EGFR mutation testing, treatment and survival in stage I-III non-small-cell lung cancer: CancerLinQ Discovery database retrospective analysis.

Aim: To describe real-world biomarker testing, treatment and survival in stage IA-IIIC non-small-cell lung cancer (NSCLC). Methods: Electronic records of USA-based patients in the CancerLinQ Discovery® database with stage IA-IIIC NSCLC (diagnosed between 2014 and 2018) were screened; a curated cohort of 14,452 records was identified for further analysis. Results: Of 3121 (21.6%) patients who had EGFR testing, 493 (15.8%) were EGFR-mutation positive. Of 974 patients who underwent surgical resection, 513 (52.7%) received adjuvant therapy. A quarter of patients with EGFR-mutation positive NSCLC received targeted adjuvant therapy. Conclusion: Approximately a fifth of patients underwent EGFR testing; biomarker testing is important to ensure optimal outcomes for patients with stage I-III NSCLC.

A study investigating how many patients with early-stage non-small-cell lung cancer (NSCLC) had mutations in a protein called EGFR and which treatments they received in routine clinical practice: The treatment recommended by medical experts for stage IA­IIIA non-small-cell lung cancer (NSCLC) is surgical removal of the growth (tumor). Patients with stage II or III, and some with stage IB disease, are recommended to receive treatment with medications such as chemotherapy or oral cancer treatments after surgery (adjuvant treatment). In some lung cancers, there are mutations in a protein called EGFR. Osimertinib, a drug that blocks the activity of mutated EGFR on cancer cells, reducing their growth and spread, is recommended as an adjuvant treatment for patients with EGFR-mutated, stage IB­IIIA NSCLC. This study aimed to understand how many patients with stage I­III NSCLC have tumors with EGFR mutations, and which treatments patients received in everyday clinical practice, before new medicines such as osimertinib (that treat EGFR-mutated NSCLC) were recommended. We looked at anonymous data from 14,452 patients with stage I­III NSCLC treated at cancer clinics in the USA between 2014 and 2018. We found that 3121 (21.6%) patients had an EGFR mutation test and 493 (15.8%) had EGFR-mutation positive NSCLC. Of patients who had surgery to remove the tumor, 55% received adjuvant therapy (treatment after surgery). It is important to perform EGFR mutation testing in patients with stage IB­IIIA NSCLC so that patients with EGFR-mutation positive NSCLC can receive appropriate treatment.

Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.

Estimating excess visual loss from neovascular age-related macular degeneration in the UK during the COVID-19 pandemic: a retrospective clinical audit and simulation model.

OBJECTIVES: To report the reduction in new neovascular age-related macular degeneration (nAMD) referrals during the COVID-19 pandemic and estimate the impact of delayed treatment on visual outcomes at 1 year. DESIGN: Retrospective clinical audit and simulation model. SETTING: Multiple UK National Health Service (NHS) ophthalmology centres. PARTICIPANTS: Data on the reduction in new nAMD referrals were obtained from four NHS Trusts comparing April 2020 with April 2019. To estimate the potential impact on 1-year visual outcomes, a stratified bootstrap simulation model was developed drawing on an electronic medical records dataset of 20 825 nAMD eyes from 27 NHS Trusts. MAIN OUTCOME MEASURES: Simulated mean visual acuity and proportions of eyes with vision ≤6/60, ≤6/24 and ≥6/12 at 1 year under four hypothetical scenarios: 0-month, 3-month, 6-month and 9-month treatment delays. Estimated additional number of eyes with vision ≤6/60 at 1 year nationally. RESULTS: The number of nAMD referrals dropped on average by 72% (range 65%-87%). Simulated 1-year visual outcomes for 1000 nAMD eyes with a 3-month treatment delay suggested an increase in the proportion of eyes with vision ≤6/60 from 15.5% (13.2%-17.9%) to 23.3% (20.7%-25.9%), and a decrease in the proportion of eyes with vision ≥6/12 (driving vision) from 35.1% (32.1%-38.1%) to 26.4% (23.8%-29.2%). Outcomes worsened incrementally with longer modelled delays. Assuming nAMD referrals are reduced to this level for 1 month nationally, these simulated results suggest an additional 186-365 eyes with vision ≤6/60 at 1 year. CONCLUSIONS: We report a large decrease in nAMD referrals during the COVID-19 lockdown and provide an important public health message regarding the risk of delayed treatment. As a conservative estimate, a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at 1 year.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Contextualizing single-arm trials with real-world data: An emulated target trial comparing therapies for neovascular age-related macular degeneration.

One-in-four ophthalmology trials are single-armed, which poses challenges to their interpretation. We demonstrate how real-world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 ETDRS letters by week 54. The findings suggest off-label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed trials when analyzed in accord to the target trial framework. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? One-in-four randomized controlled trials in ophthalmology are single-armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard-of-care arms representing the counterfactual intervention can be approximated with observational data. WHAT QUESTION DID THIS STUDY ADDRESS? How real-world cohorts representing the counterfactual intervention can aid the interpretation of single-armed ophthalmological trials. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed ophthalmological trials when undertaken in accord with the target trial framework. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval.

