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Laura Pacini,* Andrew D Jenks,* Simon Vyse,* Christopher P Wilding, Amani Arthur, Paul H Huang Division of Molecular Pathology, The Institute of Cancer Research, London, UK*These authors contributed equally to this workCorrespondence: Paul H HuangDivision of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UKTel +44 207 153 5554Email paul.huang@icr.ac.ukAbstract: Insertion mutations in exon 20 (Ex20ins) of the epidermal growth factor receptor (EGFR) gene are the largest class of EGFR mutations in non-small cell lung cancer (NSCLC) for which there are currently no approved targeted therapies. NSCLC patients with these mutations do not respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. A number of early phase clinical trials are currently underway to evaluate the efficacy of a new generation of TKIs that are capable of binding to and blocking Ex20ins. Although these agents have shown some clinical activity, patient responses have been restricted by dose-limiting toxicity or rapid acquisition of resistance after a short response. Here we review the current understanding of the mechanisms of resistance to these compounds, which include on-target EGFR secondary mutations, compensatory bypass pathway activation and acquisition of an EMT phenotype. Taking lessons from conventional EGFR inhibitor therapy in NSCLC, we also consider other potential sources of resistance including the presence of drug-tolerant persister cells. We will discuss therapeutic strategies which have the potential to overcome different forms of drug resistance. We conclude by evaluating recent technological developments in drug discovery such as PROTACs as a means to better tackle TKI resistance in NSCLC harbouring Ex20ins mutations.Keywords: EGFR, exon 20 insertions, poziotinib, lung cancer, drug resistance, PROTACs

Background: To describe the societal costs during one year of follow-up among older adults seeking chiropractic care due to a new episode of low back pain (LBP), and to determine what factors predict high societal costs in this population., Methods: Prospective cohort study, within chiropractic private practices (n = 38) in the Netherlands. 223 people ≥ 55 years of age with a new episode of LBP seeking chiropractic care participated. The primary outcome was total societal costs. High societal costs were defined as patients with costs in the top 20th percentile. The final prediction models were obtained using forward selection. Results were presented for the total population and stratified for retirement status. The model's prognostic accuracy (Hosmer-Lemeshow X 2 , Nagelkerke's R 2 ) and discriminative ability [area under the receiver operating curve (AUC)] were assessed, and the models were internally validated using bootstrapping., Results: The mean total annual societal cost per patient was €5297 [95% confidence interval (CI): 4191-6403]. The biggest cost driver was presenteeism (65% of total costs), and costs were higher among non-retired participants (€7759; 95% CI 6047-9470) than retired participants (€1892; 95% CI 1088-2695). In the total population, younger age [odds ratio (OR): 0.87 for each additional year; 95% CI 0.80-0.95], being male instead of female (OR 2.96; 95% CI 1.19-7.44), less alcohol intake (OR 0.49; 95% CI 0.20-1.19), working instead of retirement (OR 9.37; 95% CI 1.83-48.04), and more disability at baseline (OR 1.08; 95% CI 1.00-1.16) were found to be predictive of high societal costs. Working was found to be the strongest predictor for high societal costs. After internal validation, the model's fit was good, it's explained variance was moderate (28%) and their AUCs could be interpreted as moderate (0.85). For non-pensioners, the same predictive factors were identified as for the entire population. The costs for the retired participants showed too little variation to be able to predict high costs., Conclusions: This study estimated the mean total annual societal cost of older adults seeking chiropractic care due to a new episode of LBP at €5297 (95% CI 4191-6403).These costs were mainly due to high levels of presenteeism, and extensively differed based upon work status., (© 2024. The Author(s).)

Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbors unique genomic and transcriptomic alterations when compared to uterine leiomyoma (uLM), which may account for their distinct clinical behaviour. Here we undertake the first comparative proteomic analysis of IVLM and other smooth muscle tumours (comprising uLM, soft tissue leiomyoma and benign metastasizing leiomyoma) utilising data-independent acquisition mass spectrometry. We show that, at the protein level, IVLM is defined by the unique co-regulated expression of splicing factors. In particular, IVLM is enriched in two clusters composed of co-regulated proteins from the hnRNP, LSm, SR and Sm classes of the spliceosome complex. One of these clusters (Cluster 3) is associated with key biological processes including nascent protein translocation and cell signalling by small GTPases. Taken together, our study provides evidence of co-regulated expression of splicing factors in IVLM compared to other smooth muscle tumours, which suggests a possible role for alternative splicing in the pathogenesis of IVLM.

Objective: Chronic back pain (CBP) is responsible for considerable suffering across the world and is frequently associated with decreased functional capacity, quality of life, and substantial health care costs. Fear avoidance beliefs (FAB) comprise cognitions and fears about the potential for physical activities to produce pain and harm and are common among people with CBP. Collectively, research shows that FAB are frequently associated with low levels of physical activity, poorer work outcomes, and disability. Therefore, the purpose of this systematic review is to systematically locate and synthesize the current evidence regarding the effectiveness of psychological interventions on fear avoidance beliefs and fear avoidance behavior in patients with CBP., Design: A systematic literature search was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included the databases Web of Science, PubMed, Cochrane, CINAHL, Medline, and PsycINFO., Results: A total of 5,052 records were identified resulting in 2,448 documents after duplicates were removed. We screened 147 studies full text. Twenty-two studies were included in the qualitative synthesis. FAB were assessed by the Fear Avoidance Beliefs Questionnaire, the Tampa Scale of Kinesiophobia and the Avoidance Exercise Questionnaire. Interventions included cognitive behavior therapy (CBT), psychoeducation (PE), and other psychological approaches like motivational interviewing. Twelve of 22 studies demonstrated significant improvements in FAB for people with CBP who underwent a PE or CBT intervention or a different psychological approach., Conclusion: CBT and PE interventions are mainly used to address FAB among people with CBP. However, there is still inconsistent evidence as to which psychological interventions are most effective to treat FAB among people with CBP. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. FGFR aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with FGFR alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target FGFR gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer.

Background: Low back pain is a common condition among older adults that significantly influences physical function and participation. Compared to their younger counterparts, there is limited information available about the clinical course of low back pain in older people, in particularly those presenting for chiropractic care. Improving our understanding of this patient population and the course of their low back pain may provide input for studies researching safer and more effective care than is currently provided., Objectives: The primary objectives are to examine the clinical course over one year of pain intensity, healthcare costs and pain, functional status and recovery rates of low back pain in people 55 years and older who visit a chiropractor for a new episode of low back pain., Methods: An international prospective, multi-center cohort study with one-year follow-up. Chiropractic practices are to be recruited in the Netherlands, Sweden, United Kingdom and Australia. Treatment will be left to the discretion of the chiropractor. Inclusion/Exclusion criteria: Patients aged 55 and older who consult a chiropractor for a new episode of low back pain, meaning low back pain for the first time or those patients who have not been to a chiropractor in the previous six months. This is independent of whether they have seen another type of health care provider for the current episode. Patients who are unable to complete the web-based questionnaires because of language restrictions or those with computer literacy restrictions will be excluded as well as those with cognitive disorders. In addition, those with a suspected tumor, fracture, infection or any other potential red flag or condition considered to be a contraindication for chiropractic care will be excluded. Data will be collected using online questionnaires at baseline, and at 2 and 6 weeks and at 3, 6, 9 and 12 months., Discussion: This study, to our knowledge, is the first large-scale, prospective, multicenter, international cohort study to be conducted in a chiropractic setting to focus on older adults with low back pain consulting a chiropractor. By understanding the clinical course, satisfaction and safety of chiropractic treatment of this common debilitating condition in the aged population, this study will provide input for informing future clinical trials., Trial Registration: Nederlandse Trial Registrar NL7507.

Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)