Non-small Cell Lung Carcinoma Patients Research Articles

Differential Expression of miR-192, miR-221, miR-15 Among the Nodule Tissues of Sarcoidosis and Lung Cancer

Background: Patients with sarcoidosis were found to have a higher risk of lung cancer compared to the general population. Being aware of all possible associations between these two diseases and identification of biomarkers such as miRNA profiles can be helpful in differentiating the mechanisms of these two diseases, which can aid in clinical decision-making. Methods: The aim of the study was to investigate the expression of selected miRNAs (miR-192 miR-221, miR-15) in lymph nodes of patients with pulmonary sarcoidosis, non-small cell lung carcinomas (NSCLC) and control group (n = 30 per groups) by qRT-PCR. Results: Relative expression of miR-221 in sarcoidosis and NSCC patients was higher than in the control group. Furthermore, the relative expression of miR-15 in patients with sarcoidosis and NSCLC tissue was lower than in the control group. Interestingly, miR-192 is differentially expressed in sarcoidosis and NSCLC patients compared to the control group. Conclusions: The obtained results suggest that the studied miRNAs may have potential diagnostic and therapeutic implications, but further research is necessary to fully understand their roles in these diseases.

Combination Checkpoint Blockade and Laser Interstitial Thermal Therapy in Radiographically Progressive Non-Small Cell Lung Cancer Brain Metastases

Abstract Background Laser interstitial thermal therapy (LITT) is a minimally invasive surgical treatment being employed frequently for radiographically progressive brain metastases. Considerable interest exists in combining LITT-mediated in situ vaccination to license immune checkpoint blockade (ICB). No studies have examined the clinical feasibility of this combination in brain metastases. Methods All patients receiving LITT for radiographically progressive non-small cell lung carcinoma (NSCLC) brain metastases at a single center from 2015 – 2023 were retrospectively reviewed. Combination therapy was defined as ICB within 6 weeks of LITT. Clinical data, post-LITT freedom from local progression (FFLP), and overall survival (OS) were collected. Adverse events (AEs) were evaluated according to Common Terminology Criteria. Results Eighteen patients received LITT + ICB to a total of 19 lesions. Median time between therapies was 2.29 weeks (range 0.85 – 5.98). In comparison to NSCLC patients receiving LITT alone or with targeted therapy (LITT only) (n = 25), there was no decrement in procedural outcomes. Patients receiving LITT + ICB discontinued steroids at a median of 11 (4 – 147) days post-LITT vs. 24 (3 – 242) days for patients receiving LITT only (P = 0.62). At study cutoff, the local control rate was 18/19 (94.7%) lesions in the LITT + ICB group and 22/25 (88.0%) in the LITT only group. There were 3 and 5 AEs ≥ Grade 3 in the LITT + ICB and LITT only group, respectively. Conclusions Combination LITT and ICB does not compromise procedural outcomes or time to steroid discontinuation in NSCLC. Prospective studies are needed to assess biomarkers of immune response.

Cis-Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non-Small Cell Lung Carcinoma.

N6-methyladenosine (m6A) serves as one of the crucial RNA modifications for genes involved in cancer progression. Here, 7273 expression quantitative trait loci potentially regulating 30 m6A pathway genes are identified from the GTEx database, with 69 single nucleotide polymorphisms significantly associated with survival of non-small cell lung carcinoma (NSCLC) patients (n = 1523) from the ongoing genome-wide association study after false positive probability tests. Notably, the rs151198415 locus, situated in a potential enhancer region, demonstrated a prolonged survival effect with the C>CCACG insertion, which is validated in an independent prospective cohort (n = 237), yielding a pooled hazard ratio of 0.72 (p = 0.007). Mechanistically, the rs151198415 C>CCACG insertion engaged in long-range interaction with the promoter of m6A eraser ALKBH5, promoting ALKBH5 transcription by the creation of an EGR1 binding site. Then, ALKBH5 upregulated FBXL5 expression by m6A demethylation, which is dependent on the ALKBH5 H204 amino acid site and specific m6A sites on FBXL5 mRNA. Finally, the ALKBH5-FBXL5 axis reduces intracellular reactive oxygen species levels, leading to PI3K/AKT and NF-kB pathway inhibition and consequently suppresses NSCLC proliferation and metastasis in vitro and in vivo. Triggered by an insertion variant, this remote cis-regulation of m6A eraser and the downstream molecular events modulate the survival of NSCLC patients.

