Stage Non-small Cell Lung Cancer Research Articles

Sentinel Lymph Node in Non-Small Cell Lung Cancer: Assessment of Feasibility and Safety by Near-Infrared Fluorescence Imaging and Clinical Consequences.

Occult micrometastases can be missed by routine pathological analysis. Mapping of the pulmonary lymphatic system by near-infrared (NIR) fluorescence imaging can identify the first lymph node relay. This sentinel lymph node (SLN) can be analyzed by immunohistochemistry (IHC), which may increase micrometastasis detection and improve staging. This study analyzed the feasibility and safety of identifying SLNs in thoracic surgery by NIR fluorescence imaging in non-small cell lung cancer (NSCLC). This was a prospective, observational, single-center study. Eighty adult patients with suspected localized stage NSCLC (IA1 to IIA) were included between December 2020 and May 2022. All patients received an intraoperative injection of indocyanine green (ICG) directly in the peri tumoural area or by electromagnetic navigational bronchoscopy (ENB). The SLN was then assessed using an infrared fluorescence camera. SLN was identified in 60 patients (75%). Among them, 36 SLNs associated with a primary lung tumor were analyzed by IHC. Four of them were invaded by micrometastases (11.1%). In the case of pN0 SLN, the rest of the lymphadenectomy was cancer free. The identification of SLNs in thoracic surgery by NIR fluorescence imaging seems to be a feasible technique for improving pathological staging.

Developing a primary tumor and lymph node 18F-FDG PET/CT-clinical (TLPC) model to predict lymph node metastasis of resectable T2-4 NSCLC

PurposeThe goal of this study was to investigate whether the combined PET/CT radiomic features of the primary tumor and lymph node could predict lymph node metastasis (LNM) of resectable non-small cell lung cancer (NSCLC) in stage T2-4.MethodsThis retrospective study included 192 NSCLC patients who underwent tumor and node dissection between August 2016 and December 2017 and underwent 18F-fluorodeoxyglucose (18F-FDG) PET/CT scanning 1–3 weeks before surgery. In total, 192 primary tumors (> 3 cm) and 462 lymph nodes (LN > 0.5 cm) were analyzed. The pretreatment clinical features of these patients were recorded, and the radiomic features of their primary tumor and lymph node were extracted from PET/CT imaging. The Spearman’s relevance combined with the least absolute shrinkage and selection operator was used for radiomic feature selection. Five independent machine learning models (multi-layer perceptron, extreme Gradient Boosting, light gradient boosting machine, gradient boosting decision tree, and support vector machine) were tested as classifiers for model development. We developed the following three models to predict LNM: tumor PET/CT-clinical (TPC), lymph PET/CT-clinical (LPC), and tumor and lymph PET/CT-clinical (TLPC). The performance of the models and the clinical node (cN) staging was evaluated using the ROC curve and confusion matrix analysis.ResultsThe ROC analysis showed that among the three models, the TLPC model had better predictive clinical utility and efficiency in predicting LNM of NSCLC (AUC = 0.93, accuracy = 85%; sensitivity = 0.93; specificity = 0.75) than both the TPC model (AUC = 0.54, accuracy = 50%; specificity = 0.38; sensitivity = 0.59) and the LPC model (AUC = 0.82, accuracy = 70%; specificity = 0.41; sensitivity = 0.92). The TLPC model also exhibited great potential in predicting the N2 stage in NSCLC (AUC = 0.94, accuracy = 79%; specificity = 0.64; sensitivity = 0.91).ConclusionThe combination of CT and PET radiomic features of the primary tumor and lymph node showed great potential for predicting LNM of resectable T2-4 NSCLC. The TLPC model can non-invasively predict lymph node metastasis in NSCLC, which may be helpful for clinicians to develop more rational therapeutic strategies.

Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort: Implications for adjuvant therapy

ObjectivesThe landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population. Material and methodsWe performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics. ResultsIn total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases. ConclusionAs (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment.

Patterns of care and outcomes in immigrants with non-small cell lung cancer. A population-based study (Sweden).

