes. Identifying risk factors that predispose to post-TB PH may aid in developing risk stratification criteria for early identification and referral for confirmatory diagnostic tests. Given that universal screening for PH in TB survivors may be impractical and unfeasible, a targeted screening approach for high-risk individuals would be sensible. In this scoping review of post-TB PH, resulting from the proceedings of the 2nd International Post-Tuberculosis Symposium, we aim to describe the epidemiology, risk factors, and pathophysiology of post-TB PH. We emphasize diagnosing PH with an alternative set of diagnostic guidelines in resource-constrained settings where right heart catheterization may not be feasible. Research to describe the burden and distribution of post-TB PH should be prioritized as there is a current gap in knowledge regarding the prevalence and incidence of post-TB PH among persons with TB.

Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

Binary fabrication of decellularized lung extracellular matrix hybridgels for in vitro chronic obstructive pulmonary disease modeling

Limited treatments and a lack of appropriate animal models have spurred the study of scaffolds to mimic lung disease in vitro. Decellularized human lung and its application in extracellular matrix (ECM) hydrogels has advanced the development of these lung ECM models. Controlling the biochemical and mechanical properties of decellularized ECM hydrogels continues to be of interest due to inherent discrepancies of hydrogels when compared to their source tissue. To optimize the physiologic relevance of ECM hydrogel lung models without sacrificing the native composition we engineered a binary fabrication system to produce a Hybridgel composed of an ECM hydrogel reinforced with an ECM cryogel. Further, we compared the effect of ECM-altering disease on the properties of the gels using elastin poor Chronic Obstructive Pulmonary Disease (COPD) vs non-diseased (ND) human lung source tissue. Nanoindentation confirmed the significant loss of elasticity in hydrogels compared to that of ND human lung and further demonstrated the recovery of elastic moduli in ECM cryogels and Hybridgels. These findings were supported by similar observations in diseased tissue and gels. Successful cell encapsulation, distribution, cytotoxicity, and infiltration were observed and characterized via confocal microscopy. Cells were uniformly distributed throughout the Hybridgel and capable of survival for 7 days. Cell-laden ECM hybridgels were found to have elasticity similar to that of ND human lung. Compositional investigation into diseased and ND gels indicated the conservation of disease-specific elastin to collagen ratios. In brief, we have engineered a composited ECM hybridgel for the 3D study of cell-matrix interactions of varying lung disease states that optimizes the application of decellularized lung ECM materials to more closely mimic the human lung while conserving the compositional bioactivity of the native ECM. Statement of significanceThe lack of an appropriate disease model for the study of chronic lung diseases continues to severely inhibit the advancement of treatments and preventions of these otherwise fatal illnesses due to the inability to recapture the biocomplexity of pathologic cell-ECM interactions. Engineering biomaterials that utilize decellularized lungs offers an opportunity to deconstruct, understand, and rebuild models that highlight and investigate how disease specific characteristics of the extracellular environment are involved in driving disease progression. We have advanced this space by designing a binary fabrication system for a ECM Hybridgel that retains properties from its source material required to observe native matrix interactions. This design simulates a 3D lung environment that is both mechanically elastic and compositionally relevant when derived from non-diseased tissue and pathologically diminished both mechanically and compositionally when derived from COPD tissue. Here we describe the ECM hybridgel as a model for the study of cell-ECM interactions involved in COPD.

Renewable Therapy Potential of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare chronic respiratory disease characterized by progressive fibrotic changes in lung tissue of unknown origin, resulting in severe decline in lung function and poor prognosis with a median survival of 3 to 5 years. Current pharmacological therapies, including nintedanib and pirfenidone, aim to slow disease progression but are limited by side effects and lack of efficacy in reversing established fibrosis. This literature review explores emerging therapeutic approaches for IPF using data from PubMed, Google Scholar, and ScienceDirect databases. The review highlights mesenchymal stem cell (MSC) therapy, specifically allogeneic bone marrow-derived MSCs, as a promising option. MSC therapy demonstrates superior efficacy in improving forced vital capacity (FVC) by 3.7%, surpassing the effects of nintedanib (3.3%) and pirfenidone (-4.8%), while exhibiting minimal adverse effects. The findings underscore the potential of MSC therapy as a renewable treatment option for IPF, suggesting a paradigm shift towards addressing both disease progression and lung function restoration in affected individuals.

