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Purpose Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. Methods M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. Results Among 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. Conclusion Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.

Alzheimer's disease and related dementias (ADRD) often result in communication deficits that can lead to negative health outcomes as well as complications for caregiving and clinical care. Although augmentative and alternative communication (AAC) devices have demonstrated efficacy in assisting persons living with dementia (PLWD) in communicating, few devices offer customization for the person's care preferences (e.g., clothing, food, activities) or are designed for integration into clinical care and caregiving. To address this issue, our research team is developing a novel electronic AAC prototype with a touchscreen to promote communication and personhood for PLWD. The current article describes the development of this technology and uses the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement to describe the clinical trial that is planned to test its efficacy. TARGETS: PLWD and their care partners. INTERVENTION DESCRIPTION: Use of AAC Plus to promote communication and personhood for PLWD. MECHANISMS OF ACTION: AAC Plus will provide PLWD and care partners a way to communicate PLWD's daily preferences and provide clinical data for health care providers. OUTCOMES: Determine whether enhanced communication of daily preferences of PLWD will improve quality of life of PLWD and their care partners. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04571502 (Date of registration October 1, 2020). [ Research in Gerontological Nursing, 14 (5), 225–234.]

Objective To review the currently available research into romantic partner involvement during oncology consultations. Methods Studies were identified via database searches plus hand-searching. A narrative review was performed using the principles of Thematic, and Framework syntheses. The search strategy was performed according to the principles of PRISMA. Results From 631 results, 18 studies were included. The findings indicate that romantic partners are most valued by patients when they provide emotional, practical, and informational support. It is also indicated that psychosocial and sexual concerns are rarely discussed. Couples’ self-reported satisfaction with consultations appear related to the extent of romantic partner involvement, the roles that they enacted, and the extent to which psychosocial and sexual concerns were addressed. Conclusion This review indicates that romantic partner involvement during clinical consultations enhances the couple’s experience. However, there are methodological limitations to this body of research, which are discussed in this review. Practice implications Research to date has yet to offer an exploration of the social practices and conversational actions relating to romantic partner involvement during triadic oncology consultations. Future studies that draw upon recordings of these consultations, using methods capable of analysing situated social practices can address this gap.

Background There is a need to improve consultations between patients with persistent musculoskeletal low back pain and orthopaedic spine clinicians when surgery is not indicated. Poor communication and lack of education about self- management in these consultations have been shown to be associated with increased distress and higher subsequent health care seeking. Aim To develop a standardised intervention to improve spine care consultations for patients for whom surgery is not beneficial. Method The intervention was developed in six stages. The first three stages included: interviews with patients, an interactive workshop with clinicians from a mix of disciplines, and interviews with spine clinicians about their perspective of the recommendations, their perceived difficulties and potential improvements. Information from these stages was synthesised by an expert panel, creating a draft intervention structure and content. The main features of the intervention and the materials developed were then reviewed by patients and spine clinicians. Finally, the research team incorporated the recommended amendments to produce the intervention. Results In total, 36 patients and 79 clinicians contributed to the development of the intervention. The final intervention includes three components: a pre-consultation letter with information suggesting that surgery is one possible intervention amongst many, introducing the staff, and alerting patients to bring with them a potted history of interventions tried previously. The intervention includes short online training sessions to improve clinicians’ communication skills, during the consultation, in reference to listening skills, validation of patients’ pain, and use of appropriate language. Clinicians are also supplied with a list of evidence-based sources for advice and further information to share with patients. Finally, post consultation, a follow up letter includes a short summary of the patients’ clinical journey, the results of their examination and tests, and a reminder of recommendations for self-management. Conclusion The intervention includes aspects around patient education and enhanced clinician skills. It was developed with input from a multitude of stakeholders and is based on patients’ perceptions of what they would find reassuring and empowering when surgery is excluded. The intervention has the potential to improve the patients care journey and might lead to changes in practice in spine clinicians.

