Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

BACKGROUND: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines. OBJECTIVES: To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC. SEARCH METHODS: We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021. SELECTION CRITERIA: We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement. MAIN RESULTS: Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting. AUTHORS' CONCLUSIONS: Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.

Screening for anaplastic lymphoma kinase (ALK) gene rearrangements in non-small-cell lung cancer in New Zealand.

BACKGROUND: Lung cancer is a major cause of death in New Zealand. In recent years, targeted therapies have improved outcomes. AIM: To determine the uptake of anaplastic lymphoma kinase (ALK) testing, and the prevalence, demographic profile and outcomes of ALK-positive non-small-cell lung cancer (NSCLC), in New Zealand, where no national ALK-testing guidelines or subsidised ALK tyrosine kinase inhibitor (TKI) therapies are available. METHODS: A population-based observational study reviewed databases to identify patients presenting with non-squamous NSCLC over 6.5 years in northern New Zealand. We report the proportion tested for ALK gene rearrangements and the results. NSCLC samples tested by fluorescence in situ hybridisation were retested by next generation sequencing and ALK immunohistochemistry. A survival analysis compared ALK-positive patients treated or not treated with ALK TKI therapy. RESULTS: From a total of 3130 patients diagnosed with non-squamous NSCLC, 407 (13%) were tested for ALK gene rearrangements, and patient selection was variable and inequitable. Among those tested, 34 (8.4%) had ALK-positive NSCLC. ALK-positive disease was more prevalent in younger versus older patients, non-smokers versus smokers and in Maori, Pacific or Asian ethnic groups than in New Zealand Europeans. Fluorescence in situ hybridisation, ALK immunohistochemistry and next generation sequencing showed broad concordance for detecting ALK-positive disease under local testing conditions. Among patients with ALK-positive metastatic NSCLC, those treated with ALK TKI survived markedly longer than those not treated with ALK TKI (median overall survival 5.12 vs 0.55 years). CONCLUSION: Lung cancer outcomes in New Zealand may be improved by providing national guidelines and funding policy for ALK testing and access to subsidised ALK TKI therapy.

Lower limb immobilisation and venous thromboembolism risk: combined case-control studies.

BACKGROUND: Evidence from randomised controlled trials shows that low-molecular-weight heparin is effective in reducing the risk of venous thromboembolism (VTE) in the clinical setting of temporary lower limb immobilisation. Despite this, international guidelines are non-committal in advocating the use of anticoagulation in this clinical scenario. We determined the risk of VTE associated with lower limb immobilisation and the proportion of VTE events associated with lower limb immobilisation by undertaking a secondary analysis of two case-control studies that had used a similar methodology. METHODS: We undertook logistic regression analysis to investigate the association of risk factors with VTE with the OR and 95% CIs for association between lower limb immobilisation and VTE the primary outcome variable. The proportion of VTE patients with lower limb immobilisation was also calculated. RESULTS: Cases comprised 396 patients aged 18-65 years with radiologically confirmed deep vein thrombosis or pulmonary embolism attending outpatient VTE clinics. Controls, also aged 18-65 years, comprised 197 inpatients in the coronary care unit and 200 outpatients treated for upper limb injuries in the fracture clinic. The OR for association between VTE and lower limb immobilisation was 73.1 (95% CI 10.1 to 530, p<0.001). In 62/396 (16%) cases, patients had undergone lower limb immobilisation within four weeks of their presentation with VTE, representing the most common potentially preventable cause of VTE in this sample. CONCLUSIONS: Lower limb immobilisation is associated with a markedly increased risk of VTE and represents the most common potentially preventable cause in the 18-65-year age group, being present in one in seven cases treated for VTE. Consideration should be given to pharmacological prophylaxis in patients with lower limb immobilisation to reduce the substantial burden of preventable VTE.

BRAF Inhibition in BRAFV600E-Positive Anaplastic Thyroid Carcinoma.