A stability indicating method development and validation of a rapid and sensitive RP-HPLC method for Nintedanib and its application in quantification of nanostructured lipid carriers.

Nintedanib (NTB) is a multiple tyrosine kinase inhibitor, been investigated for many disease conditions like idiopathic pulmonary fibrosis (IPF), systemic sclerosis interstitial lung disease (SSc-ILD) and non-small cell lung cancer (NSCLC). NTB is available as oral capsule formulation, but its ability to detect degradants formed through oxidative, photolytic and hydrolytic processes makes it difficult to quantify. In the current work, a novel reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated. The developed method is simple, precise, reproducible, stable and accurate. The inherent stability of NTB was evaluated using the proposed analytical method approach and force degradation studies were carried out. NTB was separated chromatographically on the Shimadzu C 18 column as stationary phase (250 ×4.6 mm, 5 µm) using an isocratic elution method with 0.1% v/v triethyl amine (TEA) in HPLC grade water and acetonitrile (ACN) in the ratio 35:65% v/v. The mobile phase was pumped at a constant flow rate of 1.0 ml/min, and the eluent was detected at 390 nm wavelength. NTB was eluted at 6.77±0.00 min of retention time (t R) with a correlation coefficient of 0.999, the developed method was linear in the concentration range of 0.5 µg/ml to 4.5 µg/ml. The recovery rate was found to be in the range of 99.391±0.468% for 1.5 µg/ml concentration. Six replicate standards were determined to have an % RSD of 0.04. The formulation excipients didn't interfere with the determination of NTB, demonstrating the specificity of the developed method. The proposed approach of the analytical method developed can be used to quantify the amount of NTB present in bulk drugs and pharmaceutical formulations.

A Comparison of Nailfold Video Capillaroscopy Findings in Mixed Connective Tissue Disease Interstitial Lung Disease vs Systemic Sclerosis Interstitial Lung Disease: A Single-Centre Study.

To differentiate the nailfold capillaroscopy (NFC) findings in patients with MCTD-ILD and SSc-ILD and correlate the NFC changes and lung functions among them. In this observational study from Oct 2020 to Oct 2022, 27 patients with MCTD-ILD and 27 patients with SSc-ILD were included. NFC was performed using Jiangsu Jiahua, JH 1004, China. Statistical analysis was conducted using IBM SPSS software, version 26, and tests including Mann-Whitney U-test, student t-test, chi-square test, or Fisher's exact test were used to compare between groups. In this study, major capillaroscopic changes were more frequent in SSc-ILD group (92%) than in MCTD-ILD group (72.3%), with normal capillaries seen in 7.4% of MCTD-ILD cases. The mean FVC was higher in SSc-ILD group compared to MCTD-ILD group, and patients with capillary loss had a lower mean FVC. Loss of capillaries was more frequent in SSc-ILD group, while dilated capillaries were predominantly observed in MCTD-ILD group. A significant association was found between the severity of restriction in spirometry and NFC. There is an important role for NFC in detecting the severity of lung involvement, as the grading of restrictive severity in spirometry is strongly associated with capillaroscopic abnormalities.

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

Magnetic sphincter augmentation: A promising alternative to fundoplication for preserving lung function and protecting against chronic lung transplant rejection

BackgroundEarly laparoscopic fundoplication (LF) has been shown to slow lung function decline in chronic lung disease (CLD) patients and lung transplant (LTx) recipients. Magnetic sphincter augmentation (MSA) has emerged as an effective minimally invasive alternative to LF for the treatment of GERD. We evaluate the safety and efficacy of MSA compared to LF for GERD in CLD and LTx. MethodsA retrospective review identified CLD and LTx patients undergoing LF or MSA for GERD. Primary outcome was change in percent predicted FEV1. Secondary outcomes were 30d morbidity, mortality, operative time, and length of stay (LOS). Results77 patients met inclusion criteria, 45 (58.5 %) were LTx recipients. 35 (45.5 %) underwent Nissen, 23 (29.9 %) underwent Toupet, and 19 (24.7 %) underwent MSA. Average age was 54.2 years, 54.5 % were female, and average BMI at ARS was 24.9 kg/m2. Median FEV1 % change between pre-ARS and post-ARS was 0 % with no significant differences between groups. MSA had faster operative times at 50.5 min than Nissen (83.5 min, p = 0.002) and Toupet (72.6 min, p = 0.003) and shorter LOS at 0.8 days than Nissen (3.7 days, p = 0.002) and Toupet (2.1 days, p = 0.0008). MSA and Nissen had higher reintervention rates than Toupet, though this was not statistically significant. There were no differences in 30-day morbidities or 30-day ED visits between groups. There were no mortalities. ConclusionMSA is an advantageous alternative to LF in the CLD and LTx population with stabilization of percent predicted FEV1, equivalent safety profile, shorter operative times, and shorter length of hospital stay.