While studies have found lower cancer risks and better cancer survival in immigrant populations, it is debated whether cancer care is offered on equal terms to all residents regardless of background. Our aim was to study patterns of care and outcomes in immigrants in a country with a tax-financed universal health care system. We used a population-based database to compare clinical presentation, management and mortality between Swedish-born and immigrant patients with non-small cell lung cancer (NSCLC). Analyses were adjusted for potential confounders. We identified 40,075 patients diagnosed with NSCLC of which 84% were born in Sweden, 7% in Nordic and 9% in Non-Nordic countries. Non-Nordic immigrants were to a higher extent male, smokers, younger at diagnosis, had a better performance status and a higher educational level. No differences were seen regarding comorbidity burden or stage at diagnosis. Non-Nordic immigrants more often underwent positron emission tomography (PET) (aHR 1.32; 95% CI 1.19-1.45) and were more often discussed in a multidisciplinary team setting (aHR 1.30; 95% CI 1.17-1.44). There were no differences in treatment modalities following adjustment for age, with the exception of concurrent chemoradiotherapy in stage IIIA disease which was more common in Non-Nordic immigrants (aOR 1.34; 95% CI 1.03-1.74). Both overall and cause specific survival in non-metastatic disease were higher among Non-Nordic immigrants. Overall mortality in stage I-II: HR 0.81; 95% CI 0.73-0.90 and stage IIIA: HR 0.75; 95% CI 0.65-0.86. Following full adjustments, cause-specific mortality in stage I-II was aHR 0.86, 95% CI 0.75-0.98. Taken together, only minor differences in management and outcomes were observed between Swedish-born and immigrant patients. We conclude that lung cancer care is offered on equal terms. If anything, outcomes were better in Non-Nordic immigrants with early stage NSCLC.

Role of 18F-FDG PET/CT and sarcopenia in untreated non-small cell lung cancer with advanced stage.

Sarcopenia is essential in managing advanced stage (III-IV) non-small cell lung cancer (NSCLC) but is laborious to diagnose using currently available method. This study aimed to establish a simple approach to predict sarcopenia using 18F-FDG PET/CT parameters and clinical characteristics and determine their roles in prognostication in advanced stage NSCLC. Untreated 202 NSCLC patients with stage III-IV were retrospectively reviewed. Sarcopenia was defined using the skeletal muscle index (SMI) measured at the third lumbar vertebra (L3). 18F-FDG PET/CT metabolic parameters of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of the primary tumor (SUVmax_T, MTV_T, and TLG_T) and of whole-body lesions (MTV_WB and TLG_WB) were measured. Besides, SUVmax of the psoas major muscle (SUVmax_Muscle) was measured at the L3 level. The diagnostic endpoint was the probability of sarcopenia, and the survival endpoints included progression-free survival (PFS) and overall survival (OS). Among the enrolled 202 patients, 82 (40.6%) were diagnosed with sarcopenia. Higher age, male, lower BMI, and lower SUVmax_Muscle were correlated with a higher incidence of sarcopenia (P < 0.05), while age, sex, BMI, and SUVmax_Muscle were independently predictive of sarcopenia, and thus were utilized to construct a nomogram model. Multivariate Cox regression analysis revealed that sarcopenia score derived from the nomogram model, sarcopenia, stage, and TLG_WB were independently predictive of both PFS and OS. The incidence of sarcopenia increased with declining SUVmax_Muscle in advanced stage NSCLC. Our model using age, sex, BMI, and SUVmax_Muscle might be substituted for the complicated measurement of SMI. After adjustment by stage and TLG_WB, both sarcopenia score and sarcopenia were found to be independently predictive of PFS and OS.

31P The IOpener study: Tyrosine kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage non-small cell lung cancer

Treatment with immune checkpoint inhibitors (ICIs) is successful, but only in a subset of patients with advanced stage non-small cell lung cancer (NSCLC). Blood-based kinase profiling of peripheral blood mononuclear cells (PBMCs) has previously shown its predictive value for response to ICI treatment in a discovery cohort (Hurkmans et al., JITC 2020). The aim of the current prospective study was to perform a blind validation of the predictive value of kinase activity profiles in PBMCs for ICI response in patients with NSCLC in a standardized setting.

