Recurrence Of Non-small Cell Lung Cancer Research Articles

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Difference in efficacy of osimertinib between patients with EGFR-positive NSCLC with postoperative recurrence and those with de novo unresectable disease: A prospective, observational study

BackgroundAlthough clinical trials of systemic chemotherapy for advanced non-small-cell lung cancer (NSCLC) have included both postoperative recurrence and de novo unresectable cases, postoperative recurrence is reported to have a better efficacy and prognosis. However, there are no efficacy data of first-line osimertinib for postoperative recurrence. MethodsWe conducted a post hoc analysis of a multicenter, prospective, observational study that evaluated the efficacy of first-line osimertinib in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. The patients were divided into two groups: those with postoperative recurrence (recurrence group, n = 167) and those with de novo unresectable disease (de novo group, n = 385). ResultsThe recurrence group had a significantly better Eastern Cooperative Oncology Group performance status (ECOG-PS, p < 0.001) and fewer bone metastases (p < 0.001), brain metastases (p < 0.001), cancer pleurisy (p = 0.006), pleural dissemination (p = 0.003), liver metastases (p = 0.017), and adrenal metastases (p = 0.009) at the start of osimertinib than the de novo group. The recurrence group had a significantly better progression-free survival (PFS) and overall survival (OS) than the de novo group (hazard ratio [HR] = 0.62, 95 % confidence interval [CI], 0.49–0.81, p < 0.001; and HR = 0.58, 95 % CI, 0.43–0.79, p < 0.001, respectively). In a 1:1 propensity score-matching analysis, the matched recurrence group had significantly better PFS and OS than the matched de novo group (HR = 0.72, 95 % CI, 0.52–0.99, p = 0.034; and HR = 0.65, 95 % CI, 0.44–0.95, p < 0.001, respectively). ConclusionPatients with EGFR-positive NSCLC and postoperative recurrence have a better ECOG-PS and fewer distant metastases at the start of first-line osimertinib, and better PFS and OS than those with de novo unresectable disease. Postoperative recurrence should be considered as a stratification factor in future clinical trials for advanced EGFR-positive NSCLC.

Lymph nodes rather than pleural metabolic activity in 18F-FDG PET/CT correlates with malignant pleural effusion recurrence in advanced non-small cell lung cancer.

Frequently recurrent malignant pleural effusion (MPE) significantly hampers the life quality of advanced non-small cell lung cancer (NSCLC) patients. We aimed to explore the effects of progression patterns and local intervention on MPE recurrence and apply fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to establish a predictive model for MPE recurrence in NSCLC. We retrospectively recruited two cohorts of patients including treatment-naïve NSCLC diagnosed with MPE at the onset and receiving PET/CT scanning, as well as those with MPE and undergoing first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Pleural maximum standardized uptake value (SUVmax), metabolic tumor burden (MTV), total lesion glycolysis (TLG), and uptake patterns as well as SUVmax of lymph nodes (LN) were extracted. The primary outcome was MPE recurrence defined as re-accumulation of cytologically proven ipsilateral MPE. Step-wise multivariate Cox regression was used to identify candidate variables. Cox regression analysis and random survival forest were applied to establish models. A total of 148 treatment-naïve patients with EGFR-TKI treatment and MPE were recruited during the median follow-up period of 683 days, with 69 (46.6%) and 35 (23.6%) witnessing MPE recurrence at least once and twice. Intrapleural perfusion therapy at first recurrence was a protective factor for the second MPE recurrence (P=0.006), while intrapleural perfusion therapy at baseline could not benefit the first MPE recurrence (P=0.14). Conversely, prior systemic progression indicative of the change of systemic treatment was a protective factor for time to the first MPE recurrence (P<0.001); instead, the change of systemic treatment at the first MPE recurrence was not associated with second MPE recurrence (P=0.53). In another cohort with treatment-naïve NSCLC patients with MPE and PET/CT scanning, 103 patients regardless of the actionable mutation status were recruited during the median follow-up period of 304 days. Multivariate analysis suggested that the LN SUVmax >4.50 g/mL [hazard ratio (HR), 2.54; P=0.01], female gender (HR, 0.40; P=0.01), bone metastases (HR, 3.16; P=0.001), and systemic treatment (targeted therapy vs. chemotherapy: HR, 0.32; P=0.002; immunotherapy therapy vs. chemotherapy: HR, 0.99; P=0.97) could collectively indicate MPE recurrence with an optimal 300-day area under the curve (AUC) of 0.83. For patients with actionable mutation, LN SUVmax >4.50 g/mL (P=0.02) could forecast MPE recurrence independently. In summary, LN rather than pleural metabolic activity or uptake patterns could predict MPE recurrence for patients with or without targeted therapy. We should re-consider the application of intrapleural perfusion treatment for first-onset MPE and prompt it more at the moment of recurrent MPE. Promisingly, we could probably apply the non-invasive tool to identify the risk factors for MPE recurrence.

