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Simple Summary: KRAS plays an important role in transmitting signals from growth factors on the outside of the cell to the cell nucleus. It regulates cell proliferation, growth, and survival. The activation of KRAS occurs in multiple tumour types, either directly due to a mutation in the KRAS gene or indirectly via other proteins in the pathway. KRAS was considered an undruggable protein due to its smooth surface, but a recent discovery of a specific pocket in its structure has led to the development of several inhibitors that target the G12C mutation. Two of these, sotorasib and adagrasib, have been approved in advanced non-small-cell lung cancer, and others are currently being tested in clinical trials. Cancer cells can limit the effect of KRAS G12C inhibitors by switching on other proteins or through the development of new resistance mutations; therefore, these inhibitors will likely be used in combination with other therapies to treat patients more effectively. Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed. [ABSTRACT FROM AUTHOR]

The article explores how homelessness may impact on the educational participation of children and young people in families living in emergency accommodation in Dublin. Many difficulties arise in terms of maintaining consistent schooling for children when they are part of a homeless family, including problems getting to and from school if living at a distance from their original schools, frequent changes in school and inadequate facilities and overcrowding in their temporary accommodation. Despite the many difficulties involved in maintaining children's regular school attendance, it is evident that school may represent the only stability for a child in an otherwise insecure and changing routine.

The article explores how homelessness may impact on the educational participation of children and young people in families living in emergency accommodation in Dublin. Many difficulties arise in terms of maintaining consistent schooling for children when they are part of a homeless family, including problems getting to and from school if living at a distance from their original schools, frequent changes in school and inadequate facilities and overcrowding in their temporary accommodation. Despite the many difficulties involved in maintaining children's regular school attendance, it is evident that school may represent the only stability for a child in an otherwise insecure and changing routine. [ABSTRACT FROM AUTHOR]

Introduction: The identification of genomic "targets" through next-generation sequencing (NGS) of patient's NSCLC tumors has resulted in a rapid expansion of targeted treatment options for selected patients. This retrospective study aims to identify the proportion of patients with advanced NSCLC in the Republic of Ireland whose tumors harbor actionable genomic alterations through broad NGS panel testing., Methods: Institutional review board approval was obtained before study initiation. Patients with NSCLC whose tumors underwent genomic testing through the largest available NGS panel at a nationally funded Cancer Molecular Diagnostics laboratory (St. James's Hospital) between June 2017 and June 2022 were identified. Patient demographics and tumor-related data were collected by retrospective review from all cancer centers in Ireland, referring to the Cancer Molecular Diagnostics laboratory. A total of 203 (9%) tumor samples were excluded due to insufficient neoplastic cell content. Genomic data were collected through retrospective search of Ion Reporter software. The spectrum and proportion of patients with oncogenic driver mutations were evaluated using descriptive statistics (SPSS version 29.0)., Results: In total, 2052 patients were identified. Patients were referred from 23 different hospital sites and all four geographic regions (Leinster = 1091, 53%; Munster = 763, 37.2%; Connacht = 191, 9.3%; Ulster = 7, 0.3%). Median age was 69 (range: 26-94) years; 53% were male. The most common tumor histologic subtype was adenocarcinoma (77%, n = 1577). An actionable genomic alteration was identified in 1099 cases (53%), the most common of which was KRAS (n = 657, 32%). Less frequently, NSCLC tumors harbored the following: MET exon 14 skipping (n = 53, 2.6%), MET amplification (n = 26, 1.3%), EGFR (n = 181, 8.8%), HER2 (n = 35, 1.7%), and  BRAF (n = 72, 3.5%) mutations. Fusions were detected in 76 patients (3.7%) including ALK (n = 44, 58%), RET (n = 11, 14.5%), ROS1 (n = 16, 21%), and FGFR3 (n = 5, 6.6%), whereas no NTRK fusion was identified. Co-alterations were detected in 114 patients (5.6%), the most common of which was KRAS / PIK3CA (n = 19, 17%), EGFR/PIK3CA (n = 10, 8.5%), and KRAS/IDH1 (n = 9, 8%). Other co-alterations of interest identified included KRAS G12A/ROS1 fusion (n = 1) and KRAS G12C/BRAF G469A (n = 2)., Conclusions: This is the first retrospective study to comprehensively characterize the genomic landscape of NSCLC in Ireland, using the broadest available NGS panel. Actionable alterations were identified in 53.4% of the patients, and KRAS was the most common oncogenic driver alteration. Our study revealed a lower prevalence of patients whose tumor harbors ALK , ROS1 , and RET fusions, compared with similar data sets., Competing Interests: R Keogh has received support for attending meetings from Janssen and Merck Sharp & Dohme. McMahon has received grants or contracts from 10.13039/100004319Pfizer and 10.13039/100004337Roche; consulting fees, payments, or honoraria from Pfizer; and support for attending meetings and/or travel from Pfizer and Takeda. Finn has participated on a data safety monitoring board or advisory board for Amgen, Illumina, Pfizer, and Roche; received consulting fees, payments, or honoraria from Amgen, AstraZeneca, Pfizer, and Revolution Medicines; have stocks/shares from Revolution Medicines; and received institutional support from Roche. Naidoo has received research funding from 10.13039/100004325AstraZeneca, 10.13039/100002429Amgen, 10.13039/100002491Bristol-Myers Squibb, Mirati, Roche/10.13039/100004328Genentech, Pfizer, 10.13039/100004336Novartis, Takeda, and 10.13039/100004326Bayer; consulting fees, payments, or honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Mirati, Roche/Genentech, Pfizer, Novartis, Takeda, NGM Pharmaceuticals, Kaleido Biosciences, Elevation Oncology, and Daiichi Sankyo; and having participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, AstraZeneca, and Daiichi Sankyo. The remaining authors declare no conflict of interest., (© 2024 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)