Randomized controlled, open-label, phase IIb/III study of lurbinectedin in combination with doxorubicin versus doxorubicin alone as first-line treatment in patients with metastatic leiomyosarcoma.

TPS11590 Background: Lurbinectedin (LUR) is a synthetic chemical entity structurally related to trabectedin that inhibits oncogenic transcription and is active in tumors addicted to transcription. Synergistic activity of the combination of LUR with Doxorubicin (DOX) was found in solid tumors. Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at different doses. In a phase 2 trial in soft tissue sarcoma (STS) patients (pts) (mostly with LMS: 12/20 pts), a combination of DOX 50 mg/m2 + LUR 2 mg/m2 Day (D)1 q3wk resulted in a response rate (RR) of 35% (4/7 LMS pts responding) and a disease control rate (DCR) at 24 wks of 40% (1). A phase 1b/2 trial in 10 advanced STS pts found a RR of 60% (5 were LMS, with 3 partial responses) treated at DOX 25 mg/m2 D1 or D1,D8 + LUR 3.2 mg/m2 D1 q3wk, (2). The promising results of these trials provide a rationale for further exploring this combination in a phase 2b/3 trial as first-line therapy for metastatic LMS (SaLuDo - NCT06088290). Methods: SaLuDo is a randomized, open-label study evaluating LUR in combination with DOX compared to DOX alone as first-line treatment of pts with metastatic LMS. The primary endpoint is progression-free survival (PFS) according to Independent Radiological committee (IRC). Secondary endpoints include overall survival, PFS according to Investigator assessment (IA), overall response rate, duration of response, and clinical benefit rate (according to IRC and IA), safety profile, patient-reported outcomes, pharmacokinetics, and exploratory pharmacogenomic analysis. Main inclusion criteria include age ≥ 18 years, confirmed diagnosis of metastatic LMS, and no prior systemic treatment for metastatic disease. Exclusion criteria include prior treatment with anthracyclines, lurbinectedin or trabectedin. The phase 2b part of the study will randomize approximately 120 pts into 3 arms (1:1:1): Control arm (DOX 75 mg/m2 D1 q3wk; experimental ARM A (DOX 50 mg/m2 D1 + LUR 2.2 mg/m2 D1 + 1ry GCSF prophylaxis q3wk), and experimental ARM B (DOX 25 mg/m2 D1 + LUR 3.2mg/m2 D1 + 1ry GCSF prophylaxis q3wk). Stratification will be done according to site of primary tumor (uterine vs. soft tissue), sites of metastatic disease (lung as unique site vs. other) and time from diagnosis to study entry (≤ 12 months vs. >12 months). One of the two experimental arms will be dropped out at the end of phase 2b. The study will then enter the phase 3 part and approximately 120 pts will be randomized 1:1 between the control arm and the selected experimental arm. An Independent Data Monitoring Committee will oversee the conduct of the study. The first patient was randomized in 09/2023. The phase 2b part of the study is ongoing and recruiting patients in Europe and the USA. 1. Cote EJC 2020; 126:21-32. 2. Cote. JCO 2023; 41: Abst 11507. Clinical trial information: NCT06088290 .

Primary Human Cell-Derived Extracellular Matrix from Decellularized Fibroblast Microtissues with Tissue-Dependent Composition and Microstructure.

