Non-small Cell Lung Cancer Involvement Research Articles

Plasma fatty acid levels and risk of non-small cell lung cancer: a large-scale prospective cohort study.

Non-small cell lung cancer (NSCLC) ranks among the most prevalent and lethal malignancies globally. Fatty acids (FAs) play a significant role in diverse physiological and pathological mechanisms, yet their precise involvement in NSCLC remains poorly understood. This study utilized a large-scale prospective cohort of 249,132 participants, observed over an average of 12 years, to investigate the relationship between different FAs and NSCLC risk. Analytical approaches included Cox proportional hazards regression, Kaplan-Meier survival analysis, accelerated failure time (AFT) modeling, and restricted cubic spline (RCS) analysis. During the follow-up period, 1,460 participants were diagnosed with NSCLC. Cox regression analysis demonstrated that elevated levels of docosahexaenoic acid (DHA), linoleic acid (LA), and omega-3 were inversely associated with NSCLC risk. Kaplan-Meier curves, along with AFT models, corroborated that elevated concentrations of DHA and LA significantly delayed NSCLC onset. Additionally, RCS analysis uncovered nuanced dose-response relationships between these FAs and NSCLC. Stratified analyses highlighted variability based on smoking status, gender, and body mass index subgroups. The concentration of specific FAs exhibits a significant association with NSCLC risk. These results offer a foundation for devising dietary FA composition adjustments aimed at reducing NSCLC risk.

Spine Metastasis Is Associated with the Development of Brain Metastasis in Non-Small-Cell Lung Cancer Patients.

Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74-3.37, p < 0.001; 1.94 and 1.19-3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.

Systematic endoscopic staging of mediastinum to determine impact on radiotherapy for locally advanced lung cancer (SEISMIC): protocol for a prospective single arm multicentre interventional study

BackgroundEndobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC.MethodsConsecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy.DiscussionWith specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning.Trial registrationACTRN12617000333314, ANZCTR, Registered on 3 March 2017.

Prognostic Significance of Stromal Periostin Expression in Non-Small Cell Lung Cancer

Background: The microenvironment of solid tumours is significant in cancer development and progression. The aim of this study was to determine periostin (POSTN) expression by cancer-associated fibroblasts (CAFs) in non-small-cell lung cancer (NSCLC), as well as to assess associations with clinicopathological factors and prognosis. Materials and Methods: Immunohistochemical analysis of POSTN expression was performed on NSCLC (N = 700) and non-malignant lung tissue (NMLT) (N = 110) using tissue microarrays. Laser capture microdissection (LCM) for isolation of stromal and cancer cells of NSCLC was employed, and subsequently, POSTN mRNA expression was detected by real-time PCR. Immunofluorescence reaction and colocalisation analysis were performed by confocal microscopy. Results: Expression of POSTN in CAFs was significantly higher in NSCLC and in the adenocarcinoma (AC) and squamous cell carcinoma (SCC) subtypes compared to NMLT. POSTN expression in CAFs increased with clinical cancer stage, grades (G) of malignancy, and lymph node involvement in NSCLC. Higher POSTN expression in CAFs was an independent prognostic factor for overall survival (OS). LCM confirmed significantly higher POSTN mRNA expression in the stromal cells (CAFs) compared to the lung cancer cells. Conclusions: POSTN produced by CAFs might be crucial for NSCLC progression and can be an independent negative prognostic factor in NSCLC.

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.

MiR-93 Promotes Tumorigenesis and Metastasis of Non-Small Cell Lung Cancer Cells by Activating the PI3K/Akt Pathway via Inhibition of LKB1/PTEN/CDKN1A.