Highly sensitive and accurate detection of ALK-TKI resistance mutations by oligoribonucleotide interference-PCR (ORNi-PCR)-based methods

BackgroundPatients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) are treated with ALK tyrosine kinase inhibitors (TKIs). Although most patients benefit from ALK-TKIs, the development of resistance mutations is common and results in NSCLC recurrence. To identify ALK-TKI-resistant NSCLC at the early recurrent phase, highly sensitive and accurate methods for the detection of mutations are essential. ObjectiveThe aim of this study was to establish highly sensitive, accurate, cost-effective, and clinically practical methods for the detection of two frequent ALK-TKI resistance mutations, ALK G1202R and L1196M, by liquid biopsy. MethodsThe efficacy of oligoribonucleotide interference-PCR (ORNi-PCR) was examined by first optimizing experimental conditions to specifically amplify the ALK-TKI resistance mutant DNA corresponding to ALK G1202R and L1196M mutations. ORNi-PCR was then combined with droplet digital PCR (ddPCR) or real-time PCR to detect these mutations in cell-free DNA (cfDNA) extracted from NSCLC patients. ResultsORNi-PCR followed by ddPCR/real-time PCR detected 1–10 copy(s) of G1202R and L1196M DNA in model cfDNA. These mutations in patients’ cfDNA were identified using ORNi-PCR-based methods, whereas conventional ddPCR failed to detect them. ConclusionORNi-PCR followed by ddPCR/real-time PCR enables highly sensitive and accurate detection of ALK mutations by liquid biopsy. Although the clinical data are limited, our results show that these methods are potentially useful for identifying ALK-TKI-resistant NSCLC at the early recurrent phase.

Prognostic factors after radical local therapy for oligo-recurrence of non-small cell lung cancer.

Oligo-recurrence refers to the presence of a limited number of metachronous recurrences that can be treated with radical local therapy, and most patients have a good prognosis. However, the clinical course after local therapy for oligo-recurrence of non-small cell lung cancer (NSCLC) varies, and the prognostic factors are unclear. The aim of this study was to elucidate the prognostic factors of patients with oligo-recurrence of NSCLC who underwent radical local therapy. Between 2004 and 2015, 901 patients who underwent complete resection for NSCLC were included. We defined oligo-recurrence as two or fewer recurrences and retrospectively examined the factors that affected post-recurrence survival in patients who underwent radical local therapy for oligo-recurrence. Recurrence was confirmed in 267 patients, and among them, 125 experienced oligo-recurrence. Eighty-five patients with oligo-recurrence received local therapy, and their 5-year post-recurrence survival rate was 42.8%. Multivariable analysis of the prognostic factors of these patients revealed that single recurrence (hazard ratio = 2.19, P = 0.005) and systemic therapy (hazard ratio = 1.75, P = 0.043) were significant favorable prognostic factors associated with post-recurrence survival. However, the presence or absence of epidermal growth factor gene mutations, which is generally a prognostic factor for NSCLC recurrence, did not affect the prognosis of these patients. The number of recurrences and receiving systemic therapy are important prognostic factors for patients with oligo-recurrence who undergo radical local therapy, and these patients have a particularly favorable prognosis.

