Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

Geometrical Measurement of Central Tumor Location in cT1N0M0 NSCLC Predicts N1 but Not N2 Upstaging.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC) and normal mediastinum, the central tumor location predicts occult nodal disease (both N1 and N2). We evaluated a novel definition of central location based on a geometrical measurement of the tumor location within the lung that could predict N2, N1, or both. METHODS: This retrospective study included patients with confirmed NSCLC, radiologically and metabolically staged T1 N0 M0, who underwent invasive mediastinal staging and/or lung resection. The central tumor location was measured considering 2 ratios. The inner margin ratio (IMR) and outer margin ratio (OMR) were both calculated as the distance from the inner margin of the lung to both margins of the tumor (inner [IMR], outer [OMR]) divided by the lung width. Optimal cutoffs for IMR and OMR were calculated. Tumors with values lower than the cutoffs were considered central. Prevalences of N1 and N2 upstaging were estimated and bivariate logistic regression analysis was performed to predict the odds of N1 and N2 upstaging using IMR and OMR cutoffs. RESULTS: A total of 209 patients were included. The prevalence of N1 and N2 upstaging was 11% and 5.3%, respectively. Cutoffs of 0.5 for IMR and 0.64 for OMR were estimated. Both ratios predicted N1 upstaging (adjusted odds ratio [95% confidence interval]: 4.2 [1.5-12]; P < .007; area under the curve, 0.65) but did not predict N2 upstaging. CONCLUSIONS: Central tumor location can be assessed by means of IMR and OMR and predicts N1 upstaging in patients with radiologically and metabolically T1 N0 M0 tumors. This is important for the selection of patients for therapies that require N0 tumors.

Nodal size ranking as a predictor of mediastinal involvement in clinical early-stage non-small cell lung cancer.

In non-small cell lung cancer (NSCLC) patients, the recommended minimum requirement for an endoscopy-based mediastinal staging procedure is sampling the largest lymph node (LN) in right and left inferior paratracheal, and subcarinal stations. We aimed to analyze the percentage of cases where the largest LN in each mediastinal station was malignant in a cohort of NSCLC patients with mediastinal metastases diagnosed in the lymphadenectomy specimen. Furthermore, we investigated the sensitivity of a preoperative staging procedure in a hypothetical scenario where only the largest LN of each station would have been sampled.Prospective data of patients with mediastinal nodal metastases diagnosed in the lymphadenectomy specimens were retrospectively analyzed. The long-axis diameter of the maximal cut surface of all LNs was measured on hematoxylin and eosin-stained sections.Seven hundred seventy five patients underwent operation and 49 (6%) with mediastinal nodal disease were included. A total of 713 LNs were resected and 119 were involved. Sixty seven nodal stations revealed malignant LNs: in these, the largest LN was malignant in 39 (58%). In a "per patient" analysis, a preoperative staging procedure that sampled only the largest LN would have attained a sensitivity of 0.67; and if the largest and the second largest were sampled, sensitivity would be 0.87.In patients with NSCLC, nodal size ranking is not reliable enough to predict malignancy. In clinical practice, regardless of the preoperative staging method, systematic thorough sampling of all visible LNs is to be recommended over selective random samplings.

[Usefulness of endoscopic ultrasound-guided fine needle aspiration in the diagnosis of mediastinal lesions]. / Valor de la punción aspirativa con aguja fina guiada por ultrasonografía endoscópica en el diagnóstico de las lesiones mediastínicas.

OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a safe and effective technique for the diagnosis of focal pancreatic lesions and enlarged abdominal lymph nodes. The aim of this study was to assess the usefulness of EUS-FNA in the diagnosis of mediastinal lesions. PATIENTS AND METHODS: A retrospective review was performed of all consecutive cases in which EUS-FNA was used for the diagnosis of a mediastinal lesion between January 2001 and September 2003. We used a radial echoendoscope to assess the characteristics of the lesion and a linear-array echoendoscope to perform transesophageal needle aspiration with a 22-gauge needle. Histopathology of the resected specimen was considered as the gold standard in surgically treated patients whereas cytology obtained by EUS-FNA was the gold standard when surgery was not indicated. RESULTS: EUS-FNA was performed in 59 patients with a total of 89 lesions with mean (SD) dimensions of 2.4 (2.0) cm x 1.6 (1.4) cm. Malignant lesions were larger than benign ones (short axis, 2.7 [1.4] as compared with 1.0 [0.9] cm; P< .001). The diagnosis was obtained for 53 patients (90%) and 81 lesions (91%) with a mean of 2 (1) passes per lesion. The sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of EUS-FNA were 81%, 100%, 100%, 75%, and 88%, respectively, when analyzed by lesion, and 88%, 100%, 100%, 80%, and 92% when analyzed by patient. CONCLUSIONS: EUS-FNA is an effective technique for the diagnosis of mediastinal lesions. The likelihood of malignancy increases with size.

Transesophageal ultrasound-guided fine needle aspiration improves mediastinal staging in patients with non-small cell lung cancer and normal mediastinum on computed tomography.

The aim of the current study was to prospectively assess the value of transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) in the mediastinal staging of patients with non-small cell lung cancer (NSCLC) and CT negative for lymph node (LN) metastases, candidates for surgical resection. EUS-FNA was performed using the standard technique and LNs with at least one morphological feature suggestive of malignancy were sampled. Pathological exam of surgical specimens or tumor positive cytology was used as gold standard. Forty seven patients were included, 21% of whom had advanced disease (pN2) undetected by CT. EUS-FNA demonstrated LN metastases in 50% of them (11% of the whole series), and there were no false positives, resulting in a sensitivity, specificity, positive and negative predictive values and accuracy of 50%, 100%, 100%, 88% and 89%, respectively. In conclusion, EUS-FNA improves mediastinal staging in patients with NSCLC and CT negative for mediastinal nodes. Therefore, EUS-FNA should be considered in any patient with NSCLC and no distant metastases before any therapeutic decision is taken.

Improvement in performance status after erythropoietin treatment in lung cancer patients undergoing concurrent chemoradiotherapy.

PURPOSE: A prospective Phase II trial was carried out to evaluate the effectiveness of erythropoietin in improving or maintaining performance status as determined by the Karnofsky performance status (KPS) score and hemoglobin (Hb) levels in lung cancer patients treated with concurrent chemoradiation (CH-RT). METHODS AND MATERIALS: A total of 51 patients with lung cancer (11 with small-cell, limited stage and 40 with non-small-cell disease, 17 with Stage IIIA and 23 with Stage IIIB), who underwent three different concurrent CH-RT protocols were enrolled. Baseline Hb and KPS values were recorded, as were the nadir Hb and KPS values before concurrent CH-RT. The final Hb and KPS values were recorded the last week of concurrent CH-RT. An Hb level of