The overexpression of programmed cell death ligand 1 (PD-L1), a critical immune checkpoint protein, is associated with poor prognosis and reduced survival in lung cancer patients. Monoclonal antibodies targeting the PD-1/PD-L1 axis have been approved to disrupt this interaction and prevent immune cell exhaustion. Herein, to enhance the efficacy of PD-1/PD-L1 blockade, we investigated a bispecific αPD-L1 × αCD3 protein engager (αPD-L1 × αCD3 BIPE). The αPD-L1 × αCD3 BIPE consists of an anti-CD3 single-chain variable fragment (scFv) linked to an anti-PD-L1 scFv, allowing it to bind to CD3-positive T cells simultaneously and PD-L1-overexpressing cancer cells. In co-culture assays with T cells and non-small cell lung cancer (NSCLC) cell lines-A549, NCI-H460, and NCI-H1975-treatment with the BIPE significantly enhanced T-cell-mediated cytotoxicity. The killing efficiency correlated with PD-L1 expression levels, with the highest cytotoxic activity observed in NCI-H1975 (high PD-L1 expression), followed by NCI-H460 (moderate PD-L1 expression) and A549 (low PD-L1 expression). Furthermore, combining the BIPE with the standard chemotherapeutic agent gemcitabine further improved anti-tumor activity. This effect was likely due to gemcitabine-induced upregulation of PD-L1 and MHC class I expression on cancer cells, enhancing T-cell recognition and cytotoxicity. These findings suggest that combining αPD-L1 × αCD3 BIPE with gemcitabine is promising for enhancing immune checkpoint blockade and augmenting anti-tumor immunity in NSCLC.

Lung adenocarcinoma (LUAD) is driven by epidermal growth factor receptor (EGFR) mutations, making it a key therapeutic target. ADAM9, a member of the A disintegrin and metalloproteinase (ADAM) family, facilitates the release of growth factors and was implicated in activating the EGFR-mediated progression in several cancer types. In this study, we explored potential associations among ADAM9 single-nucleotide polymorphisms (SNPs), the EGFR mutation status, and the clinicopathological progression of LUAD in a Taiwanese population. In total, 535 LUAD patients with various EGFR statuses were enrolled, and allelic distributions of ADAM9 SNPs-located in promoter and intron regions, including rs78451751 (T/C), rs6474526 (T/G), rs7006414 (T/C), and rs10105311 (C/T)-were analyzed using a TaqMan allelic discrimination assay. We found that LUAD patients with at least one polymorphic G allele in ADAM9 rs6474526 had a lower risk of developing EGFR mutations compared to those with the wild-type (WT) TT genotype. Furthermore, G-allele carriers (TG + GG) of rs6474526 were associated with an increased likelihood of developing larger tumors (T3 or T4), particularly among patients with mutant EGFR. Conversely, in patients with WT EGFR, carriers of the T allele in rs10105311 had a lower risk of progressing to advanced stages (stage III or IV). Among females or non-smokers, G-allele carriers of rs6474526 demonstrated a higher risk of advanced tumor stages and distant metastases. In clinical data from the Genotype-Tissue Expression (GTEx) database, individuals with the polymorphic T allele in rs6474526 showed reduced ADAM9 expression in lung and whole blood tissues. Screening the genotype of rs6474526 in a set of LUAD cell lines revealed that cells carrying at least one minor G allele exhibited higher ADAM9 levels compared to those with the TT genotype. Additionally, analyses using TCGA and CPTAC databases revealed elevated ADAM9 expression in LUAD specimens compared to normal tissues. Elevated protein levels were correlated with advanced T stages, pathological stages, and worse prognoses. In summary, our results suggest that ADAM9 genetic variants of rs6474526 may affect ADAM9 expression and are associated with the EGFR mutation status. Both rs6474526 and rs10105311 were correlated with disease progression in LUAD patients. These variants could serve as potential biomarkers for predicting clinical outcomes.

With the rapid advancements in second-generation gene sequencing technologies, a growing number of driver genes and associated therapeutic targets have been unveiled for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). While they are clinically classified as non-small cell lung cancer (NSCLC), they display distinct genomic features and substantial variations in clinical efficacy, underscoring the need for particular attention. Hence, this review provides a comprehensive overview of the latest advancements in driver genes, epigenetic targets, chemotherapy, targeted therapy, and immunotherapy for LUAD and LUSC. Additionally, it delves into the distinctions in signaling pathways and pivotal facets of clinical management specific to these two categories of lung cancer. Moreover, we furnish pertinent details regarding clinical trials pertaining to driver genes and epigenetics, thus establishing a theoretical foundation for the realization of precision treatments for LUAD and LUSC.

This study analyzed prognostic factors in patients with lung adenocarcinoma and bone metastases who tested positive for epidermal growth factor receptor (EGFR) mutations.