Durvalumab after chemoradiotherapy for locoregional recurrence of completely resected non-small-cell lung cancer (NEJ056).

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection.

Perioperative immunotherapy in nonsmall cell lung cancer.

To evaluate and summarize the current clinical efficacy, safety, treatment patterns, and potential biomarkers, to guide future treatment strategies for nonsmall cell lung cancer (NSCLC), improve patient prognosis, and provide a scientific basis for personalized therapy. In recent years, the class of immune checkpoint inhibitors (ICIs), with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors at the helm, has catalyzed groundbreaking advancements within the perioperative treatment milieu for NSCLC. With the positive results of several phase III clinical trials, perioperative immunotherapy has been confirmed to significantly reduce the risk of postoperative recurrence in resectable NSCLC, becoming the new standard for perioperative treatment of stages II to III NSCLC. With the advent of the perioperative immunotherapy era, clinical issues such as the selection of the treatment population, the choice of regimen, the duration of treatment, whether patients with pCR need further adjuvant therapy, and the comprehensive management of patients throughout the perioperative period have attracted widespread attention. The perioperative treatment of NSCLC has fully entered the era of immunotherapy. Multiple clinical studies have confirmed that perioperative immunotherapy can significantly improve the survival benefit of resectable stages II to III NSCLC, establishing a new standard for the perioperative treatment of stages II to III NSCLC.

Increasing monocytes after lung cancer surgery triggers the outgrowth of distant metastases, causing recurrence

Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1–Monocyte–TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1–Monocyte–TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.

Protocol for a systematic review and meta-analysis of recurrence and metastasis of different surgical techniques for non-small cell lung cancer

IntroductionLung cancer remains the primary cause of cancer-related deaths on a global scale. Surgery is the main therapeutic option for non-small cell lung cancer (NSCLC). However, the optimal surgical approach...

Efficacy of Immune Checkpoint Inhibitors in Postoperative Recurrence of Wild-type EGFR Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of non-small cell lung cancer (NSCLC), but specific outcomes of ICIs treatment among patients with postoperative recurrence of NSCLC remain unclear. The objective of the study was to compare the efficacy of ICIs and chemotherapy with conventional chemotherapy only in patients with postoperative recurrence of epidermal growth factor receptor (EGFR) wild-type NSCLC. A retrospective analysis was performed on patients who underwent anatomical lung resection at the Nagoya University Hospital and were treated for postoperative recurrence of wild-type EGFR NSCLC. This study evaluated the prognosis for postoperative recurrence, including ICIs treatment and other clinicopathological factors. Of the 83 patients included in the analysis, 20 patients underwent chemotherapy and 63 patients underwent chemotherapy combined with ICIs. The combination of ICIs and chemotherapy significantly prolonged survival after recurrence (median survival: 33.1 months vs. 22.0 months, p=0.01). In the ICIs group, no significant differences in survival were detected between patients with different programmed death ligand 1 (PD-L1) status (Tumor Proportion Scores: <1%, 1%-49%, ≥50%, p=0.27). Multivariate analysis revealed that postoperative distant recurrence was a significant poor prognostic factor for survival after recurrence (HR=1.85, 95% CI=1.06-3.25, p=0.03), and combining ICIs with chemotherapy significantly improved survival after recurrence (HR=0.43, 95% CI=0.24-0.78, p<0.01). Combination of ICIs with chemotherapy significantly prolonged survival of postoperative recurrence with wild-type EGFR NSCLC regardless of PD-L1 status.

