Cost-Effectiveness of Next-Generation Sequencing Versus Single-Gene Testing for the Molecular Diagnosis of Patients With Metastatic Non-Small-Cell Lung Cancer From the Perspective of Spanish Reference Centers.

Purpose: The aim of this study was to assess the cost-effectiveness of using next-generation sequencing (NGS) versus single-gene testing (SgT) for the detection of genetic molecular subtypes and oncogenic markers in patients with advanced non-small-cell lung cancer (NSCLC) in the setting of Spanish reference centers.

Methods: A joint model combining decision tree with partitioned survival models was developed. A two-round consensus panel was performed to describe clinical practice of Spanish reference centers, providing data on testing rate, prevalence of alterations, turnaround times, and treatment pathways.

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors.

The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration.

Multicenter Evaluation of the Idylla GeneFusion in Non-Small-Cell Lung Cancer.

Targeted therapy in lung cancer requires the assessment of multiple oncogenic driver alterations, including fusion genes. This retrospective study evaluated the Idylla GeneFusion prototype, an automated and ease-of-use (<2 minutes) test, with a short turnaround time (3 hours) to detect fusions involving ALK, ROS1, RET, and NTRK1/2/3 genes and MET exon 14 skipping. This multicenter study (18 centers) included 313 tissue samples from lung cancer patients with 97 ALK, 44 ROS1, 20 RET, and 5 NTRKs fusions, 32 MET exon 14 skipping, and 115 wild-type samples, previously identified with reference methods (RNA-based next-generation sequencing/fluorescence in situ hybridization/quantitative PCR).

Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods.

Clinical performance evaluation of the Idylla™ EGFR Mutation Test on formalin-fixed paraffin-embedded tissue of non-small cell lung cancer.

Background: Detection of epidermal growth factor receptor (EGFR) mutations in exons 18-21 is recommended in all patients with advanced Non-small-cell lung carcinoma due to the demonstrated efficiency of the standard therapy with tyrosine kinase inhibitors in EGFR-mutated patients. Therefore, choosing a suitable technique to test EGFR mutational status is crucial to warrant a valid result in a short turnaround time using the lowest possible amount of tissue material. The Idylla™ EGFR Mutation Test is a simple, fast and reliable method designed for the detection of EGFR mutations from formalin-fixed paraffin-embedded samples.

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma.

Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone.

Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.

Background: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour.

What's in a name? Molecular subclassification of sarcomas creates fresh challenges.

This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g.

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14).

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas.

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case.

CK19 expression in breast tumours and lymph node metastasis after neoadjuvant therapy.

Aims: Neoadjuvant therapy is used in many patients with breast cancer before surgery, with the aim of reducing the tumour size, allowing conservative resections. Sentinel node biopsy is a conservative procedure for handling the axilla in breast cancer; however, the use of this technique after neoadjuvant treatment is under discussion. For sentinel node assay, methods based on the detection of cytokeratin 19 (CK19) mRNA, such as one-step nucleic acid amplification (OSNA), are available.

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer.

The Hippo signaling pathway, a conserved regulator of organ size, has emerged as an important regulatory pathway in cancer. The final transducer effectors of this pathway in mammals are the oncoproteins TAZ and YAP1, which are transcriptional coactivators of target genes involved in cell proliferation and survival. TAZ has been previously reported to play a role in tumorigenesis in breast cancer, but detailed analyses of the different breast cancer phenotypes have not been conducted thus far.

Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry.

Background: Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals.

Characterization of human mesenchymal stem cells from ewing sarcoma patients. Pathogenetic implications.

Background: Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin.

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma.

Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas.

Oncogene alterations in endometrial carcinosarcomas.

Endometrial carcinosarcomas are aggressive neoplasias composed of high-grade carcinomatous and sarcomatous elements. The pathogenesis and specific genetic alterations underlying these tumors are still not well known. We analyzed alterations in oncogenes involved in the pathogenesis of endometrial carcinomas that might represent predictive markers for specific therapies.

MicroRNA-200 family modulation in distinct breast cancer phenotypes.

The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas.

Molecular events in endometrial carcinosarcomas and the role of high mobility group AT-hook 2 in endometrial carcinogenesis.

The molecular events implicated in the development of endometrial carcinosarcoma remain poorly understood. Using complementary DNA microarrays, we analyzed a group of 15 endometrial carcinosarcomas and compared their gene expression profiles with those obtained from a group of 23 endometrioid endometrial carcinomas. We demonstrated changes in the expression of genes modulating processes such as the epithelial to mesenchymal transition, muscle differentiation, the expression of cancer/testis antigens, and immune response in endometrial carcinosarcomas.

Cutaneous Hodgkin-type lymphoproliferative lesion associated with immunomodulatory therapy for ulcerative colitis.

Immunomodulatory drugs have demonstrated efficacy in the therapy against autoimmune diseases such as rheumatoid arthritis, Crohn's disease or ulcerative colitis. Tumor necrosis factor-α (TNF-α) represents a target molecule for the treatment of these entities. Use of monoclonal antibodies can block the proinflammatory function of TNF-α.

Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma.

Endometrial carcinosarcomas (ECSs) undergo a true epithelial-mesenchymal transition (EMT). The molecular determinants of the EMT in vivo are unclear, although a role for some miRNAs, mainly involving the miR-200 family, was recently suggested from in vitro cellular models. We analysed the microRNA (miRNA) signatures associated to EMT in human carcinosarcomas, and determined their relationships with EMT markers and repressors of E-cadherin transcription.

Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries.

Background: Atherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. There may be common molecular pathways sustaining this process. Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis.

Wilms' tumour: a complex enigma to decipher.

Wilms' tumour (WT) is the most common solid tumour of childhood. The molecular signalling pathways determining the origin and behaviour of WT are very complex and several genes in several loci may participate. This review tries to briefly compile recent works on the histology and on the molecular alterations that promote the genesis, development and behaviour of WT.

SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease.

Polymorphisms of the human Delta-5 (FADS1) and Delta-6 (FADS2) desaturase genes have been recently described to be associated with the level of several long-chain n-3 and n-6 polyunsaturated fatty acids (PUFAs) in serum phospholipids. We have genotyped 13 single nucleotide polymorphisms (SNPs) located on the FADS1-FADS2-FADS3 gene cluster (chromosome 11q12-13.1) in 658 Italian adults (78% males; mean age 59.