PIK3CA Mutations and Co-Mutations in Operated Non-Small Cell Lung Carcinoma.

Background: Understanding PIK3CA mutations and co-mutations in non-small cell lung carcinoma (NSCLC) is critical to developing personalized treatment strategies. Therefore, this study aims to investigate PIK3CA mutations and the accompanying somatic variations in NSCLC. Methods: This retrospective study included 98 patients over 18 years of age who were diagnosed with NSCLC, operated on, and referred to the Molecular Pathology Laboratory between January 2019 and June 2024 for next-generation sequencing panel tests and ALK-ROS1 FISH analysis. Results: All patients were found to carry PIK3CA mutations. Among the 98 NSCLC patients analyzed, 16 (16.33%) were female and 82 (83.67%) were male. The average age of the patients was 64.53 ± 9.63 years, with an age range of 38-84 years, and the majority were 50 years or older. Of the cases, 51 presented the adenocarcinoma subtype, while the remaining 47 showed the squamous cell carcinoma subtype. A smoking history was present in 77 (78.57%) patients, while 21 (21.43%) had no smoking history. The most frequently detected pathogenic or likely pathogenic PIK3CA variations were c.1633G>A p.E545K (32.65%), c.1624G>A p.E542K (11.22%), c.3140A>G p.H1047R (11.22%), c.3140A>T p.H1047L (5.10%), c.1357G>C p.E453Q (4.08%), and c.3143A>G p.H1048R (2.04%). The top 10 mutations that most commonly accompanied PIK3CA variations were KRAS, NF1, TP53, EGFR, PTEN, BRAF, KIT, CDKN2A, SMARCA4, and ATM mutations, respectively. Conclusions:PIK3CA variations, along with other gene variations, may influence cancer progression and thus may play a crucial role in the determination of targeted treatment strategies.

The prognosis and treatment consideration for non-small cell lung carcinoma patients with tumor size of >2.0-3.0 cm and visceral pleural invasion: a SEER-based study.

Lung cancer is the most prevailing oncological disease worldwide. Visceral pleural invasion (VPI) has been proven to be a poor prognosis factor for early-stage non-small cell lung carcinoma (NSCLC) patients. However, there remains some debate regarding whether NSCLC patients with tumor size (TS) ranging from >2.0 to 3.0 cm and VPI should be considered for postoperative treatment. This study compared the prognosis of T2a and T2b NSCLC patients, specifically focusing on those with VPI and TS ranging from >2.0-3.0 cm to emphasize the severity of the disease. Additionally, the impact of adjuvant therapies on the outcome of these patients was discussed. This retrospective research utilized data from the Surveillance, Epidemiology, and End Results (SEER) database, which provided a comprehensive dataset of 10,452 patients diagnosed with pN0M0 NSCLC with TS intervals of >2.0-5.0 cm between 2010 and 2019. The SEER database, renowned for its expansive and population-based cancer data, provides a robust platform for researchers to access a large cohort of patients diagnosed with NSCLC. Survival probabilities were calculated by the Kaplan-Meier method and compared between groups with Log-rank test. Univariate and multivariate logistic analyses were used to identify independent risk factors of VPI. Patients with NSCLC and TS between >2.0 and 3.0 cm, along with VPI, had a worse 5-year overall survival rate compared to those at T2a stage (49.1% vs. 56.8%, P=0.03) and T2b stage (45.4% vs. 64.2%, P<0.0001). However, no statistical significance was observed when comparing patients with TS range between >2.0 and 3.0 cm and presenting with VPI to those staged T2b and received adjuvant chemotherapy (48.4% vs. 48.5%, P=0.54). Patients with clinical stage of T1c and VPI positive had significantly better prognosis after receiving chemotherapy (34.5% vs. 55.2%, P<0.001). Logistic analysis indicated that age older than 65 years old, poor differentiated and undifferentiated, as well as sub-lobectomy resection were independent risk factors for VPI in NSCLC. Postoperative chemotherapy can improve the prognosis of patients with TS ranging from >2.0 to 3.0 cm with VPI. According to the analysis of OS based on the postoperative chemotherapy, patients with NSCLC featuring TS extend from >2.0 to 3.0 cm and VPI may be classified within stage IIA. Consequently, the consideration of postoperative chemotherapy for this patient cohort may be warranted.

