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PURPOSE: This report details the characteristics of a case of bilateral optic neuropathy during treatment with oral lorlatinib for ALK-positive metastatic adenocarcinoma of the lung. OBSERVATIONS: A 57-year-old woman with metastatic adenocarcinoma of the lung receiving treatment with lorlatinib presented to the ophthalmology urgent care with bilateral loss of vision that had progressed to no light perception over the previous 2 weeks. She was hospitalized for an extensive autoimmune, infectious, neoplastic, and paraneoplastic workup, which revealed enhancement of both optic nerves extending up to the optic chiasm and an area of restricted diffusion in the splenium of the corpus callosum on MRI. Lorlatinib was discontinued by her oncologist and she received treatment with five days of pulse-dose intravenous solumedrol as well as five days of plasmapheresis with gradual improvement in her vision. In follow-up, her vision had improved to 20/40 and 20/30. CONCLUSION AND IMPORTANCE: There have been few reports describing vision loss associated with lorlatinib, an ALK/ROS1 targeted tyrosine kinase inhibitor used to treat metastatic lung adenocarcinoma. This report details the characteristics of a case of bilateral retrobulbar optic neuropathy as well as the treatment and recovery of such a case. Further exploration is needed in order to improve our understanding of the pathogenesis of this rare but potentially devastating adverse effect.

[This corrects the article DOI: 10.3389/fimmu.2023.1332057.].

Drs. Ramalingam and Carlisle discuss the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. The podcast provides an overview of the data from the recent Pfizer-sponsored phase 2 PHAROS (NCT03915951) study, which were the basis for the recent US Food and Drug Administration approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer. Infographic [ABSTRACT FROM AUTHOR]

Background: In first/second generation EGFR-TKIs, strong PD-L1 expression contributes to primary resistance, significantly affecting patient prognosis. The relationship between PD-L1 expression levels and third-generation TKIs remains unclear. Methods: This study analyzed advanced NSCLC who received third-generation EGFR-TKIs as first-line systemic therapy from March 2019 to June 2022. The EGFR and PD-L1 status of the patients was also assessed. Results: Overall, 150 patients were included in this study. PD-L1 expression was negative (PD-L1 tumor proportion score <1%) in 89 cases, weak (1–49%) in 42 cases, and strong (≥50%) in 19 cases. mPFS for patients with negative, weak and strong PD-L1 expressions was 23.60, 26.12 and 16.60 months, respectively. The mPFS for strong PD-L1 expression was significantly shorter than that for with weak PD-L1 expression but was not associated with negativity. The same conclusions were shown in subgroup analyses of mutation types and TKI kinds. In addition, Relative to PD-L1-negative patients, resistance to TKIs may be associated with early progression for patients with strong PD-L1 expression. Conclusion: PD-L1 expression in tumor cells influenced the clinical outcomes of patients with advanced NSCLC treated with third-generation EGFR-TKIs. Stronger PD-L1 expression in TKIs-treated patients with advanced first-line EGFR-mutated NSCLC was associated with worse PFS. Article highlights This retrospective study showed that strong PD-L1 expression predicts poor response to EGFR-TKIs therapy in patients with EGFR-mutated NSCLC. PD-L1 expression and the efficacy of three-generation TKIs in which the cut-off is 1 is not a better demarcator. PD-L1 expression can be used as a reliable biomarker for EGFR-TKI therapy to predict patient survival. PD-L1, as a biomarker for evaluating prognosis, will not change due to mutation and TKI types. PD-L1, as a biomarker for evaluating prognosis, is still applicable in non-classical mutations of EGFR. High expression of PD-L1 may be a predictive indicator for primary drug resistance in targeted therapy. The relationship between PD-L1 expression combined with gene co-mutation and the prognosis of third-generation TKI can be a future research direction. Exploring effective biomarkers to enrich the beneficiary population may be an important research direction for optimizing the application of immunotherapy in EGFR-TKIs-resistant NSCLC. [ABSTRACT FROM AUTHOR]

Background: Selective RET inhibitors have been approved by the Chinese government for the treatment of RET-rearranged non-small cell lung cancer. This study aimed to illustrate the efficacy and safety of selective RET inhibitors in a real-world clinical context in China. Methods: Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring RET rearrangement and receiving RET tyrosine kinase inhibitors (RET-TKI) in the real world were enrolled in this retrospective study. Clinical data, including baseline clinicopathological information, efficacy parameters such as objective response rate (ORR) and progression-free survival (PFS), and adverse events (AEs), were collected from the electronic medical record system. The pattern of treatment failure of first-line RET-TKI was also described. Results: Fifty-one patients were enrolled in this study. RET-TKI induced an ORR of 73.1% and a median PFS (mPFS) of 22.7 months (95%CI, 11.7–33.7) in the first-line setting. The ORR and mPFS were 58.3% and 17.7 months (95%CI, 9.1–26.2), 55.6% and 14.7 months (95%CI, 12.6–16.8) in the second-line and later-line settings, respectively. No significant difference was observed among different application lines with respect to the ORR (P = 0.534) or PFS (P = 0.795). In the first-line setting, RET-TKI significantly prolonged PFS compared to other regimens including chemotherapy-based regimens, multikinase inhibitors and other systemic regimens without chemotherapy (P < 0.05). Poor ECOG performance status was related to shorter PFS (P = 0.018). The most common AEs of grade 3 or worse were a decreased neutrophil count (11.4%) and anemia (11.4%). No new AEs or grade 5 AEs were observed. Brain metastasis was one of the most common patterns of treatment failure. In patients with baseline brain metastasis, the intracranial ORR was 50%, and the DCR was 100%. Conclusions: RET-TKI had favorable efficacy and safety in real-world contexts in China and should be considered the preferred choice for first-line treatment in RET-rearranged NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) alterations poses a substantial treatment challenge. Current HER2 -targeted therapies offer limited efficacy. Antibody-drug conjugates (ADCs) targeting HER2 have emerged as a promising therapeutic strategy. This study aimed to evaluate the clinical response to a novel ADC drug Disitamab vedotin (RC48) in advanced NSCLC with HER2 alterations. Methods: This study conducted a retrospective review of patients harboring HER2 alterations treated with RC48 in the real world. Clinical outcomes were evaluated in terms of objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: Out of 22 patients, 21 (95.5%) received RC48 combination therapy, while one received RC48 monotherapy. The ORR of all patients reached 45.5%, and the DCR stood at 90.9%. The median PFS (mPFS) was 7.5 months. Among patients receiving RC48 combination therapy, the ORR was 47.7%, and the mPFS of 8.1 months. The combination of RC48 with platinum+/- bevacizumab resulted in the highest ORR of 71.4% (5 out of 7 patients), with HER2 TKI following at a 50.0% ORR (4 out of 8 patients). First-line (1L) treatment with RC48 showed an ORR of 62.5% (5 out of 8 patients), second-line (2L) treatments had a 57.1% ORR (4 out of 7 patients), and beyond second-line (>2L) treatments exhibited a 14.3% ORR (1 out of 7 patients). Patients with 1L, 2L, or >2L treatment had a mPFS of 8.1 months, 7.2 months, and 7.4 months, respectively. Patients with HER2 mutations or amplifications, and those with concurrent mutations and amplifications at baseline, showed mPFS of 8.1 months, 9.4 months, and 7.4 months, respectively. The mPFS was significantly longer in patients with HER2 amplification. The most common adverse events included hand-foot syndrome (54.5%), asthenia (50.0%), decreased white blood cell count (45.5%), and liver impairment (45.5%). Grade 3 adverse events occurred in one (4.5%) patient. Conclusion: RC48, particularly in combination regimens, demonstrates promising efficacy in advanced NSCLC with HER2 alterations. These findings underscore the need for further research to validate RC48's application in clinical practice. [ABSTRACT FROM AUTHOR]