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of clinical lung cancer cases. MicroRNA-93 (miR-93) is an oncomiR in many types of human cancer, exerting pivotal effects in the development and progression of malignancies, including NSCLC. However, the mechanism underlying miR-93 involvement in NSCLC is unknown. Our purpose was to reveal and explain this mechanism, with the goal of contributing to the development of new diagnostic biomarkers and individualized therapeutic tools.Methods: The expression of miR-93 was determined in NSCLC cell lines A549, H1975, and H1299. The cells were transfected with control plasmids (Mock group), miR-93 overexpression plasmids (miR-93 Up group), or miR-93 inhibitor plasmids (miR-93 Down group) to generate stable miR-93-overexpressing or -depleted cells. The effects of miR-93 on proliferation, migration, and invasion of these cells were determined. The in vivo effects of miR-93 on tumor metastasis were determined in an NSCLC xenograft mouse model. The molecular mechanisms underlying these effects were investigated via dual luciferase reporter assay and western blotting.Results: MiR-93 expression levels were significantly greater in the NSCLC cell lines than in normal lung epithelial cells. Cell proliferation, migration, and invasion were significantly stimulated by miR-93 upregulation (all P<0.05) and inhibited by miR-93 downregulation. Dual luciferase reporter assay demonstrated that miR-93 directly bound with the 3′-untranslated region of the tumor suppressor gene LKB1. Western blotting analysis indicated that miR-93 activated the PI3K/Akt pathway by inhibiting LKB1, PTEN, and p21. Increased expression of miR-93 induced significant hepatic metastasis of lung cancer in the xenograft mouse model.Conclusion: Overexpression of miR-93 facilitates tumorigenesis and metastasis of NSCLC. These findings provide novel insight into the mechanism of miR-93 involvement in NSCLC, suggesting that miR-93 may serve as a potential therapeutic target.

Improved inter-observer agreement of an expert review panel in an oncology treatment trial – Insights from a structured interventional process

PurposeOncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)–positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). Material and methodsAn expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG–PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (IDMC) triggered an interventional harmonisation process, which overall involved 11 experts uttering 6855 blinded diagnostic statements. After assessing the baseline inter-observer agreement (IOA) of a blinded re-review (phase 1), a discussion process led to improved reading criteria (phase 2). Those underwent a validation study (phase 3) and were then implemented into the study routine. After 2months (phase 4) and 1year (phase 5), the IOA was reassessed. ResultsThe initial overall IOA was moderate (kappa 0.52 CT; 0.53 PET). After improvement of reading criteria, the kappa values improved substantially (kappa 0.61 CT; 0.66 PET), which was retained until the late reassessment (kappa 0.71 CT; 0.67 PET). Subjective uncertainty was highly predictive for low IOA. ConclusionThe IOA of an expert panel was significantly improved by a structured interventional harmonisation process which could be a model for future clinical trials. Furthermore, the low IOA in reporting nodal involvement in NSCLC may bear consequences for individual patient care.

Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosis-endemic area: A 5-year prospective observational study.

Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing mediastinal lymph node metastasis in non-small-cell lung cancer (NSCLC), which determines management and predicts survival. Tuberculosis (TB) is known to lead to false-positive PET-CT findings. To assess the diagnostic accuracy of PET-CT in identifying mediastinal lymph node involvement of NSCLC in a high TB-endemic area. Patients who underwent both PET-CT and lymph node tissue sampling for the investigation of suspected NSCLC were prospectively included in this observational study. Results were analysed per patient and per lymph node stage. A post-hoc analysis was performed to test the validity of a maximum standardised uptake value (SUV-max) cut-off for lymph node positivity. PET-CT had a sensitivity of 92.6%, specificity of 48.6%, positive predictive value of 56.8% and negative predictive value (NPV) of 90.0% in the per-patient analysis. Diagnostic accuracy was 67.2%. Similar values were obtained in the per-lymph node stage analysis. TB was responsible for 21.1% of false-positive results. A SUVmax cut-off of 4.5 yielded an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, but at the cost of decreasing the NPV from 90.6% to 83.5%. In a high TB-endemic area, PET-CT remains a valuable method for excluding mediastinal lymph node involvement in NSCLC. Patients with a negative PET-CT may proceed to definitive management without further invasive procedures. However, PET-CT-positive lymph nodes require pathological confirmation, and the possibility of TB must be considered.

Limited Predictive Value of Dual-Time-Point F-18 FDG PET/CT for Evaluation of Pathologic N1 Status in NSCLC Patients

