Systematic review and meta‐analysis of the prognostic impact of lymph node micrometastasis and isolated tumour cells in patients with stage I–IIIA non‐small cell lung cancer

Lymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I-IIIA non-small cell lung cancer (NSCLC). The standard evaluation of a single haematoxylin and eosin (H&E) slide of a paraffin-embedded section of a lymph node is insufficient for the detection of micrometastases, and there is a need for additional histopathological evaluation. The association of lymph node micrometastases with survival remains as yet unresolved. The aim of this systematic review and meta-analysis is to investigate if lymph node micrometastases and isolated tumour cells in patients with stage I-IIIA NSCLC, detected with multiple sectioning and/or immunohistochemistry (IHC) and/or reverse transcriptase polymerase chain reaction (RT-PCR), are associated with overall survival (OS) and disease-free survival (DFS) after surgical resection. We performed a meta-analysis of time-to-event outcomes based on 15 articles using ancillary techniques to detect micrometastases. We extracted the OS and DFS every 3-6 months after surgery, for patients with and without occult lymph node micrometastasis, from the survival curves published in each article. These data were used to reconstruct OS and DFS for 'micrometastasis' and 'no micrometastasis' groups. Based on all included studies that used IHC, serial sectioning, or RT-PCR, we found a 5-year OS of 55% (micrometastasis) vs. 75% (no micrometastasis), and a 5-year DFS of 53% (micrometastasis) vs. 75% (no micrometastasis). Patients with stage I-IIIA NSCLC with lymph node micrometastases detected by ancillary histopathological and molecular techniques have a significantly poorer OS and DFS compared to patients without lymph node micrometastases.Analysis and Stochastic

Plasma predictive features in treating egfr-mutated non-small cell lung cancer

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrea

Defining oligometastatic non-small cell lung cancer

Objective: In this review, the concept of (synchronous) oligometastatic disease in patients with non-oncogene-driven non-small cell lung cancer (NSCLC) will be placed in the context of tumor biolo

Endobronchial ultrasound in diagnosing and staging of lung cancer by Acquire 22G TBNB versus regular 22G TBNA needles

Introduction Accurate diagnosis and staging of lung cancer is crucial because it directs treatment and prognosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound with bronchoscope fine-needle aspiration (EUS-B-FNA) are important in this process by sampling hilar/mediastinal lymph nodes and centrally located lung tumours. With the upcoming of immunotherapy and targeted therapies, assessment of programmed death ligand 1 (PD-L1) expression and molecular profiling has become important but is often impossible in cytological samples obtained through standard 22G TBNA needles. Recently, a three-pronged cutting edge 22G needle was developed that allows for transbronchial needle biopsy (TBNB). Our objective is to determine if EBUS/EUS-B-guided nodal/lung tumour sampling with Acquire 22G TBNB needles results in an improved suitability rate for the assessment of PD-L1 expression in comparison to standard 22G TBNA needles in patients with a final diagnosis of lung cancer. Methods and analysis This is an investigator-initiated, parallel group randomised clinical trial. Patients are recruited at respiratory medicine outpatient clinics of participating university and general hospitals in the Netherlands, Poland and Italy. In total 158 adult patients with (suspected) lung cancer are included if they have an indication for mediastinal/hilar lymph node or lung tumour sampling by EBUS-TBNA and/or EUS-B-FNA based on current clinical guidelines. Web-based randomisation between the two needles will be performed. Samples obtained from mediastinal/hilar lymph nodes and/or primary tumour will be processed for cytology smears and cell block analysis and reviewed by blinded reference pathologists. An intention-to-treat analysis will be applied. Patients with missing data will be excluded from analysis for that specific variable but included in the analysis of other variables. This study is financially supported by Boston Scientific. Ethics and dissemination The study was approved by the local Ethics Committee (Medisch Ethische Toetsingscommissie Amsterdam Medical Center (AMC)). Dissemination will involve publication in a peer-reviewed biomedical journal.</p

Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis

OBJECTIVE: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. METHODS AND RESULTS: No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. CONCLUSION: Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability

Clinical-Pathologic Challenges in the Classification of Pulmonary Neuroendocrine Neoplasms and Targets on the Horizon for Future Clinical Practice

Diagnosing a pulmonary neuroendocrine neoplasm (NEN) may be difficult, challenging clinical decision making. In this review, the following key clinical and pathologic issues and informative molecular markers are being discussed: (1) What is the preferred outcome parameter for curatively resected low-grade NENs (carcinoid), for example, overall survival or recurrence-free interval? (2) Does the WHO classification combined with a Ki-67 proliferation index and molecular markers, such as OTP and CD44, offer improved prognostication in low-grade NENs? (3) What is the value of a typical versus atypical carcinoid diagnosis on a biopsy specimen in local and metastatic disease? Diagnosis is difficult in biopsy specimens and recent observations of an increased mitotic rate in metastatic carcinoid from typical to atypical and high-grade NEN can further complicate diagnosis. (4) What is the (ir)relevance of morphologically separating large cell neuroendocrine carcinoma (LCNEC) SCLC and the value of molecular markers (RB1 gene and pRb protein or transcription factors NEUROD1, ASCL1, POU2F3, or YAP1 [NAPY]) to predict systemic treatment outcome? (5) Are additional diagnostic criteria required to accurately separate LCNEC from NSCLC in biopsy specimens? Neuroendocrine morphology can be absent owing to limited sample size leading to missed LCNEC diagnoses. Evaluation of genomic studies on LCNEC and marker studies have identified that a combination of napsin A and neuroendocrine markers could be helpful. Hence, to improve clinical practice, we should consider to adjust our NEN classification incorporating prognostic and predictive markers applicable on biopsy specimens to inform a treatment outcome-driven classification.</p