Congenital pulmonary vein atresia (PVA) is a rare condition often associated with vascular anomalies and complex pulmonary hemodynamics. A 54-year-old woman was referred for evaluation of a nodular shadow in the right upper lobe, initially suspected to represent a pulmonary arteriovenous malformation (PAVM). Four-dimensional enhanced computed tomography (4D-CT) revealed no abnormal vessels, suggesting a PAVM in the pulmonary arterial phase. However, in the venous phase, the pulmonary vein of the right upper lobe was occluded at the trunk, with reflux via a pulmonary vein varix and an abnormal vein draining into the pulmonary vein of the right middle lobe. Due to the risk of pulmonary hypertension, thromboembolism, or varix rupture, the patient underwent right upper lobectomy. 4D-CT effectively delineates the vascular morphology by separating the pulmonary arterial and venous phases. Congenital PVA may involve pulmonary vein varices and abnormal vascular formation; 4D-CT may be valuable for diagnosis and treatment planning.

Abstract Purpose: TKIs and ADCs have transformed NSCLC therapy, yet most patients relapse without detectable resistant mutations due to drug-tolerant persister (DTP) cells. Although immune evasion and CAF-mediated remodeling are well recognized, the contribution of lung-specific epithelial and ECM components to protective niche formation remains unclear. Systems that recapitulate alveolar architecture are needed to reveal targetable mechanisms. Methods: We developed a three-dimensional system, termed MicroEnvironment-Embedded Tumor in Fibroblast-integrated Organoid Alveolar MicroStructure (MEET-FOAms), by integrating human iPSC-derived alveolar organoids with NSCLC lines harboring EGFR exon19 deletion or ERBB2 exon20 insertion. Organoids were exposed to osimertinib, erlotinib, or trastuzumab-deruxtecan. Longitudinal single-cell RNA-seq and Xenium 5K spatial transcriptomics mapped lineage trajectories, ligand-receptor networks, and ECM remodeling. Results: Analysis of cancer cell clusters revealed that, even before drug exposure, a distinct subset persisted within the alveolar organoid background. These clusters lacked resistance mutations and were transcriptionally aligned with persister-like states, suggesting that the alveolar niche may inherently sustain DTP populations independently of drug pressure. Following TKI treatment, a stress-adaptive DTP subpopulation remained stable, relying on stromal-epithelial communication and ECM-receptor engagement. Under ADC exposure, an epithelium-associated DTP program was maintained via adhesion networks originating from alveolar epithelial cells, enabling protection from cytotoxic payload delivery. Spatial multi-omics profiling delineated organized multicellular interactions underpinning these responses. Intervention studies showed: (1) ADCs with bystander effect eliminated DTPs along with surrounding niche cells; (2) neutralizing CAF-derived factors suppressed DTP expansion; and (3) blocking ECM-related adhesion pathways disrupted persister maintenance. Conclusions: With MEET-FOAms, we experimentally reconstructed lung cancer tissue architecture by introducing oncogene-driven NSCLC cells into a human iPSC-derived alveolar background, elucidating that persister-like clusters exist prior to therapy and are sustained by lung-specific niche interactions. Unlike prior models emphasizing CAFs or immune escape alone, this organoid platform highlights the underexplored role of alveolar epithelial cells and ECM in priming and maintaining DTP states. These findings suggest that such persister niches may act as reservoirs from which genetically resistant clones eventually emerge, supporting a paradigm expansion into therapeutic strategies that target multicellular remodeling in drug-tolerant NSCLC. Citation Format: Toshio Suzuki, Harry Choi, Erik Johansson, Tetsuharu Nagamoto, Ayako Suzuki, Takuji Suzuki, Katsuya Tsuchihara, Yutaka Suzuki, Yuki Yamamoto. Reconstructing drug-tolerant persister (DTP) niches in iPSC-derived alveolar lung cancer organoids for spatio-temporal dissection of cell-cell interactions and ligand-receptor targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4873.