The efficacy of targeted monotherapy for BRAF(V600E)-positive anaplastic thyroid carcinomas (ATC) is not established. We report 2 cases of BRAF(V600E)-positive ATC treated with a BRAF inhibitor. A 49-year-old woman with a T4bN1bM0 ATC manifested symptomatic metastatic disease 8 weeks after radical chemoradiotherapy. Within 1 month of BRAF inhibitor monotherapy, a complete symptomatic response was observed, with FDG-PET scan confirming metabolic and radiologic response. Treatment was terminated after 3 months because of disease progression. The patient died 11 months after primary diagnosis. A 67-year-old man received first-line BRAF inhibitor for a T4aN1bM0 ATC. Within 10 days of treatment his pain had stabilized and his tumor had clinically halved in size. Stable disease was achieved for 11 weeks but the patient died 11 months after diagnosis because of disease progression. BRAF inhibitor monotherapy in ATC may obtain clinical benefit of short duration. Upfront combination therapy should be investigated in this patient subgroup.

New Treatment Options for ALK-Rearranged Non-Small Cell Lung Cancer.

OPINION STATEMENT: ALK rearrangements are present in 3-5% of patients with non-small cell lung cancer (NSCLC) and after epidermal growth factor receptor (EGFR) mutations represent the second molecular target in NSCLC to be validated through phase III clinical trials. The PROFILE 1014 international multicentre phase III trial demonstrated the superiority of crizotinib over standard chemotherapy, establishing crizotinib as standard first-line therapy for patients with advanced ALK-positive NSCLC and indicating the requirement for ALK testing to guide selection of optimal first-line therapy for non-squamous NSCLC. Despite impressive and durable responses, progression on treatment reflecting the development of acquired resistance is inevitable. There are several mechanisms of resistance including ALK kinase mutation or copy number gain, activation of bypass pathways and potentially pharmacokinetic failure of therapy (most commonly in CNS). A broad array of newer generation ALK inhibitors are in development that appear effective in the crizotinib-resistant setting including in patients with intracranial progression. These agents, including ceritinib and alectinib, have a higher potency against ALK kinase than crizotinib, activity against mutations that confer resistance to crizotinib and potentially improved CNS penetration. While in selected patients, continued therapy with crizotinib after local ablative treatments of oligo-progressive systemic or CNS disease may be an option, for many patients use of a newer generation compound will be effective. First-line treatment with newer generation ALK inhibitors may have potential advantages over sequential treatment after crizotinib; however, the optimal sequence of therapy with ALK inhibitors has not been determined and is being explored in ongoing phase III studies.

Comparative audit of oxygen use in the prehospital setting in acute COPD exacerbation over 5†years.

BACKGROUND: In 2009 the Wellington Free Ambulance implemented an education programme to reduce high concentration oxygen delivery to patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aim of this audit was to compare pre-hospital oxygen delivery to patients with AECOPD before and after the programme. METHODS: An audit of patients who presented to Wellington Regional Hospital by ambulance with an AECOPD in 2005 and then in 2010, after implementation of the education programme. Oxygen therapy was categorised as: HIGH, supplemental high concentration oxygen therapy ≥3 L/min and/or delivery via high concentration mask; NEB, high concentration oxygen only during nebuliser use; or LOW, neither of these. RESULTS: In 2005 those in the HIGH, NEB and LOW categories were 81 (75.0%), 18 (16.7%) and 9 (8.3%) of 108 identified patients. In 2010 those in the HIGH, NEB and LOW categories were 80 (44.0%), 61 (33.5%) and 41 (22.5%) of 182 identified patients. The proportions of patients in the three oxygen groups were significantly different between 2005 and 2010 (p<0.001). CONCLUSIONS: The proportion of patients administered supplemental high concentration oxygen therapy markedly decreased between 2005 and 2010 following implementation of the education programme. However, in 2010 more than half of the patients not managed with high concentration oxygen therapy were still exposed to high concentration oxygen through the use of oxygen-driven nebulisers. To reduce exposure to high concentration oxygen in AECOPD the use of air-driven nebulisers or metered dose inhalers with spacers is required.

Access to and Timeliness of Lung Cancer Surgery, Radiation Therapy, and Systemic Therapy in New Zealand: A Universal Health Care Context.