Colorectal cancer ascertainment through cancer registries, hospital episode statistics, and self-reporting compared to confirmation by clinician: A cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: Electronic health records are frequently used for cancer epidemiology. We report on their quality for ascertaining colorectal cancer (CRC) in UK women. METHODS: Population-based, retrospective cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Postmenopausal women aged 50-74 who were diagnosed with CRC during 2001-11 following randomisation to the UKCTOCS were identified and their diagnosis confirmed with their treating clinician. The sensitivity and positive predictive value (PPV) of cancer and death registries, hospital episode statistics, and self-reporting were calculated by pairwise comparisons to the treating clinician's confirmation, while specificity and negative predictive value were estimated relative to expected cases. RESULTS: Notification of CRC events were received for 1,085 women as of 24 May 2011. Responses were received from 61% (660/1,085) of clinicians contacted. Nineteen women were excluded (18 no diagnosis date, one diagnosed after cut-off). Of the 641 eligible, 514 had CRC, 24 had a benign polyp, and 103 had neither diagnosis. The sensitivity of cancer registrations at one- and six-years post-diagnosis was 92 (95% CI 90-94) and 99% (97-100), respectively, with a PPV of 95% (95% CI 92/93-97). The sensitivity & PPV of cancer registrations (at one-year post-diagnosis) & hospital episode statistics combined were 98 (96-99) and 92% (89-94), respectively. CONCLUSIONS: Cancer and death registrations in the UK are a reliable resource for CRC ascertainment in women. Hospital episode statistics can supplement delays in cancer registration. Self-reporting seems less reliable.

Unsettling the Settlers: Principles of a Decolonial Approach to Creating Safe(r) Spaces in Post-secondary Education.

In this paper we discuss the ongoing colonial relationship between Indigenous and non-Indigenous peoples in Canada with a consideration of how to align the principles and core values of community psychology in relation to Indigenous rights, decolonization, and social justice. In working with Community Psychology values to address issues of social justice it is necessary to recognize that empowerment alone is only one half of the solution. While our discipline focuses on oppression and the empowerment of vulnerable and disenfranchised populations we generally fail to consider the relational aspects of power and justice. Specifically, in recognizing power inequities the focus is often placed on empowerment among vulnerable or subjugated communities while neglecting the requisite counterbalance of consciousness-raising and de-powerment of dominant populations. The authors provide three personal accounts from a non-Indigenous faculty member, an Indigenous doctoral student, and a recently graduated non-Indigenous Masters student. We share our experiences of conscientization and decolonization within the post-secondary and graduate education systems. We describe an educational context, a pedagogical praxis, and our efforts to bridge the theories of Settler colonialism and community psychology. From our individual and collective reflections of engagement with decolonization in the education system we present an emergent framework that highlights four principles for decolonization. In implementing these principles we discuss the co-creation of safe(r), decolonized spaces within post-secondary institutions through deconstructing dominant narratives and illuminating Indigenous narratives of self-determination with attention to the de-powerment of non-Indigenous faculty and students.

Hip Arthroscopy for Femoroacetabular Impingement in a Military Population.

BACKGROUND: Femoroacetabular impingement (FAI) can lead to hip pain and early joint degeneration. There have been few reports to date on the outcomes of hip arthroscopy for the treatment of FAI in the military population. Purpose/Hypothesis: The purpose of this study was to compare patient demographics with postoperative outcomes after hip arthroscopy for symptomatic FAI and to identify preoperative risk factors for poor outcomes. The hypothesis was that certain preoperative patient characteristics will be predictive of poorer outcomes and that lower outcomes scores will be associated with a higher likelihood of medical separation from the military. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Retrospective chart review of active-duty and dependent patients older than 18 years who underwent hip arthroscopy for symptomatic FAI from 2009 to 2014 at a single institution. RESULTS: A total of 469 (309 males and 160 females) surgeries were performed on 456 active-duty personnel and 13 dependent civilians, with a mean 2.5-year follow-up. Overall, 39% (n = 179) were able to return to duty (RTD), 18% (n = 82) were medically cleared to return to normal daily activities but did not remain on active duty, and 43% (n = 195) required referral to the Disability Evaluation System (DES). Increasing rank and male sex were positive predictors and Axis 1 psychiatric diagnosis, revision surgery, concomitant psoas tenotomy, multiple medical comorbidities, and complaints of generalized pelvic pain were negative predictors for returning to duty. US Marine Infantry and Special Forces showed improved RTD rates (50%-86%) compared with administrative, more sedentary, occupations (22%). On average, Single Alpha Numeric Evaluation (SANE) and visual analog scale (VAS) scores improved after surgery, with SANE scores improving 37 ± 28 points and VAS scores improving 2.6 ± 2.5 points. The mean postoperative SANE and VAS scores differed significantly between the RTD group and those not returning to duty; 87 and 1.2 points compared with 69 and 3.6 points, respectively ( P < .0001). CONCLUSION: Hip arthroscopy for the treatment of symptomatic FAI effectively improves pain symptoms and self-reported overall function but shows a much lower than expected return to full, unrestricted active duty in the general active-duty military population. Underlying psychiatric diagnoses, female sex, and more sedentary occupations are associated with lower RTD rates. Furthermore, lower postoperative SANE and VAS scores are associated with lower RTD rates. Only the more active and elite components of the military study population showed RTD rates consistent with previously reported outcomes of return to competitive sports after hip arthroscopy for FAI.