Common epidermal growth factor receptor mutations in north Indian patients with non-small cell lung carcinoma: evidence from real-time polymerase chain reaction.

Lung carcinoma was the ace cause of cancer deaths globally in 2022, with non-small cell lung carcinoma (NSCLC) accounting for 81% of the burden. Due to promising tyrosine kinase inhibitor (TKI) trials, NSCLC patients harboring epidermal growth factor receptor (EGFR) gene mutations are of interest. Our aim was to determine EGFR mutation prevalence in north India and its histologic and demographic correlations. We investigated the frequency of EGFR mutations in 40 patients with histologically confirmed NSCLC using real-time polymerase chain reaction. A 15% mutation frequency was observed in the study sample, involving 32 males and 8 females with a median age of 59 years. Squamous cell carcinoma (SCC) patients had only EXON20 (T790M, exon20 insertion) mutations, while adenocarcinoma patients had mutations in both EXON20 (T790M) and 21 (L858R) with mutation frequencies of 22% and 10%, respectively. 28% of the SCC patients were non-smokers, and 60% of these non-smokers had an EGFR mutation. South Indian and Asian studies have identified EXON19 (19-Del) and EXON21 (L858R) mutations as "common mutations" that account for nearly 80-90% of all mutations and respond well to TKIs. Interestingly, "common mutations" were found seldom in our study population, while the uncommon variants constitute 83% of all mutations, which we assume is due to diverse Indian genetics and ethnicity and co-existing signature mutations that involve the tyrosine kinase domain of EXON20. We suggest future genome-wide association studies to identify plausible genetic polymorphisms responsible for interethnic differences in EGFR mutation, which will contribute to better treatment and prevention of NSCLCs.

Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Treating Choroidal Metastasis from Non-small Cell Lung Cancer: A 10-Year Review.

To describe the clinical characteristics of choroidal metastasis (CM) in non-small cell lung carcinoma (NSCLC) patients and report treatment outcomes following targeted therapy versus conventional radiotherapy and/or chemotherapy. A retrospective review was conducted in two hospitals in Hong Kong between 2013-2023. Outcomes included tumor response and visual function following treatment. A total of 25 eyes of 21 Chinese patients with CM secondary to metastatic NSCLC were identified. The majority of patients were non-smokers. At the time of diagnosis, 88% of eyes were visually symptomatic with a mean visual acuity of 20/100. There were 52% of tumors locating within the macula. TKI monotherapy, TKI with radiotherapy and radiotherapy and/or chemotherapy groups were observed to demonstrate similar tumor response from 1 month, and comparable ocular progression-free indices. Untreated patients had deteriorated vision without any tumor response. Tyrosine kinase inhibitor (TKI) monotherapy group achieved the most rapid and differential vision gain than other groups. TKI achieved durable disease control in epidermal growth factor receptor mutation positive NSCLC patients with CM, while improving visual function. TKI can be considered as an alternative to conventional orbital radiotherapy or chemotherapy for these patients in view of the rapid visual recovery.