Human extracellular matrix (ECM) exhibits complex protein composition and architecture depending on tissue and disease state, which remains challenging to reverse engineer. One promising approach is based on cell-secreted ECM from primary human fibroblasts that can be decellularized into acellular biomaterials. However, fibroblasts cultured on rigid culture plastic or biomaterial scaffolds can experience aberrant mechanical cues that perturb the biochemical, mechanical, and the efficiency of ECM production. Here, we demonstrate a method for preparing decellularized ECM using primary human fibroblasts with tissue and disease-specific features with two case studies: (1) cardiac fibroblasts; (2) lung fibroblasts from healthy or diseased donors. Cells aggregate into engineered microtissues in low adhesion microwells that deposited ECM and can be decellularized. We systematically investigate microtissue morphology, matrix architecture, and mechanical properties, along with transcriptomic and proteomic analysis. Microtissues exhibited tissue-specific gene expression and proteomics profiling, with ECM complexity similar to native tissues. Healthy lung microtissues exhibited web-like fibrillar collagen compared to dense patches in healthy heart microtissues. Diseased lung exhibited more disrupted collagen architecture than healthy. Decellularized microtissues had tissue-specific mechanical stiffness that was physiologically relevant. Importantly, decellularized microtissues supported viability and proliferation of human cells. We show that engineered microtissues of primary human fibroblasts seeded in low-adhesion microwells can be decellularized to produce human, tissue and disease-specific ECM. This approach should be widely applicable for generating personalized matrix that recapitulate tissues and disease states, relevant for culturing patient cells ex vivo as well as implantation for therapeutic treatments. The online version contains supplementary material available at 10.1007/s12195-024-00809-y.

Rhodiola rosea: a review in the context of PPPM approach.

A natural "medicine and food" plant, Rhodiola rosea (RR) is primarily made up of organic acids, phenolic compounds, sterols, glycosides, vitamins, lipids, proteins, amino acids, trace elements, and other physiologically active substances. In vitro, non-clinical and clinical studies confirmed that it exerts anti-inflammatory, antioxidant, and immune regulatory effects, balances the gut microbiota, and alleviates vascular circulatory disorders. RR can prolong life and has great application potential in preventing and treating suboptimal health, non-communicable diseases, and COVID-19. This narrative review discusses the effects of RR in preventing organ damage (such as the liver, lung, heart, brain, kidneys, intestines, and blood vessels) in non-communicable diseases from the perspective of predictive, preventive, and personalised medicine (PPPM/3PM). In conclusion, as an adaptogen, RR can provide personalised health strategies to improve the quality of life and overall health status.

Lipid-Laden Macrophages in Pulmonary Diseases.

Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid metabolism lead to pulmonary surfactant damage, resulting in hyperlipidemia in response to lung injury. Lung macrophages are responsible for recycling damaged lipid droplets to maintain lipid homeostasis. The inflammatory response triggered by external stimuli such as cigarette smoke, bleomycin, and bacteria can interfere with this process, resulting in the formation of lipid-laden macrophages (LLMs), also known as foamy macrophages. Recent studies have highlighted the potential significance of LLM formation in a range of pulmonary diseases. Furthermore, growing evidence suggests that LLMs are present in patients suffering from various pulmonary conditions. In this review, we summarize the essential metabolic and signaling pathways driving the LLM formation in chronic obstructive pulmonary disease, pulmonary fibrosis, tuberculosis, and acute lung injury.

Healthy and diseased tensile mechanics of mouse lung parenchyma

The mechanics of the lung, consisting of high deformation, non-linear, rapid and cyclic loading, remain a critical unknown, hindering advancements in the field despite the pressing urgency of incurable and often fatal pulmonary diseases; such multi-scale ailments impair organ mechanical function by inducing tissue-level alterations. Here, the tensile mechanics of healthy and diseased murine lung parenchyma with induced variable fibrosis and emphysema are compared—exploring multi-rate and directional tissue elasticity and energetics. Remarkably, parenchymal tissue is found to be notably elastic and non-hysteresis prone. Additionally, chronic fibrosis-induced tissues reveal significantly reduced compliance compared to age-matched controls, indicating characteristic stiffening; moreover, maximum stress tends to be greater in exposed than controls. Emphysematous tissues tend to show lower maximum stress than controls, reflective of hallmark tissue destruction and softening. Furthermore, faster loading rate is found to generally yield elevated stiffness and maximum stress, significantly for fibrosis group exposed tissue—this interdependence between loading rate and tissue disease is notable considering the dynamics of breathing. Generally, control tissues are found to be isotropic, as are emphysematous tissues, but fibrosis may lead to increased anisotropy. Additionally, fibrotic and mature-healthy lungs are found to show age effect trends, such as increased strain energy. Along with these findings, this study additionally facilitates future analyses of other diseases by establishing lung biaxial testing protocols for small-scale murine specimens, which can serve as practical and ethical models for exploring human diseases. Overall, this study offers fundamental material characterizations which will enable future formulations of experimentally informed computational models.

