Genomic analysis of comprehensive next generation sequencing data to explore the criteria for MET amplification as an actionable biomarker in NSCLC.

Introduction: MET amplification (METamp) can be a de novo or acquired resistance driver; however, the definition of METamp that best captures patients who may respond to targeted therapy remains debated. We explored the genomic landscape of METamp NSCLC including degree of amplification, co-drivers, amplicon size, and outcomes to MET inhibitors.

Methods: Hybrid-capture NGS-based genomic profiling from 88,547 tissue and 12,428 liquid NSCLC samples were queried for METamp (copy number (CN) ≥ ploidy + 4, or amplification ratio (AmpRatio; [CN/sample ploidy] ≥ 3).

Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab.

Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis.

Landscape of potential germline pathogenic variants in select cancer susceptibility genes in patients with adult-type ovarian granulosa cell tumors.

Objective: The objective of this study was to assess the frequency of potential germline pathogenic variants that may contribute to risk of development of adult granulosa cell tumors (AGCT) given the paucity of germline testing guidelines for these patients.

Methods: This was a retrospective cross-sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022.

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.

Patients And Methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents.

Precision needle-punch tumor enrichment from paraffin blocks improves the detection of clinically actionable genomic alterations and biomarkers.

Background: While many molecular assays can detect mutations at low tumor purity and variant allele frequencies, complex biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) require higher tumor purity for accurate measurement. Scalable, quality-controlled, tissue-conserving methods to increase tumor nuclei percentage (TN%) from tumor specimens are needed for complex biomarkers and hence necessary to maximize patient matching to approved therapies or clinical trial enrollment. We evaluated the clinical utility and performance of precision needle-punch enrichment (NPE) compared with traditional razor blade macroenrichment of tumor specimens on molecular testing success.

Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results.

Aims: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible.

Methods And Results: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML).

Pan-Cancer Interrogation of Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.

Purpose: Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic variants and loss of heterozygosity (LOH) in a large pan-cancer analysis.

Effectiveness of Virtual Reality for Upper Extremity Function and Motor Performance of Children With Cerebral Palsy: A Systematic Review.

Importance: Research on the functional and motor performance impact of virtual reality (VR) as an intervention tool for children with cerebral palsy (CP) is limited.

Objective: To understand whether VR is an effective intervention to improve upper extremity (UE) function and motor performance of children diagnosed with CP.

Data Sources: Databases used in the search were EBSCOhost, One Search, PubMed, Cloud Source, CINAHL, SPORTDiscus, and Google Scholar.

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

Purpose: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types.

Experimental Design: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes.

Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic /, Germline , or Homologous Recombination Deficiency Signature.

Purpose: Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the / genes (g); however, clinical benefit has also been demonstrated in mBC with somatic / mutations (s) or germline mutations (g). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig).

Methods: A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record-derived clinical data was used.

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

Background: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models.

Methods: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D.

Effectiveness of Constraint-Induced Movement Therapy for Children With Hemiparesis Associated With Cerebral Palsy: A Systematic Review.

Importance: This systemic review synthesizes the existing literature to determine whether constraint-induced movement therapy (CIMT) is more effective than other approaches in improving upper extremity function in children diagnosed with hemiparesis associated with cerebral palsy (CP).

Objective: To advance the knowledge of the effectiveness of CIMT for occupational therapy practitioners by critiquing research conducted over the past 20 yr.

Data Sources: Databases used in the search were CINAHL, Health Source: Nursing/Academic Edition, PsycINFO, PubMed, Research Gate, and Google Scholar.

Microencapsulation of anthocyanins as natural dye extracted from fruits - A systematic review.

Anthocyanins are naturally colored compounds that can be extracted from plants, especially fruits. Their molecules are unstable under normal processing conditions; thus, they must be protected using modern technologies, such as microencapsulation. For this reason, many industries are searching for information from review studies to find the conditions that improve these natural pigments' stability.

Characterizing the treatment gap in the United States among adult patients with a new diagnosis of epilepsy.

Objective: Epilepsy is largely a treatable condition with antiseizure medication (ASM). Recent national administrative claims data suggest one third of newly diagnosed adult epilepsy patients remain untreated 3 years after diagnosis. We aimed to quantify and characterize this treatment gap within a large US academic health system leveraging the electronic health record for enriched clinical detail.

Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study.

Background: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle.

POU2AF3-rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2.

Gene fusions involving EWSR1 or FUS as the 5' partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature.

Novel approach to decision making for orphan drugs.

Background: Out of 185 orphan medicinal products (OMPs) registered in 2015-2021, a mere 110 (59 percent) were available to Czech patients, and only 54 (29 percent) were officially reimbursed. Moreover, this proportion has steadily decreased over time. After years of public debate induced by this unsatisfactory OMP patient access, the national viewpoint shifted toward creating a special pathway for the reimbursement of OMP.