In the management of advanced non-squamous non-small cell lung cancer (NSCLC) without driver gene mutations, the current therapeutic strategies encompass chemotherapy, chemotherapy combined with anti-angiogenic therapy, and chemotherapy combined with immunotherapy. For patients with high programmed death-ligand 1(PD-L1) expression, monotherapy with immune checkpoint inhibitors is a viable option. Recognizing that some patients cannot tolerate or decline chemotherapy, clinical practice has introduced non-chemotherapeutic treatment regimens, which have shown promising results. This article presents a clinical case of advanced NSCLC with low PD-L1 expression and negative driver gene mutations. The patient was treated with a chemotherapy-free regimen combining envafolimab with endostar. After 17 months of follow-up, both the primary tumor and metastatic lesions exhibited significant reduction, and no notable adverse reactions were observed. This case demonstrates the efficacy of envafolimab combined with endostar in the treatment of advanced NSCLC. This regimen enhances treatment safety and patient compliance, potentially offering a novel therapeutic option for patients with advanced NSCLC characterized by low PD-L1 expression and negative driver gene mutations. [ABSTRACT FROM AUTHOR]

Background: Multiple first-line treatment options have been developed for advanced non-small cell lung cancer (NSCLC) in each subgroup determined by predictive biomarkers, specifically driver oncogene and programmed cell death ligand-1 (PD-L1) status. However, the methodology for optimal treatment selection in individual patients is not established. This study aimed to develop artificial intelligence (AI)-based personalized survival prediction model according to treatment selection. Methods: The prediction model was built based on random survival forest (RSF) algorithm using patient characteristics, anticancer treatment histories, and radiomics features of the primary tumor. The predictive accuracy was validated with external test data and compared with that of cox proportional hazard (CPH) model. Results: A total of 459 patients (training, n = 299; test, n = 160) with advanced NSCLC were enrolled. The algorithm identified following features as significant factors associated with survival: age, sex, performance status, Brinkman index, comorbidity of chronic obstructive pulmonary disease, histology, stage, driver oncogene status, tumor PD-L1 expression, administered anticancer agent, six markers of blood test (sodium, lactate dehydrogenase, etc.), and three radiomics features associated with tumor texture, volume, and shape. The C-index of RSF model for test data was 0.841, which was higher than that of CPH model (0.775, P < 0.001). Furthermore, the RSF model enabled to identify poor survivor treated with pembrolizumab because of tumor PD-L1 high expression and those treated with driver oncogene targeted therapy according to driver oncogene status. Conclusions: The proposed AI-based algorithm accurately predicted the survival of each patient with advanced NSCLC. The AI-based methodology will contribute to personalized medicine. Trial registration: The trial design was retrospectively registered study performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (approval: 2020 − 0287). [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions This study aimed to compare long‐term clinical outcomes of percutaneous needle biopsy (PCNB) versus surgical biopsy in patients with peripheral, small‐sized clinical stage 1 non‐small cell lung cancer (NSCLC) with computed tomography (CT)‐defined visceral pleural invasion (VPI).We retrospectively analyzed patients who underwent surgery for NSCLC with CT‐defined VPI between 2010 and 2017. We excluded patients with non‐peripheral NSCLC, or cancers > 3 cm. Propensity score matching was carried out to adjust for confounding variables. The primary endpoint was ipsilateral pleural recurrence‐free survival, while secondary endpoints included overall survival and recurrence‐free survival.Of the 1671 patients with peripheral, small‐sized clinical stage 1 NSCLC with CT‐defined VPI, 805 underwent PCNB, and 866 had a surgical biopsy. Propensity score matching assigned 562 patients to each group. Before matching, the PCNB group demonstrated worse baseline characteristics, including older age, higher smoking history, and more adverse pathological findings. After matching, the 5‐year recurrence‐free survival for ipsilateral pleural recurrence (98.6% vs. 96.0%, p = 0.002) and overall survival (93.8% vs. 90.2%, p = 0.003) were significantly higher in the surgical biopsy group compared with the PCNB group. Multivariable analysis revealed that PCNB significantly increased the risks of all‐cause mortality and various recurrences before and after matching.Compared with surgery biopsy, PCNB was associated with higher risks of all‐cause mortality and recurrences, including ipsilateral pleural recurrence. PCNB should be considered with caution in cases of peripheral stage 1 NSCLC where CT‐defined VPI is suspected. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions This study aimed to evaluate the impact of antibiotic exposure on efficacy and adverse reactions in non‐small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy, and to explore any specific associations on the basis of antibiotic class.A retrospective study was conducted on NSCLC patients who received chemoimmunotherapy in two Shandong hospitals between January 2018 and October 2023. The association between antibiotic exposure and progression‐free survival (PFS), overall survival (OS), objective response rate (ORR) and incidence of immune related adverse reactions (irAE) of patients were evaluated.Of the 316 patients, 134 (42.41%) received antibiotics (ATB group), and 182 (57.59%) did not (N‐ATB group). There was no significant difference in PFS (aHR = 1.009, 95% CI: 0.770–1.323; p = 0.946) or OS (aHR = 1.420, 95% CI: 0.986–2.047; p = 0.060) between ATB and N‐ATB groups. The impact on efficacy was related to the type of antibiotic. β‐Lactams (aHR = 1.737, 95% CI: 1.148–2.629; p = 0.009), in particular β‐lactam/β‐lactamase inhibitor combinations (BLBLIs) (aHR = 1.885, 95% CI: 1.207–2.944, p = 0.005) were associated with poorer OS. However, quinolones (aHR = 1.192, 95% CI: 0.861–1.650; p = 0.291) were not associated with OS. The incidence of irAEs was not significantly different between ATB and N‐ATB groups (p = 0.073), but was higher with BLBLIs (p = 0.013).In NSCLC patients receiving chemoimmunotherapy, no significant difference was observed in efficacy and incidence of irAEs between the ATB and the n‐ATB groups. In antibiotic class analysis, β‐lactams and specifically BLBLIs were observed to be associated with worse OS. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Protein tyrosine kinase 7 (PTK7) has been found to be highly expressed in non‐small cell lung cancer (NSCLC), but its specific molecular mechanism needs to be further explored.PTK7 mRNA expression in NSCLC tumor tissues was examined by quantitative real‐time PCR. The protein levels of PTK7, ubiquitin‐specific peptidase 8 (USP8), PIK3CB, and PI3K/AKT were determined by western blot. Human monocytes (THP‐1) were induced into macrophages and then co‐cultured with the conditioned medium of NSCLC cells. Macrophage M2 polarization was assessed by detecting CD206+ cells using flow cytometry. The interaction between PTK7 and USP8 or PIK3CB was assessed by Co‐IP assay. Animal study was performed to evaluate the effects of PTK7 knockdown and PIK3CB on NSCLC tumorigenesis in vivo.PTK7 expression was higher in NSCLC tumor tissues and cells. After silencing of PTK7, NSCLC cell proliferation, invasion, and macrophage M2 polarization were inhibited, while cell apoptosis was promoted. USP8 enhanced PTK7 protein expression by deubiquitination, and the repressing effects of USP8 knockdown on NSCLC cell growth, invasion, and macrophage M2 polarization were reversed by PTK7 overexpression. PTK7 interacted with PIK3CB, and PIK3CB overexpression could abolish the regulation of PTK7 silencing on NSCLC cell progression. USP8 positively regulated PIK3CB expression by PTK7, thus activating PI3K/AKT pathway. Downregulation of PTK7 reduced NSCLC tumorigenesis by decreasing PIK3CB expression.USP8‐deubiquitinated PTK7 facilitated NSCLC malignant behavior via activating the PIK3CB/PI3K/AKT pathway, providing new idea for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Gut microbiota is considered a key player modulating the response to immune checkpoint inhibitors (ICI) in cancer. The effects of dietary pattern on this interaction is not well-studied. A prospective multicenter cohort of 95 patients with advanced non-small cell lung cancer (NSCLC) undergoing ICI therapy were enrolled. Stool shotgun metagenomic sequencing was performed. Three-day dietary patterns before ICI were assessed. Patients were categorized as hyperprogressive disease (HPD) if they exhibited a time to treatment failure of less than 2 months. All others were categorized as non-hyperprogressive disease (non-HPD). The correlation between dietary patterns, gut microbiome, and response to ICI therapy was analyzed. In the multivariate analysis, a high abundance of Firmicutes unclassified and the Ruminococcaceae family correlated with a significantly diminished progression-free survival (PFS) with an HR of 2.40 [P = 0.006] and 4.30 [P = 0.005], respectively. More specifically, within the subset of NSCLC patients treated solely with ICI therapy, a high abundance of Intestinimonas and the Enterobacteriaceae family were associated with substantially reduced PFS with an HR of 2.61 [P = 0.02] and HR 3.34 [P = 0.005], respectively. In our comprehensive dietary pattern analysis, the HPD group showed increased consumption of cholesterol, sodium, and fats beyond recommended levels compared to the non-HPD group. This group also displayed a tendency towards higher food pattern scores characterized by a high intake of fat and dairy products. Our study revealed a distinct association between the gut microbiome composition and treatment outcomes. The overall composition of diet might be related to ICI therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Mesenchymal–epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare (3%–4%) driver mutation in non‐small cell lung cancer (NSCLC). Tepotinib, a selective MET inhibitor, has shown promise in treating METex14 skipping‐mutated NSCLC. However, its feasibility for perioperative application remains unclear. This report describes a 60‐year‐old man with stage IIIA (cT2N2M0) lung adenocarcinoma harboring a METex14 skipping mutation. After initial treatment with savolitinib was discontinued due to grade 4 transaminitis, the patient was switched to tepotinib, resulting in significant tumor regression. Six months later, further shrinkage was observed, and surgery revealed remarkable pathological response with no residual tumor in lymph nodes (ypT2N0M0, IB). Postoperative tepotinib continued, with no relapse at 6‐month follow‐up. This case highlights the potential of tepotinib as neoadjuvant therapy for resectable METex14 skipping‐mutated NSCLC, warranting further clinical trials. [ABSTRACT FROM AUTHOR]

