Search

OBJECTIVES Safety-net hospitals disproportionately care for people with substance use disorders (SUDs), yet little is known about trends in hospital admissions related to specific substances. This study uses electronic health record data to describe trends in substance-specific admissions at a Midwest urban safety-net hospital. METHODS We included all admissions from 2008 through 2020 and defined them as non-SUD (N = 154,477) or SUD-related (N = 63,667). We described patient characteristics and trends in substance-specific admissions. We estimated the association of SUD diagnoses with discharge against medical advice and length of stay using logistic regression and generalized linear models. RESULTS Between 2008 and 2020, SUD-related admissions increased from 23.1% to 32.9% of total admissions. Admissions related to SUD had significantly more comorbidities than non-SUD-related admissions (4.7 vs 3.5, P

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

BACKGROUND Babesia microti has gained a foothold in Canada as tick vectors become established in broader geographic areas. B. microti infection is associated with mild or no symptoms in healthy individuals but is transfusion-transmissible and can be fatal in immunocompromised individuals. This is the first estimate of clinically significant transfusion-transmitted babesiosis (TTB) risk in Canada. STUDY DESIGN AND METHODS The proportion of B. microti-antibody (AB)/nucleic acid amplification test (NAT)-positive whole blood donations was estimated at 5.5% of the proportion of the general population with reported Lyme Disease (also tick-borne) based on US data. Monte Carlo simulation estimated the number and proportion of infectious red cell units for three scenarios: base, localized incidence (risk in Manitoba only), and donor study informed (prevalence from donor data). The model simulated 1,029,800 donations repeated 100,000 times for each. RESULTS In the base scenario 0.5 (0.01, 1.75), B. microti-NAT-positive donations would be expected per year, with 0.08 (0, 0.38) recipients suffering clinically significant TTB (1 every 12.5 years). In the localized incidence scenario, there were 0.21(0, 0.7) B. microti-NAT-positive donations, with 0.04 (0, 0.14) recipient infections (about 1 every 25 years). In the donor study informed scenario, there were 4.6 (0.3, 15.8) B. microti-NAT-positive donations expected, and 0.81 (0.05, 3.14) clinically significant TTB cases per year. DISCUSSION The likelihood of clinically relevant TTB is low. Testing would have very little utility in Canada at this time. Ongoing pathogen surveillance in tick vectors is important as B. microti prevalence appears to be slowly increasing in Canada.

Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.

Purpose Fire setters who have an intellectual disability (ID) are often identified as posing a particular danger to the community although relatively little is known about their characteristics, treatment and support needs. The paper aims to discuss this issue. Design/methodology/approach This study describes the characteristics of 134 residents of low, medium and high security ID facilities in the UK who have either an index offence of arson, a violent index offence or a sexual index offence. Findings Index arson offenders who had an ID had multiple prior convictions, a history of violent offending and a high likelihood of having a comorbid mental disorder. There were many shared characteristics across the three groups. Practical implications The current study suggests that offenders who have ID who set fires have treatment needs that are similar to those of violent and sex offenders. It follows that fire setters who have an ID may also benefit from participating in more established offending behaviour treatment programs, such as cognitive behaviour therapy programs, developed for other types of offender. Originality/value This study is one of the few which has investigated the characteristics and treatment needs of persons who have an ID who set fires. In particular, it is one of the first to compare the characteristics and treatment needs for persons with ID who set fires, to those who have committed violent and sexual offences.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2-6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2-15.0 months). In patients with known brain metastases (n = 132) versus patients without (n = 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8-5.5 months) versus 5.9 months (95% confidence interval, 4.8-7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7-12.4 months) versus 15 months (95% confidence interval, 11.1-20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAF V600-mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

Background Structured assessments have been shown to assist professionals to evaluate the risk of aggression in secure services for general offender populations and more recently among adults with intellectual disabilities. There is a need to develop intellectual disability sensitive measures for predicting risk of aggression in community samples, especially tools with a focus on dynamic variables. Methods The study prospectively followed 28 participants for up to 2 months to test whether the Current Risk of Violence (CuRV) and Short Dynamic Risk Scale (SDRS) were able to predict verbal and physical aggression in a community sample of adults with intellectual disability. Results CuRV and SDRS ratings significantly predicted verbal and physical aggression over a 2-month period. Conclusions The current study supports the use of the CuRV with adults with intellectual disability living in community settings. The CuRV and SDRS are worthy of future development and evaluation in independent investigations.

