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Background: Lung cancer remains the leading cause of cancer-related mortality worldwide with non-small cell lung cancer (NSCLC) accounting for the majority of cases. The stage of detection significantly influences survival rates with early-stage diagnosis offering the best prognosis. This study investigates the prognostic impact of the omega-6/omega-3 ratio and tumor infiltration by CD8+ lymphocytes and CD68+ macrophages on overall survival (OS) and disease-free survival (DFS) in NSCLC patients undergoing pulmonary resection. Methods: We conducted a retrospective analysis of 53 patients with early-stage NSCLC who underwent pulmonary resection between September 2017 and January 2020. The omega-6/omega-3 ratio was quantified using gas chromatography and spectrometry. Tumor infiltration by CD8 and CD68 was assessed through immunohistochemistry. Survival outcomes were evaluated using Kaplan-Meier and Cox regression analyses. Results: An increased omega-6/omega-3 ratio and higher CD68+ macrophage infiltration were associated with a trend towards worse OS and DFS in NSCLC patients, though these results did not reach statistical significance. CD8+ T-cell infiltration was associated with improved survival outcomes, confirming its role as a favorable prognostic marker. Comparative analysis with existing datasets revealed similar demographic and clinical characteristics, reinforcing the generalizability of our findings. Conclusions: The omega-6/omega-3 ratio and CD68+ macrophage infiltration serve as important factors potentially influencing prognosis in NSCLC patients undergoing pulmonary resection. These findings highlight the need for further research to refine the prognostic utility of these biomarkers and to explore therapeutic strategies targeting inflammation and immune cell infiltration. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to investigate a series of complete blood cell count-based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. Methods: Consecutive patients with pathologically diagnosed stage III/IV NSCLC and PD-L1 < 50% who underwent first-line chemoimmunotherapy were retrospectively enrolled. The clinical outcomes used for biomarker evaluation were Objective Response Rate (ORR) and Overall Survival (OS). Results: Non-responders had significantly higher values of neutrophil to lymphocyte ratio (NLR, median: 5.36; IQR: 2.78–10.82 vs. 3.31; IQR: 2.15–4.12, p = 0.019), neutrophil to monocyte ratio (NMR, median: 14.00; IQR: 8.82–21.20 vs. 9.20; IQR: 7.45–11.20, p = 0.013), and systemic inflammation index (SII, median: 1395; IQR: 929–3334 vs. 945; IQR: 552–1373, p = 0.025), but only NLR and NMR remained independently associated with clinical response in multivariate logistic regression. In the univariate analysis, white blood cells (OR:1.2202; 95% CI: 1.0339–1.4400, p = 0.019), neutrophils (OR:1.2916; 95% CI: 1.0692–1.5604, p = 0.008), NLR (OR:1.3601: 95% CI: 1.0949–1.6896, p = 0.005) and NMR (OR:1.2159; 95% CI: 1.00396–1.4221, p = 0.015) were significantly associated with survival; Cox regression models confirmed that neutrophils, NLR, and MLR were independently associated with survival; NLR, at a cut-off value of 4.0, showed the better AUC (0.749) in predicting OS. Conclusions: Baseline complete blood cell count biomarkers, especially the NLR, can predict clinical outcomes in patients with advanced NSCLC treated with first-line chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, which ranks as the first malignant tumor in mortality. The occurrence and development of NSCLC are closely related to the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are considered to be critical regulators of the occurrence and development of NSCLC, which have essential effects on multiple biological characteristics of NSCLC. The hallmarks of cancer biology have been updated recently, however, there are no reviews revisiting the function of CAFs in tumor microenvironment. This article reviews the origin, markers, and classification of CAFs, their impacts on the characteristics of NSCLC, and potential therapeutic targets of CAFs to help develop individualized treatment plans for NSCLC. [ABSTRACT FROM AUTHOR]

Non‐small‐cell lung cancer (NSCLC) accounts for the majority of lung cancer cases worldwide, with a significant proportion of patients harbouring actionable oncogenic alterations. Among these alterations, the ROS1 rearrangement represents a distinct subset with therapeutic implications. Here, we present the case of a 52‐year‐old man diagnosed with advanced NSCLC harbouring the ROS1 fusion gene. Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression‐free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1‐positive NSCLC. [ABSTRACT FROM AUTHOR]

Clinical staging in lung cancer has implications for treatment planning and prognosis. We sought to determine the rate of inaccurate clinical stage (relative to pathologic), identify risk factors for inaccuracy, and evaluate the association of inaccuracy on survival. We hypothesized that inaccurate staging was associated with poor survival. In this retrospective cohort study, adult patients who received surgical resection without neoadjuvant treatment for nonsmall cell lung cancer from 2004 to 2020 in the National Cancer Database were categorized by accuracy of clinical stage (relative to pathologic stage). Multivariate models were used to determine risk factors for inaccuracy. The association between inaccuracy and overall survival was also analyzed. We identified 255,598 patients with lung cancer, including 84,543 patients (33.1%) who were inaccurately staged. Stage inaccuracy was associated with higher tumor, node, metastasis stage (T-category 3: odds ratio [OR] = 1.2, 95% confidence interval [CI] 1.15-1.28; N-category 2: OR = 2.6, 95% CI 2.47-2.79), greater quantity of lymph nodes evaluated, and more extensive resection (extended lobectomy/bilobectomy: OR = 1.3, 95% CI 1.20-1.37; pneumonectomy: OR = 1.6, 95% CI 1.54-1.74). Patients undergoing robotic surgery were less likely to be inaccurately staged (OR = 0.89, 95% CI 0.852-0.939). Inaccurate staging was associated with worse overall survival (5-y 67.5% accurate versus 55.4% inaccurate, P < 0.001). Inaccurate staging was also associated with worse survival in a multivariate Cox model (hazard ratio [HR] = 1.3, 95% CI 1.29-1.33). Both "understaging" (path > clinical) and "overstaging" (clinical > path) were associated with inferior survival. Inaccurate clinical stage (relative to pathologic) occurs in one-third of patients receiving surgery for lung cancer. Inaccuracy is associated with poor survival. Quality improvement initiatives should focus on improving clinical staging accuracy. [ABSTRACT FROM AUTHOR]

