Operable Non-small Cell Lung Cancer Patients Research Articles

Neoadjuvant immune checkpoint inhibitor reduced recurrence in operable NSCLC patients with pathological complete response: a retrospective analysis

BackgroundThis study aimed to evaluate if neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy (CT) reduced tumor recurrence after surgery than neoadjuvant CT alone in non–small cell lung cancer (NSCLC) patients with pathologic complete response (pCR).MethodsFrom January 1st 2019 to April 30th 2022, 16 NSCLC patients with pCR who received both neoadjuvant ICI and CT were designated as ICI/CT group. Another 8 patients, who received neoadjuvant CT alone, were designated as CT group. The tumor recurrence and patients’ survival status were analyzed.ResultsSquamous cell carcinoma was the predominant histology type in both groups. The CT group had higher percentage of patients who received adjuvant CT than the ICI/CT group (100% vs. 75%, p = 0.046). All patients had been followed up for at least 20 months. At 20 months after surgery, the ICI/CT group had a tumor recurrence rate of 6.25%, which was significantly lower than 37.5% recurrence rate of the CT group. One patient of the CT group died of gastrointestinal hemorrhage and severe anemia at 11 months after surgery, and no patient in the ICI/CT group died. During adjuvant therapy, the ICI/CT group had significantly lower risk of anemia (12.5% vs. 50%) than the CT group (p = 0.046).ConclusionThe study found that in NSCLC patients with pCR, neoadjuvant ICI reduced tumor recurrence rate. This indicated that like in advanced stage NSCLC, the ICI might bring similar long-term anti-tumor effect in operable NSCLC patients.

Predicting non-small cell lung cancer lymph node metastasis: integrating ctDNA mutation/methylation profiling with positron emission tomography-computed tomography (PET-CT) scan: protocol for a prospective clinical trial (LUNon-invasive Study).

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and remains a leading cause of cancer-related death. Lymph node metastasis (LNM) significantly affects recurrence, survival rates, and treatment options. While lymph node sampling is standard for surgically removing operable NSCLC, it can lead to complications. Positron emission tomography-computed tomography (PET-CT) helps assess preoperative LNM despite false positive or negative rates. Additionally, circulating tumor DNA (ctDNA) detects minimal residual disease with high sensitivity and specificity. Whether ctDNA can predict LNM in operable NSCLC remains uncertain. Our goal is to develop a precise model for predicting NSCLC LNM using non-invasive ctDNA/methylation profiling combined with PET-CT imaging. This is a prospective study conducted in three stages. We will enroll patients with clinical stage I-IIIB [8th tumor, node, metastasis (TNM) staging] NSCLC requiring lobectomy plus lymph node sampling/dissection. The distribution of clinical stages in the enrolled population is as follows: clinical stage cN0 (n=100) and cN1/cN2 (n=100). During Stage 1, we will establish LNMs-specific ctDNA methylation signatures and compare negative predictive value (NPV) rates of LNMs using preoperative blood ctDNA somatic mutation/methylation alone or combined with PET-CT across different groups. For Stage 2, we will compare detection rates between ctDNA somatic mutation/methylation profiles alone or combined with PET-CT and traditional mediastinoscopy/endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). As for Stage 3, ctDNA-free interval (CFI) and disease-free survival between systematic lymph node presence and absence in patients will be compared with preoperative negative ctDNA profiling and/or PET-CT. In Stage 3, patients will be followed up for 5 years to collect recurrence and survival data. Post-surgery follow-up ctDNA tests will be conducted every 3 months for the first 2 years, every 6 months for years 3-4, and annually in year five. Demographics and baseline data will be summarized with mean, standard deviation, median, max, and min values. Tests will include t-tests, Welch/Behren-Fisher test, and Wilcoxon rank-sum test for continuous variables. Categorical data will be presented as counts/percentages and compared using χ2 test or Fisher's exact test. By utilizing preoperative ctDNA/methylation profiling in conjunction with PET-CT, this study is expected to yield substantial evidence for accurately predicting LNM before surgery. This will help inform surgeons in selecting the appropriate intraoperative lymph node dissection strategy for operable NSCLC patients. This study is registered on www.clinicaltrials.gov (NCT06358222).