Introduction: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. Methods: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. Results: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Background Lyme disease is emerging in Canada due to expansion of the range of the tick vector Ixodes scapularis from the United States. National surveillance for human Lyme disease cases began in Canada in 2009. Reported numbers of cases increased from 144 cases in 2009 to 2025 in 2017. It has been claimed that few (

Of the 3,500 species of mosquitoes worldwide, only a small portion carry and transmit the mosquito-borne diseases (MBDs) that cause approximately half a million deaths annually worldwide. The most common exotic MBDs, such as malaria and dengue, are not currently established in Canada, in part because of our relatively harsh climate; however, this situation could evolve with climate change. Mosquitoes native to Canada may become infected with new pathogens and move into new regions within Canada. In addition, new mosquito species may move into Canada from other countries, and these exotic species may bring exotic MBDs as well. With high levels of international travel, including to locations with exotic MBDs, there will be more travel-acquired cases of MBDs. With climate change, there is the potential for exotic mosquito populations to become established in Canada. There is already a small area of Canada where exotic Aedes mosquitoes have become established although, to date, there is no evidence that these carry any exotic (or already endemic) MBDs. The increased risks of spreading MBDs, or introducing exotic MBDs, will need a careful clinical and public health response. Clinicians will need to maintain a high level of awareness of current trends, to promote mosquito bite prevention strategies, and to know the laboratory tests needed for early detection and when to report laboratory results to public health. Public health efforts will need to focus on ongoing active surveillance, public and professional awareness and mosquito control. Canadians need to be aware of the risks of acquiring exotic MBDs while travelling abroad as well as the risk that they could serve as a potential route of introduction for exotic MBDs into Canada when they return home.

There are currently over 80 species of mosquito endemic in Canada—although only a few of these carry pathogens that can cause disease in humans. West Nile virus, Eastern equine encephalitis virus and the California serogroup viruses (including the Jamestown Canyon and snowshoe hare viruses) are mosquito-borne viruses that have been found to cause human infections in North America, including in Canada. Over the last 20 years, the incidence of most of these endemic mosquito-borne diseases (MBD) has increased approximately 10% in Canada, due in large part to climate change. It is anticipated that both the mosquito lifecycle and virus transmission patterns will be affected by climate change, resulting in an increase in both the range and local abundance of several important mosquito species. Laboratory studies and mathematical modelling suggest that increased ambient temperatures, changes in precipitation and extreme weather events associated with climate change will likely continue to drive mosquito vector and MBD range expansion, increasing the duration of transmission seasons and leading to MBD-related epidemics. Furthermore, Canada’s endemic MBDs have complex transmission cycles, involving multiple reservoir hosts (birds and mammals), multiple pathogens and multiple mosquito species—all of which may be sensitive to climate and other environmental changes, and making forecasting of potential emerging trends difficult. These expected climate-induced changes in mosquitoes and MBDs underline the need for continued (and expanded) surveillance and research to ensure timely and accurate evaluation of the risks to the public health of Canadians.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Nursing Research grant Background Medication adherence is essential to improve health outcomes in patients with heart failure (HF). Depressive symptoms contribute to decrease adherence behaviors. Although social support is helpful to improving medication adherence, perceived social support (PSS) may differ by living arrangement. How social support and living arrangement contribute to the relationship between depressive symptoms and medication adherence is not well understood in patients with heart failure. Purpose The purpose of this study was to determine whether perceived social support and living arrangement moderated the association between depressive symptoms and medication adherence. Methods This was a secondary analysis from outpatients with HF. Depressive symptoms were measured by the Patient Health Questionnaire-9. Perceived social support was assessed using Multidimensional Scale of Perceived Social Support, and patients were grouped into high and low PSS groups using a score of 79, the upper tertile value. Medication adherence was measured objectively by a medication event monitoring system for 3-months. Living arrangement was classified as (1) living with a spouse, (2) living with non-spouse family or friend, or (3) living alone. Moderated moderation analysis was conducted using PROCESS macro (Model 3) in SPSS with 5,000 bootstrap samples. Results Of the total of 208 patients (mean age = 61 ± 11.5 years, 64% male), 60% lived with spouse, 22% lived with non-spousal family or friend, and 26% lived alone. Three-way interaction (depressive symptoms*living arrangement*PSS) was significant (p = 0.0324, Figure 1). The effect of depressive symptoms on medication adherence was only significant for two groups (Figure 2): the living alone group with high PSS (effect = - 4.1855, p = 0.0021), and the living with a non-spousal family group with low PSS (effect = -1.0180, p = 0.0349). For these groups, their depressive symptoms were inversely associated with medication adherence. Conclusions: These results suggest that living arrangement and perceived social support are factors to be considered in medication adherence when planning care for patients with depressive symptoms. Future research is needed to explore whether the combined intervention of improving depressive symptoms and social support focusing on instrumental social support effectively increases medication adherence.