BACKGROUND:In patients with non-small cell lung cancer (NSCLC) and comorbid interstitial lung disease (ILD), carboplatin plus paclitaxel or nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy and safety as a first-line treatment in clinical trials. However, no standard second-line treatment has been established. METHODS:This multicenter retrospective study examined the efficacy and safety of rechallenge chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel in patients with NSCLC and ILD. The primary outcome was objective response rate (ORR), and the secondary outcomes were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Threshold and expected ORRs were set at 8.3% and 27.5%, respectively. A one-sided type I error of 5% and power of 80% were assumed, warranting a sample size of 24 patients. RESULTS:Thirty patients who received carboplatin plus paclitaxel or nab-paclitaxel rechallenge chemotherapy between January 2018 and December 2022 were enrolled in this study. The median follow-up duration was 8.2 months (range: 1.6-54.3 months). The ORR was 27% (90% confidence interval [CI]: 14-43%; 95% CI: 12-46%), exceeding the pre-specified threshold. Median PFS and OS were 3.2 months (95% CI: 2.3-3.9 months) and 9.8 months (95% CI: 6.7-14.4 months), respectively. Acute exacerbation of ILD occurred in two patients (7%), both of whom had been receiving corticosteroid therapy for ILD, and resulted in death in one patient (3%). CONCLUSION:Rechallenge chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel could be an effective and safe option for patients with pretreated NSCLC with comorbid ILD.

Alterations in the immune system, stemming from sleep/wakefulness disorders, increase the risk of inflammatory pathologies. Orexin, a hypothalamic neuropeptide, regulates sleep and wakefulness. However, the role of orexin in inflammatory responses—whether it is protective or pathological—is still unclear. In this study, our aim was to elucidate the role of orexin in sleep and inflammatory states through the examination of a lipopolysaccharide (LPS)-induced systemic inflammatory model and the effects of daridorexant, a dual orexin receptor antagonist. Intraperitoneal LPS administration significantly decreased rapid eye-movement (REM) sleep and wakefulness while increasing non-REM sleep. Pretreatment with daridorexant enhanced REM sleep recovery in LPS-induced systemic inflammation, evidenced by extended duration and increased episode frequency. Transcriptomic profiling demonstrated a rise in the expression of pro-inflammatory cytokines (Cxcl1, Ccl2, Ccl7, and Tnf) within the hypothalamus of LPS-challenged mice, which was mitigated by daridorexant administration. In addition, daridorexant mitigated LPS-induced acute lung inflammation. These findings suggest that by reducing pro-inflammatory cytokine expression, the inhibition of orexin activity mitigates the lethargy associated with systemic inflammation, while also improving sleep quality. This study explores the potential of orexin receptor antagonists as strategic options for inflammatory pathologies and their associated sleep disorders.

BACKGROUND:The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues. PATIENTS AND METHODS:This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes. RESULTS:Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8+ T cells. Progression-free survival on alectinib appeared longer in patients with high than in those with low CD8A expression; however, this difference was not statistically conclusive (HR, 0.49 [95% CI, 0.18-1.35]). CONCLUSIONS:CD8+ T cell infiltration may be associated with the alectinib efficacy in ALK-rearranged NSCLC. Anti-angiogenic therapies may enhance antitumor immunity and thereby augment the efficacy of alectinib as well as that of ICIs for such tumors.

Gasping respiration enhances survival chances during cardiac arrest by activating the suprahyoid muscles (SHMs), which are crucial for airway dilation. We previously reported that the high concentration of sevoflurane (6.5%: 2.0 minimum alveolar concentration, MAC) leads to gasping-like respiration in mice. Here, to understand the molecular mechanisms of this phenomenon, we compared the hypothalamic transcriptome profiles among control, 2.3% sevoflurane (0.7 MAC; eupnea), and 2.0 MAC groups and identified the differentially expressed genes (DEGs), in which hypocretin (orexin) precursor ( Hcrt ) gene expression was significantly elevated in the 2.0 MAC group. Notably, the intracerebroventricular administration of orexin enhanced SHM activity at 0.7 MAC. Our findings suggest that the 2.0 MAC sevoflurane-induced increases in orexin enhance activation of SHMs resulting in the involvement of gasping respiration.