ObjectiveThis study aimed to explore the perceptions of orthopaedic clinicians about consultations for people with persistent musculoskeletal low back pain (PMLBP) in which surgery is not recommended. Surgery is not recommended for the majority of PMLBP consulting in secondary care settings.SettingSecondary care sector in the UK.ParticipantsSemi-structured qualitative interviews were conducted with 24 orthopaedic team clinicians from 17 different hospitals in the UK and Ireland. Interviews explored clinicians’ perceptions of the challenges in consultations where surgery is not indicated. Interviews were transcribed verbatim and analysed using thematic analysis.ResultsTwo meta-themes, Difficulties and Enablers, each consisting of several subthemes were identified. Difficulties included challenges around the choice of appropriate terminology and labels for PMLBP, managing patients’ expectations, working with mentally vulnerable patients and explaining imaging findings. Enablers included early management of expectations, use of routine imaging, triaging, access to direct referral elsewhere, including other non-surgical practitioners in the team, training to improve communication skills and understanding of psychological issues.ConclusionThe findings highlight clinicians’ perceived need for concordance in messages delivered across the care pathway and training of orthopaedic clinicians to deliver effective reassurance and address patients’ needs in circumstances where surgery is not indicated.

Background Over the past decade, there has been an increase in the use of information technologies to educate and support people with dementia and their family caregivers. At the same time, chatbot technologies have become increasingly popular for use by the public and have been identified as having benefits for health care delivery. However, little is known about how chatbot technologies may benefit people with dementia and their caregivers. Objective This study aims to identify the types of current commercially available chatbots that are designed for use by people with dementia and their caregivers and to assess their quality in terms of features and content. Methods Chatbots were identified through a systematic search on Google Play Store, Apple App Store, Alexa Skills, and the internet. An evidence-based assessment tool was used to evaluate the features and content of the identified apps. The assessment was conducted through interrater agreement among 4 separate reviewers. Results Of the 505 initial chatbots identified, 6 were included in the review. The chatbots assessed varied significantly in terms of content and scope. Although the chatbots were generally found to be easy to use, some limitations were noted regarding their performance and programmed content for dialog. Conclusions Although chatbot technologies are well established and commonly used by the public, their development for people with dementia and their caregivers is in its infancy. Given the successful use of chatbots in other health care settings and for other applications, there are opportunities to integrate this technology into dementia care. However, more evidence-based chatbots that have undergone end user evaluation are needed to evaluate their potential to adequately educate and support these populations.

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

ObjectivesContextual components of treatment previously associated with patient outcomes include the environment, therapeutic relationship and expectancies. Questions remain about which components are most important, how they influence outcomes and comparative effects across treatment approaches. We aimed to identify significant and strong contextual predictors of patient outcomes, test for psychological mediators and compare effects across three treatment approaches.DesignProspective cohort study with patient-reported and practitioner-reported questionnaire data (online or paper) collected at first consultation, 2 weeks and 3 months.SettingPhysiotherapy, osteopathy and acupuncture clinics throughout the UK.Participants166 practitioners (65 physiotherapists, 46 osteopaths, 55 acupuncturists) were recruited via their professional organisations. Practitioners recruited 960 adult patients seeking treatment for low back pain (LBP).Primary and secondary outcomesThe primary outcome was back-related disability. Secondary outcomes were pain and well-being. Contextual components measured were: therapeutic alliance; patient satisfaction with appointment systems, access, facilities; patients’ treatment beliefs including outcome expectancies; practitioners’ attitudes to LBP and practitioners’ patient-specific outcome expectancies. The hypothesised mediators measured were: patient self-efficacy for pain management; patient perceptions of LBP and psychosocial distress.ResultsAfter controlling for baseline and potential confounders, statistically significant predictors of reduced back-related disability were: all three dimensions of stronger therapeutic alliance (goal, task and bond); higher patient satisfaction with appointment systems; reduced patient-perceived treatment credibility and increased practitioner-rated outcome expectancies. Therapeutic alliance over task (ηp2=0.10, 95% CI 0.07 to 0.14) and practitioner-rated outcome expectancies (ηp2=0.08, 95% CI 0.05 to 0.11) demonstrated the largest effect sizes. Patients’ self-efficacy, LBP perceptions and psychosocial distress partially mediated these relationships. There were no interactions with treatment approach.ConclusionsEnhancing contextual components in musculoskeletal healthcare could improve patient outcomes. Interventions should focus on helping practitioners and patients forge effective therapeutic alliances with strong affective bonds and agreement on treatment goals and how to achieve them.