Background Patients with severe SARS-CoV-2 infection have been shown to have abnormal coagulation parameters and are at increased risk of thromboembolism. The optimal thromboprophylaxis regimen that minimizes thrombosis without increased risk of serious bleeding is uncertain. Objectives To describe the efficacy and safety of increased intensity (enhanced) thromboprophylaxis in patients with COVID-19 admitted to the medical intensive care unit (MICU). Methods This is a retrospective cohort analysis of patients with a diagnosis of COVID-19 admitted to the MICU of an urban safety net hospital. With the exception of patients being supported with extracorporeal membrane oxygenation or on chronic anticoagulation who received therapeutic dosing of anticoagulation, thromboprophylaxis was given as either enoxaparin or unfractionated heparin in doses higher than those recommended for standard prophylaxis, but lower than those used for therapeutic anticoagulation. Main results Of the 120 patients managed with an enhanced thromboprophylaxis protocol, 6 (5%) experienced thromboembolism as a result of their COVID-19 disease (1 pulmonary embolus, 4 deep vein thromboses, and 1 arterial embolism). Four patients experienced major bleeding while receiving therapeutic anticoagulation. Conclusions In critically ill patients with COVID-19, increased intensity (enhanced) thromboprophylaxis appears to be effective at preventing clinically significant thromboembolic events without an increased risk of serious bleeding.

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRAS G12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered ‘undruggable’, several novel direct KRAS G12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.

Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors.The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.

Background: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication.Methods: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count. Data was collated, and Cox regression models, stratified by centre, explored the relationship between CTC count and survival. The added value of incorporating CTCs into clinico-pathological models was investigated using likelihood ratio tests.Results: A total of 367 patient records were evaluated. A one-unit increase in log-transformed CTC counts corresponded to an estimated hazard ratio (HR) of 1.24 (95% CI: 1.19-1.29, PConclusions: Higher pre-treatment CTC counts are a negative independent prognostic factor in SCLC when considered as a continuous variable or dichotomised counts of ≥15 or ≥50. Incorporating CTC counts, as a continuous variable, improves clinic-pathological prognostic models.

It is acknowledged that the COVID-19 pandemic has caused profound disruption to the delivery of healthcare services globally. This has affected the management of many long-term conditions including osteoporosis as resources are diverted to cover urgent care. Osteoporosis is a public health concern worldwide and treatment is required for the prevention of further bone loss, deterioration of skeletal micro-architecture, and fragility fractures. This review provides information on how the COVID-19 pandemic has impacted the diagnosis and management of osteoporosis. We also provide clinical recommendations on the adaptation of care pathways based on experience from five referral centres to ensure that patients with osteoporosis are still treated and to reduce the risk of fractures both for the individual patient and on a societal basis. We address the use of the FRAX tool for risk stratification and initiation of osteoporosis treatment and discuss the potential adaptations to treatment pathways in view of limitations on the availability of DXA. We focus on the issues surrounding initiation and maintenance of treatment for patients on parenteral therapies such as zoledronate, denosumab, teriparatide, and romosozumab during the pandemic. The design of these innovative care pathways for the management of patients with osteoporosis may also provide a platform for future improvement to osteoporosis services when routine clinical care resumes. Supplementary Information The online version contains supplementary material available at 10.1007/s00223-021-00858-9.

Context Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Summary We introduced a standardised reporting system in the radiology department to highlight vertebral fractures and to signpost fracture prevention services. Our quality improvement project achieved improved fracture reporting, access to the FLS service, bone density assessment and anti-fracture treatment. Purpose Identification of vertebral fragility fractures (VF) provides an opportunity to identify individuals at high risk who might benefit from secondary fracture prevention. We sought to standardise VF reporting and to signpost fracture prevention services. Our aim was to improve rates of VF detection and access to our fracture liaison service (FLS). Methods We introduced a standardised reporting tool within the radiology department to flag VFs with signposting for referral for bone densitometry (DXA) and osteoporosis assessment in line with Royal Osteoporosis Society guidelines. We monitored uptake of VF reporting during a quality improvement phase and case identification within the FLS service. Results Recruitment of individuals with VF to the FLS service increased from a baseline of 63 cases in 2017 (6%) to 95 (8%) in 2018 and 157 (8%) in 2019 and to 102 (12%) in the first 6 months of 2020 (p = 0.001). One hundred fifty-three patients with VFs were identified during the QI period (56 males; 97 females). Use of the terminology ‘fracture’ increased to 100% (mean age 70 years; SD 13) in computed tomography (n = 110), plain X-ray (n = 37) or magnetic resonance imaging (n = 6) reports within the cohort. Signposting to DXA and osteoporosis assessment was included in all reports (100%). DXA was arranged for 103/153; 12 failed to attend. Diagnostic categories were osteoporosis (31%), osteopenia (36%) or normal bone density (33%). A new prescription for bone protection therapy was issued in 63/153. Twelve of the series died during follow-up. Conclusions Standardisation of radiology reporting systems facilitates reporting of prevalent vertebral fractures and supports secondary fracture prevention strategies.

Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the ‘RASopathies’, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation–arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway., Highlights • RAS mutations have been associated with a range of malignancies and with developmental disorders called RASopathies. • Cancers associated with sporadic and germline RAS mutations are dissimilar in histological origins and mutational subtypes. • This disparity highlights our incomplete understanding of the relationship between the RAS–MAPK pathway and cancer. • Recent advances in targeting Ras G12C, HRAS and MEK have led to renewed interest in targeted therapies in this pathway.

