Debridement for surgical wounds.

BACKGROUND: Surgical wounds that become infected are often debrided because clinicians believe that removal of this necrotic or infected tissue may expedite wound healing. There are numerous methods of debridement available, but no consensus on which one is most effective for surgical wounds. OBJECTIVES: To assess the effects of different methods of debridement on the rate of debridement and healing of surgical wounds. SEARCH METHODS: In October 2021, we searched the Cochrane Wounds Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL. To identify additional studies, we searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies, reviews, meta-analyses, and health technology reports. There were no restrictions on language, date of publication, or study setting. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people with a surgical wound that required debridement, and reported time to complete wound debridement or time to wound healing, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment using the RoB 1 tool, data extraction, and GRADE assessment of the certainty of evidence. MAIN RESULTS: In this fourth update, we identified one additional study for inclusion. The review now includes six studies, with 265 participants, aged three to 91 years. Five studies were published between 1979 and 1990 and one published in 2014. The studies were carried out in hospital settings in China, Denmark, Belgium, and the UK. Six studies provided six comparisons. Due to the heterogeneity of studies, it was not appropriate to conduct meta-analyses. Four studies evaluated the effectiveness of dextranomer beads/paste; however, each study used a different comparator (Eusol-soaked dressings, 10% aqueous polyvinylpyrrolidone, 0.1% chloramine-soaked packs, and silicone foam elastomer dressing). One study compared streptokinase/streptodornase with saline-soaked dressings, and one compared endoscopic surgical debridement with conventional 'open' surgical debridement. Five studies reported time to complete debridement (reported as time to a clean wound bed) and three reported time to complete healing. One study reported effect estimates (surgical debridement via endoscopy versus surgical debridement) for time to a clean wound bed and time to complete wound healing, and it was possible to calculate effect estimates for one other study (dextranomer paste versus silicone foam elastomer) for time to complete wound healing. For the other four studies that did not report effect estimates, it was not possible to calculate time to a clean wound bed or time to complete wound healing due to missing variance and participant exclusions. None of the included studies reported outcomes pertaining to proportion of wounds completely healed, rate of reduction in wound size, rate of infection, or quality of life. All studies had unclear or high risk of bias for at least one key domain. Dextranomer paste/beads (autolytic debridement) compared with four different comparators Four studies compared dextranomer paste or beads with Eusol-soaked gauze (20 participants), 10% aqueous polyvinylpyrrolidone (40 participants), 0.1% chloramine-soaked dressings (28 participants), or silicone foam elastomer (50 participants). There is very low-certainty evidence that there may be no clear difference in time to a clean wound bed between dextranomer beads and Eusol gauze. The study did not report adverse events. There is very low-certainty evidence that there may be no difference in time to a clean wound bed between dextranomer paste and 10% aqueous polyvinylpyrrolidone gauze. There was low-certainty evidence that there may be no difference in deaths and serious adverse events. There may be a difference in time until the wounds were clinically clean and time to complete wound healing between dextranomer paste and 0.1% chloramine favouring 0.1% chloramine, but we are very uncertain. There is low-certainty evidence that there may be no difference in deaths and serious adverse events. There is very low-certainty evidence that there may be no difference in time to complete healing between dextranomer beads and silicone foam elastomer. The study did not report adverse events. Streptokinase/streptodornase solution (enzymatic) compared with saline-soaked dressings One study (21 participants) compared enzymatic debridement with saline-soaked dressings. There is low-certainty evidence that there may be no difference in time to a clean wound bed or secondary suture between streptokinase/streptodornase and saline-soaked dressings. There is very low-certainty evidence that there may be no difference in deaths and serious adverse events. Surgical debridement via endoscopic ('keyhole') surgery compared with surgical debridement by 'open' surgery (the wound is opened using a scalpel) One study (106 participants) reported time to complete wound healing and time to a clean wound bed. There is low-certainty evidence that there may be a reduction in time to complete wound healing and very low-certainty evidence that there may be no difference in time to a clean wound bed with surgical debridement via endoscopy compared to 'open' surgical debridement. The study did not report adverse events. Overall, the evidence was low to very low-certainty for all outcomes. Five included studies were published before 1991 and investigated treatments that are no longer available. Worldwide production of dextranomer products has been discontinued, except for dextranomer paste, which is currently only available in South Africa. Furthermore, Eusol, used in one study as the comparator to dextranomer, is rarely used due to risk of harmful effects on healthy tissue and the enzymatic agent streptokinase/streptodornase is no longer available worldwide. AUTHORS' CONCLUSIONS: Evidence for the effects of different methods of debridement on complete wound debridement and healing of surgical wounds remains unclear. Adequately powered, methodologically robust RCTs evaluating contemporary debridement interventions for surgical wounds are needed to guide clinical decision-making.