Evaluation of factors affecting epidermal growth factor receptor tyrosine kinase inhibitor-induced hepatotoxicity in Japanese patients with non-small cell lung cancer: a two-center retrospective study

BackgroundGefitinib and erlotinib, are epidermal growth factor receptor tyrosine kinase inhibitors, and are currently recommended for non-small cell lung cancer stage IV in the elderly and in patients with decreased performance status in the Japanese Lung Cancer Society Guideline, but they occasionally caused severe hepatotoxicity requiring postponement or modification of treatment. However, little is known about the risk factors for hepatotoxicity in patients receiving gefitinib and erlotinib. In this study, we investigated the factors influencing hepatotoxicity in Japanese non-small cell lung cancer (NSCLC) patients treated with gefitinib or erlotinib monotherapy.MethodsJapanese patients with NSCLC who started gefitinib or erlotinib monotherapy from January 2005 to December 2017 at Kanazawa University Hospital or Kanazawa Medical University Hospital were included in this study. Factors affecting hepatotoxicity were retrospectively investigated by multiple logistic regression analysis.ResultsA total of 102 patients who received gefitinib and 95 patients who received erlotinib were included in the analysis. In the gefitinib group, a body mass index (BMI) ≥ 25 was associated with an increased risk of hepatotoxicity (OR = 4.571, 95% CI = 1.486–14.056, P = 0.008). In the erlotinib group, concomitant use of acid-suppressing medications (AS), namely proton pump inhibitors or histamine-2 receptor antagonists, was associated with a reduced risk of hepatotoxicity (OR = 0.341, 95% CI = 0.129–0.900, P = 0.030).ConclusionsBMI ≥ 25 in patients treated with gefitinib increased the risk of hepatotoxicity. In contrast, AS combination with erlotinib reduced the risk of hepatotoxicity. Thus, because different factors influence the risk of hepatotoxicity, monitoring for adverse events should take into account patient background factors and concomitant medications.

High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

The protein p110γ is an isoform of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration and have been implicated in the oncogenesis of various cancers. In this study, p110γ expression in non-small cell lung cancer (NSCLC) and its association with clinicopathological factors and patient survival were evaluated. A total of 230 NSCLC tumors were immunohistochemically stained for p110γ. Of these, 174 (75.7%) and 56 (24.3%) were placed in the low and high expression groups, respectively. The positive rate of p110γ was significantly higher in adenocarcinoma than in squamous cell carcinoma (p⟨0.001). Advanced stage NSCLCs showed higher p110γ expression than those at an early stage (p=0.002). Irrespective of the histological tumor type, the patients with high p110γ expression had significantly worse overall survival than those with low p110γ expression (p=0.004). p110γ expression was an independent poor prognostic factor in the multivariate analysis. Our results suggest that p110γ may be involved in the development and progression of NSCLC, and that p110γ has promising potential as a prognostic factor or novel therapeutic target for NSCLC.

Surgery of old people-Thoracic surgery

The incidence of alarge number of diseases relevant to thoracic surgery increases with age; however, old age is still frequently considered acontraindication per se for curative interventions and extensive surgical procedures. Overview of the current relevant literature, derivation of recommendations for patient selection as well as preoperative, perioperative and postoperative optimization. Analysis of the current study situation. Recent data show that for most thoracic diseases, age alone is not areason to withhold surgical treatment. Much more important for the selection are comorbidities, frailty, malnutrition and cognitive impairment. A lobectomy or segmentectomy for stageI non-small cell lung cancer (NSCLC) in carefully selected octogenarians can provide acceptable to even comparably good short-term and long-term results as in younger patients. Selected > 75-year-old patients with stagesII-IIIA NSCLC even benefit from adjuvant chemotherapy. With appropriate selection high-risk interventions, such as pneumonectomy in > 70-year-old patients and pulmonary endarterectomy in > 80-year-old patients can be performed without an increase in mortality rates. Even lung transplantation can lead to good long-term results in carefully selected > 70-year-old patients. Minimally invasive surgical techniques and nonintubated anesthesia contribute to risk reduction in marginal patients. In thoracic surgery the biological age rather than the chronological age is decisive. In view of the increasingly older population, further studies are urgently needed to optimize patient selection, type of intervention, preoperative planning and postoperative treatment as well as the quality of life.