Background: For patients with advanced non‐small cell lung cancer (NSCLC) who have received frontline immunochemotherapy, subsequent treatment options are limited. As the first dual programmed cell death‐1 (PD‐1)/cytotoxic T lymphocyte‐associated antigen‐4 bispecific antibody approved globally, cadonilimab demonstrated potential antitumor activity in advanced NSCLC patients resistant to anti‐PD‐1/PD‐L1 antibodies. Methods: We retrospectively collected efficacy and safety data from advanced NSCLC patients treated with cadonilimab‐based regimens in later therapy lines. Results: A total of 41 advanced NSCLC patients refractory to anti‐PD‐1/PD‐L1 therapy were enrolled. More than half of the patients received cadonilimab‐based regimen as a fourth or later line of treatment. At the data cutoff date, treatment efficacy could be evaluated in 23 patients. One patient (4.3%) achieved partial response, eight patients (34.8%) experienced stable disease, and 14 patients (60.9%) progressed. The objective response rate and disease control rate were 4.3% and 39.1%, respectively. The median progression‐free survival for all evaluated patients was 108.0 days. Due to the short follow‐up period, the median overall survival has not yet been reached. Treatment‐related adverse events (TRAEs) and immune‐related AEs occurred in 63.4% and 22% patients, respectively. The most common TRAEs included gamma‐glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade ≥3 TRAEs. Conclusions: In this heavily pretreated cohort of advanced NSCLC patients, cadonilimab‐based regimens showed moderate antitumor efficacy with a generally tolerable and manageable safety profile. However, more evidence is needed to support the administration of cadonilimab in NSCLC patients refractory to previous anti‐PD‐1/PD‐L1 therapy. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC. Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach. Results: We identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events. Conclusion: These results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates. [ABSTRACT FROM AUTHOR]

Objective: Limited studies have explored the utility of whole-lesion histogram analysis in discerning the subtypes and proliferation status of non-small cell lung cancer (NSCLC), despite its potential to provide comprehensive tissue assessment through the computation of additional quantitative metrics. This study sought to assess the significance of intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram parameters in discriminating between squamous cell carcinoma (SCC) and adenocarcinoma (AC), and to examine the correlation of each parameter with the proliferative marker Ki-67. Materials and methods: Patients with space-occupying lesions detected by chest CT examination and with further routine MRI, DKI and IVIM functional sequence scans were enrolled. Based on the pathological results, seventy patients with NSCLC were selected and divided into AC and SCC groups. Histogram parameters of IVIM (D, D*, f) and DKI (Dapp, Kapp) were calculated, and the Mann–Whitney U test or independent samples t test was used to analyze the differences in each histogram parameter of the SCC and AC groups. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the histogram parameters. The correlation coefficient between histogram parameters and Ki-67 was calculated using Spearman's or Pearson's methods. Results: The D 10th percentile, D 90th percentile, D mean, D median, Dapp10th percentile, Dapp90th percentile, Dappmean, Dappmedian, Dappskewness, DappSD of the AC groups were significantly higher than those of the SCC groups, while the Kappentropy and KappSD of the SCC groups were significantly higher than those of the AC groups. All the above differences were statistically significant (all P < 0.05). ROC curve analysis revealed that Dappmean showed the best performance for differentiating AC from SCC lesions, with an area under the ROC curve of 0.832 (95% confidence interval [CI]: 0.707-0.919). But there was no statistically significant difference in diagnostic efficacy compared to other histogram parameters (all P>0.05). Dapp90thpercentile, Dappmean, Kappskewnes showed a slight negative correlation with Ki-67 expression (r value -0.340, -0.287, -0.344, respectively; P< 0.05), while the other histogram parameters showed no significant correlation with Ki-67 (all P > 0.05). Conclusions: Our study demonstrates the utility of IVIM and DKI histogram analyses in differentiating NSCLC subtypes, particularly AC and SCC. Correlations with the Ki-67 index suggest that Dappmean, Dapp90th percentile, and Kappskewness may serve as markers of tumor aggressiveness, supporting their use in NSCLC diagnosis and treatment planning. [ABSTRACT FROM AUTHOR]