NeoRad(Low): A phase 2 trial of neoadjuvant (NA) ipilimumab + nivolumab (ipi+nivo) with low dose stereotactic body radiation therapy (SBRT) as an immune stimulant in patients with resectable stage IB-III non-small cell lung cancer (NSCLC).

e20081 Background: Standard NA immune checkpoint blockade for patients with resectable NSCLC targets PD1 only and must be combined with platinum-based chemotherapy. In a randomized phase 2 NA study, ipi + nivo demonstrated greater immune-mediated efficacy compared to nivo alone with major pathologic response (MPR) 50% vs. 24%, Cascone T, et al. Nat Med. 2021;27(3):504-14). Preclinical and clinical studies have demonstrated that low doses of radiation enhance immune response by multiple mechanisms (dsDNA breaks, induction of STING, transcription of pro-inflammatory proteins, increased expression of neoantigens while sparing effector T cells). An approach incorporating low dose radiation as an immune stimulant potentially may improve immune-mediated efficacy and shorten the duration of NA treatment compared to approaches that use combined cytotoxic chemotherapy. Methods: This single-arm trial tested NA ipi (1 mg/kg d1) + nivo (3mg/kg d1, 15, 29) plus low-dose SBRT delivered as 2 fractions (4Gy x 2) to the gross primary tumor and nodal disease immediately following day 1 infusion and completed by day 3 in patients with medically operable stage IB-III NSCLC Patients went on to surgical resection between days 49 -63. The primary efficacy outcome measure was pathologic response (including MPR, and complete PR (CPR)). Secondary outcome measures included safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design was employed to stop the study for lack of efficacy if fewer than 3 of the first 9 evaluable patients achieved MPR or experienced undue toxicity. Results: Patients were treated on study: 4 men, 5 women, aged 40-71, stage IB (2), IIB (5), IIIA (1), IIIB (1); adenocarcinoma 7 (all EGFR,ALK -), squamous 2; ECOG PS 0-1 (9); all were former smokers. There were no dose limiting toxicities. Study-related toxicities were ≤ grade 2 including rash (2) and abdominal pain (1). There were no study-related surgical complications. One patient (IIIA, T1N2) experienced clinical and radiologic progression during study treatment and was confirmed to have pleural metastases at surgery. Of 7 patients resected to date, there was 1 CPR, 0 further MPR and 1 patient with surgery pending. All resected patients had some treatment effect, 3 were down staged and these elected not to receive adjuvant cytotoxic chemotherapy. The only patient to progress in 8 months med f/u was the patient progressing during NA therapy. Conclusions: Low-dose radiation with concurrent NA ipi + nivo was safe and well tolerated in this small cohort but did not improve MPR compared to historical phase 2 data of ipi + nivo alone. Standard and exploratory biomarkers of immune response will be presented to determine if patient selection played a role in these results. Clinical trial information: NCT04933903 .

Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, MET exon skipping or de novo MET amplification.

Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.

Prognostic factors and predictive model construction in patients with non-small cell lung cancer: a retrospective study

ObjectiveThe purpose of this study was to construct a nomogram model based on the general characteristics, histological features, pathological and immunohistochemical results, and inflammatory and nutritional indicators of patients so as to effectively predict the overall survival (OS) and progression-free survival (PFS) of patients with non-small cell lung cancer (NSCLC) after surgery.MethodsPatients with NSCLC who received surgical treatment in our hospital from January 2017 to June 2021 were selected as the study subjects. The predictors of OS and PFS were evaluated by univariate and multivariable Cox regression analysis using the Cox proportional risk model. Based on the results of multi-factor Cox proportional risk regression analysis, a nomogram model was established using the R survival package. The bootstrap method (repeated sampling for 1 000 times) was used to internally verify the nomogram model, and C-index was used to represent the prediction performance of the nomogram model. The calibration graph method was used to visually represent its prediction compliance, and decision curve analysis (DCA) was used to evaluate the application value of the model.ResultsUnivariate and multivariate analyses were used to identify independent prognostic factors and to construct a nomogram of postoperative survival and disease progression in operable NSCLC patients, with C-index values of 0.927 (907–0.947) and 0.944 (0.922–0.966), respectively. The results showed that the model had high predictive performance. Calibration curves for 1-year, 2-year, and 3-year OS and PFS show a high degree of agreement between the predicted probability and the actual observed probability. In addition, the results of the DCA curve show that the model has good clinical application value.ConclusionWe established a predictive model of survival prognosis and disease progression in patients with non-small cell lung cancer after surgery, which has good predictive performance and can guide clinicians to make the best clinical decision.