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies. [ABSTRACT FROM AUTHOR]

Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment. [ABSTRACT FROM AUTHOR]

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

The results of a prospective, multi-institutional randomized trial developed to assess the equality of sublobar resection versus standard lobectomy were first published in 1995. They concluded that, compared with lobectomy, sublobar resections did not show any significant improvement either in terms of postoperative morbidity and mortality nor in terms of late post-resectional cardiorespiratory function. Moreover, due to the higher mortality and local recurrence rate related to sublobar resection, lobectomy had to be judged as the best surgical option for patients diagnosed with peripheral early-stage non-small-cell lung cancer. Since then, lobectomy has been considered the best surgical option for fit patients suffering from early-stage non-small cell lung cancer. In 2022 and 2023, three non-inferiority randomized trials were published, comparing lobectomy with the sublobar resection in T1a N0 patients whose tumors were up to 2 cm in size. Although presenting some important differences, all three trials met their primary endpoints, disclosing the non-inferiority of sublobar resections in terms of overall and disease-free survival. This narrative review aims to compare the newly published results of these trials as well as to report results from recent non-randomized studies on this topic. [ABSTRACT FROM AUTHOR]

Background/Objectives: The prolonged time to reach investigation and management decisions in non-small cell lung cancer (NSCLC) patients can negatively impact long-term outcomes. This retrospective cohort study aims to assess the impact of a multidisciplinary team conference (MDT) on NSCLC care quality and outcomes. Methods: This retrospective study included resectable NSCLC patients who underwent pulmonary resection at Chiang Mai University Hospital, Thailand, from 1 January 2009 to 31 December 2021. Patients were divided into two groups: non-MDT and MDT groups, based on the initiation of MDT on 1 March 2018. The study compared overall survival, disease-free survival, and waiting times for investigation and surgery between the two groups. The effect of MDT on these outcomes was analyzed using multivariable analysis with inverse-probability weighting propensity scores. Results: The study included 859 patients, with 583 in the non-MDT group and 276 in the MDT group. MDT groups had a higher proportion of stage I and II NSCLC patients undergoing pulmonary resection (78.6% vs. 59.69%, p < 0.001). In multivariable analysis, patients in the MDT group had a significantly higher likelihood of longer survival compared to the non-MDT group (adjusted HR 0.23, 95% CI 0.09–0.55). Median waiting times for bronchoscopy (3 days vs. 12 days, p = 0.012), pathologic report (7 days vs. 13 days, p < 0.001), and surgery scheduling (18 days vs. 25 days, p = 0.001) were significantly shorter in the MDT group. Conclusions: An MDT has a survival benefit in NSCLC care and improves waiting times for investigation and treatment steps. Further studies are needed to validate these results. [ABSTRACT FROM AUTHOR]

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC. [ABSTRACT FROM AUTHOR]

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC. [ABSTRACT FROM AUTHOR]

Objective : We investigated how treating large brain metastasis (LBM) using 2-day fraction Gamma Knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for 2 consecutive days, with a biologically effective dose equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy. Methods : Between November 2017 and December 2021, 42 patients (mean age, 68.3 years; range, 50–84 years; male, 29 [69.1%]; female, 13 [30.9%]) with 44 tumors underwent 2-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (n=16), small cell lung cancer (n=7), colorectal cancer (n=7), breast cancer (n=3), gastric cancer (n=2), and other cancers (n=7). Twenty-one patients (50.0%) had a single LBM, 19 (46.3%) had a single LBM and other metastases, and two had two (4.7%) large brain metastases. At the time of the 2-day fraction GKRS, the tumors had a mean volume of 23.1 mL (range, 12.5–67.4). On each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line. Results : We obtained clinical and magnetic resonance imaging follow-up data for 34 patients (81%) with 35 tumors, who had undergone 2-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (p=0.019) and lung cancer origin (p=0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat stereotactic radiosurgery (SRS) ranged from 15–878 days (median, 263±38 days; mean, 174±43 days) after the 2-day fraction GKRS. Eight patients (18.2%) were still alive. Conclusion : Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS. [ABSTRACT FROM AUTHOR]