Introduction There is an increasing affinity for remote health consultations (including telephone and virtual platforms), enabling new models of accessing services to evolve. Whilst many key skills are transferable from traditional to remote consultations, there is even greater emphasis on verbal communication skills during these interactions. Purpose This masterclass considers the communication skills required for delivering remote health care consultations, in particular focussing on: 12 interactional features in an opening sequence of a remote call; active listening; how to offer advice using the Ask-Offer-Ask framework; and subtleties in phrasing and prosody when closing a call that may indicate a level of satisfaction (or otherwise). Implications In planning for digitally-enabled services to become mainstream, the differences in communication between remote and face-to-face consultations must be recognised and embraced., Highlights • This paper describes 12 interactional features in opening a virtual consultation. • Offering, rather than giving advice, can help build a two-way conversation. • Subtleties in phrasing and prosody when closing a call may indicate satisfaction. • Different communication is needed in remote and face-to-face consultations.

ObjectivesAmid a political agenda for integrated, high-value care, the UK is implementing its Low Back and Radicular Pain Pathway. To align care with need, it is imperative to understand the patients’ perspective. The purpose of this study was, therefore, to explore how people experience being managed for sciatica within an National Health Service (NHS) pathway.DesignQualitative interpretative study.SettingMusculoskeletal Service in an NHS, Primary Care Trust, UK.ParticipantsThe sample comprised 14 people aged ≥18 years with a clinical presentation of sciatica, who were currently under the care of a specialist physiotherapist (the specialist spinal triage practitioner), had undergone investigations (MRI) and received the results within the past 6 weeks. People were excluded if they had previously undergone spinal surgery or if the suspected cause of symptoms was cauda equina syndrome or sinister pathology. Participants were sampled purposively for variation in age and gender. Data were collected using individual semi-structured interviews (duration: 38–117 min; median: 82.6 min), which were audio-recorded and transcribed verbatim. Data were analysed thematically.ResultsA series of problems with the local pathway (insufficient transparency and information; clinician-led decisions; standardised management; restricted access to specialist care; and a lack of collaboration between services) made it difficult for patients to access the management they perceived necessary. Patients were therefore required to be independent and proactive or have agency. This was, however, difficult to achieve (due to the impact of sciatica and because patients lacked the necessary skills, funds and support) and together with the pathway issues, this negated patients’ capability to manage sciatica.ConclusionsThis novel paper explores how patients experience the process of being managed within a sciatica pathway. While highlighting the need to align with recommended best practice, it shows the need to be more person-centred and to support and empower patient agency.Trial registration numberClinicalTrials.gov reference (UOS-2307-CR); Pre-results.

Acute interstitial nephritis is a well-known cause of acute kidney injury, but its association with cocaine use is extremely rare. In this article, we chronicle the case of a patient who developed acute interstitial nephritis secondary to cocaine insufflation. Furthermore, we conducted a systematic literature search of MEDLINE, Cochrane, Embase, and Scopus databases regarding cocaine-induced acute interstitial nephritis. A comprehensive review of the search results yielded a total of 7 case reports only. The data on patient characteristics, clinical features, biochemical profiles, treatment, and outcomes were collected and analyzed. This paper illustrates that acute interstitial nephritis may be added to the list of differentials in patients with acute kidney injury and a history of cocaine use. The therapeutic approach for cocaine-related kidney disease may be different than other etiologies responsible for acute renal insult. Prompt recognition of this entity is crucial because such patients may ultimately develop severe deterioration in renal function.

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

Objective We explored patients’ experiences of using Internet-based self-management support for low back pain (LBP) in primary care, with and without physiotherapist telephone guidance. Design Exploratory descriptive qualitative study using thematic analysis, nested within a randomized feasibility trial. Methods Patients with LBP who participated in a feasibility trial of the SupportBack Internet intervention (ISRCTN: 31034004) were invited to take part in semistructured telephone interviews after the three-month intervention period (a convenience sample from within the trial population). Fifteen participants took part (age range = 36–87 years, 66.7% female, characteristics representative of the trial population). Data were analyzed thematically. Results Analysis resulted in the development of six themes (subthemes in parentheses): Perceptions of SupportBack’s design (Clarity and ease of use, Variety and range of information provided, Need for specificity and flexibility), Engaging with the SupportBack intervention, Promoting positive thought processes (Reassurance, Awareness of self-management), Managing behavior with SupportBack (Motivation and goal setting, Using activity as a pain management strategy, Preferences for walking or gentle back exercises), Feeling supported by telephone physiotherapists (Provision of reassurances and clarity, Physiotherapists are motivating), Severity and comorbidity as barriers (Preexisting condition or severity acting as a barrier, Less useful for mild low back pain). Conclusions The Internet intervention SupportBack appeared to feasibly support self-management of LBP. Reassurance and ongoing support to implement behavioral changes were central to reported benefits. The addition of physiotherapist telephone support further enhanced the patient experience and the potential utility of the intervention.

