Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system’s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade ≥ 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669–61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments.

Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes.

In recent years, non-small cell lung cancer treatment has been revolutionized. EGFR tyrosine kinase inhibitors and our improved understanding of its alterations have driven new diagnostic strategies. Liquid biopsies have emerged as a useful tool in these contexts, showing potential utility in early diagnosis combined with low-dose CT scans, as well as potential in monitoring treatment response and predicting the development of patients. We studied the circulating tumor DNA (ctDNA) of 38 EGFR-mutated non-small cell lung cancer patients at diagnosis in different moments of their disease by liquid biopsy techniques. Our results show that mean overall survival was significantly lower when a liquid biopsy was positive for the detection of EGFR mutations compared with wild-type patients in their liquid biopsy in both univariate (29 ± 4 vs. 104 ± 19 months; p = 0.004) and multivariate analysis (p = 0.008). Taking this into consideration, liquid biopsies could be key to improving the control of this disease.

Over the last few decades, an increasing amount of information has been accumulated on biomarkers in non-small cell lung cancer (NSCLC). Despite these advances, most biomarkers have been identified in the adenocarcinoma histological subtype (AC). However, the application of molecular-targeted therapies in the prognosis and treatment of SCC in the clinical setting is very limited, becoming one of the main focus areas in research. Here, we prospectively analyzed the frequency of numerical/structural abnormalities of chromosomes 5, 7, 8, 9, 13 and 22 with FISH in 48 pulmonary SCC patients. From a total of 12 probes, only abnormalities of the 7p12 and 22q12 chromosomal regions were identified as unique genetic variables associated with the prognosis of the disease. The study for these two chromosomal regions was extended to 108 patients with SCC. Overall, chromosome losses were observed more frequently than chromosome gains, i.e., 61% versus 19% of all the chromosome abnormalities detected. The highest levels of genetic amplification were detected for the 5p15.2, 7p12, 8q24 and 22q11 chromosome bands, of which several genes are potentially involved in the pathogenesis of SCC, among others, include the EGFR gene at chromosome 7p12. Patients who displayed EGFR amplification (n = 13; 12%) were mostly older than 65 years (p = 0.07) and exclusively patients in early T-primary tumor stage (pT1–pT2; p = 0.03) with a significantly shortened overall survival (OS) (p ≤ 0.001). Regarding prognosis, the clinical, biological, and histopathologic characteristics of the disease that displayed a significant adverse influence on OS in the univariate analysis included patients older than 65 years (p = 0.02), the presence of lymph node involvement (p = 0.005), metastasis (p = 0.01) and, visceral pleural invasion (VPI) at diagnosis (p = 0.04). EGFR amplification also conferred an adverse impact on patient OS in the whole series (p = 0.02) and especially in patients in early stages (pT1–pT2; p = 0.01). A multivariate analysis of the prognostic factors for OS showed that the most informative combination of independent variables to predict an adverse outcome was the presence of VPI and/or EGFR amplification (p < 0.001). Based on these two variables, a scoring system was built to stratify patients into low- (no adverse features: score 0; n = 69), intermediate- (one adverse feature: score 1; n = 29) and high-risk (two adverse features: score 2; n = 5) groups, with significantly different (p = 0.001) OS rates at 50 months, which were as following: 32%, 28% and 0%, respectively. In the present study, we show that the presence of a high level of 7p12 (EGFR) amplification, exclusively detected in early stage SCC (pT1–pT2), is an independent adverse prognostic factor for OS. The identification of the EGFR gene copy number using FISH techniques may provide a more accurate diagnosis of high-risk populations after the complete resection of the primary tumor. When combined with VPI, three groups of pulmonary SCC were clearly identified that show the extent of the disease. This is of such importance that further prospective studies are necessary in larger series of SCC patients to be classified at the time of diagnosis. This could be achieved with the combined assessment of 7p12 amplification and VPI in primary tumor samples.

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers.

Introducción y objetivo: La punción aspiración con aguja fina es el método de elección para el diagnóstico del nódulo tiroideo, permitiendo discriminar entre lesiones malignas y benignas en un alto porcentaje de pacientes. Sin embargo, las categorías diagnósticas I (No diagnóstico o insatisfactorio) y III (Atipia o Lesión folicular de Significado Incierto) del Sistema Bethesda suponen un reto en el manejo de los nódulos tiroideos. El objetivo del presente trabajo es exponer las opciones de que se disponen en el momento actual para intentar incrementar la rentabilidad de estos diagnósticos. Síntesis: En primer lugar, el abordaje multidisciplinar de los casos, la posibilidad de seguimiento, la repetición de la punción aspiración, la complementación del diagnóstico incorporando técnicas inmunohistoquímicas o moleculares, y finalmente la posibilidad de realizar una biopsiacilindro. Conclusiones: Estas alternativas son especialmente útiles en la categoría diagnóstica III, mientras que se prefiere la opción de seguimiento o repetición de PAAF en la categoría diagnóstica I.