Non–small cell lung cancer (NSCLC) has been found to have recurrent genetic abnormalities, and novel therapies targeting these aberrations have improved patient survival. In this study, specimens from benign tissue, primary tumors, and brain metastases were obtained at autopsy from a 55-year-old White female patient diagnosed with NSCLC and were examined using next-generation sequencing (NGS) and chromosomal microarray assay (CMA). No genetic aberrations were noted in the benign tissue; however, NGS identified a mutation in the KRAS proto-oncogene, GTPase (KRAS): KRAS exon 2 p.G12D in primary and metastatic tumor specimens. We observed 7 DNA copy number aberrations (CNAs) in primary and metastatic tumor specimens; an additional 7 CNAs were exclusively detected in the metastatic tumor specimens. These DNA alterations may be genetic drivers in the pathogenesis of the tumor specimen from our patient and may serve as biomarkers for the classification and prognosis of NSCLC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of Apatinib combined with epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in the treatment of patients with non-small cell lung cancer (NSCLC) and acquired EGFRTKI resistance. Methods: Clinical records of 106 patients with NSCLC at Shanxi Tumor Hospital of the Chinese Academy of Medical Sciences Cancer Hospital from January 2017 to October 2020, with acquired drug resistance after EGFR-TKI treatment were retrospectively analyzed. Among them, 52 patients received Apatinib combined with EGFR-TKI (Apatinib group), and 54 patients received a standard chemotherapy (pemetrexed combined with platinum) (chemotherapy group). Clinical efficacy indicators, follow-up results, and adverse reactions in both groups were compared. Results: There was no significant difference in the objective response rate and disease control rate between the two groups (P>0.05). The progression free survival (PFS) of the Apatinib group was significantly longer than that of the chemotherapy group (10.5 months vs. 5.7 months; P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusions: Compared with standard chemotherapy, Apatinib combined with EGFR-TKI has the same efficacy in treating NSCLC patients with EGFR-TKI resistance, and was associated with longer PFS with no significant increase in adverse reactions. [ABSTRACT FROM AUTHOR]

Objective: To compare and analyze the clinical effects of thoracoscopic lobectomy and segmentectomy in stage I nonsmall cell lung cancer (NSCLC). Method: This was a retrospective study. Eighty patients with stage I NSCLC treated in Cangzhou People’s Hospital from December 2019 to January 2022 were randomly divided into the segmentectomy group and lobectomy group, with 40 cases in each group. Further comparative analysis was carried out focusing on perioperative indexes, maximum ventilation volume (MVV), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), VAS score of postoperative pain and complications. Result: There was no significant difference in the number of dissected lymph nodes and extubation time between the two groups (p>0.05). The operation time was longer, while intraoperative blood loss was less and the stay of stay in hospital was shorter in the segmentectomy group significantly than those in the lobectomy group (p<0.05). Furthermore, no significant difference was observed in MVV%, FVC% and FEV1% between the two groups before operation (p>0.05). Meanwhile, the segmentectomy group had evidently lower VAS scores at 1 d, 3 d and 5 d postoperatively than those in the lobectomy group (p<0.05). Besides, there was a much lower total incidence of complications in the segmentectomy group than that in the lobectomy group (p<0.05). Conclusion: Compared with lobectomy, thoracoscopic segmentectomy is more effective in the treatment of stage I NSCLC, with less bleeding and mild pain, which can alleviate pulmonary function injury and reduce postoperative complications that is conducive to the improved prognosis of patients. [ABSTRACT FROM AUTHOR]

Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens. [ABSTRACT FROM AUTHOR]