Background Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. Methods This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. Results Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. Conclusions Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Background:Clinical guidelines recommend that investigations, such as magnetic resonance imaging, are offered only when likely to change management. Meanwhile, the optimal process of diagnosing radiculopathy remains uncertain and, in clinical practice, differences of opinion can occur between patient and clinician regarding the perceived importance of investigations.Objectives:To explore peoples' experiences of investigations and the effect of concordance between clinical presentation and investigation findings.Methods:In this qualitative study, 14 participants who had recently undergone investigations for a clinical presentation of radiculopathy were purposively recruited from an NHS, Primary Care Service in the United Kingdom. Based on the principles of interpretative phenomenological analysis, individual, semi-structured interviews were recorded and transcribed verbatim. Data were managed using a framework approach and analysed thematically.Findings:Although people reported wanting investigations to understand the cause of symptoms and inform management, access to them was reported to be difficult and protracted. When investigations revealed potentially relevant findings, people experienced relief, validation, empowerment and decisive decision-making. Disappointment emerged, however, regarding treatment options and waiting times, and long-term prognosis. When investigations failed to identify relevant findings, people were unable to make sense of their symptoms, relinquish their search to identify the cause, or to move forward in their management.Conclusions:This study provides the first reported in-depth interpretation of peoples' experience of undergoing investigations specifically for radiculopathy. Important implications have been identified for: investigation referral criteria; shared-decision-making; information sharing and managing expectations and disappointment.

Background: back pain guidelines endorse giving advice to enable people to self-manage and continue normal activities. Little is known however, about the content of advice that clinicians give and this project aimed to identify the advice given by clinicians to patients with back pain at their initial consultation. Methods: a secondary analysis was conducted with 25 audio-recordings and transcriptions of consultations between patients with back pain and physiotherapists in a primary care outpatients department. Using a Framework approach, the data were coded and analysed to identify the content of advice given and mode of delivery. Results: the mean duration of consultation was 38 min 59 s (range 26:21–53:16). Advice was given in 88% (n = 22/25) of consultations and 96% included additional exercise instruction. Cognitive reassurance was evident, focussing on getting people confident to ‘move your back’ despite pain and encouraging active lifestyle changes. Beyond reassurance and discussion to enhance confidence, the key topics of advice given were: activity promotion; postural changes; practical self-help advice regarding ways to sit; pain-management advice including medication and using heat. Gaps were identified in the advice given, most notably there was a lack of specificity relating to the frequency and duration of recommended tasks and activities. Conclusions: advice and reassurance are integral to enabling people to self-manage their back pain. It is important to avoid contradictory and unhelpful messages. Despite its importance, little is known about the advice offered by clinicians during initial back pain consultations highlighting the need for guidance to be patient-centred and tailored.