Lung cancer is the second most common type of cancer and is the leading cause of cancer-related deaths in the United States. Approximately 10-40% of patients with solid tumors develop brain metastases, with non-small cell lung cancer accounting for approximately 50% of all cases of patients with brain metastases. Many management options are available which can include surgery, radiation, and systemic therapy. A variety of factors go into the selection of management of brain metastases. In this review, we will focus on the treatment strategies and optimizing the management of brain metastases in patients with non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: This is the first case report describing a patient with non-small cell lung cancer (NSCLC) harboring two rare human epidermal growth factor receptor 2 (HER2) exon 21 insertion mutations, who responded to furmonertinib treatment. Furmonertinib maybe one effective and economical treatment for NSCLC patients harboring HER2 mutations with minor side effects. Case description: We present a case report of a 49-year-old female diagnosed with stage IV lung adenocarcinoma who complained of irritating dry cough symptoms followed by chest tightness. Firstly, we describe the patient's treatment history, including failed third-line combination treatments of systemic chemotherapy with bevacizumab or carrelizumab or anlotinib, primary lung tumor recurrence, bilateral lung metastases progression, and new brain metastatic lesion detection. Next, we detail the patient's fourth-line treatment with radiotherapy for brain metastases and two cycles of bevacizumab plus Abraxane and cisplatin, however, the disease progressed and relapsed. After that, comprehensive genomic profiling revealed two HER2 exon 21 insertion mutations. Subsequently, the patient received targeted therapy with furmonertinib and achieved 11 months of progression-free survival. The patient received pyrrotinib therapy for 2 months after disease progression, but the disease continued to progress. In October 2023, the patient received therapy with furmonertinib again, and a month later, the disease went into partial remission. However, the patient died due to hypoproteinemia combined with severe pneumonia in December 2023. Conclusion: Furmonertinib may be effective for NSCLC patients with HER2 T8962A and L869R mutations and further studies are needed to confirm these results in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Background: Tyrosine Kinase Inhibitors (TKIs) is an important therapy for patients with oncogene-mutated Non-Small Cell Lung Cancer (NSCLC). However, acquired resistance remains a major challenge. The efficacy of TKIs plus thoracic radiotherapy (RT) in oncogene-mutated NSCLC patients is uncertain. Therefore, we performed a meta-analysis to comprehensively evaluate the efficacy and safety of thoracic RT plus TKIs in oncogene-mutated NSCLC patients. Methods: The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane Library. Studies comparing the efficacy and safety of TKIs plus RT with TKIs alone in oncogene-mutated NSCLC patients were included in this analysis. Outcomes were median progression-free survival (mPFS), median overall survival (mOS), and incidence of adverse events (AEs). This analysis performed a subgroup analysis of the efficacy of first-line TKIs in combination with RT. Results: This meta-analysis included 12 studies with 2936 patients (n = 823 patients with TKIs plus thoracic RT, n = 2113 patients with TKIs alone). The results showed that patients who received treatment with TKIs plus thoracic RT were associated with superior mPFS and mOS than those who were treated with TKIs alone (hazard ratio [HR]: 0.42, 95% CI 0.30–0.59, p < 0.00001; HR: 0.56, 95% CI 0.41–0.70, p < 0.00001, respectively). Subgroup analyses showed that TKIs plus thoracic RT as first-line treatment was associated with better mPFS and OS (HR: 0.37, 95% CI 0.26–0.52, p < 0.00001; HR: 0.47, 95% CI 0.31–0.70, p = 0.0002, respectively). Although the combination of TKIs with thoracic RT was associated with an increased risk of total AEs (odds ratio [OR]: 1.17, 95% CI 1.06–1.29, P = 0.002), there was no significant difference in serious AEs (grade ≥ 3) (OR: 1.06, 95% CI 0.58–1.92, P = 0.86). The most frequently occurring radiation-related AEs were radiation pneumonitis, radiation esophagitis, and radiation dermatitis, with overall rates of 41.3%, 15.4%, and 11.1%, respectively. The incidence of severe radiation pneumonitis and radiation esophagitis was 4.5% and 6.2%, respectively. Conclusions: In comparison to TKIs alone, TKIs plus thoracic RT are associated with survival benefits, especially as a first-line treatment option. Although TKIs plus thoracic RT may increase the risk of total AEs, it did not increase the risk of severe AEs. Therefore, TKIs plus thoracic RT may be a promising therapeutic regimen for oncogene-mutated NSCLC patients. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common malignancies worldwide, with non-small cell lung cancer (NSCLC) being the most common type. As understanding of precise treatment options for NSCLC deepens, circulating tumor DNA (ctDNA) has emerged as a potential biomarker that has become a research hotspot and may represent a new approach for the individualized diagnosis and treatment of NSCLC. This article reviews the applications of ctDNA for the early screening of patients with NSCLC, guiding targeted therapy and immunotherapy, evaluating chemotherapy and postoperative efficacy, assessing prognosis and monitoring recurrence. With the in-depth study of the pathogenesis of NSCLC, plasma ctDNA may become an indispensable part of the precise treatment of NSCLC, which has great clinical application prospects. Article highlights Background Non-small cell lung cancer (NSCLC) has a high morbidity and mortality in the world today. There is a lack of effective means for clinical diagnosis and monitoring of NSCLC recurrence. Circulating tumor DNA (ctDNA) is a hot research direction in the precise treatment of NSCLC. Biological characteristics of circulating tumor DNA Biological characteristics of cell-free circulating DNA. Biological characteristics and genetic information sources of ctDNA. Detecting ctDNA The traditional method of ctDNA detection. The current ctDNA detection method. The advantages and disadvantages of current ctDNA detection methods. Clinical use of ctDNA detection for the diagnosis & treatment of NSCLC Early screening and diagnosis of lung cancer ctDNA detection is helpful to improve the detection rate of clinical lung cancer. ctDNA methylation was combined with imaging examination. Guiding immunotherapy and targeted therapy in patients with NSCLC ctDNA detection was used to evaluate the effect of immunotherapy in patients with NSCLC. ctDNA detection was used to evaluate the effect of targeted therapy in NSCLC patients. Evaluation of chemotherapy efficacy The advantage of ctDNA in evaluating chemotherapy in NSCLC patients. ctDNA monitoring can evaluate the sensitivity of NSCLC patients to chemotherapy. Evaluation of postoperative efficacy Postoperative ctDNA detection can evaluate the efficacy of surgery. Postoperative ctDNA monitoring can predict the risk of recurrence of NSCLC. Assessing prognosis and monitoring recurrence Expert consensus on minimal residual disease. ctDNA monitoring can evaluate the prognosis and recurrence of lung cancer after treatment. Discussion The advantages of ctDNA as a new tumor marker for NSCLC. Limitations of ctDNA detection technology. Challenges and opportunities for clinical application of ctDNA. [ABSTRACT FROM AUTHOR]

Background: Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy. We describe treatment utilization and clinical outcomes in a real-world mNSCLC cohort in a 2.7-million-member state-mandated health provider. Methods: Newly diagnosed mNSCLC patients initiating systemic anti-cancer treatment (January 2017–December 2020) were identified from the National Cancer Registry. Real-world time on treatment (rwToT) was defined as the length of time between the first and last administration date of treatment. Real-world overall survival (rwOS) was estimated using Kaplan–Meier analysis. Outcomes were assessed at a minimum of 6 months' follow-up (cutoff: 30 June 2021). Results: Among 843 patients, 85% had adenocarcinoma (NSQ) and 15% had squamous cell carcinoma (SQ) histology: of these, 43% and 26% were women, median age was 67 and 69 years, and 55% and 48% had 0–1 ECOG performance status, respectively (missing: 27% and 30%, respectively). Median follow-up for the entire cohort was 27.1 months (95% CI: 24.7–29.6). NSQ patients with no known EGFR/ALK/ROS1 aberrations received PD-1 inhibitor monotherapy (PDM) (N = 147) or combination (PDC) (N = 194) or platinum-based chemotherapy (PBC, N = 133). Median rwToT was 4.5 (95% CI: 3.5–7.6), 5.2 (95% CI: 4.6–7.6), and 2.3 (95% CI: 2.1–3.0) months, respectively; for the subgroup of patients with ECOG PS 0–1, rwToT was 9.4 (95% CI: 5.0–20.8), 7.1 (95% CI: 5.0–10.1), and 2.9 (95% CI: 2.2–4.1) months, respectively. Median rwOS from 1L was 12.5 (95% CI: 9.9–17.9), 14.8 (95% CI: 10.5–19.4), and 9.1 (95% CI: 7.1–11.5) months; for the subgroup of patients with ECOG PS 0–1, median rwOS was 25.1 [95% CI: 14.9–not reached (NR)], 17.6 (95% CI: 14.3–NR), and 11.3 (95% CI: 9.2–21.3) months, respectively. For ECOG PS 0–1 and PD-L1 ≥50% patients, median rwOS was 25.1 months (95% CI: 13.9–NR) and NR for PDM and PDC, respectively. For ECOG PS 0–1 and PD-L1 <50% patients, median rwOS was 14.3 (95% CI: 10.1–NR) and 11.2 (95% CI: 9.1–21.3) months for PDC and PBC, respectively. Conclusion: Our real-world data support the benefit of single-agent PD-1 inhibitor monotherapy for patients with PD-L1 high expression or PD-1 inhibitor combination for all patients diagnosed with mNSCLC with no known EGFR/ALK/ROS1 aberrations, initiating 1L treatment. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have suggested high concordance between tissue and circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) tests but only few of them focused on fusions. In addition, atypical breakpoints occasionally detected from DNA-based fusion detection make interpretation difficult, and their clinical significance remains unclear. This study evaluated the clinical utility of ctDNA CGP for fusion detection. Methods: The results of ctDNA CGP tests performed on patients with stage IV non-small cell lung cancer during routine clinical care were retrospectively reviewed. The concordance between ctDNA CGP and combined tissue test results was analyzed using CGP, immunohistochemistry, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction. The clinical significance of fusions detected by ctDNA CGP, including those with atypical breakpoints at the DNA level, was assessed. Results: In total, 264 patients were tested with ctDNA CGP. Fusions were detected in 27 patients (10.2%), and the fusion drivers were RET (n=12, 4.6%), ALK (n=9, 3.4%), ROS1 (n=4, 1.5%), and FGFR2 (n=2, 0.8%). The overall prevalence of fusion in tissue CGP was comparable to that in ctDNA CGP. A total of 371 ctDNA-tissue test pairs were available, and the overall positive and negative percent agreement rates were 92.9% (13/14) and 100.0% (357/357), respectively. One ALK IHC-positive and ctDNA CGP-negative case did not respond to ALK -targeted therapy. Response to targeted therapy was assessed in 16 patients, and a partial response was achieved in all patients, including four with atypical breakpoints. Conclusion: Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection. [ABSTRACT FROM AUTHOR]

This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls (P < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL (P < 0.001, P < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC (P < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs. [ABSTRACT FROM AUTHOR]

Purposes: Osimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance. Methods: A total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data. Results: The optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort. Conclusions: NGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion. [ABSTRACT FROM AUTHOR]