Purpose: Radiation pneumonitis (RP) is an obstacle for patients after surgery following induction chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). We performed a comparative analysis of the association between clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and prognosis, in LA-NSCLC patients with or without RP during induction chemoradiotherapy followed by surgery. Methods: The subjects of this analysis were 168 patients undergoing trimodality therapy for LA-NSCLC between January, 1999 and May, 2019. Patients were divided into two groups: the RP group (n = 41) and the non-RP group (n = 127). We compared the clinicopathological factors including the NLR between the groups and analyzed the association between the NLR and prognosis. Results: The RP group had more patients with tumors located in the lower lobe, more bilobar resections, shorter operative times, no implementation of postoperative adjuvant chemotherapy, and a higher postoperative NLR than the non-RP group. There were no significant differences in serious postoperative complications and the prognosis. Patients with a low postoperative NLR had a significantly better prognosis in the non-RP group, and a trend toward a better prognosis even in the RP group. Conclusion: Postoperative NLR may be a useful prognostic factor, even for patients who suffer RP after trimodality therapy for LA-NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: This single-institution retrospective cohort study was conducted to assess the prognostic significance of perioperative changes in the prognostic nutritional index (PNI) in patients who underwent surgery for non-small cell lung cancer (NSCLC). Methods: Clinicopathological data were collected from 441 patients who underwent lobectomy for NSCLC between 2010 and 2016.The PNI ratio (postoperative PNI/preoperative PNI) was used as an indicator of perioperative PNI changes. Prognostic differences were investigated based on PNI ratios. Results: The optimal cut-off value of the PNI ratio for overall survival (OS) was set at 0.88 using a receiver operating characteristic curve. The PNI ratio was inversely related to a high smoking index, interstitial lung disease, and postoperative pulmonary complications. The 5-year OS rates for the high vs. low PNI ratio groups were 88.2% vs. 68.5%, respectively (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.90–4.86). Multivariable analysis revealed that a low PNI ratio was significantly associated with poor prognosis (HR: 2.94, 95% CI: 1.77–4.87). The PNI ratio was a more sensitive indicator than postoperative PNI status alone for identifying patients at high risk of mortality, particularly those with non-lung cancer causes. Conclusion: The perioperative PNI change is a significant prognostic factor for patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: Among non-small cell lung cancers (NSCLC), 5 years is a benchmark in cancer control and treatment, but a certain percentage of cases recur after 5 years. The long-term post-recurrence outcomes remain controversial. To examine the accurate prognostic factors associated with survival and cancer recurrence among 5-year survivors, a landmark analysis that considered competing risks was performed. Methods: Complete resection of NSCLC was performed in 2482 patients between January 2003 and December 2015. A total of 1431 patients were 5-year survivors without recurrence. A landmark time analysis was applied to the overall survival (OS) and recurrence-free survival (RFS) from 5 years after surgery, and the findings were calculated using the Kaplan–Meier method. The cumulative incidence of cause-specific death and recurrence was estimated using the cumulative incidence function, while carefully considering the competing risks. Results: Postoperative recurrence was detected in 732 patients, of whom 68 (9.3%) had recurrence after 5 years. The median follow-up period was 8.2 years. In the competing risk analysis, the independent poor prognostic factors associated with cause-specific death were age ≥ 75 years, lymph node metastasis and pleural invasion. Conclusions: Patients requiring a follow-up for > 5 years were aged ≥ 75 years and had either lymph node metastasis or pleural invasion. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), significantly influences cancer-related mortality and is frequently considered by poor therapeutic responses due to genetic alterations. Cancer cells possess an inclination to develop resistance to individual treatment modalities, thus it is necessary to investigate several pathways simultaneously to obtain insights that will aid in the establishment of improved therapeutic approaches. Exploring regulated cell death (RCD) mechanisms offers promising avenues to augment immunotherapy by reshaping the tumor microenvironment (TME). Here, we investigated the prospective of microwave plasma-infused nitric oxide water (NOW) to initiate immunogenic cell death (ICD) while concurrently modulating autophagy and ferroptosis signaling in LUAD-associated A549 cells. Plasma treatment results in stable NO species nitrite/nitrate (NO 2 −/NO 3 −) in the water, altering its physicochemical properties. Analysis of ICD markers reveals increased expression of damage-associated molecular patterns (DAMPs) at both protein and mRNA levels post-NOW exposure. Intracellular reactive oxygen and nitrogen species (RONS) accumulation suggests NO-mediated mitochondrial dysfunction, triggering autophagy induction. Flow cytometry and western blotting confirm alterations in autophagy regulators Beclin 1 and SQSTM1. Furthermore, NOW treatment induces lipid peroxidation and upregulates ferroptosis-associated genes, as determined by qRT-PCR. Transmission electron microscopy (TEM) imaging reveals autophagosome formation and loss of cristae structures, corroborating the occurrence of autophagy and ferroptosis. Our findings propose that NOW may considered as inducer of ICD and the stimulation of other RCD-related proteins may enhance the anti-tumor immunogenicity. [Display omitted] • Nitric Oxide enriched water (NOW) mediates immunogenic lung cancer cells death. • Mitochondria membrane potential and activity is suppressed via NOW in cancer cells. • NOW-exposure upregulated autophagy mediating protein and gene expressions. • Ferroptosis regulating genes are sensitized after NOW exposure to cancer cells. • NOW suppressed the immunosuppressive receptor proteins; CD47 and PD-L1. [ABSTRACT FROM AUTHOR]

Purpose: Circulating tumor DNA (ctDNA) testing has become a promising tool to guide first-line (1L) targeted treatment for advanced non-small cell lung cancer (aNSCLC). This study aims to estimate the clinical validity (CV) and clinical utility (CU) of ctDNA-based next-generation sequencing (NGS) for oncogenic driver mutations to inform 1L treatment decisions in aNSCLC through a systematic literature review and meta-analysis. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Embase to identify randomized control trials or observational studies reporting CV/CU on ctDNA testing in patients with aNSCLC. Meta-analyses were performed using bivariate random-effects models to estimate pooled sensitivity and specificity. Progression-free/overall survival (PFS/OS) was summarized for CU studies. Results: A total of 20 studies were identified: 17 CV only, 2 CU only, and 1 both, and 13 studies were included for the meta-analysis on multi-gene detection. The overall sensitivity and specificity for ctDNA detection of any mutation were 0.69 (95% CI 0.63–0.74) and 0.99 (95% CI 0.97–1.00), respectively. However, sensitivity varied greatly by driver gene, ranging from 0.29 (95% CI 0.13–0.53) for ROS1 to 0.77 (95% CI 0.63–0.86) for KRAS. Two studies that compared PFS with ctDNA versus tissue-based testing followed by 1L targeted therapy found no significant differences. One study reported OS curves on ctDNA-matched and tissue-matched therapies but no hazard ratios were provided. Conclusions: ctDNA testing demonstrated an overall acceptable diagnostic accuracy in patients with aNSCLC, however, sensitivity varied greatly by driver mutation. Further research is needed, especially for uncommon driver mutations, to better understand the CU of ctDNA testing in guiding targeted treatments for aNSCLC. [ABSTRACT FROM AUTHOR]