The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R): Real-World Data on Stage III Non-Small Cell Lung Cancer Patients Treated With Curative Chemoradiation

IntroductionChemoradiotherapy (CRT) is the standard of care in inoperable non–small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. MethodsThe Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. ResultsOut of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88.6% for patients treated with cCRT and in 71.0% in the patients treated with seqCRT. Acute nonhematological 3-month toxicity (CTCAE grade ≥3 or radiation pneumonitis grade ≥2) was scored in 21.9% of the patients treated with cCRT and in 17.7% of the patients treated with seqCRT. The univariable analysis for acute toxicity showed significantly increased toxicity for cCRT (P = .008), WHO ≥2 (P = .006), and TNM IIIC (P = .031). The multivariable analysis for acute toxicity was significant for cCRT (P = .015), WHO ≥2 (P = .001) and TNM IIIC (P = .016). The univariable analysis for 3-month mortality showed significance for seqCRT (P = .025), WHO ≥2 (P < .001), higher cumulative radiotherapy dose (P < .001), higher gross tumor volume total (P = .020) and male patients (p < .001). None of these variables reached significance in the multivariable analysis for 3-month mortality. ConclusionIn this national lung cancer audit of inoperable NSCLC patients, 3-month toxicity was significantly higher in patients treated with cCRT (21.9% vs. 17.7% for seqCRT) higher TNM stage IIIC, and poor performance (WHO≥2) patients.The 3-months mortality was not significantly different for tested parameters. Age was not a risk factor for acute toxicity, nor 3 months mortality.

Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+ NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3-/CD56+, CD3-/NKp30, CD3-/NKp46+, and CD3-/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-γ, granzyme B levels.

Economic Burden of Recurrence in Completely Resected Stage IB-IIIA Non-Small Cell Lung Cancer: A Retrospective Study Using Nationwide Claims Data of South Korea.

Although many patients with early stage non-small cell lung cancer (NSCLC) experience recurrence despite complete resection, few studies have reported on the corresponding economic burden. This study aimed to understand the economic impact of recurrence by measuring healthcare costs and resource utilization in patients with recurrent stage IB-IIIA NSCLC. Using Health Insurance Review and Assessment claims data from South Korea, we included patients who underwent complete resection for stage IB-IIIA NSCLC during the index period (January 1, 2012, to October 31, 2018). Patients who experienced recurrence were matched with those who did not using 1:1 propensity score (PS) matching. The mean healthcare costs and resource utilization were analyzed from the date of complete resection to the last claims for cancer treatment. A generalized linear model (GLM) was used to estimate the impact of covariates on healthcare costs. A difference-in-difference (DID) analysis was conducted to analyze the healthcare costs between the two groups before and after recurrence. Patients with recurrence incurred higher healthcare costs, particularly in outpatient settings. The cost of targeted therapy and immune checkpoint inhibitors primarily contributed to cost differences, and medication costs increased over time after complete resection. Patients with recurrence were also hospitalized more frequently (9.3 vs. 5.0, p < 0.0001) for a longer period (74days vs. 42days, p < 0.0001) than those without recurrence. GLM analysis showed that the total cost was 2.31-fold higher in patients with recurrence (95% confidence interval: 2.19-2.44). The DID analysis showed significantly increased total costs in patients with recurrence (β = 26,269, p < 0.0001), which was mostly attributed to medication costs (β = 17,951, p < 0.0001). Recurrence of completely resected NSCLC leads to a substantial increase in healthcare costs and resource utilization. The results of this study show the economic burden of recurrence, which may help future economic analyses and resource allocation.