Nocardiosis, a rare infection occurring mostly in immunosuppressed patients can present with neurological complications including cerebral abscess formation, and is associated with high morbidity and mortality. We describe the case of a 54-year-old immunocompetent man with cerebral nocardiosis, who presented with sudden onset hemiparesis in an acute medicine unit. He required three craniotomies with excision, following failure to respond to antimicrobial therapy, with subsequent clinical improvement and radiological resolution of multiple cerebral abscesses. Challenges in diagnosis and management of hemiparesis in the acute medical unit are discussed. Successful management of cerebral nocardiosis require early communication with a neurosurgical unit, neuropathology and microbiology services to optimise management with targeted antimicrobial therapy.

BACKGROUND The Armidilo has two scales-the risk scale and the protective scale. Research has been confined to the risk scale which appears to predict future incidents with medium to large effect sizes. There have been no publications on the use of the protective scale. METHODS The Armidilo was completed on four individuals with IDD who were either moving on from their placement or whose placement was in jeopardy because of new information or altered policies in the organization. The Armidilo was completed in the usual fashion. RESULTS Risk and protective results show that for each individual, recommendations could be made that ensured the best outcome. For two participants, restrictive placements were avoided because of the data on protective factors. CONCLSIONS The protective scale can be a powerful support for the clinician's case in offenders with IDD. The protective scale should be completed routinely for clinical evaluation.

The utilization of intramedullary devices in the surgical fixation of hip fractures is increasing. Although intramedullary devices offer many advantages in the treatment of these injuries, they are also associated with a unique set of potential complications, particularly during preparation of the femoral canal. Cardiac dysrhythmia resulting from reaming the femoral canal is rare and has not been previously described in detail in the literature. We present the case of a 69-year-old male with an infected right cephalomedullary femoral nail who underwent removal of hardware and experienced reproducible, transient asystolic cardiac arrest during reaming of the femoral canal and offer potential explanations for this event.

Background We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. Patients and methods 125 patients with treatment-naive stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. Results 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with

Background. The Dynamic Risk Assessment and Management System (DRAMS) was created to measure dynamic risk in individuals with intellectual disabilities (ID). Steptoe, Lindsay, Murphy, and Young, (2...

The duration and magnitude of clinical response are unpredictable in ALK-rearranged non–small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of ALK-rearranged patients. Thirty-nine ALK-rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively. Blood samples were collected at baseline and at an early time-point (2 months) on crizotinib. Aberrant ALK-FISH patterns were examined in CTCs using immunofluorescence staining combined with filter-adapted FISH after filtration enrichment. CTCs were classified into distinct subsets according to the presence of ALK-rearrangement and/or ALK-CNG signals. No significant association between baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed. However, we observed a significant association between the decrease in CTC number with ALK-CNG on crizotinib and a longer PFS (likelihood ratio test, P = 0.025). In multivariate analysis, the dynamic change of CTC with ALK-CNG was the strongest factor associated with PFS (HR, 4.485; 95% confidence interval, 1.543–13.030, P = 0.006). Although not dominant, ALK-CNG has been reported to be one of the mechanisms of acquired resistance to crizotinib in tumor biopsies. Our results suggest that the dynamic change in the numbers of CTCs with ALK-CNG may be a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients. Serial molecular analysis of CTC shows promise for real-time patient monitoring and clinical outcome prediction in this population. Cancer Res; 77(9); 2222–30. ©2017 AACR.

Summary We introduced an electronic triage system into our osteoporosis service to actively manage referral demand in a busy outpatient service. Our study demonstrated the effectiveness of e-triage in supporting alternative management pathways, through use of virtual advice and direct to investigation services, to improve patient access. Purpose Osteoporosis referrals are increasing with awareness of the potential for prevention of fragility fracture and with complex decision making around management with long-term bisphosphonate therapy. We examined whether active triage of referrals might improve referral management processes and patient access to osteoporosis services. Methods We implemented electronic triage (e-triage) of referrals to our osteoporosis service using the Northern Ireland electronic health care record. This included the option of ‘advice only’, direct to investigation with DXA or face-to-face appointments at the consultant-led complex osteoporosis service. We anticipated that there was scope to manage patient flow direct to investigation, or to provide referring clinicians with clinical advice without the need for a face-to-face assessment, at the consultant-led specialist service. Results We reviewed e-triage outcomes of 809 referrals (692 F; 117 M) to osteoporosis specialist services (mean age 65 ± 16.5 years) over a 12-month period. There was a high degree of agreement for the triage category between the referring clinician and specialist services (741/809). 73.3% attended a face-to-face appointment at the consultant-led clinic, while active triage enabled direct to investigation (18.4%) or discharge (8.3%) in the remainder. The mean time between receipt of an electronic referral and e-triage was 3 days over the 12-month period as compared with 2.1 days (median 1.1 days) when annual leave periods were excluded. Conclusion E-triage supports effective referral management in a busy osteoporosis service. Efficiency is limited by reliance on a sole clinician and 5 day working at present. There is scope to further improve systems access through multidisciplinary team working, virtual clinics and future information technology developments.