Diabetes Causes Significant Alterations in Pulmonary Glucose Transporter Expression.

Diabetes has been identified as a significant and independent risk factor for the development or increased severity of respiratory infections. However, the role of glucose transport in the healthy and diseased lung has received little attention. Specifically, the protein expression of the predominant glucose transporter (GLUT) isoforms in the adult lung remains largely to be characterized in both healthy and diabetic states. Type 1 diabetes was induced via streptozotocin and rescued via subcutaneous semi-osmotic insulin pump for 8 weeks. The gene and/or protein expression of the most predominant GLUT isoforms from Classes I and III, including the major insulin-sensitive isoform (i.e., GLUT4) and novel isoforms (i.e., GLUT-8 and GLUT-12), was quantified in the lung of healthy and diabetic mice via qRT-PCR and/or Western blotting. Pulmonary cell surface GLUT protein was measured using a biotinylated photolabeling assay, as a means to evaluate GLUT trafficking. Diabetic mice demonstrated significant alterations of total pulmonary GLUT protein expression, which were isoform- and location-dependent. Long-term insulin treatment rescued the majority of GLUT protein expression alterations in the lung during diabetes, as well as GLUT-4 and -8 trafficking to the pulmonary cell surface. These alterations in glucose homeostasis during diabetes may contribute to an increased severity of pulmonary infection during diabetes and may point to novel metabolic therapeutic strategies for diabetic patients with concurrent respiratory infections.

The gut microbiome in end-stage lung disease and lung transplantation.

Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.

Sensitivity and specificity of the question “do you have any concerns regarding your mouth related to undergoing surgery?” for predicting perioperative oral health problems in patients with primary esophageal and lung cancer: a retrospective observational study

BackgroundPerioperative oral management contributes to the prevention of dental/systemic complications. However, a professional dental checkup before surgery is generally not performed and relies on the patient’s answer to a simple question by medical professionals other than dentists: “Do you have any concerns regarding your mouth related to undergoing surgery?” Here, we evaluated the sensitivity and specificity of this question for predicting perioperative oral health problems in patients with primary esophageal and primary lung cancer.MethodsWe performed an oral cavity check in all patients before scheduled surgery for primary esophageal and lung cancer. A total of 183 patients were enrolled (M, 112; F, 71; 24–88 years, median, 69 years), consisting of 61 with primary esophageal cancer (M, 46; F, 15; 24–85 years, median, 69 years) and 122 with primary lung cancer (M, 66; F; 56; 33–88 years, median, 69 years). All subjects provided a response to this question, and an oral cavity check was performed by dentists. The sensitivity and specificity of this question for detecting oral health problems were evaluated retrospectively.ResultsOverall sensitivity and specificity for detecting oral health problems were 0.263 and 0.898, respectively. There were no significant differences by sex or disease (primary esophageal or lung cancer).ConclusionThis simple question has low sensitivity but high specificity for detecting oral health problems. Although challenging to detect surgical patients with oral health problems by simply asking questions, the results indicated that patients with oral complaints are more likely to have problems during surgery.

Using spirometry for screening and diagnosis of chronic respiratory diseases in primary health care: findings from a community health project in rural India