Stephania tetrandra and Its Active Compound Coclaurine Sensitize NSCLC Cells to Cisplatin through EFHD2 Inhibition

Background: Adjuvant chemotherapy, particularly cisplatin, is recommended for non-small cell lung carcinoma (NSCLC) patients at high risk of recurrence. EF-hand domain-containing protein D2 (EFHD2) has been recently shown to increase cisplatin resistance and is significantly associated with recurrence in early-stage NSCLC patients. Natural products, commonly used as phytonutrients, are also recognized for their potential as pharmaceutical anticancer agents. Result: In this study, a range of Chinese herbs known for their antitumor or chemotherapy-enhancing properties were evaluated for their ability to inhibit EFHD2 expression in NSCLC cells. Among the herbs tested, Stephania tetrandra (S. tetrandra) exhibited the highest efficacy in inhibiting EFHD2 and sensitizing cells to cisplatin. Through LC-MS identification and functional assays, coclaurine was identified as a key molecule in S. tetrandra responsible for EFHD2 inhibition. Coclaurine not only downregulated EFHD2-related NOX4-ABCC1 signaling and enhanced cisplatin sensitivity, but also suppressed the stemness and metastatic properties of NSCLC cells. Mechanistically, coclaurine disrupted the interaction between the transcription factor FOXG1 and the EFHD2 promoter, leading to a reduction in EFHD2 transcription. Silencing FOXG1 further inhibited EFHD2 expression and sensitized NSCLC cells to cisplatin. Conclusions: S. tetrandra and its active compound coclaurine may serve as effective adjuvant therapies to improve cisplatin efficacy in the treatment of NSCLC.

The EXO1/Polη/Polι axis as a promising target for miR-3163-mediated attenuation of cancer stem-like cells in non-small cell lung carcinoma.

Cancer stem-like cells (CSLCs) drive tumour progression and chemoresistance. The concerted efforts of EXO1 and TLS polymerases safeguard DNA integrity against chemotherapeutic drugs. In absence of potential drug targets, non-small cell lung carcinoma (NSCLC) patients have few therapeutic options. In current scenario, microRNAs offer a potential avenue for eradicating CSLCs. EXO1 downregulation impact on CSLCs expansion was assessed via flow cytometry. Co-localisation of EXO1, Polη and Polι was validated through co-immunoprecipitation and confocal-imaging. The effects of co-downregulation of Polη and Polι on CSLC survival, repair synthesis, and mutagenesis were evaluated using flow cytometry and immunohistochemistry in cell lines and xenografts. MicroRNA targeting EXO1 was studied for its role in CSLCs regulation. EXO1 downregulation in NSCLC CSLCs induces DNA lesions, triggering apoptosis and enhances cisplatin sensitivity. It collaborates with Polη and Polι in DNA repair, contributing to cisplatin resistance in CSLCs. Absence of Polη and Polι impairs repair and reduces cisplatin-induced mutagenesis. Co-downregulation of Polη and Polι in xenografts reduces tumour proliferation significantly. MiR-3163 overexpression sensitises CSLCs to cisplatin via targeting EXO1/Polη/Polι axis, as shown in mechanistic studies. This study unveils a novel regulatory pathway involving EXO1/Polη/Polι axis and miR-3163, providing insights into CSLCs regulation in NSCLC. EXO1/Polη/Polι axistargeted by miR-3163, resulting in the inhibition of cell growth and induction of apoptosis inNSCLC CSLCs.

Searching for the key factor in nutritional deterioration of non-small cell lung carcinoma (NSCLC) patients (PTS): A prospective observational study

Searching for the key factor in nutritional deterioration of non-small cell lung carcinoma (NSCLC) patients (PTS): A prospective observational study

Exploring the impact of tertiary lymphoid structures maturity in NSCLC: insights from TLS scoring.