This article summarizes stroke rehabilitation, with a particular focus on rehabilitation from acute diagnosis to chronic impairments of stroke. The emphasis is on both pharmacologic and nonpharmacologic intervention and interdisciplinary collaboration.

Knowledge about the assessment of personality disorder (PD) in people with intellectual and developmental disabilities (IDD) has improved significantly in the last 15 years. Guidelines have been developed starting with recommendations by Alexander and Cooray (2003) that informant information, observation, and interview should be employed in a convergent assessment. Specific considerations should be given to the features of IDD itself such as delay in perspective taking abilities. While initial research found widely differing prevalence of PD in people with IDD, more recent research following guidelines, has been more consistent. It has also been demonstrated that PD has an orderly relationship with the assessment of general personality and with emotional problems. Recent alterations in the assessment of PD in the general population have been found suitable for people with IDD and it has also been found that generic services for this population are suitable for those with IDD and PD.

Regardless of efforts in improving helmet technologies, sport related concussions continue to be a problem. In an effort for advancing helmet liners, this research investigated a design comprised of interconnected fluid-filled cell structures that consist of a primary cell connecting to one or more secondary cells through a channel. When the primary cell undergoes impact, it deforms and pushes the fluid from the primary to secondary cells, which expand accordingly. This fluid motion absorbs the impact and dissipates energy, thereby reducing the force and acceleration transfer to a contacting body. Structures made with two hyper elastic polymers, silicone and polyurethane, were investigated in simulation and experimentation. For both materials, increasing the number of secondary cells in the structure will decrease the amount of force transfer and resulting acceleration. The optimized design, with one primary and two secondary cells, showed reduction of force by 25.2% and resulting acceleration of 80.7 m/s2 when using silicone, while cells made of polyurethane showed a 33.5% reduction of force and resulting acceleration of 72.5 m/s2. In comparison, a commercial liner (Vengeance DCT TPU Lateral Helmet Liner by Schutt® tested using the same test procedures, showed reduction in force by 24.3% and resulting acceleration of 87.0 m/s2.

Introduction/Background Neoadjuvant chemotherapy (NACT) is increasingly used in locally advanced or selected stage 4B endometrial cancer that is considered unsuitable for primary surgery, despite the lack of randomised evidence. In the West of Scotland Cancer Network (WoSCAN), NACT is offered to women with inoperable locally advanced disease or limited stage 4B disease (omental/peritoneal involvement and/or small volume lung metastases/pleural effusion). This study aimed to identify the proportion of patients proceeding to delayed primary surgery or interval debulking surgery following NACT for endometrial cancer and evaluate survival outcomes. Methodology Data were collected retrospectively from electronic clinical records of WoSCAN patients who commenced NACT between January 2012 and December 2016. Statistical analysis was performed using R®. OS was estimated using Kaplan-Meier method and Cox9s proportional-hazards models used to calculate unadjusted hazard ratios (HR). Results 54 patients were identified; median age was 67 years (range 36–85). All women had Stage III (57.4%) or IV (42.6%) disease. Pathological subtype consisted of serous (42.6%), endometrioid (31.5%), or other (25.9%). NACT regimen was almost exclusively Carboplatin/ Paclitaxel (92.6%); a median of 4 cycles were administered (range 1-6). 66.7% proceeded to surgery, 7.4% received primary (chemo)radiotherapy, and 25.9% received no definitive therapy. Of the 36 patients who underwent surgery, 83.3% received adjuvant radiotherapy. Data were censored in February 2018 at which time 33.3% were alive. Median OS was 31.12 months (95% CI 24.93–58.49); 40.8 months (95% CI 25.6 - Not reached) in the surgical cohort versus 18.6 months (95% CI 8.1–60.6) in patients who received NACT alone (HR 2.28 (95% CI 1.14–4.56)). Conclusion 66.7% of women proceeded to surgery following NACT. Median OS is significantly improved with surgery compared to NACT alone. NACT is a valid option in patients with advanced endometrial cancer who are not suitable for primary surgery. Disclosure Nothing to disclose.

Climate warming and other environmental changes have contributed to the expansion of the range of several tick species into higher latitudes in North America. As temperatures increase in Canada, the environment becomes more suitable for ticks and the season suitable for tick activity lengthens, so tick-borne diseases are likely to become more common in Canada. In addition to Lyme disease, four other tick-borne diseases (TBDs) have started to emerge and are likely to increase: Anaplasmosis; Babesiosis; Powassan virus; and Borrelia miyamotoi disease. Increased temperature increases the survival and activity period of ticks, increases the range of both reservoir and tick hosts (e.g. mice and deer) and increases the duration of the season when people may be exposed to ticks. Other ticks and TBDs may spread into Canada as the climate changes. The public health strategies to mitigate the impact of all TBDs include surveillance to detect current and emerging TBDs, and public health actions to prevent infections by modifying environmental and social-behavioral risk factors through increasing public awareness. Clinical care strategies include patient education, early detection, laboratory testing, and treatment.