BackgroundDevelopmental dysplasia of the hip (DDH) is a very common congenital disorder, and late-presenting cases often require surgical treatment. Surgical reduction of the hip may be complicated by avascular necrosis (AVN), which occurs as a result of interruption to the femoral head blood supply during treatment and can result in long-term problems. Some surgeons delay surgical treatment until the ossific nucleus (ON) has developed, whereas others believe that the earlier the reduction is performed, the better the result. Currently there is no definitive evidence to support either strategy.ObjectivesTo determine, in children aged 12 weeks to 13 months, whether or not delayed surgical treatment of a congenitally dislocated hip reduces the incidence of AVN at 5 years of age. The main clinical outcome measures were incidence of AVN and the need for a secondary surgical procedure during 5 years’ follow-up. In addition, to perform (1) a qualitative evaluation of the adopted strategy and (2) a health economic analysis based on NHS and societal costs.DesignPhase III, unmasked, randomised controlled trial with qualitative and health economics analyses. Participants were randomised 1 : 1 to undergo either early or delayed surgery.SettingPaediatric orthopaedic surgical centres in the UK.ParticipantsChildren aged 12 weeks to 13 months with DDH, either newly diagnosed or following failed splintage, and who required surgery. We had a target recruitment of 636 children.InterventionsSurgical reduction of the hip performed as per the timing allocated at randomisation.Main outcome measuresPrimary outcome – incidence of AVN at 5 years of age (according to the Kalamchi and MacEwen classification). Secondary outcomes – need for secondary surgery, presence or absence of the ON at the time of primary treatment, quality of life for the main carer and child, and a health economics and qualitative analysis.ResultsThe trial closed early after reaching LimitationsOveroptimistic estimates of numbers of eligible patients seen at recruiting centres during the planning of the trial, as well as an overestimation of the recruitment rate, may have also contributed to unrealistic expectations on achievable patient numbers.Future workThere may be scope for investigation using routinely available data.ConclusionsHip ’Op has highlighted the importance of accurate advance information on numbers of available eligible patients, as well as support from all participating investigators when conducting surgical research. Despite substantial consultation with parents of children in the planning stage, the level of non-participation experienced during recruitment was much higher than anticipated. The qualitative work has emphasised the need for appropriate advice and robust support for parents regarding the ‘real-life’ aspects of managing children with DDH.Trial registrationCurrent Controlled Trials ISRCTN76958754.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 63. See the NIHR Journals Library website for further project information.

Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody–drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P

IntroductionSelf-management and remaining physically active are first-line recommendations for the care of patients with low back pain (LBP). With a lifetime prevalence of up to 85%, novel approaches to support behavioural self-management are needed. Internet interventions may provide accessible support for self-management of LBP in primary care. The aim of this randomised controlled trial is to determine the clinical and cost-effectiveness of the ‘SupportBack’ internet intervention, with or without physiotherapist telephone support in reducing LBP-related disability in primary care patients.Methods and analysisA three-parallel arm, multicentre randomised controlled trial will compare three arms: (1) usual primary care for LBP; (2) usual primary care for LBP and an internet intervention; (3) usual primary care for LBP and an internet intervention with additional physiotherapist telephone support. Patients with current LBP and no indicators of serious spinal pathology are identified and invited via general practice list searches and mailouts or opportunistic recruitment following LBP consultations. Participants undergo a secondary screen for possible serious spinal pathology and are then asked to complete baseline measures online after which they are randomised to an intervention arm. Follow-ups occur at 6 weeks, 3, 6 and 12 months. The primary outcome is physical function (using the Roland and Morris Disability Questionnaire) over 12 months (repeated measures design). Secondary outcomes include pain intensity, troublesome days in pain over the last month, pain self-efficacy, catastrophising, kinesophobia, health-related quality of life and cost-related measures for a full health economic analysis. A full mixed-methods process evaluation will be conducted.Ethics and disseminationThis trial has been approved by a National Health Service Research Ethics Committee (REC Ref: 18/SC/0388). Results will be disseminated through peer-reviewed journals, conferences, communication with practices and patient groups. Patient representatives will support the implementation of our full dissemination strategy.Trial registration numberISRCTN14736486.