Case report: Single-stage facial reanimation with bilateral lengthening temporalis myoplasties for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome related developmental facial palsy.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency, typically associated with clinical features of intractable diarrhoea, type 1 diabetes mellitus and eczema. We present a case of IPEX syndrome referred to our regional facial palsy service for smile restoration surgery. The patient presented with dissatisfaction of facial appearance, including mask-like facies and no functional smile. Pre-operative electromyography confirmed normal temporalis muscle activation. Consequently, the patient was offered single-stage bilateral lengthening temporalis myoplasties. The patient reported improved satisfaction with facial appearance. Surgery resulted in good early resting and voluntary symmetry. Oral commissures were elevated at rest improving oral incompetence. This is the first description of facial animation surgery in the context of IPEX syndrome. With careful consideration and patient selection, successful surgical restoration of resting symmetry and dynamic commissural smile can be achieved in this complex cohort of patients.

Stroke in the young.

PURPOSE OF REVIEW: The purpose of this review is to review recent findings regarding stroke epidemiology, etiologies, and treatment in children and young adults. RECENT FINDINGS: Incidence in young adults is increasing, and incidence, recurrence, and survival is worse in patients with cryptogenic stroke and in developing countries. Careful consideration of patent foramen ovale closure is now recommended in young adults with cryptogenic stroke. Thrombectomy has recently been extended to carefully selected children with acute ischemic stroke, and two recent publications strongly suggest that it can be beneficial for children. Sickle cell is also an important global contributor to stroke burden, but hydroxyurea can be a cost effective medication for stroke prevention in children. Recent advances in genetic testing and treatments may improve outcomes for patients with monogenic causes of stroke, such as deficiency of adenosine deaminase 2, hemophilia, and Fabry's disease. SUMMARY: Stroke in children and young adults is a morbid disease responsible for enormous indirect societal costs and a high burden of years with disability per affected patient. Recent advances have improved access to care for children with large vessel occlusion and adults with rare causes of stroke. Future research may bring effective treatments for other monogenic causes of stroke as well as increasing access to hyperacute therapies for young stroke patients.

Evaluating patient and neurosurgeon perspectives on virtualisation of neurosurgery clinics in the COVID-19 era: a prospective mirror survey study.

BACKGROUND: The COVID-19 pandemic has compelled a global shift in healthcare service delivery towards virtualisation, including in Neurosurgery. Our study aims to elucidate the patient and neurosurgeon perceptions of virtual neurosurgery consultations (VNCs) and formulate a guidance algorithm based on our experience. METHODS: Between June 2020 and December 2020, we prospectively surveyed patients and neurosurgeons following their VNCs using a 10-item survey (four qualitative and six five-point Likert scale questions). Non-parametric hypothesis testing and grounded coding with inter-coder agreement was used to analyse quantitative and qualitative data, respectively. RESULTS: 106 patients and 10 neurosurgeons completed the survey. Wilcoxon rank-sum test revealed a statistically significant difference between the neurosurgeon and patient responses (p < 0.001). Patients perceived VNCs benefits to be enhanced efficiency (n = 142) and communication (28); and VNCs drawbacks as safety (46), technological (32), and administration (15) issues. Neurosurgeons perceived VNCs benefits to be enhanced efficiency (13), reduced COVID-19 exposure (2); and VNCs drawbacks as examination practicality (14), technological (6), and concerns for patients (6). Neurosurgeons perceived the relative indications for VNCs as postoperative follow-up clinics, and scan result discussions; and relative contraindications as neuro-oncology, new patients, and patients with worsening neurological symptoms. CONCLUSIONS: Our mirror-survey study provides preliminary evidence that VNCs render increased efficiency, communication, and safety in the current COVID-19 era. Going forward, we believe that further improvements in technology and administration are necessary, greater neurosurgeon appreciation of the patient-perceived benefits of VNCs is required, and neurosurgeons are to exercise clinical discernment on when to use VNCs.Key PointsWhat are the perceptions of patient and consultant neurosurgeons towards virtual neurosurgery consultations (VNCs)?Patient-perceived benefits of VNCs: enhanced efficiency/communication; VNC drawbacks: safety, technological, and administration issues. Neurosurgeon-perceived VNCs benefits of VNCs: enhanced efficiency, reduced COVID-19 exposure; VNC drawbacks: examination practicality, technological, and concerns for patients.Post-operative reviews and scan result discussions are perceived relative indications for VNCs; whereas new patient consultations, neuro-oncology and patients with new-onset neurological deficits are perceived relative contraindications for VNCs.Improvement in technology and administration is necessary; greater neurosurgeon appreciation of patient-perceived VNCs benefits is required, and neurosurgeons are to exercise clinical discernment on when to use VNCs.