Background Chronic respiratory diseases (CRDs) such as Chronic obstructive pulmonary disease (COPD), Asthma and post-tuberculosis lung disease (PTLD) are a growing public health concern in India. Early diagnosis and management of CRDs require a good quality spirometry test, a technician to conduct spirometry and a chest physician to interpret the results. In India, these are not available at the primary care level. This study reports the feasibility of a large-scale CRD diagnosis and management program in primary care using a unique point-of-care spirometry solution, Briota PFT in a Box™. # Methods A community-based cross-sectional study was conducted among 15,602 adults in Dindori Taluka (subdivision), Nashik, Maharashtra state. This study was part of a holistic CRD diagnosis and management program SAVE™ (Spirometry Assisted Virtually Early). Make In India point of care solution Briota PFT in a Box™ was used. A House‐to‐house community-based assessment checklist (CBAC) survey, 4-parameter spirometry test, 15-parameter pre and post-bronchodilator spirometry test and a software-assisted medical examination by the medical officer at primary care were conducted. Software was used to generate CRD diagnosis and lung health score (LHS™). The diagnosis was verified by the chest physician. Confirmed diagnosed patients were provided treatment and offered a patient support program. Interviews were conducted with the patients, nurses, doctors and public health officials for understanding feasibility and documenting learning from program SAVE™. # Results Out of 15,602 adults surveyed, total 4,937 (31.6%) were identified as “CRD high risk”. 1231 participants based on medical examination, spirometry tests and software analysis were identified as CRD candidates by medical officers at primary care. 1154 participants out of 15,602 (7.4%) were confirmed diagnosed as CRD patients post independent evaluation by chest physicians. At the time of follow-up, 537 patients (75% of 712 patients enrolled in patient support program) reported improvement in symptoms and high satisfaction with the program. District health officer, Medical officers, nurses, Accredited Social Health Activist (ASHA) from the primary health care centers confirmed ease of use and feasibility of using Briota PFT in a Box™ in program SAVE™. Outcome and learning from program SAVE™ was documented and submitted to Ministry of Health and Family Welfare Government of India. # Conclusions CRD diagnosis and management in large scale settings in primary healthcare level using a point of care spirometry solution Briota PFT in a Box™ is highly feasible.

Abstract PO2-04-04: Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM)

Abstract Background: ROSET-BM (UMIN000044995) was a multicenter, retrospective chart review study of patients (pts) who received trastuzumab deruxtecan (T-DXd) treatment for HER2-positive (HER2+) metastatic breast cancer (MBC) with brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC). Primary results (data cutoff, October 31, 2021) were presented at SABCS2022 (median progression-free survival [PFS], 16.1 months; 1-year overall survival [OS] rate, 74.9%; and median follow-up duration, 11.2 months). To confirm the long-term effectiveness of T-DXd in HER2+ MBC pts with BM and/or LMC, we conducted an updated analysis using additional 1-year follow-up data. Methods: Pts who started T-DXd treatment between May 25, 2020, and April 30, 2021, were registered for ROSET-BM. For this updated OS analysis, the extended observation period ended on October 31, 2022. OS, PFS, and time to treatment failure (TTF) were evaluated. Median survival times and 95% CIs were calculated using the Kaplan–Meier method. In addition, prespecified and exploratory subgroup analyses were performed based on patient background characteristics. Univariate and multivariate Cox proportional hazards regression models were used to evaluate baseline prognostic factors for OS. Results: 104 pts from 62 institutions were included in this updated OS analysis. Median duration of follow-up was 20.4 months. Median number of prior lines of therapy was 4 (range, 1–15). Median time from first diagnosis of MBC to first administration of T-DXd was 37.5 months. Median time from first diagnosis of BM to first administration of T-DXd was 18.9 months. The prevalence of active BM, stable BM, LMC, and unclassified (image not evaluated) was 64.4% (n=67), 11.5% (n=12), 18.3% (n=19), and 5.8% (n=6), respectively. Median OS was not reached (NR) among all pts (1-year OS rate, 74.8%; 2-year OS rate, 56.0%). Subgroup analyses showed that median OS in pts with active BM was 27.0 months (95% CI, 16.4 to NR) and that median OS was NR in pts with stable BM or LMC (2-year OS rate for pts with stable BM, 71.6%; 2-year OS rate for pts with LMC, 61.6%). The results of univariate and multivariate analyses for OS showed no relevant baseline prognostic factors. Among all pts, median PFS was 14.6 months (95% CI, 10.6–20.8). Subgroup analyses showed that in pts with active BM, stable BM, and LMC, median PFS was 13.2 months (95% CI, 10.0–20.3), NR (95% CI, 5.3 to NR), and 17.5 months (95% CI, 8.3–22.1), respectively. Among all pts, median TTF was 9.3 months (95% CI, 6.3–11.8). The most common event and adverse event leading to discontinuation of T-DXd was progressive disease (37 pts, 35.6%) and interstitial lung disease (ILD; 24 pts, 23.1%), respectively. Median time to onset of an ILD event was 5.3 months (range, 0.7–20.0). ILD was grade 1 in 14 pts (13.5%), grade 2 in 3 pts (2.9%), grade 3 in 5 pts (4.8%), grade 4 in 2 pts (1.9%), and grade 5 in 0 pts. The Table summarizes the primary and updated results of ROSET-BM. Conclusion: The updated OS results of this retrospective chart review show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. This study was funded by Daiichi Sankyo Co., Ltd. Primary and updated results from the ROSET-BM study The updated results show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. Citation Format: Takashi Yamanaka, Naoki Niikura, Takahiro Nakayama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Hironori Nomura, Shosuke Kita, Miki Yamaguchi, Tomoyuki Aruga, Nobuhiro Shibata, Akihiko Shimomura, Yuri Ozaki, Shuji Sakai, Daisuke Takiguchi, Takehiko Takata, Armin Bastanfard, Kazuhito Shiosakai, Junji Tsurutani. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-04.