Disparities in access to a multidisciplinary cancer consultation (MDCc) persist, and the role of physician relationships remains understudied. This study examined the extent to which multilevel factors, including patient characteristics and patient-sharing network measures reflecting the structure of physician relationships, are associated with an MDCc and receipt of stereotactic body radiation therapy versus surgery among patients with early-stage non-small cell lung cancer (NSCLC). In this cross-sectional study, we analyzed Surveillance, Epidemiology, and End Results (SEER)–Medicare data for patients diagnosed with stage I-IIA NSCLC from 2016 to 2017. We assembled patient-sharing networks and identified cancer specialists who were locally unique for their specialty, herein referred to as linchpins. The proportion of linchpin cancer specialists for each hospital referral region (HRR) was calculated as a network-based measure of specialist scarcity. We used multilevel multinomial logistic regression to estimate associations between study variables and receipt of an MDCc and multilevel logistic regression to examine the relationship between patient receipt of an MDCc and initial treatment. Our study included 6120 patients with stage I-IIA NSCLC, of whom 751 (12.3%) received an MDCc, 1729 (28.3%) consulted only a radiation oncologist, 2010 (32.8%) consulted only a surgeon, and 1630 (26.6%) consulted neither specialist within 2 months of diagnosis. Compared with patients residing in an HRR with a low proportion of linchpin surgeons, those residing in an HRR with a high proportion of linchpin surgeons had a 2.99 (95% CI, 1.87-4.78) greater relative risk of consulting only a radiation oncologist versus receiving an MDCc and a 2.70 (95% CI, 1.68-4.35) greater relative risk of consulting neither specialist versus receiving an MDCc. Patients who received an MDCc were 5.32 times (95% CI, 4.27-6.63) more likely to receive stereotactic body radiation therapy versus surgery. Physician networks are associated with receipt of an MDCc and treatment, underscoring the potential for leveraging patient-sharing network analysis to improve access to lung cancer care. [ABSTRACT FROM AUTHOR]

Stereotactic body radiation therapy (SBRT) versus surgery for operable early-stage non-small cell lung cancer (ES-NSCLC) remains highly debated. Herein, we used spatial proteomics to identify whether any molecular biomarker(s) associate with the efficacy of either modality, in efforts to optimize treatment selection between surgery and SBRT for this population. We evaluated biopsy tissue samples from 44 patients with ES-NSCLC treated with first-line SBRT (cohort 1) by GeoMx Digital Spatial Profiling (DSP) with a panel of 70 proteins in 5 spatial molecular compartments: tumor (panCK+), leukocyte (CD45+), lymphocyte (CD3+), macrophage (CD68+), and stroma (α-SMA+). To validate the findings in cohort 1, biopsy samples from 52 patients with ES-NSCLC who received SBRT (cohort 2) and 62 patients with ES-NSCLC who underwent surgery (cohort 3) were collected and analyzed by multiplex immunofluorescence (mIF). In cohort 1, higher CD44 expression in the lymphocyte compartment was associated with poorer recurrence-free survival (RFS) (DSP: P <.001; mIF: P <.001) and higher recurrence rate (DSP: P =.001; mIF: P =.004). mIF data from cohort 2 validated these findings (P <.05 for all). From cohort 3, higher lymphocyte CD44 predicted higher RFS after surgery (P =.003). Intermodality comparisons demonstrated that SBRT was associated with significantly higher RFS over surgery in CD44-low patients (P <.001), but surgery was superior to SBRT in CD44-high cases (P =.016). Lymphocyte CD44 may not only be a predictor of SBRT efficacy in this population but also an important biomarker (pending validation by large prospective data) that could better sharpen selection for SBRT versus surgery in ES-NSCLC. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown. Methods: Patients in the veterans affairs national precision oncology program from 1/2019–12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy. Results: Of 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 − 0.88; Poor PS: OR 0.69, 95% CI 0.44 − 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 − 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 − 1.58). Conclusion: Frail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. Methods: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). Results: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. Conclusion: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. Trial registration number: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022. [ABSTRACT FROM AUTHOR]

Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0–1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7–IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3–48·3). The 15-month local control rate was 77·6% (95% CI 67·6–87·6%) in group A and 71·2% (95% CI 60·8–81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3–4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3–4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. Programme Hospitalier de Recherche Clinique National 2014. [ABSTRACT FROM AUTHOR]

Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. This analysis included patients with treatment-naive, EGFR -mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR -mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR- mutant advanced NSCLC. [Display omitted] • Amivantamab-lazertinib significantly improved PFS in patients with detectable ctDNA at baseline versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients without ctDNA clearance at C3D1 versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with TP53 co-mutations versus osimertinib. • Amivantamab-lazertinib significantly improved PFS in patients with liver metastases versus osimertinib. • Eighty-nine percent of patients with analyzable ctDNA by NGS from MARIPOSA had at least one high-risk baseline feature. [ABSTRACT FROM AUTHOR]