An evaluation of pelvic floor disorders in a public and private healthcare setting.

INTRODUCTION AND HYPOTHESIS: The objectives were to determine whether a difference exists in the duration of pelvic floor disorder (PFD) symptoms among patients presenting to urogynecologists in two healthcare systems: private and county; and to elucidate differences in baseline characteristics, type of PFDs, symptom severity and management, stratified by healthcare plans. METHODS: A multi-center retrospective study was conducted including new patients presenting to three urogynecology clinics between March 2016 and May 2018: one private clinic (site A) and two public clinics in the same county healthcare system (sites B and C). Baseline data included age, race, BMI, parity, and comorbidities. Primary outcome was "time to presentation" defined as PFD duration in months. Secondary outcomes were symptom severity and PFD management, analyzed by healthcare setting and insurance type. RESULTS: A total of 1,055 private and 439 public patients were included. Patients in the public setting were younger (54 vs 61 years, p<0.001), largely Hispanic (76% vs 14%, p<0.001), of higher parity (4 vs 3, p=0.001), and had more comorbidities, with a predominance of county-funded healthcare plans. There was no difference in duration of symptoms between the public and private groups respectively (54 vs 56 months, p=0.94). Patients in the public setting had more severe urinary incontinence (3 vs 2 pads/day, p<0.001) and prolapse (stages 3-4, 71% vs 61%, p=0.004); however, they had lower rates of surgical management for stress incontinence and prolapse. Differences in fecal incontinence could not be evaluated owing to small sample size. CONCLUSIONS: Public patients presented younger with more severe symptoms but had lower rates of surgery for PFDs traditionally managed surgically.

Development of nanoparticle loaded microneedles for drug delivery to a brain tumour resection site.

Systemic drug delivery to the central nervous system (CNS) has been historically impeded by the presence of the blood brain barrier rendering many therapies inefficacious to any cancer cells residing within the brain. Therefore, local drug delivery systems are being developed to overcome this shortfall. Here we have manufactured polymeric microneedle (MN) patches, which can be anchored within a resection cavity site following surgical removal of a tumour such as isocitrate dehydrogenase wild type glioblastoma (GBM). These MN patches have been loaded with polymer coated nanoparticles (NPs) containing cannabidiol (CBD) or olaparib (OLA) and applied to an in vitro brain simulant and ex vivo rat brain tissue to assess drug release and distance of penetration. MN patches loaded with methylene blue dye were placed into a cavity of 0.6 % agarose to simulate brain tissue. The results showed that clear channels were generated by the MNs and the dye spread laterally throughout the agarose. When loaded with CBD-NPs, the agarose showed a CBD concentration of 12.5 µg/g at 0.5 cm from the MN insertion site. Furthermore, high performance liquid chromatography of ex vivo brain tissue following CBD-NP/MN patch insertion showed successful delivery of 59.6 µg/g into the brain tissue. Similarly, OLA-NP loaded MN patches showed delivery of 5.2 µg/g OLA into agarose gel at 0.5 cm distance from the insertion site. Orbitrap secondary ion mass spectrometry (OrbiSIMS) analysis confirmed the presence of OLA and the MN patch at up to 6 mm away from the insertion site following its application to a rat brain hemisphere. This data has provided insight into the capabilities and versatility of MN patches for use in local brain drug delivery, giving promise for future research.