PURPOSE: Lung cancer is the biggest cancer killer of indigenous peoples worldwide, including Maori people in New Zealand. There is some evidence of disparities in access to lung cancer treatment between Maori and non-Maori patients, but an examination of the depth and breadth of these disparities is needed. Here, we use national-level data to examine disparities in access to surgery, radiation therapy and systemic therapy between Maori and European patients, as well as timing of treatment relative to diagnosis. METHODS: We included all lung cancer registrations across New Zealand from 2007 to 2019 (N = 27,869) and compared access with treatment and the timing of treatment using national-level inpatient, outpatient, and pharmaceutical records. RESULTS: Maori patients with lung cancer appeared less likely to access surgery than European patients (Maori, 14%; European, 20%; adjusted odds ratio [adj OR], 0.82 [95% CI, 0.73 to 0.92]), including curative surgery (Maori, 10%; European, 16%; adj OR, 0.72 [95% CI, 0.62 to 0.84]). These differences were only partially explained by stage and comorbidity. There were no differences in access to radiation therapy or systemic therapy once adjusted for confounding by age. Although it appeared that there was a longer time from diagnosis to radiation therapy for Maori patients compared with European patients, this difference was small and requires further investigation. CONCLUSION: Our observation of differences in surgery rates between Maori and European patients with lung cancer who were not explained by stage of disease, tumor type, or comorbidity suggests that Maori patients who may be good candidates for surgery are missing out on this treatment to a greater extent than their European counterparts.

Use of Novel National Data Sets to Monitor Chemotherapy Use and Outcomes: A Retrospective Cohort Study of Non-Small-Cell Lung Cancer in Aotearoa New Zealand.

PURPOSE: Te Aho o Te Kahu, the New Zealand Cancer Control Agency, is establishing a systemic anticancer therapy (SACT) database (Anti-Cancer Therapy-Nationally Organized Workstream [ACT-NOW]) which can be linked to other national health data collections. In this article, we explore the application of ACT-NOW data in the monitoring of uptake and outcomes after the public funding of pemetrexed in Aotearoa New Zealand. METHODS: We used the ACT-NOW collection to identify patients with advanced nonsquamous non-small-cell lung cancer, who were treated with first-line platinum-based doublet chemotherapy over an 8-year period. Data were extracted for a period of 4 years before and 4 years after the national funding of pemetrexed (November 1, 2017). Treatments were classified as historical platinum doublet (cisplatin or carboplatin with gemcitabine, vinorelbine, paclitaxel, or docetaxel) or platinum pemetrexed doublet (cisplatin or carboplatin with pemetrexed). The primary outcome was the proportion of patients receiving each treatment type, before and after November 1, 2017. To prototype linkage to outcomes data, we evaluated hospitalization and 1-year overall survival (OS) rates by treatment. RESULTS: A total of 331 patients were included from four cancer centers. All patients (116 of 116) who were treated with first-line platinum-based doublet chemotherapy between November 2013 and November 2017 received historical platinum doublet chemotherapy. After the introduction of pemetrexed, between November 2017 and November 2021, 94% (203 of 215) were treated with platinum pemetrexed doublet chemotherapy and 6% (12 of 215) with historical platinum doublet chemotherapy. Linkage to outcomes data for 1-year OS, hospitalization rates, and lengths of stay outcome data were achievable. CONCLUSION: The ACT-NOW data set has the potential to facilitate evaluation of the impact of national-level SACT funding decisions on prescribing practice and specific patient outcomes. Our results support the use of these data to inform resource planning and quality improvement.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Blending space and time to talk about cancer in extended reality.

We introduce a proof-of-concept extended reality (XR) environment for discussing cancer, presenting genomic information from multiple tumour sites in the context of 3D tumour models generated from CT scans. This tool enhances multidisciplinary discussions. Clinicians and cancer researchers explored its use in oncology, sharing perspectives on XR's potential for use in molecular tumour boards, clinician-patient communication, and education. XR serves as a universal language, fostering collaborative decision-making in oncology.

The risk of serious adverse outcomes associated with hypoxaemia and hyperoxaemia in acute exacerbations of COPD.