Objectives: Comprehensive molecular analysis for patients with non‐small‐cell lung carcinoma (NSCLC) is essential for managing modern targeted therapies. This study sought to establish the feasibility of utilising real‐time PCR to perform rapid and comprehensive profiling on minimal amounts of endobronchial ultrasound‐guided (EBUS) aspirates as a fast, tissue‐sparing route of predictive profiling. Methods: A volume of 500 μL of EBUS aspirate and fixative from patients with NSCLC was decanted, and 80 μL (<1% of total specimen received) was utilised for analysis. Biocartis Idylla™ cartridges for epidermal growth factor receptor (EGFR) mutations, KRAS mutations and a GeneFusion cartridge (ALK, ROS1, RET, NTRK1/2/3 rearrangements & MET 14 exon skipping) were analysed for each case to provide molecular data on the main clinically relevant targets as per UK guidelines. Results: A total of 62 cases were included; all of which had successful DNA analysis (EGFR and KRAS cartridges). RNA analysis (GeneFusion cartridge) was successful for 42 of 51 (82%) with initial approach, with 11 of 11 (100%) achieving a successful result with modified protocol. In all, 23 KRAS mutations (37%), 5 EGFR mutations (8%) and 1 ROS fusion (2%) were identified. Average time from specimen receipt to molecular read‐out was 5 h. Conclusion: Real‐time PCR utilising the Idylla™ platform is rapid, utilises minimal amounts of tissue and provides accurate results. We propose this is a useful ancillary method to utilise alongside next‐generation sequencing (NGS) in cases of urgent clinical requirement or EBUS aspirates with inadequate quantities of tissue for NGS. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) expression is a predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). PD-L1 and glucose transporter 1 expression are closely associated, and studies demonstrate correlation of PD-L1 with glucose metabolism. Aim: The aim of this study was to investigate the association of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) metabolic parameters with PD-L1 expression in primary lung tumour and lymph node metastases in resected NSCLC. Methods: We conducted a retrospective analysis of 210 patients with node-positive resectable stage IIB–IIIB NSCLC. PD-L1 tumour proportion score (TPS) was determined using the DAKO 22C3 immunohistochemical assay. Semi-automated techniques were used to analyse pre-operative [18F]FDG-PET/CT images to determine primary and nodal metabolic parameter scores (including max, mean, peak and peak adjusted for lean body mass standardised uptake values (SUV), metabolic tumour volume (MTV), total lesional glycolysis (TLG) and SUV heterogeneity index (HISUV)). Results: Patients were predominantly male (57%), median age 70 years with non-squamous NSCLC (68%). A majority had negative primary tumour PD-L1 (TPS < 1%; 53%). Mean SUVmax, SUVmean, SUVpeak and SULpeak values were significantly higher (p < 0.05) in those with TPS ≥ 1% in primary tumour (n = 210) or lymph nodes (n = 91). However, ROC analysis demonstrated only moderate separability at the 1% PD-L1 TPS threshold (AUCs 0.58–0.73). There was no association of MTV, TLG and HISUV with PD-L1 TPS. Conclusion: This study demonstrated the association of SUV-based [18F]FDG-PET/CT metabolic parameters with PD-L1 expression in primary tumour or lymph node metastasis in resectable NSCLC, but with poor sensitivity and specificity for predicting PD-L1 positivity ≥ 1%. Clinical relevance statement: Whilst SUV-based fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography metabolic parameters may not predict programmed death-ligand 1 positivity ≥ 1% in the primary tumour and lymph nodes of resectable non-small cell lung cancer independently, there is a clear association which warrants further investigation in prospective studies. Trial registration: Non-applicable Key Points: • Programmed death-ligand 1 immunohistochemistry has a predictive role in non-small cell lung cancer immunotherapy; however, it is both heterogenous and dynamic. • SUV-based fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) metabolic parameters were significantly higher in primary tumour or lymph node metastases with positive programmed death-ligand 1 expression. • These SUV-based parameters could potentially play an additive role along with other multi-modal biomarkers in selecting patients within a predictive nomogram. [ABSTRACT FROM AUTHOR]

Lung cancer with peritoneal carcinomatosis (PC) is a rare disease presentation. The presence of peritoneal disease is a sign of poor prognosis and is hard to diagnose. Flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) is becoming more clinically significant in the management of patients with PC. A 60-year-old male presented with nonsmall cell lung cancer (NSCLC) and later showed signs of peritoneal disease on 18 F-FDG PET/CT imaging, which subsequently lead to the diagnoses of PC with histopathology from peritoneal biopsy. The patient showed an excellent initial response to their NSCLC treatment but later presented with PC that was shown by FDG-avid ascites and a soft tissue mass in the pelvic area. The abdominal-pelvic lesions were confirmed cytologically to be peritoneal metastatic disease. 18 F-FDG PET/CT demonstrated value in preoperatively directing biopsy for diagnosing PC in this case of NSCLC. Further, 18 F-FDG PET/CT was useful in the monitoring of disease progression and thus influenced management in this case of NSCLC with PC, which is often challenging to detect and manage. [ABSTRACT FROM AUTHOR]

Currently approved targeted treatment for ROS1 -rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1 -rearranged NSCLC. This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1 -rearranged, locally advanced or metastatic stage IIIB–IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov , NCT04237805. Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71–100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21–61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76–95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48–100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16–68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70–99; 19 of 21) in patients in phase 2b cohort 1. Grade 3–4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1 -rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer. [ABSTRACT FROM AUTHOR]

Lung cancer is the primary cause of cancer death worldwide, in addition to being the most prevalent type of cancer. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85% of all forms of lung cancer. Liquid biopsy in NSCLC provides a non-invasive tool that determines biomarkers in body fluids with the aim of early detection, treatment monitoring/selection, prognosis estimation, and minimal residual disease (MRD) detection. This review focuses on NSCLC. Articles with diagnostic and prognostic applications of liquid biopsy in NSCLC were collected, and 19 articles published in the last five years (2019-2024) were selected, excluding systematic and literature reviews. All the original papers examined biomarkers in blood in NSCLC patients. Human studies involving solely lung cancer were included. CTCs, ctDNAs, circulating miRNAs, and exosomes were promising in diagnosis and prognosis. However, most studies were done on advanced-stage patients with liquid biopsy's prognostic applications. The most mutated genes were EGFR, KRAS, TP53, ALK, and HER2. Consequently, a need exists to focus on early-stage NSCLC and develop multi-analyte tests using ctDNA features for diagnostic applications. [ABSTRACT FROM AUTHOR]

