Percutaneous transthoracic needle biopsy of lung lesions is a safe method associated with a very low risk of pleural recurrence.

AIM: Percutaneous transthoracic needle biopsy (PTNB), an alternative to bronchoscopic confirmation of lung lesions, is today being associated with a risk of pneumothorax and hemorrhage. Further, there are no data on the possible risk of malignant disease spreading to the pleura at the site of the PTNB. Previous studies have dealt with this risk in stage I non-small cell lung cancer only. The aim of this study was thus to assess the risk of pleural recurrence for all types of lung lesions. Secondary objectives included assessment of diagnostic yield and safety with respect to the incidence of pneumothorax and hemorrhage. METHODS: Clinical data of all patients from the University Hospital in Pilsen who had undergone PTNB of lung lesions between 1.1.2018 and 31.12.2022 were included in this retrospective study. RESULTS: Following PTNB, ipsilateral pleural effusion occurred in 4.8% of patients without prior pleural infiltration. The effusion was confirmed as malignant in one patient (0.7%). Diagnostic yield of the method was 86.6%. We recorded pneumothorax or hemorrhage in the lung parenchyma or pleural space requiring medical intervention in 3.4% and 1.1% of patients, respectively. CONCLUSION: In our study, percutaneous transthoracic needle biopsy of lung lesions showed high sensitivity and low degree of acute complications requiring an invasive solution. The risk of pleural recurrence after a biopsy was very low. Consequently, we continue to consider this method to be an alternative to bronchoscopy biopsies.

Targeted inhibition of NRF2 reduces the invasive and metastatic ability of HIP1 depleted lung cancer cells.

BACKGROUND: Non-Small Cell Lung Cancer (NSCLC) presents as a highly metastatic disease with Kras and P53 as prevalent oncogenic driver mutations. Endocytosis, through its role in receptor recycling and enrichment, is important for cancer cell proliferation and metastasis. Huntingtin Interacting Protein 1 (HIP1) is a clathrin mediated endocytic adapter protein found overexpressed in different cancers. However, conflicting roles both as a tumour promoter and suppressor are reported. HIP1 expression is found repressed at advanced stages and some HIP1-ALK fusions are reported in NSCLC patients. However, the molecular mechanisms and implications of HIP1 depletion are not completely understood. METHODS: HIP1 depletion was performed using siRNA transient transfection and validated using immunoblotting for each experiment. Gene expression dataset from TCGA, GTEX and GEO databases was analysed to explore HIP1 expression in Lung cancer patients. Kaplan-Meier Plotter database was used to analyse the survival correlation between HIP1 mRNA expression in lung cancer patients. HIP1 depleted A549 cells were analysed for deregulated global proteome using label-free LC-MS and this data is available via ProteomeXchange with identifier PXD054307. Various functional assays such as matrigel based invasion, trans-well migration, soft agar colony and angiogenesis tube formation were performed after HIP1 depletion. NRF2 inhibitor was used after HIP1 knockdown to assess its effect on invasion and soft agar colony formation. RESULTS: In silico analysis of HIP1 transcript expression reveals that it is reduced in high-grade and metastatic lung cancer patients correlating with poor survival. Global proteome profiling reveals that HIP1 depleted A549 cells are enriched in pathways associated with metabolism, proliferation and survival. Molecular and functional analysis indicate higher invasive ability of HIP1 depleted cells. The secretome from HIP1 depleted cells also increases the angiogenic potential of HUVEC cells. NRF2 inhibition significantly reverses invasion of HIP1 depleted NSCLC cells with different driver mutations. CONCLUSION: Our study shows that HIP1 depletion leads to activation of various molecular pathways responsible for cell proliferation and survival. Additionally, enhancement of invasion and anchorage-independent growth in HIP1 depleted subsets of NSCLC cells is via upregulation of NRF2 and can be reversed by its inhibitor.

Stage-Specific Guideline Concordant Treatment Impacts on Survival in Nonsmall Cell Lung Cancer: A Novel Quality Indicator.