Water T2 could predict functional decline in patients with dysferlinopathy.

BACKGROUND: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. RESULTS: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy.

BACKGROUND: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. METHODS: Quantitative MRI/31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers. RESULTS: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pHw , and remained, similar as to water T2 , abnormal for the whole study duration. Global thigh water T2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010). CONCLUSIONS: This multi-centre study has shown that quantitative MRI/31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes.

The impact of COVID-19 infection on hip fracture 30-day mortality.

Introduction: A novel virus, SARS-CoV-2, has caused a fatal global pandemic which particularly affects the elderly and those with comorbidities. Hip fractures affect elderly populations, necessitate hospital admissions and place this group at particular risk from COVID-19 infection. This study investigates the effect of COVID-19 infection on 30-day hip fracture mortality. Method: Data related to 75 adult hip fractures admitted to two units during March and April 2020 were reviewed. The mean age was 83.5 years (range 65-98 years), and most (53, 70.7%) were women. The primary outcome measure was 30-day mortality associated with COVID-19 infection. Results: The COVID-19 infection rate was 26.7% (20 patients), with a significant difference in the 30-day mortality rate in the COVID-19-positive group (10/20, 50%) compared to the COVID-19-negative group (4/55, 7.3%), with mean time to death of 19.8 days (95% confidence interval: 17.0-22.5). The mean time from admission to surgery was 43.1 h and 38.3 h, in COVID-19-positive and COVID-19-negative groups, respectively. All COVID-19-positive patients had shown symptoms of fever and cough, and all 10 cases who died were hypoxic. Seven (35%) cases had radiological lung findings consistent of viral pneumonitis which resulted in mortality (70% of mortality). 30% (n = 6) contracted the COVID-19 infection in the community, and 70% (n = 14) developed symptoms after hospital admission. Conclusion: Hip fractures associated with COVID-19 infection have a high 30-day mortality. COVID-19 testing and chest X-ray for patients presenting with hip fractures help in early planning of high-risk surgeries and allow counselling of the patients and family using realistic prognosis.

Barriers to Care Affecting Presentation to Urogynecologists in a Community Setting.

OBJECTIVE: To evaluate barriers to care for patients presenting to urogynecologists and determine how these barriers differ in private and public/county health care settings. METHODS: Standardized anonymous questionnaires were distributed from May 2018 to July 2018 to new patients presenting to a urogynecologist at three institutions: two private health care clinics (sites A and B) and one public/county hospital clinic (site C). Patients identified symptom duration, symptom severity, and factors inhibiting presentation to care from a list of barriers. Patients then identified the primary barrier to care. RESULTS: One hundred nine questionnaires were distributed, and 88 were submitted, resulting in an 81% response rate (31 from site A, 30 from site B, 27 from site C). In analysis of the private versus public setting, there was no statistical difference between age (58 years vs 57 years, P = 0.69), body mass index (28 vs 30, P = 0.301), symptom duration (24 months vs 16 months, P = 0.28), or severity respectively. When asked to identify the primary barrier to presentation, patients in the private setting stated they did not know to see a specialist (26.2%, P = 0.002), while patients in the public setting could not obtain a closer appointment time (22.2% vs 13.1%, P = 0.35. Additionally, patients in the public setting were more likely to cite lack of health care coverage as a barrier to care (18.5% vs 1.6%, P = 0.01). CONCLUSION: This study highlights barriers that can contribute to the disparity of care seen in our patient population. Efforts should be made to acknowledge and mitigate hindrances impacting access to care.

The impact of COVID-19 infection on hip fractures 30-day mortality.