Plasma metabolomics for the assessment of the progression of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading type of lung cancer with a high mortality rate worldwide. Although many procedures for the diagnosis and prognosis assessment of lung cancer exist, they are often laborious, expensive, and invasive. This study aimed to develop an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based analysis method for the plasma biomarkers of NSCLC with the potential to indicate the stages and progression of this malignancy conveniently and reliably. A total of 53 patients with NSCLC in early stages (I-III) and advanced stage (IV) were classified into the early and advanced groups based on the tumor node metastasis staging system. A comprehensive metabolomic analysis of plasma from patients with NSCLC was performed via UPLC-MS/MS. Principal component analysis and partial least squares-discriminant analysis were conducted for statistical analysis. Potential biomarkers were evaluated and screened through receiver operating characteristic analyses and correlation analysis. Main differential metabolic pathways were also identified by utilizing metaboanalyst. A total of 129 differential metabolites were detected in accordance with the criteria of VIP ≥ 1 and a P-value of ≤ 0.05. The receiver operating characteristic curves indicated that 11 of these metabolites have the potential to be promising markers of disease progression. Apparent correlated metabolites were also filtered out. Furthermore, the 11 most predominant metabolic pathways with alterations involved in NSCLC were identified. Our study focused on the plasma metabolomic changes in patients with NSCLC. These changes may be used for the prediction of the stage and progression of NSCLC. Moreover, we discussed the metabolic pathways wherein the altered metabolites were mainly enriched.

Biomarker testing of cytology specimens in personalized medicine for lung cancer patients.

Every patient with advanced non-small cell lung cancer (NSCLC) should be tested for targetable driver mutations and gene arrangements that may open avenues for targeted therapy. As most patients with NSCLC in the advanced stage of the disease are not candidates for surgery, these tests have to be performed on small biopsies or cytology samples. A growing number of other genetic changes with targetable mutations may be treatable in the near future. To identify patients who might benefit from novel targeted therapy, relevant markers should be tested in an appropriate context. In addition, immunotherapy of lung cancer is guided by the status of programmed death-ligand 1 expression in tumor cells. The variety and versatility of cytological specimen preparations offer significant advantages for molecular testing; however, they frequently remain underused. Therefore, evaluating the utility and adequacy of cytologic specimens is important, not only from a lung cancer diagnosis, but also for the large number of ancillary studies that are necessary to provide appropriate clinical management. A large proportion of lung cancers is diagnosed by aspiration or exfoliative cytology specimens; thus, optimizing strategies to triage and best use the tissue for diagnosis and biomarker studies forms a critical component of lung cancer management. In this review, we discuss the opportunities and challenges of using cytologic specimens for biomarker testing of lung cancer and the role of cytopathology in the molecular era.

Advances in stereotactic body radiation therapy for early stage non-small cell lung cancer

: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States, but as lung cancer screening expands to include younger patients with shorter smoking histories, an increasing number of cases are detected at early, more treatable stages. Stereotactic body radiation therapy (SBRT) has emerged as an effective, non-invasive treatment option for patients with medically inoperable NSCLC. Over the past decade, several retrospective and prospective studies have shown SBRT to achieve superior local control and overall survival compared to conventionally fractionated radiation therapy (CFRT). Advances in tumor targeting and radiation delivery have reduced treatment times while delivering higher doses of radiation to the tumor. SBRT is generally well-tolerated and the risk of grade 3 or greater toxicity is low with dose constraints in place to monitor and limit radiation delivered to surrounding normal tissues. Approaches to dose and fractionation vary depending on the tumor location relative to critical mediastinal structures, as toxicity profiles differ greatly among peripheral, central, and ultra-central tumors. While surgery remains the standard of care for operable patients and tumors, clinical trials are ongoing to compare SBRT with lobar and sub-lobar resection. Further studies combining SBRT with anti-PD-L1 and anti-PD-1 immunotherapy agents and radiosensitizing agents are in progress.

Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway.