LKB1 Loss Correlates with STING Loss and, in Cooperation with β-Catenin Membranous Loss, Indicates Poor Prognosis in Patients with Operable Non-Small Cell Lung Cancer.

To investigate the incidence and prognostically significant correlations and cooperations of LKB1 loss of expression in non-small cell lung cancer (NSCLC), surgical specimens from 188 metastatic and 60 non-metastatic operable stage I-IIIA NSCLC patients were analyzed to evaluate their expression of LKB1 and pAMPK proteins in relation to various processes. The investigated factors included antitumor immunity response regulators STING and PD-L1; pro-angiogenic, EMT and cell cycle targets, as well as metastasis-related (VEGFC, PDGFRα, PDGFRβ, p53, p16, Cyclin D1, ZEB1, CD24) targets; and cell adhesion (β-catenin) molecules. The protein expression levels were evaluated via immunohistochemistry; the RNA levels of LKB1 and NEDD9 were evaluated via PCR, while KRAS exon 2 and BRAFV600E mutations were evaluated by Sanger sequencing. Overall, loss of LKB1 protein expression was observed in 21% (51/248) patients and correlated significantly with histotype (p < 0.001), KRAS mutations (p < 0.001), KC status (concomitant KRAS mutation and p16 downregulation) (p < 0.001), STING loss (p < 0.001), and high CD24 expression (p < 0.001). STING loss also correlated significantly with loss of LKB1 expression in the metastatic setting both overall (p = 0.014) and in lung adenocarcinomas (LUACs) (p = 0.005). Additionally, LKB1 loss correlated significantly with a lack of or low β-catenin membranous expression exclusively in LUACs, both independently of the metastatic status (p = 0.019) and in the metastatic setting (p = 0.007). Patients with tumors yielding LKB1 loss and concomitant nonexistent or low β-catenin membrane expression experienced significantly inferior median overall survival of 20.50 vs. 52.99 months; p < 0.001 as well as significantly greater risk of death (HR: 3.32, 95% c.i.: 1.71-6.43; p <0.001). Our findings underscore the impact of the synergy of LKB1 with STING and β-catenin in NSCLC, in prognosis.

Impact of surgical approach on 90-day mortality after lung resection for nonsmall cell lung cancer in high-risk operable patients.

Non-small cell lung cancer (NSCLC) is often associated with compromised lung function. Real-world data on the impact of surgical approach in NSCLC patients with compromised lung function are still lacking. The objective of this study is to assess the potential impact of minimally invasive surgery (MIS) on 90-day post-operative mortality after anatomic lung resection in high-risk operable NSCLC patients. We conducted a retrospective multicentre study including all patients who underwent anatomic lung resection between January 2010 and October 2021 and registered in the Epithor database. High-risk patients were defined as those with a forced expiratory volume in 1 s (FEV1) or diffusing capacity of the lung for carbon monoxide (DLCO) value below 50%. Co-primary end-points were the impact of risk status on 90-day mortality and the impact of MIS on 90-day mortality in high-risk patients. Of the 46 909 patients who met the inclusion criteria, 42 214 patients (90%) with both preoperative FEV1 and DLCO above 50% were included in the low-risk group, and 4695 patients (10%) with preoperative FEV1 and/or preoperative DLCO below 50% were included in the high-risk group. The 90-day mortality rate was significantly higher in the high-risk group compared to the low-risk group (280 (5.96%) versus 1301 (3.18%); p<0.0001). In high-risk patients, MIS was associated with lower 90-day mortality compared to open surgery in univariate analysis (OR=0.04 (0.02-0.05), p<0.001) and in multivariable analysis after propensity score matching (OR=0.46 (0.30-0.69), p<0.001). High-risk patients operated through MIS had a similar 90-day mortality rate compared to low-risk patients in general (3.10% versus 3.18% respectively). By examining the impact of surgical approaches on 90-day mortality using a nationwide database, we found that either preoperative FEV1 or DLCO below 50% is associated with higher 90-day mortality, which can be reduced by using minimally invasive surgical approaches. High-risk patients operated through MIS have a similar 90-day mortality rate as low-risk patients.