BACKGROUND:Thymic carcinoma is a rare thoracic malignancy with limited first-line treatment options. Lenvatinib has shown efficacy and tolerability in previously treated patients, but its role in chemotherapy-naive patients is unclear. METHODS:We conducted a retrospective, multicentre observational study across 31 Japanese institutions. Patients with advanced or recurrent thymic carcinoma who received lenvatinib between 23 March 2021 and 31 October 2022 were included. Data cut-off was 13 November 2024. Outcomes for chemotherapy-naive patients included objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and adverse events (AEs). Subgroup analyses were stratified by age. RESULTS:Of 107 patients, 20 received lenvatinib as first-line therapy. Median observation was 23.6 months (interquartile range, 12.5-27.1). ORR was 50% (90% confidence interval [CI], 27.2-72.8%), and DCR 85% (95% CI, 62.1-96.8%). Median PFS, TTF, and OS were 10.9 months (95% CI, 5.6-17.1), 8.9 months (95% CI, 5.3-17.8), and 25.0 months (95% CI, 21.2-not reached). AEs occurred in 95% (Grade ≥ 3 in 60%); dose reductions and discontinuations occurred in 85% and 25%. Safety was consistent with prior reports. Older patients showed higher rates of Grade ≥ 3 AEs and discontinuation. CONCLUSIONS:In this real-world cohort, first-line lenvatinib demonstrated favourable efficacy and manageable safety, supporting its use in advanced or recurrent thymic carcinoma.

BACKGROUND:Olfactory stimulation with L-menthol may reduce certain discomfort sensations, including dyspnea. Chronic obstructive pulmonary disease (COPD) and idiopathic interstitial pneumonias (IIPs) have distinct physiological characteristics and may elicit different qualitative sensations of dyspnea. Therefore, the qualitative effects of L-menthol inhalation on dyspnea may differ between these chronic lung diseases (CLDs). This study aimed to determine which aspects of dyspnea are influenced by olfactory stimulation with L-menthol in patients with CLDs. METHODS:Thirty-four patients with stable COPD or IIPs (17 each) performed a 6-min walk test (6MWT) under two conditions: wearing a surgical mask alone (control) or wearing a mask with a peppermint oil aroma sticker (0.105 ml, containing 30% L-menthol). A modified Borg scale, the Multidimensional Dyspnea Profile (MDP), and the Language of Dyspnea Questionnaire (LDQ) were used to evaluate endpoints. The 6MWT was selected to induce breathlessness with and without L-menthol. RESULTS:In the COPD group, L-menthol significantly improved Mental breathing effort on the MDP, and Rapid, Gasping, and Air hunger on the LDQ. In the IIPs group, L-menthol improved only the MDP Hyperpnea dimension. No significant differences were observed in the modified Borg scale before and after the 6MWT between L-menthol and control conditions in either group. CONCLUSIONS:Olfactory stimulation with L-menthol selectively improved aspects of dyspnea in patients with COPD and IIPs, likely reflecting differences in the pathophysiology and severity of each disease. TRIAL REGISTRATION:Japan Registry of Clinical Trials (jRCTs031200400).

Background: Amikacin liposome inhalation suspension (ALIS) therapy is increasingly recognized as a promising treatment for refractory Mycobacterium avium complex (MAC) pulmonary disease. Although clinical data on the efficacy of ALIS therapy are accumulating, little is known about the challenges faced by patients and the support required for sustained ALIS therapy. Here, we present the results of interviews with three patients undergoing long-term ALIS therapy. Cases: Case 1: A 72-year-old female commenced ALIS therapy six years post-diagnosis and achieved culture conversion within two months. After 18 months of ALIS therapy, all antibiotics were discontinued, and the patient has remained relapse-free for 15 months. Case 2: A 74-year-old female commenced ALIS therapy five years post-diagnosis and has continued for 15 months. Although culture conversion has not been achieved, her symptoms and imaging findings improved. Case 3: A 75-year-old female commenced ALIS therapy 12 years post-diagnosis and has continued for 22 months. Despite ongoing positive cultures and stable computed tomography findings, her symptoms have improved. Through thematic analysis, we classified interview responses into two categories: barriers to and facilitators of continuation of ALIS therapy. Barriers include anxiety regarding inhalation techniques, challenges in managing medication and equipment, and side effects such as airway symptoms. Facilitators encompassed medical support, including encouragement and acknowledgment from healthcare providers, family support in daily life and understanding of the illness, corporate support for inhalation guidance and informational resources via the telephone, as well as intrinsic motivation of patients from symptom relief and acceptance of the inhalation routine. Patients expressed a desire for simplified inhalation procedures, including reduced dosing frequency and improved guidance. Discussion: Although adverse effect management is a known factor in sustaining ALIS therapy, this study revealed that patients experienced various concerns and difficulties associated with ALIS therapy. These findings highlight the requirement for multifaceted support, involving healthcare providers, family, and corporate entities, to address patient anxiety and foster adherence. Furthermore, patients noted the complexity of the inhalation process as a significant challenge, underscoring the potential benefit of simplifying the therapy as a facilitator. Conclusion: Recognizing the difficulties and anxieties faced by patients undergoing long-term ALIS therapy is essential. Healthcare providers should provide encouraging and appropriate information to support patient adherence. In addition, collaborative efforts involving families, and corporations may be beneficial in establishing a comprehensive support system for these patients.