The aim of the current study was to investigate the predictive value of dual-time-point F-18 FDG PET/CT for pathologic N1 metastasis in patients with non-small cell lung cancer (NSCLC). A retrospective review identified 70 patients with NSCLC patients who received dual-time-point F-18 FDG PET/CT at diagnosis of cancer. The F-18 FDG PET/CT findings for all primary NSCLC and mediastinal lymph node involvement were compared with the pathologic diagnosis within 5 weeks after surgical resection. The pathologic diagnoses of N1 state were confirmed by surgical resection. Univariate and multivariate analyses were used to analyze the associations among the pathologic N1 status and age, sex, tumor size, histology, standardized uptake value (SUV(maxE)), SUV(maxD), and %ΔSUV(max). The N1 (+) group showed statistically significant higher value of SUV(maxE) and SUV(maxD) than N1 (-) group. The %ΔSUV(max) did not show the statistical difference between pathologic N1 (+) and N1 (-) groups. Receiver operating characteristic analyses showed that the SUV(maxE) was superior to the %ΔSUV(max) for the prediction of pathologic N1 involvement in NSCLC. In univariate analysis, pathology (adenocarcinoma or nonadenocarcinoma), SUV(maxE) (>6.9 or ≤6.9), SUV(maxD) (>7.1 or ≤7.1) were factors significantly associated with pathologic N1 involvement. However, in multivariate analysis, only the SUV(maxE) was factor significantly associated with pathologic N1 involvement in NSCLC. Based on the presented results, the dual-time-point F-18 FDG PET/CT is not a useful method for the prediction of pathologic N1 status in NSCLC patients. Further studies are needed to confirm these results and improve statistical accuracy.

Lymph node involvement in T1 non-small-cell lung cancer: could glucose uptake and maximal diameter be predictive criteria?☆

The introduction of modern staging systems such as computed tomography (CT) and positron emission tomography/CT (PET/CT) with fluorodeoxyglucose ([(18)F]FDG) has increased the detection of small peripheral lung cancers at an early stage. We analyzed the behavior of pathological T1 non-small-cell lung cancer (NSCLC) to identify criteria predictive of nodal involvement, and the role of cancer size in lymph node metastases. We retrospectively analyzed 219 patients with pathological T1 NSCLC. All patients were staged by high-resolution CT and PET as stage I, and underwent anatomical resection and radical lymphadenectomy. Our data were collected based on pathological nodule size (0-10 mm; 11-20 mm; and 21-30 mm); morphological features of lung nodule and FDG uptake of the tumor measured by standardized uptake value (SUV). A total of 190 patients (87%) were pN0, 14 (6%) pN1, and 15 (7%) pN2. No nodal involvement was observed in any of the 62 patients with nodule size less than 10 mm, in 20 out of 120 patients (17%) with nodule size 11-20 mm, and in nine out of 37 tumors (28%) 21-30 mm in size (p=0.0007). All 55 patients with nodule SUV<2.0 and all 26 non-solid lesions were pN0 (respectively, p=0.0001 and p=0.03). All nodal metastases occurred among the group of 132 patients with size larger than 10 mm and SUV higher than 2.0 with a 22% rate of nodal involvement of (29 patients) (p<0.0001). The low probability of lymph node involvement in NSCLC <1 cm or showing glucose uptake <2 suggests lymphadenectomy could be avoided. A randomized trial should be performed to validate our data.

Azygos Reconstruction for Non-Small Cell Lung Cancer Involvement in Agenesis of Inferior Vena Cava

A 59-year-old man underwent an urgent thoracotomy due to a massive hemothorax caused by a computed tomographic-guided fine-needle aspiration of a right upper lobe tumor. The computed tomographic scan showed an agenesis of inferior vena cava beneath to the suprahepatic veins and a massive distended arch of the azygos vein that drains to the superior vena cava all the blood coming from the inferior side of the body (Fig 1A) azygos arch drains into the superior vena cava (white arrows), and (Fig 1B) the rudimentary inferior vena cava receives blood from the hepatic segments (black arrow).

Recursive Partitioning Analysis of Mediastinal N2 Lymph Node Involvement with Selected Biological Markers in Operable Non-small Cell Lung Cancer: A Correlative Study