Confirmation of Recurrent Lung Cancer Following Resection Using Liquid Biopsy, a Proof-of-Concept Real-World Study.

Appropriate management requires timely and accurate confirmation of non-small cell lung cancer (NSCLC) recurrence in patients who have had curative-intent surgical resection. We assessed the association between circulating tumor DNA (ctDNA) identified using amplicon sequencing and evidence of recurrence on CT surveillance. A prospective cohort study of NSCLC patients with early-stage disease undergoing curative-intent resection was conducted. Surveillance was performed post-operatively at pre-defined intervals with both liquid biopsy and chest CT imaging. Amplicon panel next-generation sequencing was performed on DNA and RNA from tumor tissue and on plasma cell-free DNA for tumor-informed ctDNA detection. Resected tumors from 78 NSCLC patients were analyzed. Alterations were detected on the DNA assay for 65 tumors and only on the RNA assay for 4 tumors. Of the 65 patients with alterations detected on the tumor DNA assay, 29 completed post-operative liquid biopsy testing. Four of those 29 patients had evidence of recurrence on imaging, of whom two had biopsy confirmation of recurrence and detectable ctDNA at the 12-month follow-up. Molecular confirmation of NSCLC recurrence can be provided through amplicon sequencing of plasma cell-free DNA in cases with imaging evidence of recurrence. Invasive tissue diagnosis may be avoidable in patients with ctDNA confirmation of recurrence that is suspected based on imaging. Further study of ctDNA assessment technologies in the setting of suspected recurrence is necessary to inform post-operative lung cancer surveillance guidelines.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Associated With Recurrence and Survival of Resectable Non–Small Cell Lung Cancer (NSCLC): A Retrospective Study

IntroductionCurative lung resection remains the key therapeutic strategy for early-stage non–small cell lung cancer (NSCLC). However, a proportion of patients still experience variable outcomes and eventually develop recurrence or die from their disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a deleterious factor that inhibits tumor cells apoptosis and leads to reduction of lymphocyte infiltration. However, there has been no research on the predicted role of PCSK9 as an immunohistochemical biomarker with survival in resectable NSCLC. MethodsOne hundred sixty-three patients with resectable NSCLC were retrospectively reviewed, and PCSK9 expression of resected NSCLC was analyzed by immunohistochemistry using tissue microarrays. ResultsPCSK9 was associated with recurrence (42.1% relapsed in the PCSK9lo group versus 57.9% relapsed in the PCSK9hi group, P = 0.006) and survival status (39.6% dead in PCSK9lo group versus 60.4% dead in PCSK9hi group, P = 0.004) in patients with resectable NSCLC. Moreover, resectable NSCLC patients with higher PCSK9 expression in tumor tissue experienced poorer disease-free survival (median disease-free survival: 10.5 versus 25.2 mo, hazard ratio = 1.620, 95% confidence interval: 1.124-2.334) and overall suvrival (median overall suvrival: 20.0 versus 54.1 mo, hazard ratio = 1.646, 95% confidence interval: 1.101-2.461) compared to those with lower PCSK9 expression. ConclusionsHigh PCSK9 expression of tumor was correlated with recurrence and worse survival status of resectable NSCLC in our retrospective study, which indicated that PCSK9 in NSCLC may be an immunohistochemical biomarker of poor prognosis for patients with resectable NSCLC. Further large-scale prospective studies are warranted to establish these results.

Ten-Year Follow-Up of Lung Cancer Patients with Resected Stage IA Invasive Non-Small Cell Lung Cancer.