Effects of Pulmonary Rehabilitation with Occupational Therapy on Occupational Performance

Aims 1) Explore occupational challenges of individuals participating in pulmonary rehabilitation (PR), and 2) examine impacts of occupational therapy, embedded within PR, on performance of, satisfaction with, dyspnea in and experience of challenging occupations. Methods A mixed methods cohort study recruited adults from a 8-week community-based PR program which incorporated targeted occupational therapy. Participant perspectives of the occupational therapy were explored using the Canadian Occupational Performance Measure (COPM) and Modified Borg Dyspnea Scale. Results Seventeen participants with either Chronic Obstructive Pulmonary Disease, Bronchiectasis, or Interstitial Lung Disease were recruited (age 71 ± 7(SD) identifying 269 problematic occupations. Nine participants completed the program obtaining clinically and statistically significant improvements in COPM performance, satisfaction scores and Modified Borg Dyspnea Scale, maintained at 12 wk, and validated through participants reporting they ‘now do things differently’. Conclusion People with chronic respiratory conditions are occupational beings. Occupational therapy embedded within PR can influence participants’ engagement in challenging occupations.

Single-cell RNA-seq analysis of cell-cell communications in human lung reveals a novel role of VEGF-D in acute lung injury

BACKGROUND: Vascular disorders are a prominent pathological feature across many pulmonary diseases, such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and COVID-19. Paracrine signals are enriched throughout the lung tissue and are critical in maintaining functional microvascular homeostasis. In this study, we applied comprehensive computational tools to analyze single-cell RNA-seq (scRNAseq) datasets in healthy and diseased lungs and identified a local component in human lung microvascular niche VEGF-D exhibiting barrier protective property in ALI/ARDS animal models. METHODS: Leveraging scRNAseq-based ligand-receptor analysis, we studied the cell-cell crosstalk signals in the human lung microvascular niche among healthy adults and in IPF and COPD individuals. The impact of identified ligands on vascular barrier function and anti-inflammation was further assessed in vitro assays and lipopolysaccharide (LPS)-induced lung injury models. RESULTS: scRNAseq datasets reveal over 24 cell populations in the human lung microvascular niche. We applied Connectome to map the averaged gene expression per cell type to known ligand-receptor interactions cataloged in the NicheNet database. Using microvascular ECs, such as EC Aerocyte and EC General Capillary, as signal receivers (Senders) and the putative adjacent cell types (alveolar fibroblast, ATI, ATII, pericyte, plasma cell, etc.) in the microvascular niche as signal senders (Ligands), we identified several specific and abundant ligand-receptor pairs based on their expression levels in the niche, including SLIT2-ROBO4, ANGPT1-TEK, ADM-RAMP2, VEGFD-VEGFR2, BMP5-BMPR2, etc. Interestingly, these highly produced ligands were significantly reduced in patients with IPF or COPD. Upon treatment with these ligands on human lung endothelial cells, we found that VEGF-D could significantly increase the barrier function, unlike its analogs, VEGF-A and VEGF-C. Additionally, VEGF-D exerts barrier-protective properties against tumor necrosis factor-α, interleukin 1-β, and thrombin challenges. The blockage of VEGFR2 through either siRNA or pharmacological inhibitor SU5614 attenuates the impact of VEGF-D. Furthermore, intravenous administration of VEGF-D significantly reduced vascular permeability and immune cell infiltration in the LPS-induced lung injury model. CONCLUSIONS: This study highlights the cell-cell crosstalk signals in lung microvascular niche between healthy and diseased individuals and determines a novel and potentially therapeutic role of VEGF-D in improving lung vascular integrity during acute lung injury. NIH K99HL159261 (Y.Y.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.