Tertiary Lymphoid Structures (TLS) are lymphoid structures commonly associated with improved survival of cancer patients and response to immunotherapies. However, conflicting reports underscore the need to consider TLS heterogeneity and multiple features such as TLS size, composition, and maturation status, when assessing their functional impact. With the aim of gaining insights into TLS biology and evaluating the prognostic impact of TLS maturity in Non-Small Cell Lung Carcinoma (NSCLC), we developed a multiplex immunofluorescent (mIF) panel including T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (FDC) (CD21, CD23) and mature dendritic cell (DC-LAMP) markers. We deployed this panel across a cohort of primary tumor resections from NSCLC patients (N=406) and established a mIF image analysis workstream to specifically detect TLS structures and evaluate the density of each cell phenotype. We assessed the prognostic significance of TLS size, number, and composition, to develop a TLS scoring system representative of TLS biology within a tumor. TLS relative area, (total TLS area divided by the total tumor area), was the most prognostic TLS feature (C-index: 0.54, p = 0.04). CD21 positivity was a marker driving the favorable prognostic impact, where CD21+ CD23- B cells (C-index: 0.57, p = 0.04) and CD21+ CD23- FDC (C-index: 0.58, p = 0.01) were the only prognostic cell phenotypes in TLS. Combining the three most robust prognostic TLS features: TLS relative area, the density of B cells, and FDC CD21+ CD23- we generated a TLS scoring system that demonstrated strong prognostic value in NSCLC when considering the effect of age, sex, histology, and smoking status. This TLS Score also demonstrated significant association with Immunoscore, EGFR mutational status and gene expression-based B-cell and TLS signature scores. It was not correlated with PD-L1 status in tumor cells or immune cells. In conclusion, we generated a prognostic TLS Score representative of the TLS heterogeneity and maturity undergoing within NSCLC tissues. This score could be used as a tool to explore how TLS presence and maturity impact the organization of the tumor microenvironment and support the discovery of spatial biomarker surrogates of TLS maturity, that could be used in the clinic.

Molecular Modeling Studies to Mimic the Binding Hypothesis of NEU3 Sialidase and EGFR in Nonsmall Cell Lung Carcinoma

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic ([Formula: see text]-H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients.

NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated NADK at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.

Inverted Sandwich-Type e-LCR Aided by Lambda Exonuclease-RecJf Combination Enables Ultrasensitive Detection of Low-Frequency EGFR-L858R Mutation in NSCLC.

Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.

PD-L1 expression in non-small cell lung carcinoma in Latin America: a systematic review and meta-analysis.

Programmed cell death ligand 1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC) is a crucial factor in predicting responses to immunotherapy. This systematic review and meta-analysis focuses on the prevalence of PD-L1 expression and clinicopathological features among Hispanic/Latino (H/L) populations. Embase, LILACS, Medline, and Virtual Health Library were searched for studies that evaluated the prevalence of PD-L1 in H/L patients. The protocol was submitted to PROSPERO with ID CRD42023488547. We employed the Joanna Briggs Institute Checklist for Systematic Reviews and Research Syntheses to assess the methodological quality and applicability of the included studies. Meta-analyses were done to determine the prevalence using a random effects model. The meta-analysis, encompassing 21 articles with 16,486, revealed that 80.2% of patients had PD-L1 expression data available (n=13,222). The prevalence calculated of PD-L1 expression in Latino NSCLC patients was 55% [95% confidence interval (CI): 0.54-0.55], with 31% (95% CI: 0.27-0.36) showing a tumoral proportion score (TPS) of 1-49%, and 23% (95% CI: 0.16-0.30) registering a TPS ≥50%. Higher expression was observed in male gender, smoking, adenocarcinoma subtypes, poor tumor differentiation, and advanced stages. PD-L1 expression was most frequent in EGFR wild-type status (82.5%) with a odds ratio (OR) 1.54 (95% CI: 1.24-1.92) and PD-L1 expression was associated with ALK positive (OR =1.54; 95% CI: 1.24-1.92). This meta-analysis provides a comprehensive overview of PD-L1 expression in NSCLC in the H/L population. The findings underscore the significant prevalence of PD-L1 expression and emphasize the relevance of immunotherapy in this population. Understanding the clinicopathological features associated with PD-L1 expression can contribute to tailored treatment strategies for NSCLC in Latin America.

Alectinib treatment for 2 non-small cell lung carcinoma patients carrying different novel ALK fusions.