Auscultation is a simple physical examination that provides important clinical information. Many educational materials are available to facilitate students’ understanding of lung auscultation. Some studies and teaching materials have visualized lung sounds as spectrograms. However, their effectiveness as educational tools remains unclear. Accordingly, this study evaluates the effect of auscultation education using lung sound visualization on medical students’ diagnostic skills. Participants were medical students completing their four-week clinical clerkship (CC) in the Department of Respiratory Medicine of Chiba University Hospital. Sixty-three students participated in this study between November 2022 and July 2023. They were divided into two groups: the full-term visualization group (n = 31) and the half-term visualization group (n = 32). Although both groups were taught lung sound visualization using simple diagrams, there was a two-week difference in the length of exposure. We taught visualization to the full-term visualization group on the first day of the CC, and to the half-term visualization group after the midpoint test. Thus, the full-term visualization group practiced lung auscultations with visualization for four weeks, while the half-term visualization group had two weeks of practice. All the students performed lung auscultation tests with a simulator three times: pre-test at the beginning, midpoint at the end of the second week, and post-test at the end of CC. In addition, they responded to questionnaires regarding lung auscultation at the beginning and end of CC. The score gain from baseline in the lung auscultation tests at the midpoint was 0.5; p = 0.018). The increase in scores at the post-test was not significantly different between the two groups (median full-term, + 3.6; half-term, + 2.3; p = 0.060). The self-reported confidence, clinical reasoning ability, activity, and frequency of lung auscultation improved in both groups. The questionnaire responses indicated that the students accepted the value of lung sound visualization. Differing the duration of exposure to lung sound visualization (two weeks and four weeks) showed no significant difference in medical students’ auscultation skills.

Background: No previous studies have compared respiratory clinics and respiratory specialized facilities regarding causative diseases for bloody sputum and hemoptysis in Japan. Methods: We retrospectively compared causative diseases for bloody sputum and hemoptysis between 3 respiratory clinics (clinic group) and 7 departments of respiratory medicine at hospitals (hospital group) in Japan. Results: We collected data from 231 patients (median age, 51 years; age range, 24-96 years; 109 men (47.2%)) in the clinic group and 556 patients (median age, 73 years; age range, 21-98 years; 302 men (54.3%)) in the hospital group. In the former group, the main causative disease was acute bronchitis (91 patients, 39.4%), acute upper respiratory tract infection (34 patients, 14.7%), and bronchiectasis (BE) (29 patients, 12.6%). In the latter group, the main causative diseases were BE (102 patients, 18.3%), lung cancer (97 patients, 17.4%), and non- tuberculous mycobacterial disease (NTM) (89 patients, 16%). In particular, in patients >= 60 years old, BE was an important causative disease for bloody sputum and hemoptysis in both groups. Conclusions: The present study is the first to compare respiratory clinics and respiratory specialized facilities. Depending on the facility in which the patient is examined, lung cancer, BE, and NTM were identified as diseases requiring special attention as causes of bloody sputum and hemoptysis.

BACKGROUND:Prognostic factors in patients with newly diagnosed idiopathic interstitial pneumonia (IIP) have rarely been analyzed using prospective data. This study investigated prognostic factors in patients with IIP. METHODS:Central interstitial lung disease (ILD) experts established the diagnoses for fibrotic ILD. Prognostic factors using baseline data, including the pathological confidence level of usual interstitial pneumonia (UIP) assessed on a 0%-100% linear analog scale by high-resolution CT (HRCT), pulmonary function tests, and patient-reported outcomes were investigated. RESULTS:Overall, 866 eligible patients were registered. Patients with unclassifiable idiopathic interstitial pneumonia (n = 272) survived longer than those with idiopathic pulmonary fibrosis (IPF) (n = 469) (hazard ratio [HR] = 0.67; [95% confidence interval [CI]: 0.47-0.95]; P = 0.022); however, IPF as IIPs classification was not a significant prognostic factor at diagnosis (P = 0.577). UIP pattern on HRCT, age, body mass index, forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and St. George's Respiratory Questionnaire were risk factors for survival (P < 0.05). Patients with proposed progressive pulmonary fibrosis (PPF) had poorer prognoses than those without proposed PPF (HR = 5.63; [95% CI: 3.17-10.00]; P < 0.001). Patients with progressive fibrosing ILD (PF-ILD) had poorer prognoses than those without PF-ILD (HR = 7.85; [95% CI: 3.38-18.3]; P < 0.001). CONCLUSIONS:A prospective registry of patients with newly diagnosed IIP provided evidence that the UIP pattern on HRCT by analog scale was a prognostic predictor. Proposed PPF and PF-ILD were valuable for discriminating prognosis. (JIPS Registry, ClinTrials.gov, NCT03041623).