Purpose: There exists a dearth of research concerning non-small cell lung cancer (NSCLC) patients experiencing overall progressive disease concomitant with shrinking lesions after immunotherapy. This is a special type of mixed response. We aim to evaluate the clinical characteristics and treatment options of these patients during immunotherapy. Patients and Methods: We categorized patients into two groups: Progressive Disease with Mixed Responses (PDMR) (n = 31) and Progressive Disease with None Mixed Responses (PDNMR) (n = 144), depending on whether at least one target lesion had shrunk by ≥ 30% at the point of overall progression. Computed tomography scans and magnetic resonance imaging were utilized to evaluate the clinicopathological significance of these patients, and a multivariate analysis was conducted to scrutinize the clinical characteristics and prognosis-influencing factors in these patients. Results: Patients in the PDMR group had worse staging and a greater proportion of previous radiotherapy. The median overall survival (mOS 22 vs 36.4 months; P = 0.019) and median progression-free survival (mPFS 5.83 vs 9.03 months; P = 0.031) of the PDMR group were shorter than PDNMR group. Longer subsequent OS with continued immunotherapy after PDMR compared with patients who do not continue with immunization after PDMR (mOS 23.9 vs 6.5 months; P = 0.024). Conclusion: PDMR was primarily observed in stage IV patients and previously irradiated patients. OS and PFS were inferior in patients with PDMR compared to patients with PDNMR. The continuation of immunotherapy in PDMR patients could extend their survival. [ABSTRACT FROM AUTHOR]

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

Non-small cell lung cancer (NSCLC) is the most pervasive lung cancer subtype. Recent studies have shown that immune checkpoint inhibitors achieved favorable clinical benefits in resectable NSCLC; however, the associated mechanism remains unclear. The role of T cells in antitumor immunity has received considerable attention, while the antitumor effects of tumor-infiltrating B cells (TIBs) in NSCLC remain poorly understood. Here, we conducted a single-cell RNA sequencing analysis of immune cells isolated from 12 patients with stage IIIA NSCLC to investigate B cell subtypes and their functions following neoadjuvant chemoimmunotherapy. We confirmed the simultaneous existence of the 4 B cell subtypes. Among them, memory B cells were found to be associated with a positive therapeutic effect to neoadjuvant chemoimmunotherapy. Furthermore, we found that G protein–coupled receptor 183 was most prevalent in memory B cells and associated with a positive therapeutic response. Multiplex immunofluorescence and flow cytometry experiments in an additional cohort of 22 treatment-naïve and 30 stage IIIA/IIIB NSCLC patients treated with neoadjuvant chemoimmunotherapy verified these findings. Overall, our analysis revealed the functions of TIBs and their potential effect on clinical treatment in NSCLC. [ABSTRACT FROM AUTHOR]

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3. [ABSTRACT FROM AUTHOR]

The treatment of non-small cell lung cancer (NSCLC) is known as a significant level of unmet medical need in spite of the progress in targeted therapy and personalized therapy. Overexpression of the Na+/K+-ATPase contributes to NSCLC progression, suggesting its potentiality in antineoplastic approaches. Epi-reevesioside F, purified from Reevesia formosana, showed potent anti-NSCLC activity through inhibiting the Na+/K+-ATPase, leading to internalization of α1- and α3-subunits in Na+/K+-ATPase and suppression of Akt-independent mTOR-p70S6K-4EBP1 axis. Epi-reevesioside F caused a synergistic amplification of apoptosis induced by gefitinib but not cisplatin, docetaxel, etoposide, paclitaxel, or vinorelbine in both NCI-H460 and A549 cells. The synergism was validated by enhanced activation of the caspase cascade. Bax cleavage, tBid formation, and downregulation of Bcl-xL and Bcl-2 contributed to the synergistic apoptosis induced by the combination treatment of epi-reevesioside F and gefitinib. The increase of membrane DR4 and DR5 levels, intracellular Ca2+ concentrations, and active m-calpain expression were responsible for the caspase-8 activation and Bax cleavage. The increased α-tubulin acetylation and activation of MAPK (i.e., p38 MAPK, Erk, and JNK) depending on cell types contributed to the synergistic mechanism under combination treatment. These signaling pathways that converged on profound c-Myc downregulation led to synergistic apoptosis in NSCLC. In conclusion, the data suggest that epi-reevesioside F inhibits the Na+/K+-ATPase and displays potent anti-NSCLC activity. Epi-reevesioside F sensitizes gefitinib-induced apoptosis through multiple pathways that converge on c-Myc downregulation. The data support the inhibition of Na+/K+-ATPase as a switch-on mechanism to sensitize gefitinib-induced anti-NSCLC activity. [ABSTRACT FROM AUTHOR]

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Identifying biomarkers in non-small cell lung cancer (NSCLC) can improve diagnosis and patient stratification. We evaluated plasmas and sera for interleukins (IL)-11, IL-6, IL-8, IL-17A, and IL-33 as biomarkers in primary NSCLC patients undergoing surgical treatment against normal volunteers. Exhaled-breath condensates (EBCs), a potential source without invasive procedures, were explored in normal individuals. Due to separate recruitment criteria and intrinsic cohort differences, the NSCLC and control cohorts were not well matched for age (median age: 65 vs. 40 years; p < 0.0001) and smoking status (p = 0.0058). Interleukins were first assessed through conventional ELISA. IL-11 was elevated in NSCLC plasma compared to controls (49.71 ± 16.90 vs. 27.67 ± 14.06 pg/mL, respectively, p < 0.0001) but undetectable in sera and EBCs by conventional ELISA. Therefore, high-sensitivity PCR-based IL-11 ELISA was repeated, albeit with concentration discrepancies. IL11 gene and protein upregulation by RT-qPCR and immunohistochemistry, respectively, were validated in NSCLC tumors. The lack of detection sensitivity across IL-6, IL-8, IL-17A, and IL-33 suggests the need for further, precise assays. Surprisingly, biomarker concentrations can be dissimilar across paired plasmas and sera. Our results identified a need to optimize detection limits for biomarker detection and caution against over-reliance on just one form of blood sample for biomarker assessment. [ABSTRACT FROM AUTHOR]

ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg–0.7 µg/kg, with a half-life of approximately 13–29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1–2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. NCT04272203 [ABSTRACT FROM AUTHOR]

Background: For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations. Objective: We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting. Methods: This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan–Meier analyses. Results: Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively). Conclusions: Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments. [ABSTRACT FROM AUTHOR]

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRASG12C in lung cancer. [ABSTRACT FROM AUTHOR]

Background: In non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC. Methods: The impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients' survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing. Results: TFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells). Conclusions: This work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Artificial intelligence image recognition has applications in clinical practice. The purpose of this study was to develop an automated image classification model for lung cancer cytology using a deep learning convolutional neural network (DCNN). Methods: Liquid-based cytology samples from 8 normal parenchymal (N), 22 adenocarcinoma (ADC), and 15 squamous cell carcinoma (SQCC) surgical specimens were prepared, and 45 Papanicolaou-stained slides were scanned using whole-slide imaging. The final dataset of 9,141 patches consisted of 2,737 N, 4,756 ADC, and 1,648 SQCC samples. Densenet-121 was used as the DCNN to classify N versus malignant (ADC+SQCC) and ADC versus SQCC images. AdamW optimizer and 5-fold cross-validation were used in the training. Results: For malignancy prediction, the sensitivity, specificity, and accuracy were 0.97, 0.85, and 0.94, respectively, in the patch-level classification, and 0.92, 0.88, and 0.91, respectively, in the case-level classification. For SQCC prediction, the sensitivity, specificity, and accuracy were 0.86, 0.91, and 0.90, respectively, in the patch-level classification and 0.73, 0.82, and 0.78, respectively, in the case-level classification. Conclusion: The DCNN model performed excellently in predicting malignancy and histological types of lung cancer. This model may be useful for predicting cytopathological diagnosis in clinical situations by reinforcing training. [ABSTRACT FROM AUTHOR]

Objective: Non-small cell lung cancer (NSCLC) patients undergoing chemotherapy and immunotherapy experience disturbances in the gut microbiota. This study intends to find out the correlation between gut microbiota and clinical indices before and after radiotherapy for NSCLC. Methods: Ten patients with primary NSCLC were screened, and plasma and fecal samples were collected before and after radiotherapy, respectively. Inflammatory indices in plasma were detected. Genomic DNA was extracted from fecal specimens and sequenced on on Illumina HiSeq2000 sequencing platform. Thee sequenced data were subjected to Metagenome assembly, gene prediction, species annotation, and gene function analysis to study and analyze gut microbiota and metabolic functions. The correlation between the diversity of gut microbiota and the clinical indicators of NSCLC patients was evaluated, and the changes of gut microbiota before and after radiotherapy were observed. Results: The diversity of gut microbiota in NSCLC patients did not correlate with smoking, pathology, and inflammatory markers. The abundance of phylum (p)_Bacteroidetes increased; p_Firmicutes and p_Bacteroidetes accounted for the highest proportion in NSCLC patients, and the abundance of both was dominantly exchanged after radiotherapy. There was a decrease in genus (g)_Bifidobacterium after radiotherapy in NSCLC patients. There was no significant correlation between the diversity of gut microbiota after radiotherapy and radiotherapy sensitivity, and the structural composition and abundance of gut microbiota remained stable. Conclusion: The diversity of gut microbiota is altered after radiotherapy in NSCLC patients, showing an increase in harmful bacteria and a decrease in beneficial bacteria. [ABSTRACT FROM AUTHOR]

AbstractBiomarker enrichment clinical trial designs are versatile tools to assess the treatment effect and increase the efficiency of clinical trials. In this article, we propose a two-stage enrichment clinical trial design with survival outcomes, and consider the situation where the biomarker assay and classification are possibly subject to errors. Specifically, the first stage is a randomized design, stratified by the biomarker appeared status. Depending on the result of the interim analysis and a pre-specified futility criterion, the second stage can be either enriched with only the biomarker appeared positive patients, or remain as the stratified design with both biomarker appeared positive and biomarker appeared negative patients. Compared to continuous and binary outcomes, test statistics for survival outcomes to account for biomarker misclassification are much more complicated and require special care. We develop log-rank statistics for the interim and final analyses, with an adjustment for the sensitivity and specificity of the biomarker assay. Control of Type I error rate is achieved by considering correlations between adjusted log-rank statistics from the same and/or different stages. R code is developed to calculate critical values, global/marginal power, and sample size. Our method is illustrated with examples of a recently successful development of immunotherapy in non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance. Methods: The expression levels of miR‐33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments. Results: The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model. Conclusions: HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) are at increased risk of central nervous system (CNS) metastasis at initial diagnosis and throughout treatment. In a phase 3 trial, lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival. In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Case Presentation: Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. Conclusion: The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases. [ABSTRACT FROM AUTHOR]