Background: Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Methods: Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Results: Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). Conclusions: ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073. [ABSTRACT FROM AUTHOR]

Lung enteric-type adenocarcinoma (ETAC) is a rare subtype of non-small cell lung cancer (NSCLC), comprising approximately 0.6% of all primary lung adenocarcinomas. It is characterized by a tendency for early metastasis and a prognosis comparable to that of common lung adenocarcinoma. This case report described a patient with lung-ETAC who developed gastric metastasis. The patient underwent treatment with chemotherapy and a PD-1 inhibitor, resulting in disease remission with a progression-free survival (PFS) of 8 months. The follow-up time was 13 months. This case report was aimed to enhance understanding of the biological behavior of this rare tumor and provide insights into potential future treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Previous reports indicated still low implementation rates of multigene testing for advanced non‐small cell lung cancer (NSCLC) in Japan. Methods: This is a retrospective study launched at the initiative of lung cancer patients. Patients with stage IV NSCLC from January 2019 to December 2022 were investigated for testing of 8 actionable oncogenic drivers with targeted therapies available as of 2022. Results: A total of 15,719 patients were included. Between 2019 and 2022, the percentage of patients who were not tested for any actionable oncogenic drivers remained the same, ranging from 21.5% to 33.1%. However, since late 2021, the percentage of patients tested for five or more actionable oncogenic drivers has increased. Across hospital categories and regions, the number of actionable oncogenic drivers tested was similar. Conclusions: This patient‐initiated national survey in Japan reveals the recent nationwide increase in testing rates for actionable oncogenic drivers in Advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is among the most prevalent and serious forms of cancer, characterized by an allogenic phenotype that presents significant therapeutic challenges. Materials and Methods: We analyzed medical records from January 2022 to August 2023, focusing on individuals aged 18 and older diagnosed with resectable NSCLC who received neoadjuvant chemo-immunotherapy prior to surgical intervention. Results: The cohort comprised 56 patients, predominantly smokers (95%) and male (74%), with 80% presenting the disease at stage III. Of the participants, 44 underwent surgery, with 95% receiving lobar resection. Clinical assessments via PET-CT imaging revealed an 86% rate of response or disease stabilization, while pathological evaluations showed complete and major pathological responses in 61% of cases. Conclusions: This real-world data supports the safety and efficacy of incorporating immune checkpoint inhibitors in the neoadjuvant treatment of NSCLC, followed by surgical resection. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. Ciclopirox olamine (CPX), an off-patent fungicide, has been identified as a new anticancer agent. Prexasertib (PRE), a Chk1 inhibitor, is in phase 1/2 clinical trials in various tumors. The anticancer effect of the combination of CPX with PRE on NSCLC cells is unknown. Here, we show that CPX is synergistic with PRE in inhibiting cell proliferation and inducing apoptosis of NSCLC (A549 and A427) cells. Combined treatment with CPX and PRE significantly increased the cell population in the G1/G0 and sub-G1 phases, compared to the single treatment with CPX or PRE. Concurrently, the combined treatment downregulated the protein levels of cyclins (A, B1), cyclin-dependent kinases 4, 6, 2 (CDK4, CDK6, CDK2), cell division cycle 25 B, C (Cdc25B, Cdc25C), and upregulated the protein levels of the CDK inhibitors p21 and p27, leading to decreased phosphorylation of Rb. In addition, the combined treatment increased DNA damage, evidenced by increased expression of γH2AX. In line with this, the combined treatment induced more apoptosis than either single treatment. This was associated with increased expression of DR4, DR5, Fas, and FADD and decreased expression of survivin, resulting in activation of caspase 8 and caspase 3 as well as cleavage of poly (ADP ribose) polymerase (PARP). Taken together, the results suggest that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes real-world outcomes for advanced, non-oncogene addicted non-small cell lung cancer patients treated with atezolizumab monotherapy following platinum-based chemotherapy, based on data from two academic institutions in Serbia. Progression-free survival did not significantly differ between patients receiving atezolizumab as a second, third, or later line of therapy, indicating consistent efficacy across treatment lines. Additionally, the number of prior chemotherapy cycles had no significant impact on progression-free survival, suggesting that a higher prior treatment burden did not compromise atezolizumab effectiveness. Importantly, a good ECOG performance status emerged as the strongest predictor of prolonged progression-free survival, highlighting the importance of patients' health status at treatment initiation. Immune checkpoint inhibitors (ICIs) like atezolizumab have improved outcomes in advanced non-small cell lung cancer (NSCLC) patients, especially in the second-line setting after progression on platinum-based chemotherapy. However, access to ICIs remains limited in many developing nations. This study evaluated the efficacy of atezolizumab as a second-line versus later-line treatment for advanced NSCLC patients in Serbia. Methods: This retrospective study involved 147 advanced NSCLC patients treated with atezolizumab following progression on prior platinum-based chemotherapy at two academic centers in Serbia. Data on demographics and clinical, pathological, and molecular characteristics were collected. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and multivariable Cox proportional hazards regression identified outcome predictors. Results: The median PFS was 7.13 months, and median OS was 38.6 months. The overall response rate (ORR) was 15%, with a disease control rate (DCR) of 57.9%. No significant PFS differences were observed between patients treated with atezolizumab in the second line versus later lines. Patients with good performance status (ECOG 0–1) had significantly better PFS compared to those with poorer status (12.03 vs. 1.63 months, p < 0.0001). Conclusions: Atezolizumab is effective in both second-line and later-line settings for advanced NSCLC, particularly in patients with good performance status. This highlights the importance of patient selection based on performance status, as well as the need for wider access to ICIs in resource-limited regions. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer-related deaths and early detection is crucial for better outcomes. This study focuses on methylation, a new method for detecting and monitoring NSCLC using a blood test that looks for changes in DNA. These changes can be found in tiny fragments of tumor DNA circulating in the blood. By analyzing existing research, the authors found that this method is accurate and reliable, showing promise for early diagnosis and the better management of NSCLC patients. The findings suggest that this approach could be a valuable tool in clinical practice, potentially leading to improved survival rates by allowing for earlier and more precise treatment. Background: Non-Small Cell Lung Cancer (NSCLC) remains a challenging disease to manage with effectiveness. Early detection and precise monitoring are crucial for improving patient outcomes. Circulating tumor DNA (ctDNA) offers a non-invasive cancer detection and monitoring method. Emerging biomarkers, such as ctDNA methylation, have shown promise in enhancing diagnostic accuracy and prognostic assessment in NSCLC. In this review, we examined the current evidence regarding ctDNA methylation's role in NSCLC detection through a systematic review of the existing literature and meta-analysis. Methods: We systematically searched PubMed, Medline, Embase, and Web of Science databases up to 26 June 2024 for studies on the role of ctDNA methylation analysis in NSCLC patients. We included studies from 2010 to 2024 on NSCLC patients. We excluded case reports, non-English articles, studies on cell lines or artificial samples, those without cfDNA detection, prognostic studies, and studies with non-extractable data or mixed cancer types. Funnel plots were visually examined for potential publication bias, with a p value < 0.05 indicating bias. Meta-analysis was conducted using R packages (meta, forestplot, and mada). Combined sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR−), positive and negative predictive values, diagnostic odds ratio (DOR), and 95% confidence intervals (95% CI) were calculated. A summary receiver operating characteristic curve (SROC) and area under the curve (AUC) with related Standard Error (SE) were used to evaluate the overall diagnostic performance. Additionally, RASSF1A, APC, SOX17, SEPT9, and RARβ2 were analyzed, since their methylation was assessed in two or more studies. Results: From 38 candidate papers, we finally identified 12 studies, including 472 NSCLC patients. The pooled sensitivity was 0.62 (0.47–0.77) and the specificity was 0.90 (0.85–0.94). The diagnostic odds ratio was 15.6 (95% CI 9.36–26.09) and the area under the curve was 0.249 (SE = 0.138). The positive and negative predictive values were 5.38 (95% CI 3.89–7.44) and 0.34 (95% CI 0.22–0.54), respectively. For single genes, the specificity reached 0.83~0.96, except for RARβ2, but the sensitivity was relatively low for each gene. Significant heterogeneity across the included studies, the potential publication bias for specificity (p = 0.0231), and the need to validate the clinical utility of ctDNA methylation for monitoring treatment response and predicting outcomes in NSCLC patients represent the main limitations of this study. Conclusions: These results provide evidence of the significant potential of ctDNA methylation as a valuable biomarker for improving the diagnosis of NSCLC, advocating for its integration into clinical practice to enhance patient management. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 25% of non-small cell lung cancer (NSCLC) patients subsequently experience isolated locoregional recurrence following definitive radiation therapy (RT). For these scenarios, thoracic reirradiation (re-RT) has become an increasingly common consideration, with improved feasibility due to technological advancements that have made it safer to deliver high doses of RT in the retreatment setting. Proton beam therapy (PBT) is an attractive choice for re-RT due to its ability to spare radiation to adjacent previously treated normal tissues. Here, we evaluate outcomes with PBT for the definitive re-RT of recurrent NSCLC within the previously irradiated thorax. Background/Objectives: This retrospective study evaluates outcomes of 66 patients who underwent reirradiation (re-RT) with proton beam therapy (PBT) for recurrent non-small cell lung cancer. Methods: Toxicity was scored via the CTCAE v5.0, and outcomes estimated using the Kaplan–Meier method, with associations evaluated via Cox proportional hazards and logistic regression analyses. Results: Patients were treated to a median re-RT prescription of 66 Gy/33 fxs (BED10 = 79 Gy; IQR: 71–84 Gy) at an interval of 1.4 years from prior RT. Half (50%) received concurrent chemotherapy. At 14 months follow-up, the median OS and PFS were 5 months (95%CI: 13–17) and 12.5 months (95%CI: 10–15), respectively. On multivariable analysis, a higher RT dose (BED10 > 70 Gy) [HR0.37; 95%CI: 0.20–0.68, p = 0.001] and concurrent chemotherapy (HR0.48; 95%CI: 0.28–0.81, p = 0.007) were associated with improved PFS, while treatment site overlap was adversely associated (HR1.78; 95%CI: 1.05–3.02, p = 0.031). The median PFS for definitive RT with concurrent chemotherapy (n = 28), definitive RT alone (BED10 > 70 Gy) [n = 22], and lower prescription RT (BED10 < 70 Gy) [n = 16] was 15.5 months (95%CI: 7.3–23.7), 14.1 months (95%CI: 10.9–17.3), and 3.3 months (95%CI: 0–12.3), respectively (log-rank, p = 0.006), with corresponding 2-year estimates of 37% (±9), 18% (±8), and 12.5% (±8), respectively. The incidence of Grade 3+ toxicity was 10.5% (6% pulmonary; 3% esophageal; and 1.5% skin), including one Grade 4 bronchopulmonary hemorrhage but no Grade 5 events. Cases with central site overlap had higher composite Dmax to the esophagus (median 87 Gy [IQR:77–90]), great vessels (median 120 Gy [IQR:110–138]), and proximal bronchial tree (median 120 Gy [IQR:110–138]) as compared to other cases (p ≤ 0.001 for all). However, no significant associations were identified with Grade 3+ events. Conclusions: Thoracic re-RT with PBT is an option for recurrent NSCLC with acceptable outcomes and toxicity for select patients. When feasible, higher prescription doses (BED10 > 70 Gy) should be delivered for definitive intent, and concurrent chemotherapy may benefit individual cases. [ABSTRACT FROM AUTHOR]