Introduction: A novel virus, SARS-CoV-2 has caused a fatal global pandemic which particularly affects the elderly and those with co-morbidities. Hip fractures affect elderly populations, necessitate hospital admissions, and place this group at particular risk from COVID-19 infection. This study investigates the effect of COVID-19 infection on 30-day hip fracture mortality. Method: Data related to seventy-five adult hip fractures admitted to two units during March and April 2020 was reviewed. The mean age was 83.5 years (range 65-98 years) and most (53, 70.7%) were females. The primary outcome measure was 30-day mortality associated with COVID-19 infection. Results: The COVID-19 infection rate was 26.7% (20 patients), with a significant difference in the 30-day mortality rate in COVID-19 positive group (10/20, 50%) compared to COVID-19 negative group (4/55, 7.3%), with mean time to death of 19.8 days (95% confidence interval 17.0-22.5). The mean time from admission to surgery was 43.1 hours and 38.3 hours, in COVID-19 positive and COVID-19 negative groups, respectively. All COVID-19 positive patients had shown symptoms of fever and cough, and all ten cases who died were from hypoxia. Seven (35%) cases had radiological lung findings consistent with viral pneumonitis which resulted in mortality (70% of mortality). 30% (n = 6) contracted the COVID-19 infection in the community and 70% (n = 14) developed symptoms after hospital admission. Conclusion: Hip fractures associated with COVID-19 infection have a high 30-day mortality. COVID-19 testing and chest x-ray for patients presenting with hip fractures, helps in early planning of high-risk surgeries and allows counselling of the patients and family using realistic prognosis.

A systematically collated library of prescribing safety indicators for people with chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) have high levels of co-morbidity and polypharmacy placing them at increased risk of prescribing-related harm. Tools for assessing prescribing safety in the general population using prescribing safety indicators (PSIs) have been established. However, people with CKD pose different prescribing challenges to people without kidney disease. Therefore, PSIs designed for use in the general population may not include all PSIs relevant to a CKD population. The aim of this study was to systematically collate a library of PSIs relevant to people with CKD. METHODS: A systematic literature search identified papers reporting PSIs. CKD-specific PSIs were extracted and categorised by Anatomical Therapeutic Chemical (ATC) classification codes. Duplicate PSIs were removed to create a final list of CKD-specific PSIs. RESULTS: Nine thousand, eight hundred fifty-two papers were identified by the systematic literature search, of which 511 proceeded to full text screening and 196 papers were identified as reporting PSIs. Following categorisation by ATC code and duplicate removal, 841 unique PSIs formed the final set of CKD-specific PSIs. The five ATC drug classes containing the largest proportion of CKD-specific PSIs were: Cardiovascular system (26%); Nervous system (13.4%); Blood and blood forming organs (12.4%); Alimentary and metabolism (12%); and Anti-infectives for systemic use (11.3%). CONCLUSION: CKD-specific PSIs could be used alone or alongside general PSIs to assess the safety and quality of prescribing within a CKD population.

Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore.

BACKGROUND: Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. METHODS: In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. RESULTS: Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell-like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. CONCLUSION: Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.

The dystroglycan receptor maintains glioma stem cells in the vascular niche.

Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.

The humanistic burden of advanced non-small cell lung cancer (NSCLC) in Europe: a real-world survey linking patient clinical factors to patient and caregiver burden.

PURPOSE: Advanced non-small cell lung cancer (aNSCLC) impacts the lives of patients and their caregivers. This analysis examined the association between patient clinical characteristics and patient and caregiver humanistic burden. METHODS: Data for patients with aNSCLC and their informal caregivers in France, Germany and Italy, were collected between May 2015 and June 2016 via chart review and patient and caregiver surveys. Patients and caregivers completed validated instruments to evaluate their health state (EuroQol-5-dimensions-3-levels [EQ-5D-3L]), work and activity impairment (Work Productivity Activity Impairment [WPAI]) and health-related quality of life (HRQoL; European Organisation for Research and treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]). Caregivers also completed the Zarit Burden Interview (ZBI). Univariate and regression analyses were stratified by patient Eastern Cooperative Group Performance Status (ECOG-PS 0, 1, 2 or 3/4). RESULTS: In total, 1030 patients and 427 accompanying informal caregivers participated. Regression analyses indicated that patients reported lower EQ-5D-3L utility index, EQ-VAS and EORTC QLQ-C30 global health status and greater work and activity impairment with worsening ECOG-PS (all p < 0.05). Caregivers also reported greater activity impairment and higher ZBI scores with worsening ECOG-PS of the patient they were providing care for (all p < 0.05). CONCLUSIONS: As patients' functionality deteriorates as measured by the ECOG-PS, so do their outcomes related to health utility, work productivity, activity impairment and HRQoL. This deterioration is also reflected in increased caregiver burden and activity impairment. There is a need for interventions to maintain patients' physical function to relieve the humanistic burden of both patients and caregivers.