Estimating the impact of adjuvant atezolizumab in preventing recurrences and reducing costs in resectable early PD-L1 high non-small cell lung cancer in Europe.

e20501 Background: Recurrences of non-small cell lung cancer (NSCLC) after surgery remain common and are associated with significant morbidity and mortality. Loco-regional or metastatic disease recurrence can lead to a substantial health care resource use and economic burden. The aim of this study was to estimate the effect of treating patients with early-stage NSCLC with adjuvant atezolizumab (ATZ) on the number of recurrences and direct healthcare costs in Germany, Spain, France Italy and the UK, together referred to as EU5. Methods: Using an epidemiological model, we estimated the reduction in loco-regional (LR) recurrences or distant metastases (DM) after adjuvant ATZ treatment following chemotherapy in operable NSCLC patients with PDL-1 expression of ≥ 50% on tumor cells (PD-L1 high), stage II-IIIA (AJCC 7th edition staging), without EFGR or ALK alterations. We used data from cancer registries, published literature sources, and market research to obtain incidence rates, staging distribution, biomarker status data, and adjuvant treatment rates. Moreover, we used evidence on the disease-free survival (DFS) of patients on adjuvant ATZ from the IMpower010 (NCT02486718) clinical trial to calculate the projected reduction in the number of LR recurrences or DM over a 10-year period post-ATZ launch relative to best supportive care (BSC). The model considers the costs associated with treatment, management of adverse events, monitoring of the disease, and follow-up healthcare. Results: We project that between 2023 and 2033, 20,483 patients with resected PD-L1 high stage II-IIIA NSCLC would experience recurrence (LR, or DM, or both) in the EU5 if they were treated with BSC (adjuvant platinum-based chemotherapy) alone (Table 1). Assuming peak ATZ uptake of 75%, the model estimates that following adjuvant ATZ and chemotherapy, a total of 4,665 recurrences would be prevented in this patient population in the EU5 over 10 years, representing a 23% decrease in recurrence relative to BSC. These avoided recurrences in EU5 could translate into a considerable reduction in direct healthcare costs. Conclusions: Adjuvant ATZ following chemotherapy results in a considerable population-level reduction of loco-regional recurrence or distant metastasis in resected PD-L1 high stage II-IIIA NSCLC patients. This could translate into a substantial decrease in the economic and societal burden caused by the disease. [Table: see text]

240 Discovery of biomarkers of resistance to immune checkpoint blockade in non-small-cell lung cancer (NSCLC) using high-plex digital spatial profiling