Background: Superior outcomes have been obtained for neoadjuvant treatment with immune checkpoint inhibitors (ICI) plus chemotherapy over neoadjuvant chemotherapy alone, especially in patients with high programmed cell death ligand 1 (PD‐L1) expression. However, it is not always possible to obtain sufficient tumor specimens for biomarker testing before surgery. In this study, we explored clinical factors that can predict high PD‐L1 expression. Methods: We retrospectively enrolled 340 lung cancer patients who received pulmonary resection between 2014 and 2023 and who had PD‐L1 expression data. Chi‐squared tests and logistic regression analyses were used to identify clinical factors associated with high PD‐L1 status. Results: Univariable and multivariable analyses revealed that smoking, high maximum standardized uptake value (SUVmax) of 18F‐fluorodeoxyglucose positron emission computed tomography (18F‐FDG PET/CT), and high plasma fibrinogen are independent predictors of high PD‐L1 expression. A predictive score for high PD‐L1 expression (ranging from 0 to 3) was developed based on these parameters. Notably, only 5% of patients with a score of 0 exhibited high PD‐L1 expression, whereas this proportion increased to 53% for patients with a score of 3. Conclusion: These results showed that plasma fibrinogen, smoking history, and SUVmax are predictors of high PD‐L1 expression, providing a basis for identifying patients expected to benefit from neoadjuvant ICI treatment. [ABSTRACT FROM AUTHOR]

Background: Limited information is available regarding the impact of sarcopenia on the prognosis of antiangiogenic therapy in individuals with advanced non‐small cell lung cancer (NSCLC). This study primarily sought to examine the prognostic significance of sarcopenia in individuals with advanced NSCLC undergoing antiangiogenic therapy. Methods: We retrospectively enrolled all patients who met the inclusion and exclusion criteria from 2019 to 2021 at Nantong University Hospital. Patients were grouped according to the presence or absence of sarcopenia. After propensity score matching (PSM), progression‐free survival (PFS), overall survival (OS), and adverse event rates were compared between the two groups. Factors associated with prognosis were screened using univariate and multivariate analyses. Results: A total of 267 patients were included, with a total of 201 matched at baseline after PSM (77 in the sarcopenia group and 124 in the non‐sarcopenia group). The sarcopenia group had lower PFS (p = 0.043) and OS (p = 0.011) than the non‐sarcopenia group and a higher incidence of adverse events (p = 0.044). Multivariate analysis suggested that sarcopenia is an independent prognostic risk factor for OS in advanced NSCLC patients receiving antiangiogenic therapies (p = 0.009). Results of subgroup analyses showed some differences in the impact of sarcopenia on survival prognosis in populations with different characteristics. Conclusion: Patients with advanced NSCLC with comorbid sarcopenia exhibit a worse prognosis when treated with antiangiogenic therapy, and preventing and ameliorating sarcopenia may lead to better survival outcomes in patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: The identification of gene mutations in the modern medical workup of metastatic spine tumors has become more common but has not been highly utilized in surgical planning. Potential utility of these genetic markers as surrogates for cancer behavior in current prognosis scoring systems and overall survival (OS) remains underexplored in existing literature. This study seeks to investigate the association of frequently identified tumor markers, EGFR, ALK, and PD-L1, in metastatic non-small cell lung cancer (NSCLC) to the spine with Tokuhashi prognosis scoring and OS. Methods: Patients with NSCLC metastasis to spine were identified through chart review. EGFR, ALK, and PD-L1 wild type vs. mutant type were identified from targeted chemotherapy genetic testing. Multiple linear regression was performed to assess gene profile contributions to Tokuhashi score. Cox Proportional Hazards models were generated for each tumor marker to assess the relationship between each marker and OS. Results: A total of 119 patients with NSCLC spine metastasis were identified. We employed a multiple linear regression analysis to investigate the influence of EGFR, ALK, and PD-L1 genotypes on the Tokuhashi score, revealing statistically significant relationships overall (p = 0.002). Individual genotype contributions include EGFR as a non-significant contributor (p = 0.269) and ALK and PD-L1 as significant contributors (p = 0.037 and p = 0.001 respectively). Overall survival was not significantly associated with tumor marker profiles through Kaplan-Meier analysis (p = 0.46) or by multivariable analysis (p = 0.108). Conclusion: ALK and PD-L1 were significantly associated with Tokuhashi score while EGFR was not. Tumor markers alone were not predictive of OS. These findings indicate that genetic markers found in NSCLC metastases to the spine may demonstrate prognostic value. Therefore, employing standard tumor markers could enhance the identification of appropriate surgical candidates, although they demonstrate limited effectiveness in predicting overall survival. [ABSTRACT FROM AUTHOR]

Due to the recent advances in the systemic treatment of non-small cell lung cancer, the management of locoregional recurrences, especially after initial radiotherapy (with or without concurrent chemotherapy), is of increasing significance. The potential alternatives in this setting include: a salvage local strategy (based on surgery, radiotherapy or thermoablative treatment), promising approach, but sometimes difficult to implement in often frail patients, and whose modalities remain under-researched; or alternatively, the initiation of systemic treatment, where the prognosis aligns with that of de novo metastatic patients. This comprehensive literature review focused on salvage radiotherapy treatment of recurrent non-small cell lung carcinomas, after initial radiotherapy, with or without associated systemic treatment. It aims to present the main findings on this area, from patient selection and preparation, to key characteristics, including dosimetric aspects, and the main limitations and uncertainties associated with this therapeutic modality. [ABSTRACT FROM AUTHOR]