BACKGROUND: Depatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic pressure engenders tumor adaptations, it is important to understand the stability of biomarkers targeted by precision medicine approaches such as depatux-m. Therefore, we assessed EGFR amplification (amp) and expression in longitudinally-sampled GBMs from patients (pts) treated +/- depatux-m to explore biomarker stability. MATERIAL AND METHODS: Formalin-fixed, paraffin embedded GBM tumor tissue was analyzed from 68 patients who underwent at least 2 surgeries; EGFR amp was detected by in situ hybridization (e.g., FISH) or next-generation sequencing in all samples. Fifty-six pts did not receive depatux-m; among 12 pts who did, EGFR expression was also evaluated by RNA sequencing. RESULTS: Of 56 pts who did not receive depatux-m, 31 (55%) had tumors harboring EGFR amp at 1st surgery (initial diagnosis); among those, EGFR amp was maintained at re-operation in 27 (87%), and not maintained in 4 (13%). None of the 25 cases without baseline EGFR amp acquired it at the 2nd surgery. Of 12 pts treated with depatux-m between surgeries, 9 cases harbored EGFR amp at baseline which was maintained in 4 (44%) at the 2(nd) surgery, all 4 of which had the highest levels of EGFR expression at baseline. Of the 3 cases without EGFR amp at baseline, none acquired amplification at the 2(nd) surgery, and all 3 had the lowest levels of EGFR expression at study start. CONCLUSION: The presence of EGFR amp in GBM tissue at baseline was maintained at 2(nd) surgery in 87% of pts who received treatment other than depatux-m, and in 44% following depatux-m exposure. Therefore, depatux-m exposure appears to reduce EGFR amp maintenance (p=0.0159 by Fisher’s exact test); accordingly, the therapeutic approach may influence EGFR status. In no case was EGFR amp acquired at recurrence, regardless of depatux-m therapy. Ongoing analyses of additional tumor samples will increase power and further examine concordance among EGFR amp assays.

Background Patients with radicular symptoms can experience high levels of pain and disability with at least a third experiencing on-going symptoms 12 months after onset. Aims To explore ‘what matters’ about living with radicular symptoms at the point of seeing a spinal specialist and to consider how care can be aligned to best address need. Methods In this qualitative study, based on the principles of interpretative phenomenological analysis, 14 participants with a clinical presentation of radicular symptoms were purposively recruited from an NHS, Musculoskeletal Service in the UK. Individual, semi-structured interviews were undertaken, audio-recorded and transcribed verbatim. Data were managed using a Framework approach and analysed thematically. Findings Radicular symptoms were experienced as a protracted journey of acute exacerbations of symptoms that were difficult to make sense of. Adversely affecting almost all aspects of life, participants struggled to maintain their physical and functional independence; their important relationships; social networks and the roles and activities that provided joy and purpose. The impact of radicular symptoms was a ‘life on hold’ and an uncertain future, and 3/14 reported suicidal thoughts. Conclusions This paper, the first to focus on the lived experience of radicular symptoms at the point of seeing a spinal specialist, reveals the severity and devastating impact of radicular symptoms. Important implications have been identified regarding the need for clinicians to legitimise the symptoms and impact of radicular symptoms; to identify early those patients who might benefit from injection/surgery; and to signpost appropriate patients to sources of psychological support.

BACKGROUND: We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C). METHODS: In this multicenter phase I dose escalation study, patients received depatux-m (0.5–1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined. RESULTS: Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses. CONCLUSION: Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

To evaluate the rates and characteristics of musculoskeletal disorders (MSDs) in physical therapists (PTs) according to their specialty and setting.Participants completed an online questionnaire including 15 demographic questions, 7 work-related and 8 injury-related questions for 9 different body parts.Complete responses were obtained from 121 PTs; 96% reported MSD symptoms during the previous 12 months, 64% affecting at least 3 body parts. The body parts with the highest prevalence of symptoms were the low back (66%) and the neck (61%). For PTs specialized in acute care, geriatrics and pediatrics, the body part most commonly affected was the low back, while for PTs specialized in orthopedics and neurology, the body part most commonly affected was the neck. Regarding work settings, the low back was the most commonly affected for PTs working in skilled nursing facilities, outpatient clinics and hospitals, and the neck in PTs working in academic and home health settings.MSDs are common among PTs; the body parts most often affected were the low back and neck. The prevalence and body parts affected varied by practice setting and specialty area. The findings can help informing the design of evidence-based rehabilitation, prevention, training and educational programs.Rehabilitation of injured physical therapists needs to address the symptoms of the multiple body parts that are usually affected (e.g. back, wrists and hands). Rehabilitation of injured physical therapists needs to take into consideration their job demands, practice setting and specialty area. The findings can inform the design of rehabilitation, prevention, training and educational programs for physical therapists.

Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.

Background Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. Methods In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. Results Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. Conclusions Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3383-5) contains supplementary material, which is available to authorized users.