Early warning systems to predict infectious disease outbreaks have been identified as a key adaptive response to climate change. Warming, climate variability and extreme weather events associated with climate change are expected to drive an increase in frequency and intensity of mosquito-borne disease (MBD) outbreaks globally. In Canada, this will mean an increased risk of endemic and emerging MBD outbreaks such as West Nile virus and other MBDs. The availability of timely information on the risk of impending MBD outbreaks has important public health implications, by allowing implementation of mosquito control measures and targeted communications regarding the need for increased personal protective measures-before an outbreak occurs. In Canada, both mechanistic and statistical weather-based models have been developed to predict West Nile virus outbreaks. These include models for different species of mosquitoes that transmit West Nile virus in different geographical areas of Canada. Although initial results have been promising, further validation and assessment of forecasting skill are needed before wide scale implementation. Weather-based forecasting for other emerging MBDs in Canada, such as Eastern equine encephalitis, may also be feasible.

OBJECTIVE To determine whether ganciclovir (GCV) treatment reduces sensorineural hearing loss in cytomegalovirus (CMV)-infected mice. The effects of GCV on viral load, absolute neutrophil count (ANC), and outer hair cell (OHC) integrity were also investigated. METHODS Infected BALB/c mice were inoculated with murine CMV on postnatal day 3. Those treated with GCV received an intraperitoneal injection twice a day for 14 days. Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing 4 weeks after inoculation. Temporal bones were used for determination of viral load by quantitative polymerase chain reaction and hair cell quantification by scanning electron microscopy. ANCs were completed by an automated hematology analyzer, with manual review for confirmation. RESULTS GCV-treated CMV-infected mice had lower ABR (P

Background: Osteopetrosis is a group of rare inherited skeletal dysplasias, with each variant sharing the hallmark of increased bone mineral density (BMD). Abnormal osteoclast activity produces overly dense bone predisposing to fracture and skeletal deformities. Whilst no cure for these disorders exists, endocrinologists play an important role in surveillance and management of complications. Clinical Cases: A 43-year-old female had findings suggestive of increased BMD on radiographic imaging performed to investigate shoulder and back pain. X-ray of lumbar spine demonstrated a ‘rugger jersey’ spine appearance, while shoulder X-ray revealed mixed lucency and sclerosis of the humeral head. DXA scan showed T-scores of +11 at the hip and +12.5 at the lumbar spine. MRI of head displayed bilateral narrowing and elongation of the internal acoustic meatus and narrowing of the orbital foramina. Genetic assessment confirmed autosomal dominant osteopetrosis with a CLCN7 variant. Oral colecalciferol supplementation was commenced and multi-disciplinary management instigated with referral to ophthalmology and ENT teams. A 25-year-old male presented with a seven-year history of low back pain and prominent bony swelling around the tibial tuberosities and nape of neck. Past medical history included repeated left scaphoid fracture in 2008 and 2018. Recovery from his scaphoid fracture was complicated by non-union requiring bone grafting with open reduction and fixation. Plain X-rays of the spine again demonstrated ‘rugger jersey’ spine. DXA scan was notable for elevated T scores; +2.9 at hip and +5.8 lumbar spine. MRI spine showed vertebral endplate cortical thickening and sclerosis at multiple levels. The patient declined genetic testing and is under clinical review. A 62-year-old male was referred to the bone metabolism service following a DXA scan showing T scores of +11. 7 at the hip and +13 at the lumbar spine. His primary complaint was of neck pain and on MRI there was multi-level nerve root impingement secondary to facet joint hypertrophy. Past medical history was significant for a long history of widespread joint pains; previous X-ray reports described generalized bony sclerosis up to 11 years previously. Clinical and radiological monitoring continues. Conclusion: Individuals with osteopetrosis require a multidisciplinary approach to management. There is no curative treatment and mainstay of therapy is supportive with active surveillance for complications.

SUMMARYWidespread access to the internet is offering new possibilities for data collection in surveillance. We explore, in this study, the possibility of using an electronic tool to monitor occurrence of the tick vector of Lyme disease, Ixodes scapularis. The study aimed to compare the capacity for ticks to be identified in web-based submissions of digital images/photographs, to the traditional specimen-based identification method used by the provincial public health laboratory in Quebec, Canada. Forty-one veterinary clinics participated in the study by submitting digital images of ticks collected from pets via a website for image-based identification by an entomologist. The tick specimens were then sent to the provincial public health laboratory to be identified by the ‘gold standard’ method using a microscope. Of the images submitted online, 74·3% (284/382) were considered of high-enough quality to allow identification. The laboratory identified 382 tick specimens from seven different species, with I. scapularis representing 76% of the total submissions. Of the 284 ticks suitable for image-based species identification, 276 (97·2%) were correctly identified (Kappa statistic of 0·92, Z = 15·46, P < 0·001). This study demonstrates that image-based tick identification may be an accurate and useful method of detecting ticks for surveillance when images are of suitable quality.

