Prognostic significance of radiological pleuroparenchymal fibroelastosis in Mycobacterium avium complex lung disease: a multicentre retrospective cohort study.

BACKGROUND: Mycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear. METHODS: This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models. RESULTS: Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p<0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p<0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p<0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p<0.001). INTERPRETATION: This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established.

Effect of Hypoxia on Pulmonary Endothelial Cells from Bleomycin-Induced Pulmonary Fibrosis Model Mice.

Pulmonary fibrosis is a progressive and fatal disorder characterized by dysregulated repair after recurrent injury. Destruction of the lung architecture with excess extracellular matrix deposition induces respiratory failure with hypoxia and progressive dyspnea. The impact of hypoxia on pulmonary endothelial cells during pulmonary fibrogenesis is unclear. Using a magnetic-activated cell sorting system, pulmonary endothelial cells were isolated from a mouse model of pulmonary fibrosis induced by intratracheally administered bleomycin. When endothelial cells were exposed to hypoxic conditions, a hypoxia-inducible factor (HIF)-2α protein was detected in CD31- and α-smooth muscle actin (SMA)-positive cells. Levels of plasminogen activator inhibitor 1, von Willebrand factor, and matrix metalloproteinase 12 were increased in endothelial cells isolated from bleomycin-treated mice exposed to hypoxic conditions. When endothelial cells were cultured under hypoxic conditions, levels of fibrotic mediators, transforming growth factor-ß and connective tissue growth factor, were elevated only in endothelial cells from bleomycin-treated and not from saline-treated lungs. The increased expression of α-SMA and mesenchymal markers and collagen production in bleomycin- or hypoxia-stimulated endothelial cells were further elevated in endothelial cells from bleomycin-treated mouse lungs cultured under hypoxic conditions. Exposure to hypoxia damaged endothelial cells and enhanced fibrogenesis-related damage in bleomycin-treated pulmonary endothelial cells.

[A CASE OF MILIARY TUBERCULOSIS ORIGINATED FROM CUTANEOUS INFECTION].

An 86-year-old woman with severe dementia had been treated with oral prednisolone at 2 mg/day for autoimmune bullous dermatosis for several years. One year ago, she referred to our hospital due to an ulcerative skin lesion over the right tibial tuberosity. The lesion was treated by an iodine-containing ointment, but did not heal. Subsequently, a new skin lesion appeared in the right popliteal fossa. One month ago, the patient had increased sputum production that was accompanied by fever, anorexia, and dyspnea; consequently, she visited our department. Chest computed tomography revealed diffuse micronodules with ground-glass attenuation. Acid-fast bacteria staining of the sputum was positive and the polymerase chain reaction detected Mycobacterium tuberculosis. In addition, the bacilli were also found in the skin lesions of the right limb. Therefore, a diagnosis of cutaneous, and miliary tuberculosis was made. Although the anti-tuberculous combination chemotherapy consisting of isoniazid, rifampicin, and ethambutol was immediately initiated, her condition did not improve. She died on day 19 of hospitalization. Drug susceptibility testing revealed no resistance to all the three drugs; hence, it was concluded that the time-delay in diagnosis of cutaneous tuberculosis lead to the progression to miliary tuberculosis and subsequent death.

Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. PATIENTS AND METHODS: Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. RESULTS: Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). CONCLUSION: Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.

Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas.

Genotyping epidermal growth factor receptor (EGFR) is an essential process to indicate lung adenocarcinoma patients for the most appropriate treatment. Liquid biopsy using circulating tumor DNA (ctDNA) potentially complements the use of tumor tissue biopsy for identifying genotype-specific mutations in cancer cells. We assessed the performance of a high-fidelity sequencing method that uses molecular barcodes called the nonoverlapping integrated read sequencing system (NOIR-SS) for detecting EGFR L858R-mutated alleles in 33 advanced or recurrent patients with L858R mutation-positive lung adenocarcinoma revealed by matched tissue biopsy. We compared NOIR-SS with site-specific droplet digital PCR (ddPCR), which was taken as the reference, in terms of sensitivity and ability to quantify L858R variant allele fractions (VAFs). NOIR-SS and ddPCR had sensitivities of 87.9% (29/33) and 78.8% (26/33) for detecting L858R alleles, respectively. The VAFs measured by each assay were strongly correlated. Notably, one specimen was positive with a VAF of 30.12% for NOIR-SS but marginally positive with that of 0.05% for ddPCR because of a previously poorly recognized mechanism: two-base substitution-induced L858R (c.2573_2574delinsGA). These results indicate that NOIR-SS is a useful method for detecting ctDNA, potentially overcoming a limitation of ddPCR which highly depends on the binding ability of primers to specific targeting sequences.

Body composition changes successfully classify prognosis in patients with mycobacterium avium complex lung disease.

OBJECTIVES: Loss of body weight, a manifestation of cachexia, is frequently found in patients with Mycobacterium avium complex lung disease (MAC-LD) and known as a prognostic determinant. However, the involvement of body composition changes in the prognosis of patients with MAC-LD remains unclear. METHODS: The cross-sectional-area of the erector spinea muscle (ESMCSA) and mean attenuation of the erector spinae muscles (ESMMA) in patients with MAC-LD, as determined by computed tomography imaging, were measured in two independent cohorts (137 and 111 patients, respectively). RESULTS: Patients with MAC-LD showed significantly smaller ESMCSA together with lower body mass index (BMI), but no difference in ESMMA in both cohorts compared with controls. Smaller ESMCSA, body mass index decline, and decreased ESMMA were associated with worse survival in the patients. Among them, decreased ESMMA showed prognostic significance in the multivariate analyses. Importantly, assessment by ESMMA together with BMI successfully divided the patients into three groups with distinct prognoses. CONCLUSION: Changes in body composition, especially decreased ESMMA, had prognostic significance in patients with MAC-LD. Additionally, combined assessment of ESMMA and BMI accurately predicted the prognosis of MAC-LD, which may be a helpful tool for disease management.

Lupus Pleuritis with Silicotic Nodules in the Parietal Pleura.

A 63-year-old man with occupational exposure to silica presented with cutaneous ulcer, pleuritic pain, and a fever. Laboratory data showed lymphopenia and positive serum antinuclear and anti-DNA antibodies. Computed tomography of the chest showed egg shell-like calcification of the hilar and mediastinal lymph nodes without pulmonary parenchymal involvement of silicosis. A surgical biopsy showed silicotic nodules with surrounding infiltration of lymphocytes and plasma cells in the parietal pleura. With a diagnosis of systemic lupus erythematosus (SLE), systemic corticosteroid therapy was given, which led to the resolution of symptoms and laboratory abnormalities. We discuss the relationship between silica exposure and the development of SLE.

Preexisting Interstitial Lung Disease and Lung Injury Associated with Irinotecan in Patients with Neoplasms.

BACKGROUND/AIM: The aim of this study was to reveal risk factors for lung injury following irinotecan administration for the treatment of neoplasms. PATIENTS AND METHODS: This study included 204 patients who received irinotecan from October 2005 to November 2014 and had evaluable chest CT images before initiation of irinotecan. RESULTS: Six (2.9%) patients developed lung injury and, of these, 2 had preexisting interstitial lung disease (pre-ILD). The frequency of lung injury in patients with pre-ILD was 11% (2 of 19) while that in patients without pre-ILD was 2.2%. Risk factor analysis for the lung injury showed pre-ILD was the most predictable factor [odds ratio (OR) 5.00, p=0.07]. Combination with other agents, origin of neoplasms (lung or not), initial dose or minimum interval were not observed to be related to risk. CONCLUSION: The risk of lung injury with irinotecan was high when pre-ILD was present and the risk was comparable with previously reported other agents.

Clinical impact of minocycline on afatinib-related rash in patients with non-small cell lung cancer harboring epidermal growth factor receptor mutations.

BACKGROUND: The management of skin toxicity is crucial for efficient afatinib treatment, but the role of tetracycline class antibiotics (TCs) in managing these rashes is relatively unknown. METHODS: We reviewed the clinical records of patients who were administered afatinib for the treatment of non-small cell lung cancer harboring epidermal growth factor receptor mutations between October 2014 and November 2016. Twenty-five patients, who received TCs for the management of afatinib-related skin disorders, were enrolled. RESULTS: Minocycline was administered orally to participants. Afatinib-related toxic effects, such as rash, diarrhea, and paronychia, were observed in 92%, 92%, and 40% of cases, respectively. Although 24% of diarrhea and 4% of paronychia cases were rated grade 3 or higher, no severe cases of rash were observed during afatinib treatment. Of the 18 afatinib dose reductions, 14 (78%), three (17%), and one (6%) resulted from diarrhea, paronychia, and stomatitis, respectively; no patients required a dose reduction because of rash. When minocycline treatment started, 21 patients (84%) had a rash of grade 1 or less, and three patients had a grade 2 rash. A response to afatinib was observed in 18 patients (72%) and the median duration of afatinib administration was 501 days. An adverse event related to minocycline (grade 1 nausea) was observed in one patient. CONCLUSIONS: A large proportion of the study patients started minocycline before grade 2 rash development and the severity of afatinib-related rash was lower than that previously reported. Oral TCs may be beneficial, especially if started early.

Distinctive impact of pre-existing interstitial lung disease on the risk of chemotherapy-related lung injury in patients with lung cancer.

PURPOSE: Pre-existing interstitial lung disease (pre-ILD) increases the risk of chemotherapy-related lung injury (CRLI). However, whether the risk varies by type of anti-cancer cytotoxic agent in patients with pre-ILD is unknown. In this study, we hypothesized that S-1, an oral fluoropyrimidine agent, is associated with a smaller CRLI risk than docetaxel (DTX) and investigated these agents together with radiological evaluations of pre-ILD via pre-treatment chest computed tomography (CT). METHODS: After reviewing 234 and 352 patients who underwent evaluable chest CT within 6 months prior to the administration of S-1 or DTX, respectively, from January 2006 to October 2014, 60 and 89, respectively, of these patients with pre-ILD were retrospectively analysed. RESULTS: In total, 2 persons administered S-1 (3 %) and 16 treated with DTX (18 %) developed CRLI (p = 0.007) after the initial treatment (mean, 61 days), of whom 1 and 7, respectively, died because of respiratory failure. Pre-treatment CT revealed that 9 S-1-treated patients (16 %) and 15 DTX-treated patients (17 %) had pre-ILD occupying more than 25 % of the lung field. Multivariate analysis demonstrated that DTX administration increased the risk of CRLI by 6.47-fold versus S-1 therapy (p = 0.016). Of note, the area occupied by pre-ILD was also associated with the risk of CRLI (<25 %; odds ratio 0.309, p = 0.045). CONCLUSIONS: Our results indicated that S-1 is associated with a smaller risk of CRLI than DTX. The area occupied by pre-ILD should also be noted when administrating anti-cancer agents.