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality in the world. Growth and differentiation factor 15 (GDF15) has been proved to play an important role in regulating tumor progression. However, the influence of GDF15 on NSCLC remains unclear. We aimed to investigate the regulatory role of GDF15 in NSCLC. The correlation between GDF15 expression and prognosis, stage of NSCLC was examined with bioinformatics method. The cell proliferation was detected with CCK8 and EdU staining. Wound healing, Transwell, flow cytometry assays were used to measure cell migration, invasion, and apoptosis, respectively. High expression of GDF15 is correlated with worse survival and malignant progression of NSCLC. Knockdown of GDF15 restrained the proliferation, invasion, migration, but accelerated apoptosis of lung cancer cells through regulating PTEN/PI3K/AKT signaling pathway. sh-GDF15 suppressed epithelial mesenchymal transition (EMT) process and promoted the chemotherapy sensitivity of lung cancer cells. GDF15 plays an important role in NSCLC progression. GDF15 mediated PTEN/PI3K/AKT signaling pathway might be the potential therapeutic targets for the prevention and treatment of GDF15.

Quantitative Proteomics Indicate Radical Removal of Non-Small Cell Lung Cancer and Predict Outcome.

Non-small cell lung cancer (NSCLC) is associated with low survival rates, often due to late diagnosis and lack of personalized medicine. Diagnosing and monitoring NSCLC using blood samples has lately gained interest due to its less invasive nature. In the present study, plasma was collected at three timepoints and analyzed using proximity extension assay technology and quantitative real-time polymerase chain reaction in patients with primary NSCLC stages IA-IIIA undergoing surgery. Results were adjusted for patient demographics, tumor, node, metastasis (TNM) stage, and multiple testing. Major histocompatibility (MHC) class 1 polypeptide-related sequence A/B (MIC-A/B) and tumor necrosis factor ligand superfamily member 6 (FASLG) were significantly increased post-surgery, suggesting radical removal of cancerous cells. Levels of hepatocyte growth factor (HGF) initially increased postoperatively but were later lowered, potentially indicating radical removal of malignant cells. The levels of FASLG in patients who later died or had a relapse of NSCLC were lower at all three timepoints compared to surviving patients without relapse, indicating that FASLG may be used as a prognostic biomarker. The biomarkers were confirmed using microarray data. In conclusion, quantitative proteomics could be used for NSCLC identification but may also provide information on radical surgical removal of NSCLC and post-surgical prognosis.

Perioperative and Oncological Outcomes of Robotic-Assisted, Video-Assisted Thoracoscopic and Open Lobectomy for Patients with N1-Metastatic Non-Small Cell Lung Cancer: A Propensity Score-Matched Study.

(1) Background: Despite the fact that robotic-assisted thoracoscopic lobectomy (RATL) has been prevalently applied for early stage non-small cell lung cancer (NSCLC), its superiorities are still to be fully revealed for patients with metastatic N1 lymph nodes (LNs). We aim to evaluate the advantages of RATL for N1 NSCLC. (2) Methods: This retrospective study identified consecutive pathological N1 NSCLC patients undergoing RATL, video-assisted thoracoscopic lobectomy (VATL), or open lobectomy (OL) in Shanghai Chest Hospital between 2014 and 2020. Further, perioperative and oncological outcomes were investigated. (3) Results: A total of 855 cases (70 RATL, 435 VATL, and 350 OL) were included. Propensity score matching resulted in 70, 140, and 140 cases in the RATL, VATL, and OL groups, respectively. RATL led to (1) the shortest surgical time (p = 0.005) and lowest intraoperative blood loss (p &lt; 0.001); (2) the shortest ICU (p &lt; 0.001) and postsurgical hospital (p &lt; 0.001) stays as well as chest tube duration (p &lt; 0.001); and (3) the lowest morbidities of postsurgical complications (p = 0.016). Moreover, RATL dissected more N1 (p = 0.027), more N1 + N2 (p = 0.027) LNs, and led to a higher upstaging incidence rate (p &lt; 0.050) than VATL. Finally, RATL achieved a comparable 5-year disease-free and overall survival in relation to VATL and OL. (4) Conclusions: RATL led to the most optimal perioperative outcomes among the three surgical approaches and showed superiority in assessing N1 and total LNs over VATL, though it did achieve comparable oncological outcomes in relation to VATL and OL for N1 NSCLC patients.