Background: The prognosis of patients with coronavirus disease 2019 (COVID-19) was poor although its survival rate has been improved after the occurrence of the Omicron strain. Autoimmune pulmonary alveolar proteinosis (APAP), a lung disease caused by macrophage dysfunction induced by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)-neutralizing autoantibodies, is characterized by the deposition of proteinaceous material in the alveolar spaces. The clinical course of COVID-19 in patients with APAP remains unclear and this study aimed to clarify it. Methods: The data of 23 patients with APAP, who were diagnosed with COVID-19 between January 2020 and May 2023 and collected through a nationwide questionnaire surveillance system, were retrospectively reviewed. Results: Based on the epidemiological frequency at disease onset, suspected strains of severe acute respiratory syndrome coronavirus 2 were Omicron (n = 18) and non-Omicron (n = 5). Fifteen patients were vaccinated. Six and three patients received anti-viral drugs and corticosteroids, respectively. One patient in the third trimester of pregnancy died despite treatment in the intensive care unit. Six patients were complicated by pneumonia and/or required supplemental oxygen. These patients were suspected to have non-Omicron strains (p = 0.087). Vaccination status showed a significant association with suspected Omicron strains. The radiological findings in four patients and shortness of breath improved in two of the four patients after COVID-19. Conclusions: The severity and prognosis of the patients were not worse than those predicted based on the results of a previous study. The transition from a non-Omicron strain to an Omicron strain and the vaccination status may have affected these results.

Rationale: In hypoxic pulmonary hypertension (PH), pulmonary vascular remodeling is characterized by the emergence of activated adventitial fibroblasts, leading to medial smooth muscle hyperplasia. Previous studies have suggested that CD26/dipeptidyl peptidase-4 (DPP4) plays a crucial role in the pathobiological processes in lung diseases. However, its role in pulmonary fibroblasts in hypoxic PH remains unknown. Therefore, we aimed to elucidate the functional role of CD26/DPP4 in hypoxic PH by focusing on lung fibroblasts. Methods:Dpp4 knockout (Dpp4 KO) and wild-type (WT) mice were exposed to hypoxia for 4 weeks, after which pulmonary hemodynamics and lung tissues were examined. We also performed RNA sequencing of human lung fibroblasts (HLFs) treated with negative control siRNA (Control) or DPP4-siRNA (DPP4 KD) cultured under normoxic or hypoxic condition, to explore the potential effects of CD26/DPP4 on HLFs under hypoxic condition. Results: Right ventricular systolic pressure (RVSP) was significantly higher in chronic hypoxic WT than in normoxic WT mice (p < 0.001), and in Dpp4 KO than in WT mice housed under chronic hypoxic conditions (p < 0.001). The medial wall thickness of the small pulmonary vessels tended to be greater in chronically hypoxic WT than in normoxic WT mice (p = 0.085). Additionally, this effect was significantly higher in Dpp4 KO than in WT mice under chronic hypoxic condition (p < 0.0001). These data suggest that CD26/DPP4 plays a suppressive role in the development of hypoxic PH. In vitro, enrichment analysis using the transcriptome of HLFs cultured under hypoxic condition revealed that gene ontology relevant terms upregulated by DPP4 KD included “regulation of TGF-beta production,” “regulation of TGF-beta2 production,” and “extracellular matrix organization” and “TGF-beta signaling pathway” in Kyoto Encyclopedia of Genes and Genomes pathway relevant terms. TGFB2, TGFB3, and TGFA were all upregulated after DPP4 KD in HLFs cultured under hypoxic condition, suggesting that CD26/DPP4 exerts suppressive effects on fibroblast activation via the TGFβ signaling pathway in chronic hypoxic conditions. Conclusions: CD26/DPP4 may play a suppressive role in TGFβ signal-regulated fibroblast activation under hypoxic conditions and be a potential therapeutic target for PH associated with chronic hypoxia.