BACKGROUND: Lung cancer in Australia contributes 9% of all new cancer diagnoses and is the leading cause of cancer death and burden. Clinical practice guidelines provide evidence-based treatment recommendations for best practice management. We aimed to determine the extent of delivery of guideline-concordant treatment (GCT) and to identify modifiable variables influencing receipt of GCT and survival. METHODS: Data was sourced from the Victorian Lung Cancer Registry (VLCR) in Victoria, Australia. Descriptive statistics were used to summarize patient and disease characteristics according to treatment type: GCT versus non-GCT versus no/declined treatment. Statistical analyses included multiple logistic regression, multiple COX regression and Kaplan-Meier survival estimates. RESULTS: 52% of patients were treated with GCT, 32.8% non-GCT and 15.2% declined or received no treatment. GCT treated patients were younger, never smoked, had no comorbidities, had better performance status, had early stage cancer, were discussed at a multidisciplinary meeting or had treatment at a higher volume hospital. Overall, patients that received GCT had a 24% lower risk of mortality compared to patients that received non-GCT. CONCLUSION: Modifiable variables impacting likelihood of receiving GCT included age, smoking status and treating hospital characteristics. Several modifiable variables were identified with positive impacts on survival including increased treatment of the elderly, smoking cessation, delivery of GCT, and treatment in higher volume hospitals. The measurement and reporting of delivery of GCT has positive impacts on survival and therefore merits consideration as an evidence-based quality indicator in the reporting of lung cancer quality and safety outcomes.

Radiomics-based Support Vector Machine Distinguishes Molecular Events Driving Progression of Lung Adenocarcinoma.

INTRODUCTION: An increasing number of early-stage lung adenocarcinoma (LUAD) are detected as lung nodules. The radiological features related to LUAD progression remain further investigation. Exploration is required to bridge the gap between radiomics features and molecular characteristics of lung nodules. METHODS: Consensus clustering was applied to the radiomics features of 1,212 patients to establish stable clustering. Clusters were illustrated using clinicopathological and next-generation sequencing (NGS). A classifier was constructed to further investigate the molecular characteristic in patients with paired CT and RNA-seq data. RESULTS: Patients were clustered into 4 clusters. Cluster 1 was associated with a low consolidation-to-tumor ratio (CTR), pre-invasion, grade I disease and good prognosis. Clusters 2 and 3 showed increasing malignancy with higher CTR, higher pathological grade and poor prognosis. Cluster 2 possessed more spread through air spaces (STAS) and cluster 3 showed higher proportion of pleural invasion. Cluster 4 had similar clinicopathological features with cluster 1 except higher proportion of grade II disease. RNA-seq indicated that cluster 1 represented nodules with indolent growth and good differentiation, whereas cluster 4 showed progression in cell development but still had low proliferative activity. Nodules with high proliferation were classified into clusters 2 and 3. Additionally, the radiomics classifier distinguished cluster 2 as nodules harboring an activated immune environment, while cluster 3 represented nodules with a suppressive immune environment. Furthermore, gene signatures associated with the prognosis of early-stage LUAD were validated in external datasets. CONCLUSION: Radiomics features can manifest molecular events driving progression of lung adenocarcinoma. Our study provides a molecular insight into radiomics features and assists in the diagnosis and treatment of early stage LUAD.

Early Mortality After Curative-intent Radiotherapy in Patients With Locally Advanced Non-small Cell Lung Cancer-A Population-based Cohort Study.

AIMS: In patients with locally advanced non-small cell lung cancer (LA-NSCLC), curative-intent radiotherapy (RT) or chemoradiotherapy (CRT) is associated with considerable toxicity, and approximately half of the patients die within two years. A better understanding of early mortality is needed to improve patient selection and guide supportive interventions. In this population-based, nationwide cohort study, we investigated the incidence, temporal distribution, and risk factors of early mortality. MATERIALS AND METHODS: Patients with stage II-III NSCLC treated with curative-intent RT/CRT in Denmark from 2010-2017 were included. Patients treated with preoperative or postoperative RT/CRT or stereotactic body radiation therapy were excluded. Early mortality was defined as all-cause death within 180 days from RT/CRT initiation. Multiple logistic regression was used to assess the impact of clinical and demographic variables. RESULTS: We included 1742 patients. The early mortality rate was 10%. The temporal distribution of deaths was uniform across the first year following RT/CRT, indicating the absence of a high-risk period. In multivariable analysis, increasing age and performance status, male sex, and unspecified histology (NSCLC not otherwise specified) were associated with an increased risk. By contrast, the Charlson Comorbidity Index (CCI), TNM stage, and treatment period did not significantly alter the risk of early mortality. Overall survival rates improved throughout the inclusion period but early mortality rates did not. CONCLUSION: No high-risk period for early mortality could be identified. Early mortality was not associated with CCI and other tools should be explored to quantify comorbidity for risk stratification in this setting.

Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC).

BACKGROUND: Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. METHODS: In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. RESULTS: In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DISCUSSION: Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

Mechanisms of primary resistance to immune checkpoint inhibitors in NSCLC.

Immune checkpoint inhibitors (ICIs) redefined the therapeutics of non-small cell lung cancer (NSCLC), leading to significant survival benefits and unprecedented durable responses. However, the majority of the patients develop resistance to ICIs, either primary or acquired. Establishing a definition of primary resistance to ICIs in different clinical scenarios is challenging and remains a work in progress due to the changing landscape of ICI-based regimens, mainly in the setting of early-stage NSCLC. The mechanisms of primary resistance to ICIs in patients with NSCLC include a plethora of pathways involving a cross-talk of the tumor cells, the tumor microenvironment and the host, leading to the development of an immunosuppressive phenotype. The optimal management of patients with NSCLC following primary resistance to ICIs represents a significant challenge in current thoracic oncology. Research in this field includes exploring other immunotherapeutic approaches, such as cancer vaccines, and investigating novel antibody-drug conjugates in patients with NSCLC.

Functional resilience and overall survival in adults treated for advanced non-small-cell lung cancer.

PURPOSE: As more treatments emerge for advanced, stage IV non-small-cell lung cancer (NSCLC), oncologists have difficulty predicting functional resiliency versus functional decline throughout cancer treatment. Our study evaluates functional resilience among patients with advanced NSCLC. METHODS: Functional status was evaluated through 12 months of follow-up based on disability score using the modified EQ-5D-5L (mEQ-5D-5L) survey. Participants were classified into 4 groups: functional maintenance, decline, resilient, or variable. Characteristics of 207 participants with newly diagnosed NSCLC included demographics, comorbidities, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), mEQ-5D-5L scores, psychological symptoms, and lung cancer-specific symptoms. Treatment toxicity and grade were recorded. Resilience was defined as improvement from baseline disability scores. A 1-point increase in functional status score represents a 0.5 standard deviation change on the mEQ-5D-5L. Differences between the 4 groups were determined through Fisher's exact test or ANOVA. Kaplan-Meier curves describe overall survival (baseline through 18 months) stratified by baseline mEQ-5D-5L scores. RESULTS: Among participants, 42.0 % maintained functional status, 37.7 % experienced functional decline, 10.6 % were resilient, and 9.7 % had variable functional status. Participants with the best baseline function (score of 0) had the longest overall survival and participants with the worst baseline function (score of 5 + ) had the shortest overall survival. Among the healthiest patients, early score increases indicated shorter overall survival. Baseline ECOG PS was not associated with overall survival (p = 0.47). CONCLUSION: Baseline functional status may help better predict functional resiliency and overall survival than ECOG PS among patients receiving treatment for advanced NSCLC.

Low-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by boosting MHC I expression in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a highly aggressive type of lung cancer with poor responses to traditional therapies such as surgery, radiotherapy, and chemotherapy. While immunotherapy has become an effective approach for treating multiple types of cancer, solid tumors frequently exhibit immune escape through various mechanisms, including downregulation of MHC I expression. However, whether the upregulation of MHC I expression can improve the immunotherapeutic effect on NSCLC remains unexplored. Suberoylanilide hydroxamic acid (SAHA) is a potent histone deacetylase (HDAC) inhibitor that has been applied clinically to treat lymphoma, but a high dose of SAHA kills tumor cells and normal cells without preference. Here, we report that low-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by upregulating MHC I expression in NSCLC cells. METHODS: Flow cytometric analysis, quantitative real-time PCR and western blot were used to analyze the expression of MHC I, STAT1 and Smad2/3 in both human and mouse NSCLC cell lines after SAHA treatment. The nuclear translocation of phosphorylated STAT1 and Smad2/3 was investigated by western blot and immunofluorescence staining. The mechanisms underlying STAT1 and Smad2/3 upregulation were analyzed through database searches and chromatin immunoprecipitation-qPCR. Finally, we assessed the antitumor effect of specific CD8+ T cells with SAHA treatment in vivo and in vitro. RESULTS: We showed that low-dose SAHA upregulated the expression of MHC I in NSCLC cell lines without affecting cell viability. We also provided evidence that high levels of MHC I induced by SAHA promoted the activation, proliferation, and cytotoxicity of specific CD8+ T cells in mouse models. Mechanistically, low-dose SAHA increased the levels of H3K9ac and H3K27ac in the promoters of the STAT1, Smad2 and Smad3 genes in NSCLC cells by inhibiting HDAC activity, resulting in elevated expression levels of STAT1, Smad2 and Smad3. The nuclear translocation of phosphorylated STAT1 and Smad2/3 markedly upregulated the expression of MHC I in NSCLC cells. CONCLUSIONS: Low-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by boosting MHC I expression in NSCLC cells. Thus, we revealed a key mechanism of SAHA-mediated enhanced antitumor immunity, providing insights into a novel immunotherapy strategy for NSCLC.

Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines.

The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.

Long-term progression-free survival in non-small cell lung cancer patients: a spotlight on bevacizumab and its biosimilars.

INTRODUCTION: In the era of immunotherapy, bevacizumab seems to be losing its place in NSCLC treatment algorithms. The aim of this work is to try to define the advantages and disadvantages of NSCLC treatment with bevacizumab in combination regimens. AREAS COVERED: We conducted a literature search in PubMed and Google Scholar to review the most important topics regarding bevacizumab treatment in NSCLC, with or without driver mutations, including trials with checkpoint inhibitors. Special emphasis was placed on the analysis of data on the treatment of patients with CNS metastases. EXPERT OPINION: Bevacizumab is an antiangiogenic compound whose addition to chemotherapy made the first major breakthrough in the treatment of NSCLC. However, for the last 10 years or so, the use of combination immunotherapy regimens has suppressed the use and acquisition of new knowledge about bevacizumab. Newer data are primarily related to the treatment of EGFR-positive NSCLC patients with bevacizumab, with only a few larger studies investigating the use of a combination of bevacizumab and checkpoint inhibitors. The basic task remains to define the place of bevacizumab in treatment algorithms.

Development and characterisation of [18F]TTDP, a novel T cell immunoglobulin and ITIM domain tracer, in humanised mice and non-human primates.

PURPOSE: The T cell immunoglobulin and ITIM domain (TIGIT) blockade immunotherapy response is directly associated with individual differences of TIGIT expression on tumour-infiltrating lymphocytes (TILs) in tumour immune microenvironment (TIME) of non-small cell lung cancer (NSCLC). Here, we developed a TIGIT-targeted PET tracer to evaluate its feasibility in predicting immunotherapy efficacy, aiming to manage NSCLC patients accurately. METHODS: We synthesised a 18F-labeled TIGIT-targeted D-peptide, [18F]TTDP, and investigated the specificity of [18F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [18F]TTDP PET imaging was performed in humanised immune system (HIS) mice models bearing NSCLC patient-derived xenografts (PDXs) to evaluate the predictive value of FDA-approved combination immunotherapy of atezolizumab plus tiragolumab. Lastly, rhesus macaque was applied for [18F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates. RESULTS: [18F]TTDP showed high specificity for both murine TIGIT and human TIGIT in vitro and in vivo. The HIS NSCLC PDX platform was successfully established for [18F]TTDP PET imaging, and tumour uptake of [18F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [18F]TTDP PET imaging, in predicting treatment response to the combination immunotherapy in NSCLC HIS-PDX models, showed a sensitivity of 83.33% and a specificity of 100%. In addition, [18F]TTDP PET also showed cross-species consistency of the tracer biodistribution between non-human primate and murine animals, and no adverse events were observed. CONCLUSION: The combined implementation of the [18F]TTDP and HIS-PDX model creates a state-of-the-art preclinical platform that will impact the identification and validation of TIGIT-targeted PET image-guided diagnosis, treatment response prediction, beneficial patient screening, novel immunotherapies, and ultimately the outcome of NSCLC patients. We first provided in vivo biodistribution of [18F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.

