41 research outputs found
Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma.
The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance
Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries
Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely
Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland
Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care
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Localization-based Signaling Pathway Dependence of ROS1 Fusions and a Novel Role for Ras in EML4-ALK-Driven Lung Cancer
Receptor tyrosine kinase (RTK) fusions are recently described drivers in lung adenocarcinoma that arise from chromosomal rearrangements, resulting in the C-terminal kinase domain of an RTK attached to a variety of N-terminal fusion partners. Here, we elucidate the importance of N-terminal partners of ROS1 and ALK fusions in driving oncoprotein localization and downstream signaling pathway activation. ROS1 gene fusions involve rearrangements with several 5’ genes, and we have discovered that the resultant N-terminal partner mediates the intracellular localization of the fusion. This localization, in turn, dictates which downstream pathways these fusions are able to engage, which determines signaling pathway dependency in ROS1 fusion-positive cells. We find that some ROS1 fusions are present on endosomes and are able to activate the RAS/MAPK pathway, while the most common fusion, CD74-ROS1, is found on the endoplasmic reticulum (ER), where it is unable to engage this pathway. Mislocalization of CD74-ROS1 from the ER to the endosome results in activation of the MAPK pathway by this fusion, demonstrating that localization is critical in driving downstream signaling pathway activation. These findings have clinical significance, as we reveal that ROS1 fusions that can activate MAPK form more aggressive tumors and are less responsive to the targeted ROS1 inhibitor crizotinib in vivo. The most common ALK fusion seen in lung cancer is EML4-ALK variant 1 (v1), and here we demonstrate that EML4-ALKv1 exists in intracellular non-membrane-associated clusters, and that this localization and cluster formation is dependent on oligimerization domains present within EML4. Additionally, we reveal that EML4-ALKv1 is able to engage the RAS/MAPK pathway despite the absence of a membrane, which runs counter to the canonical idea that RAS requires a membrane scaffold for downstream pathway activation. In summary, my findings demonstrate both the importance of N-terminal RTK fusion partners in driving downstream oncogenic signaling pathways, which may inform therapeutic approaches for treatment of ROS1 and ALK fusion-positive patients, and uncovers a novel signaling role for cytoplasmic RAS, representing a shift in how we understand a central node of signaling biology
Secrets of Drug Resistance in NSCLC Exposed by New Molecular Definition of EMT
Non-small cell lung carcinoma (NSCLC) metastasis and drug resistance has been associated with epithelial-to-mesenchymal transition (EMT). This study reports the development of a robust gene expression signature of EMT in NSCLC and reveals new insights into the key molecular events that underlie EMT and drug resistance in NSCLC