BACKGROUND:Chemotherapy-induced peripheral neuropathy (CIPN) and its associated pain negatively affect patient outcomes and quality of life (QoL). The two-part MiroCIP study included interventional and prospective observational studies. Here, we report the latter, describing CIPN incidence, risk factors, and outcomes. RESEARCH DESIGN AND METHODS:This 1-year, multicenter, prospective registry study (May 2021-April 2023) included patients aged ≥ 20 years with colorectal, gastric, non-small cell lung, or breast cancer who were scheduled to undergo chemotherapy with oxaliplatin or taxane. The primary endpoint was Grade ≥ 2 sensory CIPN incidence within 12 months after chemotherapy initiation. Subjective and objective symptoms, QoL, and pain were evaluated. RESULTS:Overall, 216 patients (female, 64.4%; mean age, 60.3 years) were included. Ninety-one (42.1%) and 131 (60.6%) patients received oxaliplatin- and taxane-based chemotherapy, respectively (six received both and were included in both groups). Grade ≥ 2 CIPN occurred in 96 patients (44.4%; 72.8/100 person-years), with 70.8% (68/96 patients) developing symptoms within 90 days. The most prominent CIPN symptoms were limb numbness/tingling and decreased vibration sensibility. No clinically meaningful risk factors were identified. CONCLUSIONS:We clarified CIPN incidence in cancer patients. Subjective symptoms (limb numbness/tingling, decreased vibration sensibility) and pain are important CIPN symptoms requiring careful monitoring. TRIAL REGISTRATION:jRCTs031210101.

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder that is occasionally complicated by pulmonary hypertension (PH). In most cases where PH is associated with HHT, it is typically of a post-capillary type, while pre-capillary PH is relatively rare. Herein, we report a rare case of pre-capillary PH in a 44-year-old woman. She presented with recurrent epistaxis, mucocutaneous telangiectasias, a family history of hemorrhagic events, and hepatic arteriovenous malformations. She met the four Curaçao criteria and was diagnosed with HHT. Right heart catheterization demonstrated severe pulmonary arterial hypertension in the absence of portal hypertension. Given the risks of bleeding, management of both HHT and PH presents notable challenges. In this case, treatment with riociguat improved pulmonary vascular resistance (PVR) without exacerbating epistaxis or causing other adverse effects. These findings suggest that riociguat may represent a promising therapeutic option for HHT-associated pre-capillary PH.

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary sarcoidosis with extrapulmonary lesions (EPL) confers poor prognoses. The transcriptomic features of peripheral blood mononuclear cells (PBMCs) could be crucial in sarcoidosis pathogenesis. However, the gene expression characteristics associated with EPL development remain unknown. Methods: Bulk PBMCs were collected from 26 healthy controls and 14 patients with pulmonary sarcoidosis stratified into those with (n = 9) or without (n = 5) EPL. None of the participants were receiving immunosuppressive agents. PBMC transcriptomic analysis was conducted using RNA sequencing. Results: Principal component analysis (PCA) revealed a clear distinction between pulmonary sarcoidosis and healthy control groups, with 227 differentially expressed genes (88 upregulated, 139 downregulated), including upregulated (CLEC7A, GBP5, JAK2, IL15, IL1B, CXCL8, and CXCL10) and downregulated (TNFRSF13C, CD40LG, CD28, and ID3) genes in pulmonary sarcoidosis group. Enrichment analysis revealed upregulated immunological pathways related to granuloma formation in pulmonary sarcoidosis PBMCs, including T helper 17 and tumor necrosis factor-alpha signaling pathways, IL-1B, IL-6, and IL-17 production, and response to external stimuli. Furthermore, patients with and without EPL showed 206 differentially expressed genes (131 upregulated, 75 downregulated), including upregulated (IFNG and IFNLR1) and downregulated (SOCS3, MMP9, and CXCL10) genes. Gene ontology (GO) analysis revealed that interleukin 6 (IL-6) and IL-23 production were upregulated in patients with EPL. Conclusions: These findings elucidate the mechanisms underlying granuloma formation in sarcoidosis and demonstrate the differential transcriptomic features of PBMCs in patients with and without EPL. The upregulation of IFNG and IFNLR1 may be related to EPL development and could serve as potential therapeutic targets for sarcoidosis.