Highlights: FOXO3 was decreased, while LA and FBXO22 were increased in NSCLC patients. LA promoted cisplatin resistance in NSCLC in vitro and in vivo. SQFZ inhibited LA-induced cisplatin resistance in NSCLC by regulating FOXO3. FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. SQFZ inhibited cisplatin resistance in NSCLC by FOXO3/FBXO22/p53 axis. Background: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Cisplatin (DDP)-based combination chemotherapy is the main treatment of NSCLC. Due to resistance to DDP, 5-year overall survival rate of NSCLC patients is very low. Shenqifuzheng injection (SQFZ) is essential for lung cancer progression. However, whether SQFZ plays a role in DDP resistance in NSCLC and its molecular mechanism remains unclear. Methods: Levels of FOXO3, FBXO22 and p53 in NSCLC tissues and cells were assessed by RT-qPCR and Western blot. Cell proliferation and apoptosis were analyzed utilizing CCK-8, Colony formation and Flow cytometry assays. Lactate (LA) levels were tested via ELISA. ChIP and Dual luciferase reporter assays validated regulatory relationship between FOXO3 and FBXO22. Immunoprecipitation assay evaluated p53 ubiquitination levels. The subcutaneous tumor model of nude mice was constructed. TUNEL staining detected apoptosis in tissues, and IHC assessed expression of Ki67, FOXO3, FBXO22 and p53. Results: FOXO3 was decreased, whereas LA and FBXO22 were increased in NSCLC patients. LA led to a higher DDP resistance in A549/DDP cells, while SQFZ reversed this effect by upregulating FOXO3. Furthermore, FBXO22 was a downstream effecter of FOXO3 and FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. We next found SQFZ inhibited LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 axis. Finally, SQFZ regulated LA-mediated DDP resistance in NSCLC nude mice. Conclusion: SQFZ influences LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 pathway, providing a promising agent for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Non-small cell lung adenocarcinoma (LUAD) is the predominant form of lung cancer originating from lung epithelial cells, making it the most prevalent pathological type. Currently, reliable indicators for predicting treatment efficacy and disease prognosis are lacking. Despite extensive validation of autophagy-dependent cell death (ADCD) in solid tumor studies and its correlation with immunotherapy effectiveness and cancer prognosis, systematic research on ADCD-related genes in LUAD is limited. We utilized AddModuleScore, ssGSEA, and WGCNA to identify genes associated with ADCD across single-cell and bulk transcriptome datasets. The TCGA dataset, comprising 598 cases, was randomly divided into training and validation sets to develop an ADCD-related LUAD prediction model. Internal validation was performed using the TCGA validation set. For external validation, datasets GSE13213 (119 LUAD samples), GSE26939 (115 LUAD samples), GSE29016 (39 LUAD samples), and GSE30219 (86 LUAD samples) were employed. We evaluated the model's accuracy and effectiveness in predicting prognostic risk. Additionally, CIBERSORT, ESTIMATE, and ssGSEA techniques were used to explore immunological characteristics, drug response, and gene expression in LUAD. Real-time RT-PCR was conducted to assess variations in mRNA expression levels of the gene XCR1 between cancerous and normal tissues in 10 lung cancer patients. We identified 249 genes associated with autophagy-dependent cell death (ADCD) at both single-cell and bulk transcriptome levels. Univariate COX regression analysis revealed that 18 genes were significantly associated with overall survival (OS). Using LASSO-Cox analysis, we developed an ADCD signature based on five genes (BIRC3, TAP1, SLAMF1, XCR1, and HLA-DMB) and created the ADCD-related risk scoring system (ADCDRS). Validation of this model demonstrated its ability to predict disease prognosis and its correlation with clinical characteristics, immune cell infiltration, and the tumor microenvironment. To enhance clinical applicability, we integrated an ADCDRS nomogram. Furthermore, we identified potential drugs targeting specific risk subgroups. We successfully identified a model based on five ADCD genes to predict disease prognosis and treatment efficacy in LUAD, as well as to assess the tumor immune microenvironment. An efficient and practical ADCDRS nomogram was designed. [ABSTRACT FROM AUTHOR]

The eighth edition of lung cancer nodal staging assignment includes the location of lymph node metastasis, but does not include single-nodal and multiple-nodal descriptors. Do the single-nodal and multiple-nodal statuses stratify the prognosis of patients with non-small cell lung cancer (NSCLC)? Using the National Cancer Database, we analyzed patients with pathologically staged N1 and N2 NSCLC. Nodal descriptors were classified into pathological single N1 (pSingle-N1), pathological multiple N1 (pMulti-N1), pathological single N2 (pSingle-N2), and pathological multiple N2 (pMulti-N2). Survival analysis was performed using the Kaplan-Meier method and multivariable Cox regression models. In the general analysis cohort, 24,531, 22,256, 8,528, and 21,949 patients with NSCLC demonstrated pSingle-N1, pMulti-N1, pSingle-N2, and pMulti-N2 disease, respectively. Patients with pMulti-N1 and pMulti-N2 disease showed a shorter survival than those with pSingle-N1 and pSingle-N2 disease, respectively (hazard ratio, 1.22 [ P <. 0001] for N1 and 1.39 [ P <. 0001] for N2). After adjusting age, sex, and histologic findings, the hazard ratio for pSingle-N2 compared with pMulti-N1 disease was 1.05 (P =. 0031). Patients with pN1 disease were categorized by metastatic lymph node count (1, 2, 3, ≥ 4), showing significant prognostic differences among groups (P <. 0001). In the sensitivity analysis cohort (limited to R0 resection, lobectomy, or more; survival ≥ 30 days; ≥ 10 examined lymph nodes; and without neoadjuvant therapy; n = 34,904) and the external validation cohort (n = 708), analyses supported these results. Patients with NSCLC with one metastatic lymph node, whether in N1 or N2 stations, showed better survival than those with more than one lymph node involved. Patients with NSCLC with a single-skip N2 lymph node metastasis showed survival similar to patients with multiple N1 lymph nodes, and the number of lymph nodes involved in N1 resections up to four or more was sequentially prognostic. [ABSTRACT FROM AUTHOR]

The initial management of patients with lung cancer is growing more complex in the context of an expanding number of precision medicine treatments. These challenges are accompanied by opportunities to deliver more efficacious and less toxic treatments to patients. Indications for these treatments are also expanding, and patients with lung cancer across multiple stages now require biomarker testing. Given their role in the initial management of patients being diagnosed with lung cancer, pulmonologists must have fundamental knowledge regarding the importance, indications, and implications of biomarker testing across the spectrum of histology and stage. The purpose of this review is to provide fundamental knowledge regarding biomarker testing, its incorporation into the initial diagnostic and staging evaluation, and guidance for working within a multidisciplinary team to achieve timely and comprehensive biomarker testing to direct the use of precision medicine treatments. [ABSTRACT FROM AUTHOR]