BackgroundDespite the clinical effectiveness of Immune Checkpoint Inhibitors (ICI) in lung cancer, only around 20% remain disease free at 5 years. Predictive biomarkers for ICIs are neither sensitive nor specific. Here, we used the GeoMx Digital Spatial Profiler (DSP) (NanoString, Inc.) to analyze high-plex protein in a quantitative and spatially resolved manner from single formalin-fixed paraffin embedded tissue sections toward the goal of identification of new biomarkers with better predictive value.MethodsPre-treatment samples from 56 patients with NSCLC treated with ICI were collected, represented in Yale tissue microarray 471 (YTMA471), and analyzed. A panel of 71 photocleavable oligonucleotide-labeled primary antibodies (NanoString Human IO panel) was used for protein detection. Protein expression was measured in 4 molecularly defined tissue compartments, defined by fluorescence co-localization (tumor [panCK+], leukocytes [CD45+/CD68-], macrophages [CD68+] and an aggregate stromal immune cell compartment, defined as the sum of leukocyte and macrophage expression [panCK-/CD45+/CD68+]) generating 284 variables representing potential predictive biomarkers. Promising candidates were orthogonally validated with Quantitative Immunofluorescence (QIF). Pre-treatment samples from 40 patients with NSCLC (YTMA404) that received ICI, and 174 non-ICI treated operable NSCLC patients (YTMA423) were analyzed to provide independent cohort validation. All statistical testing was performed using a two-sided significance level of α=0.05 and multiple testing correction (Benjamini-Hochberg method, FDR &lt; 0.1).ResultsInitial biomarker discovery on 284 protein variables were generated by univariate analysis using continuous log-scaled data. High PD-L1 expression in tumor cells predicted longer survival (PFS; HR 0.67, p=0.017) and validated the training cohort. We found 4 markers associated with PFS, and 3 with OS in the stromal compartment. Of these, expression of CD66b in stromal immune cells predicted significantly shorter OS (HR 1.31, p=0.016) and shorter PFS (HR 1.24, p = 0.04). Tertile analysis using QIF on all three tissue cohorts for CD66b expression, assessed by QIF, showed that CD66b was indicative but not prognostic for survival [discovery cohort, YTMA471 (OS; HR 3.02, p=0.013, PFS; HR 2.38, p=0.023), validation cohort; YTMA404 (OS; HR 2.97, p=0.018, PFS; HR 1.85, p=0.1), non-ICI treated cohort YTMA423 (OS; HR 1.02, p&gt;0.9, PFS; HR 0.72, p=0.4)].ConclusionsUsing the DSP technique, we have discovered that CD66b expressed in the stromal immune [panCK-/CD45+/CD68+] molecular compartment is associated with resistance to ICI therapy in NSCLC. This observation was validated by an orthogonal approach in an independent ICI treated NSCLC cohort. Since CD66b identifies neutrophils, further studies are warranted to characterize the role of neutrophils in ICI resistance.AcknowledgementsDr Moutafi is supported by a scholarship from the Hellenic Society of Medical Oncologists (HESMO)Ethics ApprovalAll tissue samples were collected and used under the approval from the Yale Human Investigation Committee protocol #9505008219 with an assurance filed with and approved by the U.S. Department of Health and Human Services

Cost-effectiveness evaluation of robotic-assisted thoracoscopic surgery versus open thoracotomy and video-assisted thoracoscopic surgery for operable non-small cell lung cancer

BackgroundThis study aimed to evaluate the cost-effectiveness of robotic-assisted thoracoscopic surgery (RATS) over open thoracotomy (OT) and video-assisted thoracoscopic surgery (VATS) for operable non-small cell lung cancer (NSCLC) from the perspective of Chinese healthcare payer. MethodsThe Markov decision model was developed to assess the 5-year costs and quality-adjusted life year (QALY) of RATS versus OT and VATS for operable NSCLC patients. The propensity-matched cohorts were generated from our clinical center to determine the surgical costs and complication rates. An individual patient data meta-analysis was conducted to estimate model probabilities of progression and survival risks. Other model inputs were abstracted from available studies. The primary outcome was incremental cost-effectiveness ratios (ICERs). ResultsRATS contributed to an incremental 0.28 QALYs at an additional cost of $3,104.82, making for an ICER of $10,967.41 per QALY versus OT. Robotic approach harvested an incremental 0.05 QALYs at an additional cost of $4006.86, making for an ICER of $80324.98 per QALY over VATS. RATS shown a same cost-effectiveness probability (0.50) versus OT and VATS at a willing-to-pay (WTP) threshold of $12,000 per QALY and $75,800 per QALY, respectively. The probabilities of cost-effectiveness for RATS were 0.64 and 0.21 at a presupposed WTP threshold of $ 30,000 per QALY versus OT and VATS, respectively. ConclusionsRATS was evaluated to be cost-effective versus OT for patients with operable NSCLC from the perspective of Chinese healthcare payer. To the contrary, robotic approach was associated with less cost-effective than VATS.