The purpose of this study was to assess 10-year follow-up outcomes after surgical resection in patients with stage IA invasive non-small cell lung cancer (NSCLC) based on postoperative pathological diagnosis. Patients with stage IA invasive NSCLC who underwent resection between December 2008 and December 2013 were reviewed. Patients were categorized into the pure-ground glass opacity (pGGO), mixed-ground glass opacity (mGGO), and solid groups based on consolidation to tumor ratio (CTR). Postoperative survival and risk of recurrence and developing secondary primary lung cancer were analyzed in each group. Among the 645 stage IA invasive NSCLC, the 10-year overall survival and recurrence-free survival rate was 79.38% and 77.44%, respectively. The 10-year overall survival for pGGO, mGGO, and solid group of patients was 95.08%, 86.21%, and 72.39%, respectively. The respective recurrence-free survival rate was 100%, 89.82%, and 65.83%. Multivariable Cox regression analysis associated tumor size and GGO components with recurrence and younger age, and tumors with GGO components were associated with longer overall survival. The cumulative incidence curve indicated no recurrence of GGO lung cancer ≥ 5 years postoperatively. Our cohort indicated that the number and stations of dissected lymph node did not influence long-term prognosis of IA invasive NSCLC. Recurrence of invasive stage IA NSCLC with GGO was more prevalent in patients with tumor size >1cm and CTR > 0.5, occurring within 5 years after surgery. This will provide important evidence for follow-up strategies in these patients.

The Current Achievements of Multi-Gene Panel Tests in Clinical Settings for Patients with Non-Small-Cell Lung Cancer.

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings.

Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.

The effect of harmonization on the variability of PET radiomic features extracted using various segmentation methods

PurposeThis study aimed to examine the robustness of positron emission tomography (PET) radiomic features extracted via different segmentation methods before and after ComBat harmonization in patients with non-small cell lung cancer (NSCLC).MethodsWe included 120 patients (positive recurrence = 46 and negative recurrence = 74) referred for PET scanning as a routine part of their care. All patients had a biopsy-proven NSCLC. Nine segmentation methods were applied to each image, including manual delineation, K-means (KM), watershed, fuzzy-C-mean, region-growing, local active contour (LAC), and iterative thresholding (IT) with 40, 45, and 50% thresholds. Diverse image discretizations, both without a filter and with different wavelet decompositions, were applied to PET images. Overall, 6741 radiomic features were extracted from each image (749 radiomic features from each segmented area). Non-parametric empirical Bayes (NPEB) ComBat harmonization was used to harmonize the features. Linear Support Vector Classifier (LinearSVC) with L1 regularization For feature selection and Support Vector Machine classifier (SVM) with fivefold nested cross-validation was performed using StratifiedKFold with ‘n_splits’ set to 5 to predict recurrence in NSCLC patients and assess the impact of ComBat harmonization on the outcome.ResultsFrom 749 extracted radiomic features, 206 (27%) and 389 (51%) features showed excellent reliability (ICC ≥ 0.90) against segmentation method variation before and after NPEB ComBat harmonization, respectively. Among all, 39 features demonstrated poor reliability, which declined to 10 after ComBat harmonization. The 64 fixed bin widths (without any filter) and wavelets (LLL)-based radiomic features set achieved the best performance in terms of robustness against diverse segmentation techniques before and after ComBat harmonization. The first-order and GLRLM and also first-order and NGTDM feature families showed the largest number of robust features before and after ComBat harmonization, respectively. In terms of predicting recurrence in NSCLC, our findings indicate that using ComBat harmonization can significantly enhance machine learning outcomes, particularly improving the accuracy of watershed segmentation, which initially had fewer reliable features than manual contouring. Following the application of ComBat harmonization, the majority of cases saw substantial increase in sensitivity and specificity.ConclusionRadiomic features are vulnerable to different segmentation methods. ComBat harmonization might be considered a solution to overcome the poor reliability of radiomic features.

NUF2 Expression in Cancer Tissues and Lymph Nodes Suggests Post-Surgery Recurrence of Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection.