Background Expressions of various biomarkers in non-small cell lung cancer (NSCLC) have been linked with the prognosis and involvement of mediastinal lymph nodes. Methods In this study, we utilized recursive partitioning analysis (RPA) by using P53, c-erb-B2, and P-glycoprotein (PGP) expressions evaluated by immunohistochemistry to estimate retrospectively the likelihood of the occult N2 mediastinal lymph node involvement in patients with operable NSCLC. Results In univariate tests, immunohistochemical staining of the primary tumor for these 3 markers in 61 patients undergoing surgery revealed no direct relationship with the N2 involvement. However, RPA demonstrated in patients aged &lt;75 and with ≥4 mediastinal lymph nodes removed that, high PGP expression frequency (≥20%) predicted an increased likelihood of the N2 involvement (46.7%, R2 = 0.25). Univariate nominal logistic regression analysis revealed that RPA group affiliation, and the number of mediastinal lymph nodes resected (logarithmic transformation) were associated with the metastasis to N2 lymph nodes (χ2 = 17.59, p = 0.0005, and χ2 = 2.40, p = 0.0654, respectively). Multivariate analysis confirmed that only RPA group affiliation predicted the N2 involvement (χ2 = 14.63, p = 0.0022). Conclusion This study shows for the first time that PGP expression of the primary tumor may help to predict the occult N2 mediastinal lymph node involvement in NSCLC. Thus, further research is required to understand whether PGP expression may aid in the decision process for preoperative mediastinoscopy.

Endoscopic Ultrasound/Fine-Needle Aspiration Diagnosis of a Malignant Subcarinal Lymph Node in a Patient With Lung Cancer and a Negative Positron Emission Tomography Scan

Transesophageal, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and positron emission tomography (PET) scanning are new modalities for staging non-small cell lung cancer (NSCLC), the roles of which are still being defined. A 78-year-old man with a right lower lobe (RLL) mass and mediastinal adenopathy seen on CT scan had a PET scan that revealed only a RLL hypermetabolic area. EUS/FNA cytology of a subcarinal lymph node (LN) revealed the presence of NSCLC. This is a case of a false-negative PET scan for nodal involvement in NSCLC that was diagnosed with EUS/FNA. Patients with NSCLC and suspicious lymphadenopathy may benefit from EUS/FNA of enlarged posterior mediastinal LNs, even with negative findings of PET scanning.

Small bowel metastases in non-small cell lung cancer

A case report of stage I adenocarcinoma of the lung in a 43-year-old female with recurrence in the small bowel and liver 11 months after pneumonectomy is presented. In addition, a cohort of 733 patients with non-small cell lung cancer (NSCLC) in all pretreatment stages (stages I–IV) with a total of 218 autopsies are evaluated, and the literature on the topic is reviewed, in order to define the frequency of metastases from NSCLC to the small bowel. There were 10 cases with and 208 cases without small bowel involvement among 218 consecutive autopsies (autopsy rate, 30%). The frequency of small bowel involvement was 4.6% (95% confidence interval, 2.2–8.3%), and all were in patients with adenocarcinoma of the lung. All patients with small bowel involvement at autopsy had also other concurrent metastatic sites as well and the following were the most frequent: adrenals (90% of cases), mediastinal lymph nodes (80%), liver (70%), pleura (60%), contralateral lung (60%), bones (60%), and brain (50%). Significantly more metastatic sites were observed in patients with than without small bowel involvement, both totally ( P=0.0001) and with respect to number of extrathoracic ( P=0.0001) and intrathoracic ( P=0.01) metastatic sites. In conclusion, small bowel involvement in NSCLC is relatively infrequent. As a unique finding, over-representation of patients with poorly differentiated tumors ( P=0.03) and patients having solid carcinoma with mucus formation after histologic subtyping ( P=0.04) among cases with small bowel involvement was observed. This indicates, that small bowel metastases is an epiphenomonen of NSCLC tumors with certain biological characteristics, although as yet undiscovered, which leads to a high metastatic potential. If such biological characteristics could be identified, they may be used in the selection of treatment options for individual patients, e.g. indicating a need for adjuvant or neoadjuvant chemotherapy in addition to surgery in resectable or marginally resectable NCSLC patients.

Mediastinal Staging in Non-small-cell Lung Cancer

Decision analysis was used to study the approach to staging mediastinal involvement in patients with non-small-cell lung cancer (NSCLC). Various diagnostic strategies for mediastinal disease staging using computed tomography (CT), mediastinoscopy, and bronchoscopy with transbronchial needle aspiration (TBNA), either individually or in series, were compared and found to result in similar patient life expectancies. Two strategies, one using bronchoscopy and TBNA alone and the other using it in combination with CT, were consistently least expensive across a wide range of prior probabilities, test characteristics, and charges. The authors conclude that strategies for staging mediastinal involvement in NSCLC that rely on bronchoscopy and TBNA are preferable because they are least expensive.