Objective To investigate the effects of ballroom and Latin American dancing classes on turning in people with Parkinson’s. Design This study employed a randomised, controlled, experimental design. Setting Dance classes were performed in a community dance centre in Southern England and all assessments took place a gait laboratory. Participants Twenty-seven people with mild-moderate Parkinson’s participated. Intervention Participants were randomly allocated to receive either 20, 1-h dancing classes over 10 weeks (n = 15), or a ‘usual care’ control group (n = 12). Main outcome measure Twelve, 180° on-the-spot turns to the predicted/un-predicted and preferred/un-preferred direction were analysed for each participant, using 3-dimensional motion analysis before and after the intervention period, alongside clinical measures. Results Movement of the head, pelvis, and feet during turning in people with Parkinson’s are affected by dancing with tighter coupling of body segments. Significant 4-way interactions between the groups, over time and turn style, with longer latency of the head (p = 0.008) and greater rotation in the pelvis (p = 0.036), alongside a trend of slower movement of the first (p = 0.063) and second (p = 0.081) foot in controls were shown, with minimal change in dancers. All interactions were affected by the type of turn. No significant differences were found in the centre of mass displacement, turn time or clinical measures. Conclusion Those who danced were better able to coordinate their axial and perpendicular segments and surprisingly became more ‘en bloc’ in their turning behaviour, suggesting this may be a beneficial adaptation, rather than a maladaptive result of Parkinson’s, as previously suggested.

Background. The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods. In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results. As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion. ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Item does not contain fulltext PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. DESIGN: Case series. PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

Background: Depatux-M (ABT-414) is an antibody-drug-conjugate consisting of an antibody (ABT-806) bound to the toxin monomethylauristatin-F. A randomized phase II trial on EGFR-amplified recurrent glioblastomas (GBMs) showed an improvement (p=0.06 in the primary analysis, p=0.024 in follow-up analysis) in overall survival in the Depatux-M+TMZ arm when compared to the control arm (CCNU or TMZ). In this study, we performed targeted next generation sequencing and correlated molecular features with response to treatment in order to better identify patients that benefit from the combination. Material and Methods: DNA and RNA was isolated from samples, collected at initial diagnosis, and selected for regions with highest tumor content. Target selection was done using the Trusight 170 gene panel (Illumina) which interrogates somatic variants and copy number, RNA levels and fusion genes in a set of known cancer genes. Variant calling was done using the Illumina Basespace sequence hub. For this trial, patients were eligible with centrally confirmed EGFR amplification, defined as EGFR/CEP 7 (centromere) ratio ≥ 2 in 15% of cells (FISH). Results: DNA and RNA data were generated from 233 and 234 samples respectively (of the 260 study patients). High-copy gene amplification was detected in EGFR (n=202), MDM2 (n=20), MDM4 (n=22), CDK4 (n=24) and CDK6 (n=5) which correlated with high expression levels. With this assay, 17 tumors did not show EGFR copy number (cn) aberrations (cn < 2.8), a further 14 showed copy number changes consistent with trisomy only (2.8< cn < 4). Most EGFR amplified tumors also had additional genetic changes in the EGFR locus including point mutations (111/202), splice variants (132/202, the most common being EGFRvIII n=96) or fusion genes (13/202). Twenty-one samples did not contain additional genetic changes and expressed only EGFRwt. Response (OS) to treatment was not correlated to EGFR gene expression or amplification levels though, since EGFR amplification was a pre-requisite for inclusion, the majority of cases expressed high levels of EGFR (not shown). Preliminary analysis suggests that subjects with EGFR amplification but without EGFRvIII expression had a trend towards superior clinical benefit from Depatux-M +TMZ (median survival 14.3 v. 8.9 and 8.1 months in the Depatux-M +TMZ, TMZ|CCNU and Depatux M arms respectively; HR 0.56, P=0.047 v. Depatux M monotherapy and HR 0.54, P=0.055 v. TMZ|CCNU ). Conclusion: Depatux-M in combination with TMZ showed a trend towards improved OS in EGFR amplified recurrent glioblastoma. This trend may be greater for subjects with an absence of EGFRvIII expression. Citation Format: Pim J. French, Johan M. Kros, Iris de Heer, Marica Eoli, Juan Manuel Sepulvada, Annemiek Walenkamp, Jean-Sebastian Frenel, Alba Brandes, Paul Clement, Michael Weller, Peter Ansell, Jim Looman, Earle Bain, Lisa Roberts-Rapp, Marie Morfouace, Thierry Gorlia, Vassilis Golfinopoulos, Martin van den Bent. Patients with EGFR amplification but without EGFRvIII expression have improved benefit compared to those with EGFRvIII expression in samples of the INTELLANCE2/EORTC1410 randomized phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4886.