Despite advances in precision medicine for non-small cell lung cancer (NSCLC), biomarker testing for these therapies remains frequently underused, delayed, and inequitable. Pulmonologists often play a critical role in the initial diagnostic steps for patients with lung cancer, and previous data show variability in their knowledge and practices regarding biomarker testing. The purpose of this study is to better understand how pulmonologists view their role in lung cancer care. With the increasing importance of biomarker testing and precision medicine, how do pulmonologists view their role in lung cancer care? An electronic survey consisting of 31 items focused on attitudes and practices regarding diagnostic steps for NSCLC was randomly distributed to a sample of practicing pulmonologists in the American College of Chest Physicians (CHEST) analytics database. Inferential statistics were performed using χ2 tests and multivariable logistic regression models. A total of 401 pulmonologists responded to the survey. Most (92%) were general pulmonologists, and more than one-half (62%) indicated they order biomarker testing. Longer practice tenure, higher case volumes, and participation in a multidisciplinary tumor board were associated with ordering biomarkers (P <.05). Pulmonology was identified to have the leading responsibility for the initial diagnostic biopsy by most respondents (83%) and less often for staging (45%), leading discussions about biomarker testing with patients (28%), and for ordering biomarkers (22%). The most common reasons for not ordering biomarkers included the following: oncology was responsible (84%), it was not within their scope of practice (46%), or lack of the necessary knowledge (51%). This study shows that pulmonologists vary in their practices for ordering biomarkers, and many defer this responsibility to oncology. Despite the role of bronchoscopy and pulmonology societal guidelines for staging, many defer leadership of this process. Many pulmonologists lack the necessary resources and multidisciplinary infrastructure likely required to efficiently accomplish biomarker testing. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non‐small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. Methods: This prospective cohort study included 55 metastatic NSCLC patients and seven age‐matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. Results: We observed a higher survival rate in NSCLC patients with high performance in the timed up‐and‐go (+320%; p =.007), sit‐to‐stand (+256%; p =.01) and six‐minute walking (+323%; p =.002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p >.05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (−54.2%; p <.0001) and cell proliferation (−44.9%; p =.007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. Conclusion: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism. We found that patients with better performance in the timed up‐and‐go, sit‐to‐stand and six‐minutes walking test lived longer in this cohort. Moreover, plasma from NSCLC patients with low physical performance impaired oxygen consumption and extracellular acidification rate and decreased the proliferation of primary human myotubes. Unbiased metabolomics revealed several metabolites differentially expressed in the plasma of NSCLC patients with low physical performance compared to healthy control subjects, with serine and M22G being the most reduced and increased metabolites, respectively. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma is one of the most fatal types of cancer worldwide, with non-small cell lung cancer being the most common subtype. Therefore, there is need for improved treatment approaches. Tumor growth results from the proliferation of a very small number of tumor stem cells, giving rise to the theory of cancer stem cells (CSCs). Lung CSCs are associated with lung cancer development, and although chemotherapy drugs can inhibit the proliferation of lung cancer cells, they have difficulty acting on lung CSCs. Even if the tumor appears to have disappeared after chemotherapy, the presence of a small number of residual tumor stem cells can lead to cancer recurrence and metastasis. Hence, targeting and eliminating lung CSCs is of significant therapeutic importance. In this study, we cultured A549 cells in sphere-forming conditions using B27, EGF, and bFGF, isolated peripheral blood mononuclear cells (PBMCs), and induced and characterized dendritic cells (DCs). We also isolated and expanded T lymphocytes. DC vaccines were prepared using A549 stem cell lysate or A549 cell lysate for sensitization and compared with non-sensitized DC vaccines. The content of IFN-γ in the supernatant of cultures with vaccines and T cells was measured by ELISA. The cytotoxic effects of the vaccines on A549 cells and stem cells were assessed using the Cytotox96 assay, and the impact of the vaccines on A549 cell migration and apoptosis was evaluated using Transwell assays and flow cytometry. DC vaccines sensitized with human lung CSC lysates induced significant in vitro cytotoxic effects on A549 lung cancer cells and CSCs by T lymphocytes, while not producing immune cytotoxic effects on human airway epithelial cells. Moreover, the immune-killing effect induced by DC vaccines sensitized with lung CSC lysates was superior to that of DC vaccines sensitized with lung cancer cells. [ABSTRACT FROM AUTHOR]

Treatment options for epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) following tyrosine kinase inhibitor (TKI) failure are limited, and platinum-based chemotherapy remains the main treatment. The development of effective immunotherapy for this disease has been challenging. In the present study, 37 patients with EGFR-mutant advanced NSCLC who were treated with programmed cell death-1 (PD-1) inhibitor-based combinations after TKI failure were reviewed. The total cohort had a median progression-free survival (mPFS) of 5.2 months (95% CI, 4.077-6.323 months) and a median overall survival (mOS) of 18.3 months (95% CI, 12.932-23.668 months). Patients with Eastern Cooperative Oncology Group performance-status (ECOG-PS) scores of 0 or 1 had longer mPFS than those with ECOG-PS scores of 2 (5.4 vs. 2.4 months; P=0.006). In addition, a PFS benefit was observed in patients with EGFR T790M-negative compared with EGFR T790M-positive tumors (mPFS 6.2 vs. 4.4 months; P=0.041). Patients treated with immunotherapy-based combinations as a front-line therapy had a longer mPFS than those in which the combinations were used as a late-line therapy (6.2 vs. 2.4 months; P<0.001). PD-1 inhibitor combined with chemotherapy and bevacizumab did not show a clear advantage over PD-1 inhibitor combined with chemotherapy alone (mPFS, 6.2 vs. 4.4 months; P=0.681), although it resulted in an improved overall response rate (ORR) and disease control rate. Notably, the 7 patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score of ≥50% had an ORR of 100% and an mPFS of 8.3 months. Therefore, it is suggested that PD-1 inhibitor-based combinations should be a priority treatment option in selective populations, such as those with low ECOG-PS scores, T790M-negative status or high PD-L1 expression in EGFR-mutant NSCLC after TKI failure. The use of immunotherapy and chemotherapy in combination with antiangiogenic agents appears to be a promising combination therapy for such patients. [ABSTRACT FROM AUTHOR]

Background: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood–brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. Methods: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan–Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. Results: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43–0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18–0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). Conclusion: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population. [ABSTRACT FROM AUTHOR]

Interstitial lung abnormalities (ILAs) are immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-P) risk factors. However, the relationship between imaging patterns and immunotherapy outcomes, and treatment strategies remain unclear in patients with non-small cell lung cancer (NSCLC) and ILAs. We retrospectively evaluated patients with ILAs-complicated NSCLC who received ICI therapy. ILAs were subcategorized as non-subpleural, subpleural non-fibrotic, and subpleural fibrotic (SF) based on the 2020 position paper by the Fleischner Society. We investigated ICI-P incidence, ICI-P risk factors, lung cancer prognosis, and ILAs radiological progression. Of the 481 ICI-treated patients, 79 (16.4%) had ILAs (45 non-SF and 34 SF). The ICI-P cumulative incidence (hazard ratio, 4.57; 95% confidence interval [CI], 1.90–10.98; p = 0.001) and any grade and grade ≥ 3 ICI-P incidences were higher in patients with SF-ILAs than in those with non-SF-ILAs (all grades: 7/45 [15.6%)] vs. 18/34 [52.9%]; p < 0.001; grade ≥ 3: 1/45 [2.2%] vs. 10/34 [29.4%]; p = 0.001). According to multivariate analysis, SF-ILAs independently predicted ICI-P (odds ratio, 5.35; 95% CI 1.62–17.61; p = 0.006). Patients with SF-ILAs had shorter progression-free and overall survival and higher ICI-P-related respiratory failure death rates than those with non-SF-ILAs. Approximately 2.5 times more patients with SF-ILAs showed progression by the 2-year follow-up than those with non-SF-ILAs. SF-ILAs is an independent strong predictor of ICI-P development in patients with NSCLC, may increase ICI-P severity, worsen prognosis, and accelerate ILAs progression. ILAs subcategorization is an important treatment strategy for patients with lung cancer treated with ICIs. [ABSTRACT FROM AUTHOR]

To build a risk stratification by incorporating PET/CT-based deep learning features and whole-body metabolic tumor volume (MTV wb), which was to make predictions about overall survival (OS) and progression-free survival (PFS) for those with non-small cell lung cancer (NSCLC) as a complement to the TNM staging. The study enrolled 590 patients with NSCLC (413 for training and 177 for testing). Features were extracted by employing a convolutional neural network. The combined risk stratification (CRS) was constructed by the selected features and MTV wb , which were contrasted and integrated with TNM staging. In the testing set, those were verified. Multivariate analysis revealed that CRS was an independent predictor of OS and PFS. C-indexes of the CRS demonstrated statistically significant increases in comparison to TNM staging, excepting predicting OS in the testing set (for OS, C-index = 0.71 vs. 0.691 in the training set and 0.73 vs. 0.736 in the testing set; for PFS, C-index = 0.702 vs. 0.686 in the training set and 0.732 vs. 0.71 in the testing set). The nomogram that combined CRS with TNM staging demonstrated the most superior model performance in the training and testing sets (C-index = 0.741 and 0.771). The addition of CRS improves TNM staging's predictive power and shows potential as a useful tool to support physicians in making treatment decisions. [ABSTRACT FROM AUTHOR]