The Influence of Socio-economic Deprivation on Mobility, Participation, and Quality of Life Following Major Lower Extremity Amputation in the West of Scotland.

OBJECTIVE: Lower extremity amputation (LEA) is more common in people from lower socio-economic groups. This study examined this further by investigating the influence of socio-economic status on mobility, participation, and quality of life (QoL) after LEA. METHODS: Prospective data were gathered for all LEAs performed in one year in one Scottish Health Board, commencing March 2014. A postcode derived Scottish Index of Multiple Deprivation (SIMD) was applied by quintile (SIMD 1 = most deprived). Routine data were collected on the cohort of 171 patients; 101 participants consented and received postal questionnaires on QoL (EQ-5D-5L), participation (Reintegration to Normal Living Index [RNLI]), and mobility (Prosthetic Limb User Survey of Mobility), six (n = 67) and 12 months (n = 50) after LEA. RESULTS: The mean ± SD age of the cohort was 66.2 ± 11.4 years; 75% were male and 53% had diabetes. In total, 67% lived in SIMD 1 and 2 and 11.1% in SIMD 5. Sixty per cent had a transtibial amputation. Mortality was 6% at 30 days 17% at six, and 29% at 12 months. Those in SIMD 1 were significantly younger (62.9 years) than those in SIMD 5 (76.3 years). Significantly more participants with a transfemoral amputation (TFA) lived in SIMD 1 (44%) compared with SIMD 5 (11%) (p = .004). Participation was low (RNLI scores: 6 months = 55.7; 12 months = 56.6) and PLUS M scores suggested mobility was poor overall at six (39.1) and 12 months (38.9). Mean QoL was 0.37 at 6 months and 0.33 at 12 months. CONCLUSION: Although this study observed more LEAs in those from low socio-economic areas, it is impossible to conclude whether QoL after LEA is truly influenced by socio-economic status. There was an association between the disproportionately high rate of LEAs in SIMD groups 1 and 2 and the high prevalence of smoking, 61% vs. only 21% of those in the least deprived areas (SIMD 3, 4, and 5) being current smokers.

EphA3 Pay-Loaded Antibody Therapeutics for the Treatment of Glioblastoma.

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist.

Eph receptors have emerged as targets for therapy in both neoplastic and non-neoplastic disease, however, particularly in non-neoplastic diseases, redundancy of function limits the effectiveness of targeting individual Eph proteins. We have shown previously that a soluble fusion protein, where the EphA4 ectodomain was fused to IgG Fc (EphA4 Fc), was an effective therapy in acute injuries and demonstrated that EphA4 Fc was a broad spectrum Eph/ephrin antagonist. However, a very short in vivo half-life effectively limited its therapeutic development. We report a unique glycoengineering approach to enhance the half-life of EphA4 Fc. Progressive deletion of three demonstrated N-linked sites in EphA4 progressively increased in vivo half-life such that the triple mutant protein showed dramatically improved pharmacokinetic characteristics. Importantly, protein stability, affinity for ephrin ligands and antagonism of cell expressed EphA4 was fully preserved, enabling it to be developed as a broad spectrum Eph/ephrin antagonist for use in both acute and chronic diseases.

Nuclear factor one B (NFIB) encodes a subtype-specific tumour suppressor in glioblastoma.

Glioblastoma (GBM) is an essentially incurable and rapidly fatal cancer, with few markers predicting a favourable prognosis. Here we report that the transcription factor NFIB is associated with significantly improved survival in GBM. NFIB expression correlates inversely with astrocytoma grade and is lowest in mesenchymal GBM. Ectopic expression of NFIB in low-passage, patient-derived classical and mesenchymal subtype GBM cells inhibits tumourigenesis. Ectopic NFIB expression activated phospho-STAT3 signalling only in classical and mesenchymal GBM cells, suggesting a mechanism through which NFIB may exert its context-dependent tumour suppressor activity. Finally, NFIB expression can be induced in GBM cells by drug treatment with beneficial effects.

EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia.

Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation.