Emerging trends in the coexistence of primary lung Cancer and hematologic malignancy: a comprehensive analysis of clinicopathological features and genetic abnormalities.

BACKGROUND: The incidence of multiple primary cancers (MPC), especially involving primary lung cancer (PLC) and primary hematologic malignancies (PHM), is rising. This study aims to analyze clinicopathological features, gene abnormalities, and prognostic outcomes in individuals diagnosed with PLC-PHM MPC. METHODS: A retrospective analysis included 89 patients diagnosed with PLC-PHM MPC at the Respiratory or Hematology Departments of Ruijin Hospital from 2003 to 2022 (a total of 842,047 people). Next-generation sequencing (NGS) assessed lung cancer specimens, while Polymerase Chain Reaction (PCR) and NGS were used for hematologic malignancy specimens. Statistical analysis involved survival analysis and Cox regression. RESULTS: PLC-PHM MPC incidence surged from 1.67 per year (2011-2013) to 16.3 per year (2020-2022). The primary demographic for PLC-PHM MPC consists predominantly of elderly (average age 66 years) males (59.6%), with a high prevalence of metachronous MPC (89.9%). The prevailing histological types were lung adenocarcinoma (70.8%) in lung cancer (LC) and mature B-cell lymphomas (50.6%) in hematologic malignancies (HM). Notably, in a molecular testing cohort of 38 LC patients, 84.2% of lung cancer cases exhibited driver mutations, in which EGFR mutations frequence prevalent was 74.2%. In total group of 85 cases achieved a median overall survival (mOS) of 46.2 months, with a 5-year survival rate of 37.9% and advanced LC patients with LC gene mutations achieved a mOS was 52.6 months, with a 5-year OS rate of 30.6%. The median progression-free survival (PFS) following first-line treatment of 11 advanced patients with lung cancer-associated driver gene mutations is 26.6 months. Multivariate Cox regression revealed a favorable OS associated with surgery for LC, favorable PS score, adenocarcinoma pathology of LC, and the presence of genetic abnormalities associated with HM. CONCLUSION: PLC-PHM MPC incidence is rising, characterized by a significant proportion of lung adenocarcinoma and a high prevalence of positive driver genes, especially in EGFR. Despite suffering from two primary tumors, the PLC-PHM MPC patients had superior data of both PFS and OS, suggesting an inherently intricate background of genetic abnormalities between the two kinds of tumors.

SDH mutations, as potential predictor of chemotherapy prognosis in small cell lung cancer patients.

PURPOSE: Small cell lung cancer (SCLC) is an aggressive and rapidly progressive malignant tumor characterized by a poor prognosis. Chemotherapy remains the primary treatment in clinical practice; however, reliable biomarkers for predicting chemotherapy outcomes are scarce. METHODS: In this study, 78 SCLC patients were stratified into "good" or "poor" prognosis cohorts based on their overall survival (OS) following surgery and chemotherapeutic treatment. Next-generation sequencing was employed to analyze the mutation status of 315 tumorigenesis-associated genes in tumor tissues obtained from the patients. The random forest (RF) method, validated by the support vector machine (SVM), was utilized to identify single nucleotide mutations (SNVs) with predictive power. To verify the prognosis effect of SNVs, samples from the cbioportal database were utilized. RESULTS: The SVM and RF methods confirmed that 20 genes positively contributed to prognosis prediction, displaying an area under the validation curve with a value of 0.89. In the corresponding OS analysis, all patients with SDH, STAT3 and PDCD1LG2 mutations were in the poor prognosis cohort (15/15, 100%). Analysis of public databases further confirms that SDH mutations are significantly associated with worse OS. CONCLUSION: Our results provide a potential stratification of chemotherapy prognosis in SCLC patients, and have certain guiding significance for subsequent precise targeted therapy.

Risk factors and prognostic role of renal adverse event in patients receiving immune checkpoint inhibitor therapy: analysis of data from a retrospective cohort study.

Background: Along with the widespread use of immune checkpoint inhibitors (ICIs), there has been a surge in immune-related adverse events which can limit the efficacy of ICIs. However, to date, there is a paucity of reports on renal adverse events (RAEs) related to ICIs. Therefore, this study reports the incidence, risk factors, pathological features of RAEs in patients receiving ICI therapy and its association with overall survival. Methods: The medical records of patients who received at least 1 cycle of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) monoclonal antibody (mAb) between January 1st 2018 and July 31th 2021 were retrospectively reviewed. All available serum creatinine data were extracted and used to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and RAEs were defined as a 25% decrease in eGFR from baseline. Logistic regression was used to analyze the risk factors for RAEs. The Kaplan-Meier method was used to compare the survival among patients with and without RAEs. Results: A total of 328 patients receiving ICI therapy were enrolled and 42 developed RAEs. Patients with RAEs had a lower median baseline acute monocyte count (AMC), higher median baseline ratio of lymphocyte and monocyte (LMR), were more likely to have hypertension, coronary heart disease, and distant metastasis, and were more likely to be receiving more cycles of ICI therapy. Multivariate analysis revealed that RAEs were associated with distant metastasis and the number of cycles of ICI therapy. RAEs were not associated with baseline creatinine, eGFR, ICI type, nor the line of ICI therapy. Regardless of whether patients were receiving first-line ICI therapy or non-first line ICI therapy, patients with RAEs had lower survival rates compared to patients without RAEs. Of the patients with RAEs, 2 received renal biopsies and were pathologically confirmed with acute interstitial nephritis (AIN). Conclusions: RAEs were not a rare complication in patients receiving ICIs treatment. Distant metastasis and the number of cycles of ICI therapy were associated with RAEs. Patients who developed RAEs were associated with worse survival.

Efficacy, prognosis and safety analysis of anti-PD-1/PD-L1 inhibitor rechallenge in advanced lung cancer patients: a cohort study.

Background: The rechallenge of immune checkpoint inhibitors (ICI) is now an optional strategy for patients who discontinued ICI due to immune-related adverse events (irAEs) or disease progression. However, little data is available for the prognosis and prognostic factors of patients receiving ICI rechallenge treatment in advanced lung cancer patients. Our study aimed to explore the efficacy, prognosis and safety of patients who received anti-programmed cell death-1/programmed cell death ligand 1 (anti-PD-1/PD-L1) inhibitor rechallenge. Methods: In our retrospective cohort study, data of advanced lung cancer patients who received anti-PD-1/PD-L1 inhibitor and discontinued due to irAEs or disease progression were collected from December 2016 to August 2021. Enrolled patients were categorized into two groups: rechallenge group (R group) and non-rechallenge group (NR group). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety data were analyzed. Cox model and subgroup analysis were analyzed according to baseline characteristics, ICI type, the reason for discontinuing ICI, etc. According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), evaluation was performed routinely every 6-8 weeks after initiating treatment with the PD-1/PD-L1 inhibitor. The last follow-up in the study was on September 20, 2021. Results: Eighty-one patients who met our inclusion criteria were enrolled. In the whole cohort, the R group achieved better OS than the NR group [hazard ratio (HR) =0.176; 95% confidence interval (CI): 0.065-0.477; P=0.001). In the irAEs group, the survival analyses showed a trend toward improved OS in the rechallenge subgroup (HR =0.287; 95% CI: 0.081-1.025; P=0.055), and a promising DCR of 75% after an ICI rechallenge. Additionally, the exploration of safety outcomes indicated an acceptable recurrence rate (22.5%) of irAEs and an early onset of irAEs after an ICI rechallenge. In the disease progression group, the rechallenge subgroup did not improve OS (HR =0.214; 95% CI: 0.027-1.695; P=0.144), and the DCR of the rechallenge subgroup was 40% after ICI rechallenge. Conclusions: ICI rechallenge might be an attractive option for patients who discontinue treatment due to irAEs. For patients with disease progression, further research should be conducted. The recurrence of irAEs and their early onset during the second round of ICI should be considered.

Two severe adverse events triggered by an anti-PD-1 immune checkpoint inhibitor in an advanced lung cancer patient: a case report and review of the literature.

Anti-programmed death 1 (PD-1) immune checkpoint inhibitors have produced robust tumor responses in several solid tumors including lung cancer by enhancing the antitumor activity of the immune system. In general, the adverse events triggered by anti-PD-1/PD-L1 mAbs appear to be less severe when compared with traditional chemotherapy. However, a subgroup of patients will experience various autoimmune adverse events, such as skin, gastrointestinal, pulmonary, hepatic, renal, and endocrine events, among others. In previous studies, only one irAE was reported in a patient who received immunotherapy. However, in this report, we presented an advanced non-small cell lung cancer patient who was positive for PD-L1 in 20% of tumor cells and negative for actionable molecular markers such as KRAS, EGFR, ALK, MET, and ROS1 alterations. He received a PD-1 inhibitor combined with chemotherapy according to the guidelines of the Chinese Society of Clinical Oncology (CSCO) non-small cell lung cancer [2020] and experienced severe hepatitis and pneumonitis successively, which were recovered after the treatment of systemic glucocorticoids. This situation increased the difficulty of diagnosis and treatment of immune-related adverse events (irAEs). This case illustrates the potential toxicity caused by immunotherapy, and more attention should be paid to its prevention, treatment, and association with antitumor efficacy. Multidisciplinary discussions should be undertaken to improve patient prognosis.

A narrative review of exploring potential salivary biomarkers in respiratory diseases: still on its way.

Saliva is abundant with proteins, metabolites, DNA, and a diverse range of bacterial species. During the past two decades, saliva has emerged as a novel diagnostic and evaluation medium for several diseases. Collection of saliva samples is simple, minimally invasive, and convenient even in infants, children, and patients with anxious. Furthermore, with the development of hypersensitive techniques [e.g., microsensor arrays, enzyme-labeled immunosensors, nanoparticle-labeled immunosensors, capacitive or impedimetric immunosensors, magneto immunosensors, field effect transistor immunosensors, and surface enhanced Raman spectroscopy (SERS)], the sensitivity and accuracy of saliva diagnostic procedures have been improved. Nowadays, saliva has been used as a potential medium for several disease diagnosis and assessment, such as periodontitis, caries, cancers, diabetes mellitus, and cardiovascular diseases. Saliva has been used widely for studying microbiomics, genomics, transcriptomics, proteomics, and metabolomics of respiratory diseases, however, the use of salivary biomarkers for the diagnosis, prognosis, and monitoring of respiratory disease is still in its infancy. Herein, we review the progress of research on salivary biomarkers related to several respiratory diseases, including bronchial asthma, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), pneumonia, tuberculosis (TB), Langerhans cell histiocytosis (LCH) and cystic fibrosis (CF). Furthermore, several limitations of saliva test such as the lack of standard protocol for saliva collection and reasonable reference values for saliva test are also mentioned in this review.

EGFR/BRAF/MEK co-inhibition for EGFR-mutated lung adenocarcinoma patients with an acquired BRAFV600E mutation: a case report and review of literature.

Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), most advanced non-small-cell lung cancers (NSCLCs) progress eventually due to therapeutic resistance. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs. In the presented case, BRAFV600E mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib (a third-generation EGFR-TKI). The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAFV600E mutation, consistent with the review of the literature (eight cases). Additionally, our case highlights the important role of sample type, method, and platform of gene detection in patient management, life quality, and prognosis, as well as the understanding of acquired resistance mechanism.

Gender differences of chronic obstructive pulmonary disease associated with manifestations on HRCT.

BACKGROUND AND AIMS: Patients with chronic obstructive pulmonary disease (COPD) have been shown to have significant gender differences in terms of susceptibility, severity and response to therapy. We hypothesized that this was due to differences in functional and pathologic changes in the airway, which can be revealed by high-resolution computed tomography (HRCT) in addition to pulmonary function test (PFT). METHODS: A total of 84 patients with COPD were enrolled in the study. Within 1 week of enrollment, a history of each patient's current illness was obtained. PFT and chest HRCT scan were performed. RESULTS: The patients were classified as phenotype A, E and M based on the chest HRCT presentations. No significant gender differences were found in COPD severity (χ2 = 4.993, P = 0.172). Male patients have more smoking history and smaller average age compared with female patients. Female patients showed a significantly higher FEV1 /FVC, lower inspiratory capacity and milder residual volume/total lung capacity than that of male patients. Based on the HRCT results, more males were classified as phenotype M, whereas females tended to be phenotype A. Males had a greater grade of low attenuation areas and were more likely to show evidence of emphysema on a HRCT scan than females (χ2 = 15.373, P = 0.001), whereas females had less airway wall thickening than males, although this change had no statistical significance. (χ2 = 0.163, P = 0.922). CONCLUSION: Gender differences of COPD patients were seen in ages of onset, smoking history, and PFT and HRCT presentations. The use of HRCT imaging indicates that there are significant gender differences in the clinical manifestations of COPD.

Low-dose theophylline restores corticosteroid responsiveness in rats with smoke-induced airway inflammation.

Patients with chronic obstructive pulmonary disease (COPD) respond poorly to corticosteroids. Histone deacetylase-2 (HDAC-2) plays a pivotal role in many cases of steroid insensitivity. The main aim of this study was to restore the smoking-induced reduction in corticosteroid sensitivity by increasing HDAC-2 activity using low-dose theophylline. Rats were exposed to cigarette smoke (CS) and treated with budesonide and two doses of theophylline. Besides the pathologic examination and cell counting in the bronchoalveolar lavage fluid (BALF), the expression of HDAC-2 and CXC chemokine ligand-8 (CXCL-8) were measured. Airway inflammation induced by CS was demonstrated by pathologic changes of lung tissue and increased level of CXCL-8. CS exposure also markedly decreased HDAC-2 expression. Moreover, a negative correlation was found between HDAC-2 activity and a lung destruction index. The index was restored to control levels with inhaled corticosteroid treatment in combination with a low, not a high, dose of theophylline. These results indicate that low-dose theophylline might provide protection from smoke damage and improve the anti-inflammatory effects of steroids by increasing HDAC-2 activity.

[Characteristics of chronic obstructive pulmonary disease phenotypes based on high-resolution CT and the relationship with interleukin-6].

OBJECTIVE: To classify the high-resolution CT (HRCT) phenotypes of COPD, and to investigate the clinical characteristics of various phenotypes and the relationship with airway inflammation. METHODS: Chest HRCT and pulmonary function tests were performed in 84 COPD patients. The patients were classified into 3 phenotypes according to the visual HRCT findings. Exhaled breath condensate was gathered from 30 patients and the interleukin (IL)-6 level was measured by ELISA. RESULTS: The COPD patients were classified into 3 phenotypes: Phenotype A, absence of emphysema, with or without bronchial wall thickening (n = 34); Phenotype E, emphysema without bronchial wall thickening (n = 23); and Phenotype M, emphysema with bronchial wall thickening (n = 27). The 3 phenotypes of COPD showed different characteristics in several aspects. Patients with phenotype A showed a higher body mass index [(25.1 +/- 4.4) kg/m(2) vs phenotype E (22.5 +/- 4.1) kg/m(2) and phenotype M (21.3 +/- 3.4) kg/m(2), F = 6.732, P < 0.01]. The prevalence of patients with milder dyspnea was lower in phenotype A compared with others (15/34) vs phenotype E (2/23) and phenotype M (6/27), chi(2) = 9.097, P < 0.05. The patients who complained of severe expectoration in phenotype E were fewer than those in other groups (0/23) vs phenotype A (2/34) and phenotype M (4/27), chi(2) = 8.702, P < 0.05. The FEV(1)/FVC and FEV(1)% in phenotype M [(53 +/- 14)% and (51 +/- 25)%] were significantly lower as compared with those in other phenotypes [(67 +/- 11)% and (72 +/- 24)% in phenotype A, and (53 +/- 14)% and (52 +/- 26)% in phenotype E], F = 10.252, F = 6.508, P < 0.01. The ratio of inspiratory capacity to total lung capacity (IC/TLC) in phenotype A was higher [phenotype A (41 +/- 17)%, phenotype E (33 +/- 13)%, phenotype M (28 +/- 13)%, F = 5.964, P < 0.01], while the ratio of residual volume to total lung capacity (RV/TLC) was lower [phenotype A (37 +/- 9)%, phenotype E (44 +/- 10)%, phenotype M (45 +/- 8)%, F = 6.954, P < 0.01]. Patients with different phenotypes showed various levels of IL-6 in exhaled breath condensate [phenotype A (19.9 +/- 6.3) ng/L, phenotype E (16.7 +/- 2.1) ng/L, phenotype M (25.6 +/- 4.4) ng/L, F = 7.749, P < 0.01]. CONCLUSION: Various morphological phenotypes of COPD based on HRCT showed different clinical characteristics and airway inflammation.