FBP1 inhibits NSCLC stemness by promoting ubiquitination of Notch1 intracellular domain and accelerating degradation

The existence of cancer stem cells is widely acknowledged as the underlying cause for the challenging curability and high relapse rates observed in various tumor types, including non-small cell lung cancer (NSCLC). Despite extensive research on numerous therapeutic targets for NSCLC treatment, the strategies to effectively combat NSCLC stemness and achieve a definitive cure are still not well defined. The primary objective of this study was to examine the underlying mechanism through which Fructose-1,6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme, functions as a tumor suppressor to regulate the stemness of NSCLC. Herein, we showed that overexpression of FBP1 led to a decrease in the proportion of CD133-positive cells, weakened tumorigenicity, and decreased expression of stemness factors. FBP1 inhibited the activation of Notch signaling, while it had no impact on the transcription level of Notch 1 intracellular domain (NICD1). Instead, FBP1 interacted with NICD1 and the E3 ubiquitin ligase FBXW7 to facilitate the degradation of NICD1 through the ubiquitin–proteasome pathway, which is independent of the metabolic enzymatic activity of FBP1. The aforementioned studies suggest that targeting the FBP1-FBXW7-NICD1 axis holds promise as a therapeutic approach for addressing the challenges of NSCLC recurrence and drug resistance.

Increased expression of SSEA-4 on TKI-resistant non–small cell lung cancer with EGFR-T790M mutation

Non-small cell lung cancer (NSCLC), a major life-threatening disease accounting for 85% of all lung cancer cases, has been treated with tyrosine kinase inhibitors (TKIs), but often resulted in drug resistance, and approximately 60% of TKI-resistant cases are due to acquired secondary (epithelial growth factor receptor) EGFR-T790M mutation. To identify alternative targets for TKI-resistant NSCLC with EGFR-T790M mutation, we found that the three globo-series glycosphingolipids are increasingly expressed on this type of NSCLC cell lines, and among them, the increase of stage-specific embryonic antigen-4 (SSEA-4) expression is the most significant. Compared to TKI-sensitive cell lines, SSEA-4 and the key enzyme β3GalT5 responsible for the synthesis of SSEA3 are more expressed in TKI-resistant NSCLC cell lines with EGFR-T790M mutation, and the expression levels strongly correlate with poor survival in patients with EGFR mutation. In addition, we demonstrated that a SSEA-4 targeted monoclonal antibody, especially the homogeneous glycoform with well-defined Fc glycan designed to improve effective functions, is highly effective against this subpopulation of NSCLC in cell-based and animal studies. These findings provide a direction for the prediction of tumor recurrence and treatment of TKI-resistant NSCLC with EGFR-T790M mutation.

SAMA: A Self-and-Mutual Attention Network for Accurate Recurrence Prediction of Non-Small Cell Lung Cancer Using Genetic and CT Data.

Accurate preoperative recurrence prediction for non-small cell lung cancer (NSCLC) is a challenging issue in the medical field. Existing studies primarily conduct image and molecular analyses independently or directly fuse multimodal information through radiomics and genomics, which fail to fully exploit and effectively utilize the highly heterogeneous cross-modal information at different levels and model the complex relationships between modalities, resulting in poor fusion performance and becoming the bottleneck of precise recurrence prediction. To address these limitations, we propose a novel unified framework, the Self-and-Mutual Attention (SAMA) Network, designed to efficiently fuse and utilize macroscopic CT images and microscopic gene data for precise NSCLC recurrence prediction, integrating handcrafted features, deep features, and gene features. Specifically, we design a Self-and-Mutual Attention Module that performs three-stage fusion: the self-enhancement stage enhances modality-specific features; the gene-guided and CT-guided cross-modality fusion stages perform bidirectional cross-guidance on the self-enhanced features, complementing and refining each modality, enhancing heterogeneous feature expression; and the optimized feature aggregation stage ensures the refined interactive features for precise prediction. Extensive experiments on both publicly available datasets from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) demonstrate that our method achieves state-of-the-art performance and exhibits broad applicability to various cancers.