Syndrome of acute anxiety among marines after recent arrival at high altitude.

Management of mental health is critical for maintenance of readiness in austere military environments. Emerging evidence implicates hypoxia as an environmental trigger of anxiety spectrum symptomatology. One thousand thirty-six unacclimatized infantry Marines ascended from sea level to the Marine Corps Mountain Warfare Training Center (2,061-3,383 m) for a 30-day exercise. Within the first 6 days of training, 7 servicemen presented with severe, acute anxiety/panic with typical accompanying signs of sympathetic activation and no classic symptoms of acute mountain sickness (including headache). Four had a history of well-controlled psychiatric diagnoses. Invariably, cardiopulmonary and neurological evaluations were unrevealing, and acute cardiopulmonary events were excluded within limits of expeditionary diagnostic capabilities. All patients responded clinically to oxygen, rest, and benzodiazepines, returning to baseline function the same day. The unexpected onset of 7 cases of acute anxiety symptomatology coincident with recent arrival at moderate-to-high altitudes represents a highly unusual incidence and temporal distribution, suggestive of hypobaric hypoxemia as the proximal cause. We propose acute hypoxic physiological anxiety (AHPA) as a unique member of the spectrum of altitude-associated neurological disorders. Recognition of AHPA is particularly relevant in a military population; warfighters with anxiety spectrum diagnoses may have a recognizable and possibly preventable vulnerability.

Colour-encoded paramagnetic microbead-based direct inhibition triplex flow cytometric immunoassay for ochratoxin A, fumonisins and zearalenone in cereals and cereal-based feed.

A combined (triplex) immunoassay for the simultaneous detection of three mycotoxins in grains was developed with superparamagnetic colour-encoded microbeads, in combination with two bead-dedicated flow cytometers. Monoclonal antibodies were coupled to the beads, and the amounts of bound mycotoxins were inversely related to the amounts of bound fluorescent labelled mycotoxins (inhibition immunoassay format). The selected monoclonal antibodies were tested for their target mycotoxins and for cross-reactivity with relevant metabolites and masked mycotoxins. In the triplex format, low levels of cross-interactions between the assays occurred at irrelevant high levels only. All three assays were influenced by the sample matrix of cereal extracts to some extent, and matrix-matched calibrations are recommended for quantitative screening purposes. In a preliminary in-house validation, the triplex assay was found to be reproducible, sensitive and sufficiently accurate for the quantitative screening at ML level. The triplex assay was critically compared to liquid chromatography-tandem mass spectrometry using reference materials and fortified blank material. Results for the quantification of ochratoxin A and zearalenone were in good agreement. However, the fumonisin assay was, due to overestimation, only suitable for qualitative judgements. Both flow cytometer platforms (Luminex 100 and FLEXMAP 3D) performed similar with respect to sensitivity with the advantages of a higher sample throughput and response range of the FLEXMAP 3D and lower cost of the Luminex 100.

High altitude headache and acute mountain sickness at moderate elevations in a military population during battalion-level training exercises.

Few studies have evaluated high altitude headache (HAH) and acute mountain sickness (AMS) in military populations training at moderate (1,500-2,500 m) to high altitudes (>2,500 m). In the current study, researchers interviewed active duty personnel training at Marine Corps Mountain Warfare Training Center. Participants were asked about HAH and AMS symptoms, potential risk factors, and medications used. In a sample of 192 U.S. Navy and Marine Corps personnel, 14.6% reported AMS (Lake Louise Criteria > or = 3) and 28.6% reported HAH. Dehydration and recent arrival at altitude (defined as data collected on days 2-3) were significantly associated with AMS; decreased sleep allowance was significantly associated with HAH. Although ibuprofen/Motrin users were more likely to screen positive for AMS, among AMS-positive participants, ibuprofen/Motrin users had decreased likelihood of reporting robust AMS relative to non-ibuprofen/Motrin users (p < 0.01). These results suggest that maintenance of hydration and adequate sleep allowance may be critical performance requirements at altitude. Further, ibuprofen/Motrin may be a reasonable treatment for the symptoms of AMS and HAH, although further study is warranted.