BackgroundThere is limited empirical information on service-level outcome domains and indicators for the large number of people with intellectual disabilities being treated in forensic psychiatric hospitals.AimsThis study identified and developed the domains that should be used to measure treatment outcomes for this population.MethodA systematic review of the literature highlighted 60 studies which met eligibility criteria; they were synthesised using content analysis. The findings were refined within a consultation and consensus exercises with carers, patients and experts.ResultsThe final framework encompassed three apriorisuperordinate domains: (a) effectiveness, (b) patient safety and (c) patient and carer experience. Within each of these, further sub-domains emerged from our systematic review and consultation exercises. These included severity of clinical symptoms, offending behaviours, reactive and restrictive interventions, quality of life and patient satisfaction.ConclusionsTo index recovery, services need to measure treatment outcomes using this framework.

PurposeOver the last ten years, there has been greater interest in the diagnosis of personality disorder (PD) in people with intellectual and developmental disabilities (IDD). One important characteristic of a diagnostic system is that it should have validity as a contribution to utility. PD has been found to have a predictive relationship with violence and the purpose of this paper is to review two methods for the diagnosis of PD in offenders with IDD in order to evaluate the utility of the diagnoses.Design/methodology/approachIn total, 212 offenders with ID were recruited from three settings – maximum-security, medium/low security and community services. Diagnoses of PD in the case files were compared with a structured system of diagnosis based on DSM-IV traits.FindingsThere were significant differences between the two systems with a significantly higher frequency of PD diagnosis in the community forensic setting in the structured assessment system. There was no relationship between the case files diagnosis of PD and future violence but there was a significant predictive relationship between the structured diagnosis of PD and future violence with an AUC=0.62.Research limitations/implicationsAs with all such studies, the research is limited by the quality of the case files available to the researchers.Practical implicationsOnly the structured assessment of PD had utility for the prediction of violence. Reasons for the differences between the systems are discussed and suggestions made on how a diagnosis of PD can be structured for the busy clinician.Social implicationsThe accurate diagnosis of PD has important implications since the PD is a crucial addition to any violence risk evaluation.Originality/valueThis study is the first of its kind to review the way in which clinicians assess PD.

SUMMARYEastern equine encephalitis (EEE) is a rare but severe emerging vector-borne disease affecting human and animal populations in the northeastern United States where it is endemic. Key knowledge gaps remain about the epidemiology of EEE virus (EEEV) in areas where its emergence has more recently been reported. In Eastern Canada, viral activity has been recorded in mosquitoes and horses throughout the 2000s but cases of EEEV in humans have not been reported so far. This study was designed to provide an assessment of possible EEEV human exposure by modelling environmental risk factors for EEEV in horses, identifying high-risk environments and mapping risk in the province of Quebec, Canada. According to logistic models, being located near wooded swamps was a risk factor for seropositivity or disease in horses [odds ratio (OR) 4·15, 95% confidence interval (CI) 1·16–14·8) whereas being located on agricultural lands was identified as protective (OR 0·75, 95% CI 0·62–0·92). A better understanding of the environmental risk of exposure to EEEV in Canada provides veterinary and public health officials with enhanced means to more effectively monitor the emergence of this public health risk and design targeted surveillance and preventive measures.

Introduction Lung cancer is the most common cause of cancer-related death. Carcinogenic and endogenous processes driving somatic mutation acquisition in cancer can be extracted and defined as mutational signatures using whole genome sequencing (WGS). Tobacco smoke is the main aetiological cause of lung cancer, with mutational signature 4 representing the characteristic C>A transversions produced by smoking. Whilst smoking cessation has been shown to reduce lung cancer risk in epidemiological studies, there has been little exploration into the persistence of smoking 4 in NSCLC genomes after a patient has quit smoking. We investigated the extent and persistence of signature 4 in NSCLC genomes of current, ex- and never-smokers, correlating in particular with clinical history of smoking cessation. Methods 132 NSCLC samples were resected from 131 patients in Greater Manchester. These samples were submitted to the 100,000 Genomes Project (Genomics England). WGS was performed on tumour specimens and matched blood samples. Data generated was processed by a standard pipeline devised by Genomics England. Tumour mutational burden (TMB), mutational signatures and copy number variation (CNV) were obtained. Clinical data collected included: smoking status, date of diagnosis, TNM stage, date of relapse and date of death (where relevant). Fisher's exact tests and Kruskal-Wallis tests were used for statistical comparisons, with Kaplan-Meier plots for survival. Results Signature 4 was associated with a smoking history in 102/119 (85.7%) NSCLCs with a detailed smoking history available. In 17/119 (14.3%) patients with a smoking history but no signature 4 NSCLC, 15/17 (88.2%) patients quit smoking a median of 22 years ago (range 0.006 - 45 years). 6/7 (85.7%) never-smoker NSCLCs were non-signature 4 NSCLCs. 60/75 (80%) ex-smokers had sufficient smoking data to assess signature 4 persistence. Signature 4 endured in the lung tissue prior to tumour diagnosis for a median of 180 months (15 years) (range 1 - 600 months). There was no association between the time of smoking cessation and the time to NSCLC diagnosis (R2=0.0009, p=0.82). Non-signature 4 NSCLCs had a more diverse signature profile (signature 4: mean 4.36, 95% CI 4.13-4.58; non-signature 4: mean 5.52, 95% CI 4.95-6.09; p= Conclusion The genomic alterations introduced by smoking persist for many years after smoking cessation. NSCLCs arising from smoking carry a distinctive identity compared to those from never-smokers, with higher TMBs driven primarily by signature 4. Whilst survival analysis is limited in this cohort, the pervasive contributions from smoking suggest that lung cancer screening programmes should include all patients with a smoking history. Citation Format: Pantelis A. Nicola, Shereen Rafee, George Burghel, Andrew Wallace, Helene Schlecht, Eleanor Baker, Katie Baker, Lynsey Priest, Mathew Carter, Sharzad Moghadam, Jane Rogan, Robert G. Bristow, William Newman, Fiona H. Blackhall, Colin Lindsay. Persistence of smoking signature 4 in the non-small cell lung cancer genome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3810.