We retrospectively reviewed the records of 117 patients with lung adenocarcinoma and bone metastases who were followed up at a single institution for 0.2 months to 66 months. Of these 117 patients, 45 were EGFR mutation-positive and further analysis was performed for these patients. Median survival times and five-year survival rates were investigated according to performance status (PS), oligometastatic status, radiotherapy and EGFR-tyrosine kinase inhibitor (TKI) administration.

The five-year survival rate of EGFR mutation-positive patients was 9.2%, and median survival time was 22.7 months; their mean age was 69.5 years. Many EGFR mutation-positive patients had a PS of 2, and the median survival time showed significant differences according to PS (0/1/2 vs. 3/4) and oligometastatic status.

Although there was no difference in the mean survival time between patients receiving or not receiving bone radiotherapy, the treatment effectively reduced pain and prevented paralysis. As a first-line treatment in EGFR mutation-positive patients, first- or second-generation TKIs followed by third-generation TKIs showed favorable outcomes.

TP53 is the most frequently mutated gene in non-small-cell lung cancer. Although TP53 co-mutation is associated with poor responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutated adenocarcinoma, its impact in resected early-stage lung adenocarcinoma remains unclear. In this study, we evaluated the effect of TP53 co-mutation on clinicopathological features, prognosis, and recurrence patterns in resected early-stage EGFR-mutated lung adenocarcinoma.

We analyzed 400 patients with completely resected lung adenocarcinoma across pathological stages I-III, screening for EGFR and TP53 mutations using whole-exome sequencing. Among 121 patients positive for EGFR mutations, we categorized those with TP53 co-mutations and those with wild-type TP53. We then compared clinicopathological features, prognostic outcomes, recurrence patterns, and the efficacy of EGFR-TKI treatment postrecurrence between these groups.

TP53 co-mutations were identified in 22 cases (18.2%). The TP53 co-mutation group had significantly more lymphovascular invasion (P = .037) and a higher tumor mutation burden (P = .007) compared with the TP53 wild-type group. Moreover, the co-mutation group exhibited markedly poorer recurrence-free and overall survival rates [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.12-4.85, P = .025; HR 2.54, 95% CI 1.01-6.36, P = .047, respectively]. However, progression-free survival in patients treated with EGFR-TKIs postrelapse did not differ significantly between the groups.

TP53 co-mutations may negatively affect the prognosis of patients with resected early-stage EGFR-mutated lung adenocarcinoma. Larger studies are needed to confirm these findings.

The differences in clinical characteristics and treatment prognosis in NSCLC patients harboring primary and acquired BRAF mutations are still poorly understood.

From Oct 2017 to Dec 2023, 10, 211 lung cancer patients at Shanghai Ruijin Hospital were reviewed. 88 primary and 15 acquired BRAF-mutated NSCLC patients resistant to EGFR TKIs were included in the study.

Primary BRAF-mutated patients preferentially occurred in the elderly (median age: 67 vs 61, p=0.015), males (53.4% vs 26.7%, p=0.056), former/current smokers (36.5% vs 6.7%, p=0.033), non-adenocarcinoma (11.4% vs 0%, P=0.351) compared to acquired BRAF-mutated patients. Significant differences in gender (33.3% vs 62.3%, p=0.012), smoking history (22.2% vs 43.1%, p=0.063), and adenocarcinomas (100% vs 83.6%, p=0.028) were observed between primary BRAF/EGFR co-mutated and non-co-mutated groups. While primary and acquired BRAF/EGFR co-mutated patients had similar clinical characteristics, with EGFR mutations being the most common coexisting oncogene (30.7% and 93.3%). The genotype of EGFR mutations differed, with acquired BRAF-mutated cases showing more complexity and a higher rate of dual EGFR mutations (35.7%) compared to primary cases. For primary BRAF/EGFR co-mutated patients, no matter what kinds of therapies, the EGFR 19del patients had a better prognosis than non-19del patients, and the first line mPFS was NR and 9.0 months (95% CI: 7.7-10.3 months) (p=0.0062), respectively. Dabrafenib and trametinib plus 3rd EGFR TKIs improved the prognosis of primary BRAF/EGFR non-19del co-mutated patients, achieving ORR and mPFS of 100% (3/3) and 12 months. For acquired co-mutated patients, the mPFS for 5 patients was 8.6 months (95% CI: 5.4-11.8 months). No new safety concerns and > grade 3 AEs were noted.

Together, our study demonstrates that primary and acquired BRAF-mutant patients show distinct differences in some clinical and molecular characteristics, but acquired BRAF/EGFR co-mutated and primary BRAF/EGFR non-19del co-mutated patients may both respond to triple-targeted therapy.

Lung adenocarcinoma (LUAD) is a typical inflammation‑associated cancer, and anti‑inflammatory medications can be valuable in cancer therapy. Loratadine, a histamine receptor H1 (HRH1) antagonist, shows both anti‑inflammatory and anticancer properties. The present study aimed to evaluate impacts of loratadine on LUAD cells as well as in a LUAD xenograft mouse model, and explore underlying mechanisms. Mechanistic investigations were conducted through using western blotting, flow cytometry, immunohistochemistry, acridine orange staining, TUNEL assays, and in silico analyses of loratadine‑modulated genes in LUAD specimens. It was observed that loratadine inhibited LUAD cell proliferation and colony formation by inducing autophagy‑mediated apoptotic cell death independently of HRH1. In a LUAD xenograft model, loratadine decreased tumor proliferation and angiogenesis while enhancing autophagy and apoptosis. Mechanistically, loratadine induced protein phosphatase 2A (PP2A) activation to deactivate c‑Jun N‑terminal kinase (JNK)1/2 and p38 in H23 and PC9 LUAD cells. Additionally, loratadine inhibited signal transducer and activator of transcription 3 (STAT3) activation via a PP2A‑independent pathway. Furthermore, the combination of loratadine with inhibitors for JNK, p38 and STAT3 all enhanced proliferation inhibition of loratadine alone in both cell lines. In the clinic, patients with LUAD expressing high PP2A had favorable prognoses. The present study suggests that loratadine can be used as a PP2A activator for LUAD treatment, and the combination of repurposing loratadine with inhibitors of STAT3, JNK and p38 would be an effectively strategy for inhibiting LUAD growth.

We assessed the association between a genome-wide polygenic risk score (PRS) developed for lung adenocarcinoma (LUAD) risk and mutation on the EGFR gene in 998 East Asian never-smoking female LUAD cases (518 EGFR-positive; 480 EGFR-negative) and 4544 never-smoking controls using case-case and multinomial regression analyses. We found that the PRS was more strongly associated with EGFR-positive LUAD compared with EGFR-negative LUAD, where the association between the fourth quartile of the PRS and EGFR-positive LUAD (odds ratio = 8.63, 95% confidence interval: 5.67-13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR-negative LUAD (odds ratio = 3.50, 95% confidence interval: 2.44-5.00) (p-heterogeneity = 3.66 × 10-3). Our findings suggest that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female East Asian patients depending on the cancer's mutation status, which may have important public health and clinical implications.

The global burden of cancer remains a major public health challenge, with Kirsten rat sarcoma viral oncogene homolog (KRAS) emerging as the most common mutated oncogene across diverse malignancies. Once considered "undruggable" due to its unique structure, KRAS has garnered intense research focus, resulting in significant advancements. This paper aims to review recent developments in our understanding of KRAS biology, including its structural and functional aspects, and to explore the latest insights into its mutations across various cancer types. Emphasis is placed on prognosis, predictive roles, and emerging therapeutic strategies targeting KRAS. This review aspires to deepen our comprehension of KRAS and potentially enhance treatment outcomes for cancer patients harboring KRAS mutations in the future.

Pleural metastasis is a common metastatic pattern in patients with epidermal growth factor receptor-mutant lung adenocarcinoma (EGFR-LUADm); however, the value of palliative surgery for these patients remains controversial. The purpose of the present study aims to investigate whether palliative surgery benefits in stage IVA LUADm patients with pleural metastasis, who achieved complete remission of pleural lesions following targeted therapy.

From November 2014 to November 2023, patients with stage IVA EGFR-LUADm with pleural metastasis at Shanghai Pulmonary Hospital were retrospectively included in this study. All the patients received EGFR-tyrosine kinase inhibitor (TKI) monotherapy. The patients were divided into surgical- and non-surgical treatment subgroups. To reduce any selection bias, a 1:2 propensity score matching (PSM) was performed before comparing oncological outcomes between the two groups. The Kaplan-Meier method and log-rank test were used to identify the prognostic factors of these patients.

A total of 134 patients who met the inclusion and exclusion criteria were enrolled in this study. Of the 134 patients, 13 received EGFR-TKI monotherapy followed by palliative surgical treatment (the surgical group), and 121 received EGFR-TKI monotherapy alone (the non-surgical group). No significant differences in the baseline characteristics were observed between the subgroups. After PSM, the surgical and non-surgical groups comprised 13 and 26 patients, respectively. The survival analysis showed that the patients in the surgical group had significantly better progression-free survival (PFS) than those in the non-surgical group {surgical vs. non-surgical: median PFS: 43 [95% confidence interval (CI): 30-not available] vs. 11 (95% CI: 10-26, P<0.001)}.

Compared with EGFR-TKI monotherapy, palliative surgery combined with EGFR-TKI treatment prolonged the PFS of pleural metastatic EGFR-LUADm patients. A subset of EGFR-LUADm patients with pleural metastasis might be suitable for palliative surgery.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. In Asian populations, epidermal growth factor receptor (EGFR) mutations are particularly prevalent, leading to the development of EGFR tyrosine kinase inhibitors (TKIs) to improve patient outcomes. While extensive research has been conducted on the prognosis of patients receiving EGFR-TKIs, the estimation of 5-year survival in this population remains an underexplored area.

This study aimed to provide real-world evidence and conduct a comprehensive analysis of the determinants influencing the 5-year survival rate in patients with EGFR-mutated NSCLC. Considering the factors identified in this study, a scoring system was developed to predict the likelihood of patients achieving this goal.

A retrospective cohort study utilizing a training cohort of 1,873 patients and a validation cohort of 484 patients.

A logistic regression model was constructed to evaluate the weighting of factors and develop a scoring system. The Kaplan-Meier model estimated the overall survival probability, and patients were categorized into four risk groups based on their likelihood of five-year survival. The prediction performance of both the training and validation cohorts was evaluated using the area under the curve (AUC), accuracy, precision, sensitivity, specificity, and F1-score.

Results indicated that age > 65 years; performance score of 2-4; metastasis to the liver, brain, bone, or pleura; and poor disease control were associated with a decreased likelihood of 5-year survival. The estimated 5-year survival rate was 23.4% (odds ratio [OR]: 20.56; 95% confidence interval [CI]: 9.06-46.64; p < 0.0001), 16.1% (OR: 12.88; 95% CI: 5.82-28.49; p < 0.0001), 7.2% (OR: 5.23; 95% CI: 2.36-11.60; p < 0.0001), and 1.5% (OR: reference) for the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively. The validation cohort further confirmed these findings, showing survival probabilities of 52.6% (OR: 96.67; 95% CI: 11.07-844.23; p < 0.0001), 21.3% (OR: 23.49; 95% CI: 3.13-176.46; p = 0.002), 14.9% (OR: 15.21; 95% CI: 2.03-114.25; p = 0.008), and 1.1% (OR: reference) for the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively. The training cohort demonstrated an AUC of 0.79 (95% CI: 0.75-0.82) and a model quality score of 0.75, indicating good predictive performance. Calibration plots demonstrated a good fit for the scoring system. For the external validation cohort, the AUC, precision, sensitivity, and specificity were 0.71, 0.74, 0.35, 0.33, respectively. The model achieved an F1-score of 0.47, reflecting adequate performance in predicting 5-year survival probabilities.

This study identified critical prognostic factors and developed a validated scoring system for estimating 5-year survival in patients with EGFR-mutated NSCLC receiving EGFR-TKIs. While the model demonstrated robust predictive performance within the study cohort, broader applicability beyond Taiwan may require further refinements and alternative study designs.

To evaluate the efficacy and safety of aumolertinib combined with pemetrexed and carboplatin as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation (exon 19 deletion or exon 21 L858R).

In phase II trial (NCT04646824), patients received aumolertinib 110 mg once daily plus pemetrexed (500 mg/m2) and carboplatin (area under curve = 5) once every 3 weeks for 4 cycles, followed by maintenance aumolertinib (110 mg once daily) and pemetrexed (500 mg/m2 once every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

From November 2020 to October 2021, 34 patients were included for analysis. The median PFS was 28.0 months (95% CI, 18.7-36.9). The ORR was 91.2% (31/34), and the DCR was 100%. The median OS was not reached. Of 28 patients with circulating tumor DNA (ctDNA) testing, 22 (78.6%) showed clearance of EGFR mutation after 2 or 4 cycles. The median PFS was 31 months in patients with EGFR mutation clearance in ctDNA, and the ORR of them was higher than those without EGFR mutation clearance in ctDNA (90.9% vs 33.3%). The most common grade ≥ 3 treatment-related adverse event was decreased neutrophil count (22 [64.7%]).

Aumolertinib plus chemotherapy shows potential as first-line treatment for patients with EGFR-mutant advanced NSCLC, which deserves to be investigated in randomized controlled trials. CtDNA clearance may be a prognostic marker.

The causal relationship between family history of lung cancer and allergic rhinitis remains unclear. This study aimed to explore the association between family history of lung cancer and allergic rhinitis, along with potential mediating mechanisms, using Mendelian randomization.

A bidirectional two-sample Mendelian randomization analysis was conducted to assess the causal relationship between family history of lung cancer (including parental, paternal, maternal, and sibling histories) and allergic rhinitis, using genetic variants associated with family history of lung cancer as instrumental variables. Additionally, mediation Mendelian randomization analysis was performed to investigate the role of specific metabolites in mediating this relationship.

The analysis revealed a significant causal relationship between parental history of lung cancer and allergic rhinitis, with maternal lung cancer history showing a strong protective effect against allergic rhinitis (OR = 0.28, p<0.05). Mediation analysis further indicated that metabolites such as 1-linoleoyl-GPE (18:2) and N-palmitoyl-sphingosine exhibited negative mediating effects in the association between maternal lung cancer and allergic rhinitis. Lower levels of these metabolites enhanced the protective effect of maternal lung cancer history on allergic rhinitis.

This study demonstrates a significant causal relationship between maternal lung cancer history and allergic rhinitis, with specific metabolites potentially playing a mediating role. Changes in the levels of 1-linoleoyl-GPE (18:2) and N-palmitoyl-sphingosine are associated with the protective effect of maternal lung cancer history on allergic rhinitis, suggesting that metabolites may be crucial in regulating this relationship. These findings provide new insights into the relationship between family history of lung cancer and immune-related diseases, offering potential directions for future clinical prevention and treatment strategies.

The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.

In the treatment of advanced non-small cell lung cancer (NSCLC), the mutation status of the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene has been shown to be a key factor affecting the efficacy of immune checkpoint inhibitors (ICIs), which is an important guideline for physicians to develop personalized treatment strategies. However, existing mutation prediction studies have primarily focused on the feature representation of individual patient medical data, ignoring the complex semantic relationships among patients in diverse clinical features. This study aimed to accurately identify KRAS gene status, which will not only assist physicians in accurately screening the patient population most likely to benefit from immunotherapy, but also reduce patient burden by avoiding unnecessary treatment attempts.

A multi-view adaptive semantics-aware heterogeneous graph framework (MVASA-HGN) based on multimodal medical data was developed to accurately predict KRAS mutation status in NSCLC patients. The framework first parses the relational semantics through clinical feature clustering and constructs a heterogeneous graph by combining computed tomography (CT) image and clinical features. In the second step, the heterogeneous graph is split into relational subgraphs under multiple views, and the node representations are constructed and updated gradually through a two-stage strategy of single-view graph representation learning and multi-view heterogeneous information fusion. In the single-view phase, we enhance the node self-embedding and construct the adjacency embedding of neighbors with the same type of relationship to ensure that the relational subgraph under each semantic preserves the complete local structure. Two attention mechanisms are introduced in the multi-view fusion phase to capture the enriched semantics preserved in nodes and heterogeneous relations, respectively. Finally, a comprehensive node representation is obtained through adaptive aggregation of different view neighborhood information and enhanced node embedding without predefined meta-paths.

The classification results were evaluated on cooperative hospitals and The Cancer Imaging Archive (TCIA) datasets, and ablation experiments and comparison experiments were performed on the components of the framework, while exploring the framework's rationality and interpretability. Accuracy reached 85.29% and specificity reached 89.67% on the test set, indicating that our framework has significant advantages in deeply modeling complex heterogeneous semantics in local structures and fully exploiting and utilizing the rich semantic information preserved in heterogeneous relationships. The source code of MVASA-HGN is available at https://github.com/Yangwanter37/MVASA-HGN.

Our proposed MVASA-HGN framework provides a new perspective for multimodal information fusion and creates a new avenue to explore the potential link between images and genes, and the framework provides a non-invasive and cost-effective solution for identifying KRAS mutation status, which has a broad application prospect.

Sex-based differences in histological subtypes, in frequencies of mutations, and differences in response to the various therapeutic approaches in lung cancer are well studied. In general, the literature is controversial, and the large majority of the investigations may not provide evidence from the last decade.

The objective of the current study was to reveal timely sex-based differences in patients with lung cancer in the era of immunotherapy and molecularly targeted agents.

We retrospectively analyzed a consecutive cohort of 286 patients (female:male ratio 134:152/47 %:53 %) who were diagnosed with lung cancer between 2020 and 2022 in the pulmonology department of the Medical University of Vienna, Austria. Demographic characteristics, histological subtypes, the PD-L1 expression on tumor cells, presence of mutations, treatment, and survival of male and female patients were compared.

The smoking rate in women with lung cancer was significantly lower than in men (p = 0.005). The rate of targetable mutations was significantly higher in female patients (52 % vs. 30 %, p = 0.011). There were no significant differences in age at diagnosis, body mass index, lung function parameters, histological subtypes, PD-L1 protein expression, disease stage, and survival between men and women (all p > 0.05).

Female Caucasian patients seem to have a higher susceptibility to lung cancer. Although the rate of genetic alterations is similar in both sexes, actionable driver mutations are significantly more common in women.

With the wide use of CT scan in clinical practice, more lung cancer was diagnosed in resectable stage. Pathological examination and genetic testing have become a routine procedure for lung adenocarcinoma following radical resection. This study analyzed special pathological components and gene mutations to explore their relationship with clinical characteristics and overall survival.

Clinical, pathological, and gene mutation data from 1,118 patients were collected. All patients underwent surgery at the Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University. Patients were grouped based on pathological components and gene mutations. Differences in clinical features and overall survival were analyzed as well.

Patients with mucinous, neuroendocrine, and poor-differentiated components were presented with more prognostic risk factors, including pleural invasion, carcinothrombosis, STAS, and advanced stages, along with varying frequencies of gene mutations. These factors significantly shortened overall survival. ALK and KRAS mutations were also associated with risk factors such as solid nodules, pleural invasion, STAS, and later stages. However, a significant reduction in overall survival was observed only in patients with the KRAS mutation. Relationship between gene mutations and pathological components still requires further investigation.

Special pathological components (mucinous, neuroendocrine, and poor-differentiated) and gene mutations had an influence on biological behavior of tumors, resulting in different clinical characteristics and prognosis.

The benefit of treatment with tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR-TKI) for lung adenocarcinoma (ADC), stratified by ethnicity, has not yet been fully elucidated.

We searched PubMed, Embase, and Cochrane databases for studies that investigated EGFR-TKI for lung ADC. We computed hazard ratios (HRs) or risk ratios (RRs) for binary endpoints, with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses.

A total of 18 studies, comprising 4,497 patients with lung ADC randomized to TKIs or chemotherapy alone. TKIs significantly improved OS (HR 0.91; 95% CI 0.88-0.95), PFS (HR 0.60; 95% CI 0.38-0.97), and ORR (HR 0.34; 95% CI 0.25-0.48) in Asian patients, compared with the chemotherapy alone. In Caucasian patients, TKIs significantly improved PFS compared with chemotherapy alone (HR 0.34; 95% CI 0.25-0.48) and ORR(RR 2.35; 95% CI: 1.05-5.28). TKIs significantly reduced any adverse events of any grade in patients with mixed ethnicity (RR 0.86; 95% CI 0.76-0.98) and any adverse events of grade ≥ 3 in Caucasian patients (RR 0.67; 95% CI 0.51-0.89).

This is the first meta-analysis to reveal the ethnic influence on the outcomes of oncologic treatments for patients with lung ADC. In collaboration with in-depth molecular characterization, these data will allow the creation of a clinical-pathological predictive model to increase the magnitude of the expected benefit for patients from different ethnic groups.

Lung cancer is one of the major causes of cancer morbidity and mortality. Subtyping of non-small cell lung cancer is necessary owing to different treatment options. This study is to evaluate the value of immunohistochemical expression of glypican-1 in the diagnosis of lung squamous cell carcinoma (SCC). This retrospective study included a total of 68 cases, of which 36 were diagnosed as SCC and 32 as adenocarcinoma (ADC). Furthermore, glypican-1 expression was compared with the expressions of p63, thyroid transcription factor-1 (TTF-1), and napsin A. All cases of SCC except one showed positive immunostaining to glypican-1; 35/36 (97.2%) cases, and predominantly scored 3 + . While only 5 cases of ADC showed positive immunostaining to glypican-1, having a score of 1 + or 2 + . The difference between glypican-1 expression of the two tumor types was highly significant (p value < 0.001). The sensitivity, specificity, and overall accuracy of glypican-1 expression for differentiating lung SCC from ADC were 97.2%, 84.4%, and 91.2%, respectively. The sensitivity of glypican-1 is more than p63 in the diagnosis of lung SCC. Glypican-1 can be added as a new diagnostic marker to help in the accurate discrimination between poorly differentiated lung SCC and solid predominant adenocarcinoma cases.

Brain metastases (BMs) are the most common intracranial tumors in adults and occur 3-10 times more frequently than primary brain tumors. Despite intensive multimodal therapies, including resection, radiotherapy, and chemotherapy, BMs are associated with poor prognosis and remain challenging to treat. BMs predominantly originate from primary lung (20-56%), breast (5-20%), and melanoma (7-16%) tumors, although they can arise from other cancer types less frequently. The metastatic cascade is a multistep process involving local invasion, intravasation into the bloodstream or lymphatic system, extravasation into normal tissue, and colonization of the distal site. After reaching the brain, circulating tumor cells (CTCs) breach the blood-brain barrier (BBB).The selective permeability of the BBB poses a significant challenge for therapeutic compounds, limiting the treatment efficacy of BMs. Understanding the mechanisms of tumor cell interactions with the BBB is crucial for the development of effective treatments. This review provides an in-depth analysis of the brain barriers, including the BBB, blood-spinal cord barrier, blood-meningeal barrier, blood-arachnoid barrier, and blood-cerebrospinal fluid barrier. It explores the molecular and cellular components of these barriers and their roles in brain metastasis, highlighting the importance of this knowledge for identifying druggable targets to prevent or limit BM formation.

Squamous cell carcinoma is the second most prevalent type of non-small cell lung cancer. Analyzing the molecular mechanisms underlying lung carcinoma requires useful tools, such as squamous lung cancer cell lines.