Deep learning-based image analysis predicts PD-L1 status from 18F-FDG PET/CT images in non-small-cell lung cancer.

Background: There is still a lack of clinically validated biomarkers to screen lung cancer patients suitable for programmed dead cell-1 (PD-1)/programmed dead cell receptor-1 (PD-L1) immunotherapy. Detection of PD-L1 expression is invasively operated, and some PD-L1-negative patients can also benefit from immunotherapy; thus, the joint modeling of both deep learning images and clinical features was used to improve the prediction performance of PD-L1 expression in non-small cell lung cancer (NSCLC). Methods: Retrospective collection of 101 patients diagnosed with pathology in our hospital who underwent 18F FDG PET/CT scans, with lung cancer tissue Tumor Propulsion Score (TPS) ≥1% as a positive expression. Lesions were extracted after preprocessing PET/CT images, and using deep learning 3D DenseNet121 to learn lesions in PET, CT, and PET/CT images, 1,024 fully connected features were extracted; clinical features (age, gender, smoking/no smoking history, lesion diameter, lesion volume, maximum standard uptake value of lesions [SUVmax], mean standard uptake value of lesions [SUVmean], total lesion glycolysis [TLG]) were combined for joint modeling based on the structured data Category Embedding Model. Results: Area under a receiver operating characteristic (ROC) curve (AUC) and accuracy of predicting PD-L1 positive for PET, CT, and PET/CT test groups were 0.814 ± 0.0152, 0.7212 ± 0.0861, and 0.90 ± 0.0605, 0.806 ± 0.023, 0.70 ± 0.074, and 0.950 ± 0.0250, respectively. After joint clinical feature modeling, the AUC and accuracy of predicting PD-L1 positive for PET/CT were 0.96 ± 0.00905 and 0.950 ± 0.0250, respectively. Conclusion: This study combines the features of 18F-FDG PET/CT images with clinical features using deep learning to predict the expression of PD-L1 in NSCLC, suggesting that 18F-FDG PET/CT images can be conducted as biomarkers for PD-L1 expression.

Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism of Protopanaxadiol Triphenylphosphate Derivative in Non-Small-Cell Lung Cancer.

The objective of this study was to enhance the membrane permeability and anticancer effectiveness of (20S)-protopanaxadiol (PPD) by introducing triphenylphosphonium into the OH group at the C-3 site. This study shows that the anti-proliferation activity of CTPPPPD, with an IC50 value of 1.65 ± 0.10 µmol/L, was 33-times better than that of PPD (with an IC50 value of 54.56 ± 4.56 µmol/L) and superior to that of cisplatin (with an IC50 value of 1.82 ± 0.25 µmol/L) against A549 cells. Biological examinations suggested that CTPPPPD treatment reduced the growth rate of A549 cells, increased the permeability of cell membranes, and changed the structure of chromosomal DNA in a concentration-dependent manner. Annexin V/PI assay and flow cytometry were employed to detect the effect of CTPPPPD on the apoptosis of A549 cells. The results showed that CTPPPPD could induce the apoptosis of A549 cells, and the apoptosis rate of A549 cells treated with 0, 1.0, 2.0, and 4.0 µM of CTPPPPD for 24 h was 0%, 4.9%, 12.7%, and 31.0%, respectively. The integration of transcriptomics and metabolomics provided a systematic and detailed perspective on the induced antitumor mechanisms. A combined analysis of DEGs and DAMs suggested that they were primarily involved in the central carbon metabolism pathway in cancer, as well as the metabolism of aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate. Central carbon metabolism in cancer-related genes, i.e., SLC16A3, FGFR3, LDHA, PGAM1, and SLC2A1, significantly reduced after treatment with CTPPPPD. In particular, the dominant mechanism responsible for total antitumor activity may be attributed to perturbations in the PI3K-AKT, MAPK, and P53 pathways. The findings derived from transcriptomics and metabolomics were empirically confirmed through q-PCR and molecular docking. Further analyses revealed that CTPPPPD could be a promising lead for the development of protopanaxadiol for non-small-cell lung cancer (NSCLC) drugs.

Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors.

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFRL858R/T790M/C797S with an IC50 value of 0.005 µM, and exhibited anti-proliferation activity in BaF3-EGFRL858R/T790M/C797S cells with the IC50 value of 0.865 µM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFRL858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFRL858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.

Immune checkpoint inhibitor-induced cholangitis-a three-case series.

Over the last decade, immune checkpoint inhibitors (ICIs) have dramatically improved the systemic treatment of multiple solid tumour types. However, they can also induce inflammation in an extensive range of normal tissues types. The entity of ICI-induced cholangitis is rare and has not been widely described. We present three cases of ICI-induced cholangitis which illustrate the difficulties associated with its diagnosis and management. We also present associated radiological findings that include intrahepatic duct abnormalities consistent with sclerosing cholangitis-progressive worsening of intrahepatic duct dilatation and pericholecystic haziness suggesting inflammation characteristic of this rare, but severe, toxicity.

Safety and Efficacy of Neoadjuvant Chemoimmunotherapy versus Chemotherapy for Non-Small Cell Lung Cancer Undergoing Sleeve Resection.

The prognosis of locally advanced non-small cell lung cancer (NSCLC) remains poor despite the addition of neoadjuvant chemotherapy, as it has been shown to improve 5-year absolute benefit survival by only 5%. Recently, neoadjuvant immunotherapy with immune checkpoint inhibitors (ICIs), combined with chemotherapy has shown promise in the treatment of locally advanced NSCLC. For NSCLC invading the main bronchus, sleeve resection has become the preferred modality to avoid pneumonectomy and reserve more cardiac or pulmonary function and to reduce postoperative morbidity and mortality. However, there has been a paucity of evidence to evaluate the safety and efficacy of neoadjuvant chemoimmunotherapy on bronchial-vascular reconstruction owing to the limited number of patients treated by sleeve lobectomy. Despite promising initial results, key knowledge gaps remain, including the impact on bronchial-vascular reconstruction, biomarkers predictive of ICI response, and the potential for specific perioperative complications associated with neoadjuvant chemoimmunotherapy in the context of sleeve resection. This review summarizes the latest literature evidence on the efficacy and safety of neoadjuvant chemoimmunotherapy approaches to address the unmet needs of sleeve resection of NSCLC treatment, describes the biomarkers predictive of ICI responses, and perioperative outcomes of sleeve resection after neoadjuvant chemoimmunotherapy.

Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the "last patient in" date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23-0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08-0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Contemporary Video-Assisted Thoracoscopic Lobectomy for Early-Stage Lung Cancer.

The treatment of non-small cell lung cancer (NSCLC) has evolved tremendously in recent decades as innovations in medical therapies advanced concomitantly with minimally invasive surgical techniques. Despite early skepticism regarding its benefits, video-assisted thoracoscopic surgery (VATS) techniques for the surgical resection of early-stage NSCLC have now become the standard of care. After being the subject of many studies since its inception, VATS has been shown to cause less postoperative pain, have shorter recovery time, and have fewer overall complications when compared to conventional open approaches. Furthermore, some studies have shown it to have comparable oncological outcomes, though more higher evidence studies are needed. Newer technologies and improved surgical instruments, advancements in nodule localization techniques, and improved preoperative staging procedures have allowed for the development of newer, less invasive techniques such as uniportal VATS and parenchymal-sparing sublobar resections, which might further improve postoperative rates of complications in specific cases. These minimally invasive approaches have allowed surgeons to offer surgery to high-risk patients and those who would otherwise not tolerate conventional thoracotomy, though some relative contraindications still exist. This review aims to describe the evolution of VATS lobectomy, current techniques, its indications, contraindications, preoperative testing, benefits, and outcomes in patients with stage I and II NSCLC.