BACKGROUND: Prehospital high concentration oxygen therapy leads to worse clinical outcomes in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Less is known about the risks of hypoxaemia despite oxygen treatment. Current respiratory and ambulance guidelines recommend titration of supplemental oxygen to a target oxygen saturation range of 88%-92%. AIM: To explore the association between PaO(2) and risk of serious adverse clinical outcomes in AECOPD. METHODS: A retrospective review of consecutive patients presenting via ambulance to the Wellington Regional Hospital Emergency Department with AECOPD between June 2005 and January 2008. Patients with an arterial blood gas taken within 4 h of triage were included in the study and were categorised as hypoxaemic (PaO(2)<60 mm Hg), normoxaemic (PaO(2) 60-100 mm Hg) or hyperoxaemic (PaO(2)>100 mm Hg). Serious adverse outcome was defined as a composite of hypercapnic respiratory failure, assisted ventilation or inpatient death. Multivariate logistic regression analysis examined the association between PaO(2) category and the composite outcome. RESULTS: Of the 680 patients presenting with AECOPD in the review period, 254 presentations in 180 patients had data suitable for analysis. Hyperoxaemia occurred in 61/254 (24%) presentations and was strongly associated with serious adverse outcome compared with normoxaemia (OR 9.17, 95% CI 4.08 to 20.6). Hypoxaemia was also associated with an increased risk of serious adverse outcome compared with normoxaemia (OR 2.16, 95% CI 1.11 to 4.20). Compared with the recommended target oxygen saturation range of 88%-92%, the risk of a serious adverse outcome was increased in both the <88% group (OR 2.0, 95% CI 1.03 to 3.80) and the >96% group (OR 2.37, 95% CI 1.34 to 4.20). CONCLUSIONS: In patients presenting via ambulance to the Emergency Department with AECOPD, serious adverse clinical outcomes are associated with both hypoxaemia and hyperoxaemia. These data provide further support for the principle of titrating supplemental oxygen therapy to target oxygen saturations.

Osimertinib in NSCLC: Real-World Data From New Zealand.

INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) are more effective than chemotherapy in patients with EGFR-mutant NSCLC. Disease progression on EGFR TKI therapy occurs most often owing to acquired resistance from the gain of an EGFR T790M mutation. Osimertinib, a third-generation EGFR TKI, significantly improves outcomes in patients with EGFR T790M mutation-positive NSCLC compared with platinum-pemetrexed chemotherapy. We retrospectively reviewed clinical outcomes for patients receiving osimertinib through a compassionate access program in New Zealand. METHODS: Patients with a biopsy-proven or plasma-circulating tumor-DNA-proven EGFR T790M mutation received osimertinib. Data on patient and tumor characteristics, treatments, and outcomes were collected retrospectively. Survival outcomes were calculated from the time of osimertinib commencement. RESULTS: A total of 39 patients were enrolled, and data from 37 patients were analyzed. EGFR T790M status was found from plasma samples in six of 37 (16%) patients. A total of 27 of 37 patients (73%) used osimertinib as a second-line treatment. At the time of data analysis, median follow-up was 18.8 months (range 1.5-29). Overall response rate was 70% (95% confidence interval [CI]: 53-84) (26 of 37). Progression-free survival (PFS) at 12 months was 62% (95% CI: 44.8-77.5), and median PFS was 14.6 months (95% CI: 12.4-16.8). Median overall survival was not reached. Osimertinib was well tolerated, with grade 1 gastrointestinal and skin toxicity as the most common adverse effects. Three patients required dose adjustments or cessation owing to toxicity. CONCLUSION: Osimertinib is an effective treatment for New Zealanders with EGFR T790M mutated NSCLC who have progressed after first or subsequent lines of therapy.

Crizotinib Associated Renal Cysts [CARCs]: incidence and patterns of evolution.