A novel new lung squamous cell carcinoma cell line, OMUL-1, was developed from the primary lung cancer of a 74-year-old man. We assessed the characteristics and behavior of OMUL-1 cells were examined, including their growth kinetics, tumorigenicity in mice, histological properties, gene expression profiles using reverse transcription polymerase chain reaction (RT-PCR), and RNA sequencing and invasion assays.

OMUL-1-an adherent cell line-resulted in 100% tumor formation when subcutaneously injected into mice. Histological analysis of the subcutaneous tumor using hematoxylin and eosin staining revealed squamous cell carcinoma with characteristics similar to those of the primary tumor (p40 and p63 were positive, and TTF-1 was negative). An invasion assay demonstrated that OMUL-1 had a lower invasion ability compared to that of other developed cell lines. RT-PCR analysis and RNA sequencing indicated that OMUL-1 cells expressed FGFR1, FGFR2, FGFR3, FGFR4, EGFR, HER2, ErbB3, ErbB4, VEGFR3, IGF1R, c-MET, PDGFRa, and PDGFRb. Additionally, picropodophyllin (an IGF1R inhibitor) significantly inhibited the growth of OMUL-1 cells. Immunohistochemistry revealed that IGF1R and PD-L1 were expressed in both the primary and subcutaneous tumors.

We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1.

Kristen rat sarcoma viral oncogene homolog (KRAS) mutations play a major role in the carcinogenesis of many types of solid tumors including non-small cell lung cancer (NSCLC). Among KRAS mutations, p.G12C single-nucleotide variant (KRASG12C) is the most frequently reported in NSCLC patients, with a prevalence of about 12-13 %. For many decades, KRAS mutations including KRASG12C were considered "undruggable" because of the lack of effective and well-tolerated selective therapies. Noteworthy, CodeBreaK100 and KRYSTAL-1 clinical trials have recently demonstrated that sotorasib and adagrasib, two novel selective KRASG12C inhibitors, have clinical activity with acceptable adverse-event profile for the treatment of advanced NSCLC patients with KRASG12C mutation. On the other hand, no selective therapies are approved for the treatment of advanced NSCLC patients with non-G12C KRAS mutations. As a result, these patients receive the same treatments as those without KRAS mutations. In this paper, we describe the role of KRAS mutations in NSCLC focusing on the clinical and molecular characteristics which potentially identify specific subtypes of NSCLC patients based on different KRAS mutations. We also provide an overview of the main clinical trials testing novel selective KRASG12C inhibitors as well as novel potential therapeutic strategies for NSCLC patients with non-G12C KRAS mutations.

Tumor-derived cell-free DNA (cfDNA) has been exploited as an effective liquid biopsy biomarker for early cancer diagnosis. However, the fragmented and low-abundance nature in circulating blood pose challenges for highly sensitive cfDNA quantification. Herein, a multifunctional plasmonic biosensor termed Interfacial cfDNA Enrichment, Amplification and Sensing with on-chip Thermoplasmonics (INEAST) is developed for cfDNA-based liquid biopsy and lung cancer diagnosis. The INEAST biosensor achieved in situ thermoregulation and label-free cfDNA biosensing by simultaneously harnessing interfacial thermoplasmonics and localized surface plasmon resonance. Typical cfDNA biomarkers, including epidermal growth factor receptor (EGFR), tumor protein 53 (TP53), phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and cyclin-dependent kinase inhibitor (CDKN2A), are quantified with detection limits down to femtomolar-level. Through further validation using blood samples from lung cancer patients, the proposed INEAST bioassays demonstrated superior reliability for lung cancer screening, particularly when combined with clinically available tumor-protein metrics. This study demonstrated that the INEAST biosensor enables rapid and sensitive cfDNA quantification, yielding a promising and compatible liquid biopsy for early-stage lung cancer diagnosis.

We present a meta-analytics approach to quantify NSCLC disease burden by integrative survival models. Aggregated survival data from public sources were used to parameterize the models for early as well as advanced NSCLC stages incorporating chemotherapies, targeted therapies, and immunotherapies. Overall survival (OS) was predicted in a heterogeneous patient cohort based on various stratifications and initial conditions. Pharmacoeconomic metrics (life years gained (LYG) and quality-adjusted life years (QALY) gained), were evaluated to quantify the benefits of specialized treatments and improved early detection of NSCLC. Simulations showed that the introduction of novel therapies for the advanced NSCLC sub-group increased median survival by 8.1 months (95 % CI: 5.9, 10.0), with corresponding gains of 2.9 months (95 % CI: 2.2, 3.6) in LYG and 1.65 months (95 % CI: 1.2, 2.0) in QALY. Scenarios representing improved detection of early cancer in the whole patient cohort, revealed up to 17.6 (95 % CI: 16.5, 19.0) and 15.7 months (95 % CI: 14.8, 16.6) increase in median survival, with respective gains of 6.2 months (95 % CI: 5.9, 6.4) and 5.2 months (95 % CI: 4.9, 5.4) in LYG and 6.6 months (95 % CI: 6.4, 6.7) and 6.0 months (95 % CI: 5.9, 6.2) in QALY for conventional and optimal treatment. This integrative modeling platform, aimed at characterizing cancer burden, allows to precisely quantify the cumulative benefits of introducing specialized therapies into the treatment schemes and survival prolongation upon early detection of the disease.

Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions.

Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action.

Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority.

Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials.

ObjectivesSignificant progress has been made in the treatment of patients with pulmonary adenocarcinoma (ADCA) based on molecular profiling. However, no such molecular target exists for squamous cell carcinoma (SQCC). An exome sequence may provide new markers for personalized medicine for lung cancer patients of all subtypes. The current study aims to discover new genetic markers that can be used as universal biomarkers for non-small cell lung cancer (NSCLC).MethodsWES of 19 advanced NSCLC patients (10 ADCA and 9 SQCC) was performed using Illumina HiSeq 2000. Variant calling was performed using GATK HaplotypeCaller and then the impacts of variants on protein structure or function were predicted using SnpEff and ANNOVAR. The clinical impact of somatic variants in cancer was assessed using cancer archives. Somatic variants were further prioritized using a knowledge-driven variant interpretation approach. Sanger sequencing was used to validate functionally important variants.ResultsWe identified 24 rare single-nucleotide variants (SNVs) including 17 non-synonymous SNVs, and 7 INDELs in 18 genes possibly linked to lung carcinoma. Variants were classified as known somatic (n = 10), deleterious (n = 8), and variant of uncertain significance (n = 6). We found TBP and MPRIP genes exclusively associated with ADCA subtypes, FBOX6 with SQCC subtypes and GPRIN2, KCNJ18 and TEKT4 genes mutated in all the patients. The Sanger sequencing of 10 high-confidence somatic SNVs showed 100% concordance in 7 genes, and 80% concordance in the remaining 3 genes.ConclusionsOur bioinformatics analysis identified KCNJ18, GPRIN2, TEKT4, HRNR, FOLR3, ESSRA, CTBP2, MPRIP, TBP, and FBXO6 may contribute to progression in NSCLC and could be used as new biomarkers for the treatment. The mechanism by which GPRIN2, KCNJ12, and TEKT4 contribute to tumorigenesis is unclear, but our results suggest they may play an important role in NSCLC and it is worth investigating in future.

Aim: To understand physicians' attitudes and behaviors regarding EGFR testing and retesting strategies in newly diagnosed metastatic non-small cell lung cancer patients.Materials & methods: Oncologists and pathologists completed an online, cross-sectional survey.Results: Most oncologists (73.3%) and pathologists (53.4%) agreed that concurrent testing increases sensitivity for detecting EGFR mutations. Upon tissue insufficiency, oncologists and pathologists reported using liquid biopsy 77.0% and 39.0% of the time, respectively. Tumor accessibility, smoking status, patient willingness and age were key drivers of tissue re-biopsy. Most oncologists reported high confidence in proceeding to first-line therapy based solely on liquid biopsy (60.7-80.0%); fewer pathologists (37.9%) were comfortable with this decision.Conclusion: Variation in physicians' perceptions of testing and retesting highlights the need for greater stakeholder consensus.

Cigarette smoking causes multiple cancers by directly influencing mutation burden of driver mutations. However, the mechanism between somatic mutation caused by cigarette smoking and bladder tumorigenesis remains elusive. Smoking-related mutation profile of bladder cancer was characterized by The Cancer Genome Atlas cohort. Integraticve OncoGenomics database was utilized to detect the smoking-related driver genes, and its biological mechanism predictions were interpreted based on bulk transcriptome and single-cell transcriptome, as well as cell experiments. Cigarette smoking was associated with an increased tumor mutational burden under 65 years old (p = 0.031), and generated specific mutational signatures in smokers. RB1 was identified as a differentially mutated driver gene between smokers and nonsmokers, and the mutation rate of RB1 increased twofold after smoking (p = 0.008). RB1 mutations and the 4-aminobiphenyl interference could significantly decrease the RB1 expression level and thus promote the proliferation, invasion, and migration ability of bladder cancer cells. Enrichment analysis and real-time quantitative PCR (RT-qPCR) data showed that RB1 mutations inhibited cytochrome P450 pathway by reducing expression levels of UGT1A6 and AKR1C2. In addition, we also observed that the component of immunological cells was regulated by RB1 mutations through the stronger cell-to-cell interactions between epithelial scissor+ cells and immune cells in smokers. This study highlighted that RB1 mutations could drive smoking-related bladder tumorigenesis through inhibiting cytochrome P450 pathway and regulating tumor immune microenvironment.