Introduction: Kirsten rat sarcoma viral oncogene (KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), occurring in approximately 30% of cases. Recent work suggests KRAS -mutant (KRASm) NSCLC is a microcosm for diverse immune checkpoint inhibitor responses, partly dictated by its co-mutation with TP53 (“KP” group=~1/3 cases, “immune hot”), STK11 (“KL” group=~1/3 cases, “immune cold”) or CDKN2A (“KC” group=~1/3 cases). Here we identify and describe genomic and clinical associations of a further subset of KRASm NSCLC defined by “triple WT” status for common KRASm co-mutations. Method: Sequencing results from 364 early-stage NSCLC cases from the Cancer Research UK TRACERx program (whole-exome sequencing) and the Genomics England 100,000 genome program (whole-genome sequencing) were analyzed for KRASm, associated co-mutations in TP53, STK11 and CDKN2A, copy number changes in the RAS-RAF-MEK-ERK axis, tumor mutational burden (TMB) and mutational signatures. Clinical demographics and factors including tumor size, nodal status and stage were ascertained and assessed for statistical associations with sequencing data using the Mann-Whitney and Fisher’s exact tests. Results: Overall, 143/364 lung cancer cases (39%) were KRASm with 65/143 (45%) tumors identified as “KP,” 26/143 (18%) as “KL,” and 3/143 (2%) as “KC.” There were 49/143 KRASm cases (34%) with no co-mutation in TP53, STK11 or CDKN2A, defined as “triple wild-type” (triple WT). Relative to the KP, KL and KC genotypes, there was a positive association of the KRAS G12D mutation with triple WT status: 10/49 cases, 20%; KP/KL/KC: 6/94 cases, 6%; p=0.022). In the 100,000-genome cohort, TMB was similar for the triple WT and KL groups but significantly lower than that observed for KP (KP: median 10.55 mut/Mb, 95% CI 8.8-15.33; triple WT: median 6.96, 95% CI 4.87-12.53; p=0.036). Despite this lower median TMB, smoking-associated mutational signature 4 was common in triple WT tumors (triple WT: 13/14 pts, 93%; overall 76/114 pts, 67%). In the triple WT group overall, there was a reduction of >50% in cancers with copy number changes of NF1 and NRAS. There was an inverse association between pathologic stage III tumors and KRASm triple WT genotype (p=0.0014). Conclusion: There are a significant proportion of KRASm NSCLC patients whose tumors are triple WT for TP53, STK11 and CDKN2A. Despite their high frequency of smoking-associated mutational signatures, these tumors are characterized by low TMB and are more common in early-stage disease. They also associate more commonly with KRAS G12D. Our observations suggest a discrete KRASm subset that may have implications for stratification in trials of immune checkpoint inhibitors and/or targeted therapeutics of KRASm tumors. Citation Format: Colin R. Lindsay, Pantelis Nicola, Mariam Jamal-Hanjani, Andrew Wallace, Gareth Wilson, George Burghel, Helene Schlecht, Katie Baker, Eleanour Baker, Lynsey Priest, Jane Rogan, Sharzad Moghadam, Mathew Carter, Caroline Dive, Robert G. Bristow, Charles Swanton, William Newman, Fiona Blackhall. “Triple wild-type” co-mutational profile in early-stage KRAS-mutant lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B49.

The clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial.Baseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established.CTCs were detected in 60% (45/75) of patients (range 0-3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients.We report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making.ClinicalTrials.gov identifier: NCT00433563.

KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).

This study was supported by Cancer Research UK, AstraZeneca and Pfizer UK. Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx. Publisher PDF