BACKGROUND: Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. An increased incidence of renal cystic lesions, often with features concerning for malignancy or infection, has been reported in patients with anaplastic lymphoma kinase (ALK) - rearranged advanced non-small cell lung cancer (NSCLC) treated with Crizotinib. Many of these lesions undergo spontaneous resolution despite developing complex features on imaging. We assess the incidence and patterns of evolution of Crizotinib Associated Renal Cysts [CARCs] at our institute and provide histopathology correlation of their benign nature. METHODS: A retrospective analysis of renal lesions in computerised tomography (CT) scans of 35 patients with advanced ALK-rearranged NSCLC who had been prescribed crizotinib at our institution was performed by three radiologists, who analysed the evolution of these lesions, particularly for pre-defined significant and complex changes. RESULTS: Of 26 patients eligible for this analysis, 4 (15%) had cysts at baseline that remained stable on crizotinib treatment while 11(42%) developed significant change in 28 renal cysts. Commonest pattern of cyst evolution was enlargement from baseline followed by spontaneous regression (17/28 lesions) while other patterns noted were stable lesions, regression from baseline and ongoing enlargement. The median maximum size reached was 23 mm (range 9 - 67 mm) after a median of 178 days (160 to 1342) on crizotinib. Complex change occurred in 12 cysts, in 7/26 (27%) patients and within 60 days of starting Crizotinib in 10 cysts. Imaging features were falsely concerning for malignancy or abscess in 4/26 patients. CONCLUSION: Most CARCs resolve spontaneously, or have a benign evolution despite enlargement and other features concerning for malignancy or infection on imaging. This unusual manifestation of chemotherapy should be recognised, particularly by radiologists, so that inappropriate treatment decisions are avoided.

Venous thromboembolism risk associated with protracted work- and computer-related seated immobility: A case-control study.

OBJECTIVE: To examine the association between venous thromboembolism and prolonged work- and computer-related seated immobility. DESIGN: A case-control study. PARTICIPANTS AND SETTING: Cases were 200 patients attending venous thromboembolism clinics with a history of deep vein thrombosis and/or pulmonary embolism in the past six months, and controls were 200 patients treated in fracture clinic for an upper limb injury in the past six months. MAIN OUTCOME MEASURES: Logistic regression was used to estimate the association between venous thromboembolism and prolonged work- and computer-related seated immobility in the 28 days before the index event. Prolonged work- and computer-related seated immobility was defined firstly as a categorical variable with at least 10 h seated in a 24-h period, including at least 2 h without getting up; and secondly as the actual time spent seated in a 24-h period. RESULTS: Prolonged work- and computer-related seated immobility (categorical variable) was present in 36 (18%) cases and 31 (15.5%) controls. In multivariate analysis, there was no significant association between prolonged seated immobility and venous thromboembolism, odds ratio 1.18 (95% CI 0.56 to 2.48), P = 0.67. For the mean and maximum number of hours seated in a 24-h period, the odds ratios for the association per additional hour seated with venous thromboembolism were 1.08 (95% CI 1.01 to 1.6), P = 0.02 and 1.04 (95% CI 0.99 to 1.09), P = 0.08, respectively. CONCLUSION: This study found a weak association between venous thromboembolism and prolonged work- and computer-related seated immobility, with increasing mean hours seated associated with a higher risk of venous thromboembolism.

Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions.

Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC.

Delivery of titrated oxygen via a self-inflating resuscitation bag.

AIM: To investigate whether titration of inspired oxygen can be achieved through adjustment of oxygen flow into a self-inflating resuscitation bag with a reservoir of a type used in standard ambulance practice. METHODS: In a series of bench experiments, oxygen was delivered via a flow metre to a 1500 ml self-inflating resuscitation bag with a 2500 ml reservoir bag and connected to a test lung. The oxygen concentration delivered to the test lung by manual inflation of the resuscitation bag was measured using an anaesthetic machine while the delivered tidal volume was measured using a respirometer. The delivered oxygen concentration was measured at flows of 0.5, 2, 6, 12 and 15 l min(-1) for tidal volumes of 300, 600, and 900 ml with bag inflation rates of 10, 20 and 30 min(-1). RESULTS: A wide range of delivered oxygen concentrations ranging between 24% and 99.5% were achieved with different oxygen flows, tidal volumes, and inflation rates. Overall, the mean delivered oxygen concentration increased significantly with each of the increments of oxygen flow tested (p<0.001 for all comparisons). CONCLUSIONS: Effective titration of oxygen delivery can be achieved using adjustment of oxygen flow with a standard self-inflating resuscitation bag and reservoir.