Clinicopathological and prognostic features of operable non-small cell lung cancer patients with diabetes mellitus.

The aim of this study was to investigate the clinicopathological and prognostic features of operable non-small cell lung cancer (NSCLC) patients with diabetes mellitus (DM). A total of 1231 surgically resected NSCLC patients were retrospectively reviewed. Clinicopathological characteristics were compared between patients with DM (DM group, n = 139) and those without DM (non-DM group, n = 1092). The clinical factors associated with postoperative complications and prognostic factors were identified. The DM group had distinct clinicopathological features. No significant differences in histological invasiveness or stage were found. The presence and control status of DM were independent predictors of postoperative complications. No significant differences in recurrence-free survival or cancer-specific survival were observed; however, the DM group had worse overall survival (OS). The DM group had a higher number of deaths from other diseases than the non-DM group, and these patients had significantly higher postoperative hemoglobin A1c levels than patients with cancer-related death. The presence and control status of preoperative DM are useful predictors of both postoperative complications and OS in operable NSCLC patients. Concomitant diabetes-related complications have a negative effect on long-term survival in diabetic NSCLC patients, and long-term glycemic control is important to prolong OS.

1219P AI-powered prediction of 2-year relapse-free survival in operable NSCLC patients using peritumoral radiomic features according to tumour size in chest CT images

To evaluate the ability of radiomic features inside and outside the tumor and the effect of the external range according to the size of the tumor in predicting 2-year relapse-free survival of operable non-small cell lung cancer (NSCLC) patients from chest CT images.

Delivering safe and effective stereotactic body radiation therapy for patients with centrally located early stage non-small cell lung cancer.

Stereotactic body radiation therapy (SBRT) combines accurate anatomic targeting of a tumor with the precise delivery of high doses of radiation per fraction in an attempt to ablate the tumor while sparing surrounding normal tissues (1). SBRT has been described in the treatment of lung cancer since the mid-1990s (2). The initial uses of lung SBRT were in patients with early-stage non-small cell lung cancer (NSCLC) who were medically inoperable or refused surgery, but it has also emerged as an effective treatment option for medical operable NSCLC patients (3,4), patients with early stage SCLC (5), and patients with parenchymal metastasis from lung and other malignancies.

P2.03-56 Polymorphism ICAM-1 and Beta-3 Integrin Are Associated with the Development of Non-Small Cell Lung Cancer and the Prognostic Role of ICAM-1

Lung cancer is widespread cancer in the worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. ICAM-1 and β3 integrin have been have been found to be associated with the angiogenesis, tumor growth and metastasis in various tumor types. Our primary aim in this study was to explore gene polymorphisms in ICAM-1 and β3 integrin molecular pathway in NSCLC patients and to clarify whether these values are effective on the etiopathogenesis and prognosis of the disease. Sixty-nine patients with operable (T1-4N0-1M0) NSCLC patients and 120 healthy individuals between January 2012 and June 2018 were included in the study. The tumor samples were taken after resected specimen. Blood samples of the patients were also collected before surgical resection. ICAM-1 and β3 integrin gene polymorphisms were determined by using PCR-RFLP techniques. Also serum ICAM levels were determined by ELISA method. The stages of the tumor were constructed according to 8th staging system. There was no statistically significant difference between patient with NSCLC and healthy control groups with regard to β3 Integrin Leu33Pro gene polymorphism(p=0.182). However, in patients with NSCLC, AG genotype frequency and G allele carriers of ICAM K469E variant were found to be higher than the control group and the difference was statistically significant (OR:2,710 95%CI:1,364-5,376; p=0.005). It has been determined that having a G allele increased approximately 2,95 fold the risk of disease and also carrying of AGTC combined genotype increased (OR:2,95 95%CI:1,366-6,373; p=0.049). When patients were evaluated according to tumor stage, serum levels of ICAM-1 gene in early tumor stage was found to be significantly higher than in advanced tumor stage (p=0,013). No significant difference was found between the range of histopathological subtypes and serum ICAM levels (p>0,05). Also, no statistically significant association was found between serum ICAM levels and angiolymphatic invasion (p=0.101, perineural invasion(p=0.054), lymph node metastasis (p=0.585). ICAM-1 as an intercellular adhesion molecule seems to play an important role in lung carcinogenesis and it might play a role in the invasiveness of the tumor. However, β-3 integrin was not found to be associated with lung cancer development. The role of ICAM-1 in the genesis of lung cancer as well as immune mechanism should be further investigated.