The genomic fusions of the anaplastic lymphoma kinase (ALK) gene have been widely recognized as effective therapeutic targets for non-small cell lung carcinoma (NSCLC). The Second Xiangya Hospital of Central South University has treated 2 NSCLC patients with 2 distinct novel ALK gene fusions. Case 1 was a 55-year-old male with a solid nodule located in the right hilar lobe on enhanced CT scan. Case 2 was a 47-year-old female with enhanced CT showing involvement of the left upper lobe of lung. Histopathological examination of tumor tissues confirmed lung adenocarcinoma in both cases. Immunohistochemical (IHC) staining demonstrated positivity for thyroid transcription factor-1 (TTF-1) and ALK-D5F3 in tumor cells, while negativity for P40. The next-generation sequencing (NGS) tests identified a PNPT1-ALK (Exon22:Exon20) fusion variant in case 1 and a TCEAL2-ALK (Exon3:Exon19) fusion variant in case 2. The TCEAL2-ALK fusion was further confirmed by amplification refractory mutation system (ARMS)-PCR at the mRNA level. Both patients were treated with oral alectinib at a dosage of 600 mg twice daily. The tumors in both patients were significantly decreased after alectinib treatment, achieving partial response. At the time of submission, there was an absence of disease progression and the progression-free survival (PFS) had surpassed 1 year. It offered compelling evidences that the individuals with NSCLC and harboring either a PNPT1-ALK (Exon22:Exon20) fusion or a TCEAL2-ALK (Exon3:Exon19) fusion, experience favorable therapeutic outcomes through the administration of alectinib. This study expands the known ALK fusion variants database and supports the precision treatment of NSCLC using ALK tyrosine kinase inhibitors (TKIs).

Immune checkpoint expression as prognostic biomarker candidates in non-small cell lung carcinoma patients.

Cancer immunotherapy has had an important role in oncologic therapeutics for patients with non-small cell lung cancer (NSCLC) using checkpoint inhibitors. We will explore the possible prognosis biomarker candidates such as: soluble OX40 (sOX40), OX40L (sOX40L), Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR), and their ligand (GITRL), 4-1BB or tumor necrosis factor receptor superfamily 9 (TNFRS9) and inducible T cell co-stimulator (ICOS) in peripheral blood of NSCLC patients. Fifty-eight patients were diagnosed with advanced NSCLC between January 2019 and March 2020. High sOX40 and low s4-1BB levels in smokers compared non-smoker NSCLC patients. Lower sOX40L levels were found in the male than female (p < 0.05). High sOX40 and sGITRL in stage III compared to the stage IV (p < 0.05). With follow-up at 21.4 months, 44.1% and 91.1% were alive in the sGITRhigh and sGITRlow groups, respectively (p = 0.02), and 73.3% and 27.7% were alive in the sGITRLhigh and sGITRLlow groups, respectively (p = 0.02). At 22 months, 38.7% and 92.3% were alive in the sOX40Lhigh and sOX40Llow groups, respectively (p = 0.01). sGITR, sGITRL, and sOX40L levels were potential prognostic biomarkers and could have an important role as new targets of immunotherapy in NSCLC patients. sGITR, sGITRL, sOX40L, and sOX40 levels were associated with smoking, sex, stage, and age in NSCLC.

Landscape of gene fusions and METex14 skipping in non-small cell lung carcinoma among the Chinese population: Insights from targeted RNA sequencing.