Effectiveness of immunological agents in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) continues to claim millions of lives worldwide. Although its poor prognosis is largely attributed to the lack of adequate and precise detection technologies, cancer cells' suppression of the immune system adds on to the difficulty of identifying abnormal NSCLC tumors in their early stages. Therefore, cancer immunotherapy, which activates the immune system and helps it fight tumors, has recently become the most sought-after technique, especially in the advanced stages of NSCLC, where surgery or chemotherapy may or may not bring about the desired survival benefits in patients. This review focuses on the various immunotherapeutic interventions and their efficacy in advanced NSCLC clinical trials. Monoclonal antibodies like anti-PD-1/PD-L1 agents and anti-CTLA-4 antibodies, cancer vaccines, oncolytic viruses and adoptive T cell therapy have been discussed in brief. Furthermore, the effects of gender, age, and race on the efficacy of immune checkpoint inhibitors and suggest plausible future approaches in the realm of immuno-oncology. Immunotherapy is used alone or in combination either with other immunological agents or with chemotherapy. However, the efficacy of these strategies depends extensively on various demographic variables, as some patients respond perfectly well to immunotherapy, while others do not benefit at all or experience disease progression. By targeting a "hallmark" of cancer (immune evasion), immunotherapy has transformed NSCLC management, though several barriers prevent its complete effectiveness. All these immunological strategies should be interpreted in the current setting of synergistic treatment, in which these agents can be combined with chemotherapy, radiotherapy, and, or surgery following patient and tumor characteristics to proportionate the best-individualized treatment and achieve superior results. To better pursue this goal, further investigations on cost-effectiveness and sex-gender, race, and age differences in immunotherapy are needed.

Characterization of Radiographic Changes Following Lung Stereotactic Body Radiotherapy – A Dose-Based Radiomic Analysis

<h3>Purpose/Objective(s)</h3> Evaluation of diagnostic imaging following lung stereotactic body radiotherapy (SBRT) can be challenging. We hypothesize that radiation dose maps can be used to characterize post-SBRT changes utilizing radiomics. <h3>Materials/Methods</h3> We retrospectively identified patients with early stage (T1-T2, N0) non-small cell lung cancer treated at a single center with SBRT to a dose of 48-55 Gy in 3-5 fractions between 2017 and 2020. Pre-SBRT and the 1-year post-SBRT diagnostic CT scans with IV contrast and 1mm slice thickness were imported into MIM (MIM Software Inc. Cleveland OH). A semi-automated workflow consisted of biologically effective dose (BED) maps generation, rigid fusions of planning CT with each diagnostic scan prioritizing alignment of the gross tumor volume, contouring the lung, and lung volumes of interest (VOI) generation corresponding to high-dose (BED10 >= 100 Gy), intermediate-dose (BED10>=24.48 Gy), and low-dose (BED10<24.48 Gy). Using open-source software and a bin width of 25 Hounsfield units, dose-based VOI masks were used for radiomic analysis of pre- and post-SBRT diagnostic scans. Changes in radiomic features were evaluated with paired 2-sample t-tests and p<0.05 indicating significance Comparing pre- and post-SBRT scans, feature differences were considered treatment related if a significant difference was detected in the intermediate or high dose VOI but not the low dose VOI. <h3>Results</h3> Among 28 patients, 86% were stage T1a-T1c, with the most common dose of 50 Gy in 5 fractions. Diagnostic CT scans were an average of 3.6 months before SBRT and follow up scans were an average of 13.1 months after completion of SBRT. Of 106 radiomic features extracted from each image set, 8 were significant in both intermediate and high dose VOI and 5 were significant in the high dose VOI only (see Table). <h3>Conclusion</h3> We demonstrate the feasibility of a semi-automated workflow for dose related radiomic analysis of diagnostic CT scans in patients treated with SBRT and identify possible radiomic features pertinent to treatment related changes. The workflow can be leveraged to investigate predictive capabilities and assist interpretation of post-SBRT radiologic changes.