Statistical approach to mediastinal staging in NSCLC with M.E.S.S.i.a. software.

The exclusion of pathological involvement of mediastinal lymph nodes in patients affected by NSCLC plays a central role in assessing their prognosis and operability. Ceron et al. developed a software - called M.E.S.S.i.a (Mediastinal Evaluation with Statistical Support; instan approach) - that allows the calculation of the residual probability of lymph node involvement after a certain number of tests has been done, by integrating every test result with the pre-test prevalence. M.E.S.S.i.a. bridges a gap of current American College of Chest Physicians (ACCP) guidelines, providing probability values of mediastinal metastasis for a correct clinical decision. We conducted a preliminary retrospective study in a series of 108 patients affected by non small cell lung cancer (NSCLC). Pathological staging was compared to the probability of nodal involvement calculated by M.E.S.S.i.a. software. Forty-two out of 108 subjects (39%) had a calculated post-test probability <8%; none of these had proven N2/N3 metastasis at surgical staging (negative predictive value, NPV: 100%). In 12/41 cases M.E.S.S.i.a. was able to avoid invasive procedures. The remaining 66 (61%) patients did not reach the surgical threshold; among these, 11 displayed N2 positivity at pathological staging. Receiving operator curve (ROC) analysis produced an area under curve (AUC) value of 0.773 (p<0.001). These preliminary data show high accuracy of M.E.S.S.i.a. software in excluding N2/N3 lymph node involvement in NSCLC. We have therefore promoted a prospective multicenter study in order to to get a validation of the calculator at different levels of probability of lymph node involvement. The recruitable subjects are potentially operable NSCLC patients; the gold standard for detection of mediastinal disease is the surgical lymph node dissection.

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients.

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

GAP43, a novel metastasis promoter in non-small cell lung cancer

BackgroundBrain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC.MethodsWe performed high-throughput Luminex assays to profile the transcriptional levels of 36 genes in 70 operable NSCLC patients, among whom 37 developed brain metastases as the first relapse within 3 years after surgery. The Cox proportional hazards regression model was used to evaluate the association between genes and brain metastases. Wound healing assay and transwell assay was carried out to estimate the function of target gene in vitro. And left ventricular injection on nude mice was used to evaluate the effect of target gene in vivo.ResultsGrowth-associated protein 43 (GAP43) was found to be related to brain metastasis. Multivariate Cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.29-fold increase in the risk for brain metastasis compared with those with low levels (95% confidence interval: 1.55–7.00; P = 0.002). Kaplan–Meier survival curves revealed that GAP43 was also associated with overall survival. Analysis of a cohort of 1926 NSCLC patients showed similar results: patients with high levels of GAP43 had worse progression-free and overall survival rates. Furthermore, in vitro experiments showed that GAP43 facilitated cell migration. Animal studies demonstrated that GAP43-silenced NSCLC cells were less likely to metastasize to the brain and bone than control cells. Immunofluorescence and F-actin/G-actin in vivo assays indicated that GAP43 knockdown triggered depolymerization of the F-actin cytoskeleton. Rho GTPase activation assays showed that Rac1 was deactivated after GAP43 was silenced.ConclusionsOur findings suggest that GAP43 is an independent predictor of NSCLC brain metastasis and that it may facilitate metastasis by regulating the Rac1/F-actin pathway.