e20041 Background: Targeted RNA Sequencing is crucial for detecting gene fusions and exon-skipping mutations in non-small cell lung carcinoma (NSCLC). This study delineates the landscape of RNA-based fusion and METex14 skipping in the Chinese NSCLC population, compares the consistency with DNA-based fusion detection, and further explores the relationship between fusion-positive cases and immune markers. Methods: We profiled 294 NSCLC tumor tissues using targeted RNA sequencing, focusing on 29 fusion genes and 6 reference genes. Of these, 229 samples were concurrently assessed for fusions using a DNA panel. Patients with gene fusions or METex14 skipping were categorized as 'FUSION-POS'. Additionally, the expression of PD-L1 was evaluated. Results: In 294 NSCLC patients, 33 types of fusions and METex14 skipping were detected from 45 patients based on RNA detection. Actionable gene fusions/METex14 skipping were present in 11.22% (33/294) of patients, with the most prevalent being ALK (4.4%), METex14 skipping (2.7%), ROS1 (1.4%), and RET (1.0%). The partners of ALK, RET and ROS1 were EML4 (n= 12)/ LCLAT1(n=1), KIF5B (n=3) /PARD3(n=1) and CD74(n=2)/LRIG3(n=1)/EZR (n=1), respectively. Notably, we also identified two patients harboring FGFR2-ATE1 fusion and CD74-NRG1 fusion, respectively. Except for MET 14skipping, ST7-MET fusion was detected in 2 patients. Comparing the consistency of actionable fusions/METex14 skipping between RNA and DNA assessments in 229 NSCLC patients, RNA detection yielded a higher number of cases (24 patients vs 15 patients, 10.5% vs 6.5%), with all 15 fusions/ METex14 skipping detected by DNA also identified by RNA. Furthermore, we observed that PD-L1 expression was significantly elevated in the FUSION-POS group within lung adenocarcinoma patients (TPS: P=0.015). Conclusions: Our findings indicate that 11.22% of Chinese LUAD patients possess actionable fusions and METex14 skipping. The detection rate of fusions/ METex14 skipping via RNA is higher than that via DNA, with RNA detection fully encompassing all fusions/ METex14 skipping identified by DNA. Meanwhile, the association between fusions and PD-L1 expression suggests potential synergies for combining targeted therapy and immunotherapy in NSCLC.

Double lung transplantation in patients with metastatic lung-limited non-small cell lung carcinoma (NSCLC): A case series.

8643 Background: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. Double lung transplantation (DLT) may offer curative treatment for metastatic lung-limited NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 02/2024 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study cohort A (NCT05671887). Exclusion criteria includes presence of extrapulmonary disease. Results: Six patients with stage IVA NSCLC who underwent lung transplantation were included. Five (83.3%) patients underwent double lung, and one (16.7%) patient single lung transplantation. Four (66.7%) patients had invasive mucinous, and two (33.3%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-71; one (16.7%) was Asian, five (83.3%) were White, four (66.7%) were male, and three (50%) had a history of smoking. One (16.7%) patient had a past medical history of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). The median pretransplant treatment lines were 2 (1-5). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C &gt; T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 28, 18, 8, 8, 5, and 4-month posttransplant follow-up. Conclusions: Six patients underwent DLT successfully without significant complications. All patients were alive and in good health. Ongoing DREAM study will continue to investigate the role of DLT in metastatic lung-limited NSCLC patients (especially in pN0). Clinical trial information: NCT05671887 .

A Novel Dual-labeled Peptide for Multimodal Imaging of EGFR with L858R Mutation.

The development of molecular imaging agents targeting epidermal growth factor receptor (EGFR) with L858R mutation may help with the selection of non-small cell lung carcinoma (NSCLCL) patients who may benefit from EFGR tyrosine kinase inhibitor (TKI) therapy. In this study, we developed 99mTc STHHYYP-GHEG-ECGK-tetramethylrhodamine (STHHYYP-ECGK-TAMRA) to target EGFR with L858R mutation in NSCLC tumors and verified its probability as a molecular imaging agent. Fmoc solid-phase peptide synthesis was used to synthesize STHHYYP-ECGKTAMRA. 99mTc labelled STHHYYP-ECGK-TAMRA was prepared. Gamma imaging, fluorescent imaging and biodistribution were performed in murine models bearing NCI-H1975 and NCI-H1650 tumors. The binding affinity value (Kd) of 99mTc STHHYYP-ECGK-TAMRA was estimated to be 130.6 ± 29.2 nM in NCI-H1975 cells. The gamma camera images showed a substantial uptake of 99mTc STHHYYP-ECGK-TAMRA in the NCI-H1975 tumor. The % injected dose/gram of the NCI-H1975 tumor tissue was 2.77 ± 0.70 and 3.48 ± 1.01 at 1 and 3 h, respectively. Specific binding of 99mTc STHHYYP-ECGK-TAMRA to L858R-mutated EGFRpositive NCI-H1975 cells and tumors was demonstrated in in vivo and in vitro studies. The results suggest that 99mTc STHHYYP-ECGK-TAMRA is a good candidate agent for dualmodality imaging targeting EGFR with L858R mutation.