Abstract 1083: GAP43, a novel potential metastases promoter in non-small cell lung cancer

Abstract Metastasis is a serious sequela with dismal prognosis in non-small cell lung cancer (NSCLC). To identify novel biomarkers for predicting NSCLC metastasis, we performed high-throughput Luminex assays to profile the transcriptional level of 36 genes in 37 operable NSCLC patients who had distant metastases within 3 years after surgery and 33 paired patients without relapse after operation. Among the 36 genes, growth associated protein 43 (GAP43), an axonal membrane protein, was identified related to distant metastases. Multivariate cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.71-fold increase in risk for metastasis than those with low levels (95% confidence interval 1.69-8.14, P = 0.001). Analysis of a patient cohort of 1,926 NSCLC revealed that patients with high levels of GAP43 had worse progression-free and overall survival. In vitro experiments showed that GAP43 knockdown suppressed NSCLC cell migration and invasion, while GAP43 overexpression facilitated their migration and invasion. Immunofluorescence assay indicated that the linear polymer microfilament F-actin became cracked after GAP43 knockdown. Furthermore, animal studies using left ventrical injection demonstrated that GAP43 silenced NSCLC cells were less likely to metastasize to brain and bone than the controls. Together, our findings suggest that GAP43 may be an independent predictor for NSLCL metastasis, and it may facilitate distant metastasis through targeting F-actin. Citation Format: Fanrong Zhang, Jiaoyue Jin, Junzhou Wu, Kaiyan Chen, Minran Huang, Herbert Yu, Lisha Ying, Dan Su. GAP43, a novel potential metastases promoter in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1083.

The role of endobronchial and endoscopic ultrasound guided fine needle aspiration for mediastinal nodal staging of non-small-cell lung cancer.

Mediastinal and hilar nodal staging is one of the key points for differentiating treatment modalities in patients with non-small-cell lung cancer (NSCLC). The aim of the present study was to determinate the diagnostic yields of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and combined EBUS-TBNA and EUS-FNA modalities for nodal staging in potentially operable NSCLC patients. Twenty consecutive patients were prospectively enrolled in the study between March 2014 and November 2015. All patients had a potentially operable NSCLC diagnosis before endosonographic procedures. Thirty lymph nodes were sampled by EBUS-TBNA and 17 lymph nodes were sampled by EUS-FNA in all 20 patients. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of F-18 fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT), EBUS-TBNA, EUS-FNA and combined EBUS-TBNA and EUS-FNA were 100%, 33.3%, 64.7%, 100% and 70.0%; 81.8%, 100%, 100%, 81.8% and 90%; 81.8%, 100%, 100%, 75% and 88.2%; 90.9%, 100%, 100%, 90.0% and 95.0%, respectively. The combined EBUS-TBNA and EUS-FNA technique is a successful procedure for nodal staging in potentially operable NSCLC patients.

Physical behavior and associations with health outcomes in operable NSCLC patients: A prospective study

ObjectivesOur objectives were to 1) characterize daily physical behavior of operable non-small cell lung cancer (NSCLC) patients, from preoperative to six months postoperative using accelerometry, and explore if physical behavior preoperative or one month postoperative is associated with better health outcomes at six months postoperative. MethodsA prospective study with 23 patients (13 female) diagnosed with primary NSCLC and scheduled for curative lung resection was performed. Outcome measures were assessed two weeks preoperative, and one, three and six months postoperative, and included accelerometer-derived physical behavior measures and the following health outcomes: six minute walking distance (6MWD), questionnaires concerning health-related quality of life (HRQOL), fatigue and distress. ResultsOn group average, physical behavior showed significant changes over time. Physical behavior worsened following surgery, but improved between one and six months postoperative, almost reaching preoperative levels. However, physical behavior showed high variability between patients in both amount as well as change over time. More time in moderate-to-vigorous physical activity in bouts of 10 min or longer in the first month postoperative was significantly associated with better 6MWD, HRQOL, distress, and fatigue at six months postoperative. ConclusionAs expected, curative lung resection impacts physical behavior. Patients who were more active in the first month following surgery reported better health outcome six months postoperative. The large variability in activity patterns over time observed between patients, suggests that physical behavior ‘profiling’ through detailed monitoring of physical behavior could facilitate tailored goal setting in interventions that target change in physical behavior.