Preclinical Research The quest for a well-validated, non-invasive biomarker to aid in clinical decision making has remained elusive in the cancer space over the last 30 years. Much promise has been attached to circulating tumor cells (CTCs) as prognostic, predictive, and pharmacodynamic biomarkers with the potential to eliminate the need for invasive tumor biopsies and improve on the clinical value of other circulating tumor markers. The CellSearch® system (Veridex, LLC., Raritan, NJ, USA) cleared the U.S. Food and Drug Administration when the presence of CTCs was shown to have prognostic significance in patients with breast, prostate, and colorectal cancer. However, CTCs are not, at present, routinely being used in the clinic to guide treatment decisions. This paper discusses key attributes that a biomarker must possess, the status of other potential cancer biomarkers, and advancements in the capture and characterization of CTCs that will enable actualization of their potential as a reliable and efficient biomarker of disease diagnosis, progression, and response to therapy in the clinic.

Aim To explore the significance of circulating tumor cells (CTCs) detection in the course of preoperative chemotherapy (PC) and their effect on the outcomes. Methods Fifty-five patients with stage II/III invasive breast cancer were enrolled into a preoperative clinical trial. Patients were given PC with sequential single-agent doxorubicin and paclitaxel vs paclitaxel followed by doxorubicin. Blood samples (8 mL) were collected from patients before PC, after each phase, and at 6 months intervals during follow-up. Peripheral blood mononuclear cells were isolated and enriched for epithelial cells. Quantitative RT-PCR was used to determine the presence of cytokeratin 19 (CK19) mRNA. Samples were considered positive when the PCR curve crossed the standard threshold curve. Results After the first phase of chemotherapy, there was a 59% overall reduction in the median tumor volume. The percentage of volume reduction did not differ between patients who presented with detectable CTCs at baseline and those who did not (p=0.89). After the second phase of chemotherapy, there was a further decrease in the median tumor volume to 93% from baseline. There was no correlation between the lack of response and the presence of CTCs either after the first (p=0.36) or second (p=0.5391) phases of PC. The presence of CTCs was a predictor of local or distant relapse (p=0.0411). The detection of CTCs did not affect overall survival (p=0.2569). Conclusion CTCs can be used as predictors of relapse after definitive treatment of locally advanced breast cancer; however, CTCs detection in peripheral blood during the course of PC does not implicate a particular pattern of response to treatment.

Background The ability of physiotherapists to make clinical decisions is a vital component of being an autonomous practitioner, yet this complex phenomenon has been under-researched in cardiorespiratory physiotherapy. The purpose of this study was to explore clinical decision-making (CDM) by experienced physiotherapists in a scenario of a simulated patient experiencing acute deterioration of their respiratory function. Objectives The main objective of this observational study was to identify the actions, thoughts, and behaviours used by experienced cardiorespiratory physiotherapists in their clinical decision-making processes. Design A mixed-methods (qualitative) design employing observation and think-aloud, was adopted using a computerised manikin in a simulated environment. Setting The participants clinically assessed the manikin programmed with the same clinical signs, under standardised conditions in the clinical skills practice suite, which was set up as a ward environment. Participants Experienced cardiorespiratory physiotherapists, recruited from clinical practice within a 50-mile radius of the University(*). Methods Participants were video-recorded throughout the assessment and treatment and asked to verbalise their thought processes using the 'think-aloud' method. The recordings were transcribed verbatim and managed using a Framework approach. Results Eight cardiorespiratory physiotherapists participated (mean 7years clinical experience, range 3.5–16years. CDM was similar to the collaborative hypothetico-deductive model, five-rights nursing model, reasoning strategies, inductive reasoning and pattern recognition. However, the CDM demonstrated by the physiotherapists was complex, interactive and iterative. Information processing occurred continuously throughout the whole interaction with the patient, and the specific cognitive skills of recognition, matching, discriminating, relating, inferring, synthesising and prediction were identified as being used sequentially. Conclusions The findings from this study were used to develop a new conceptual model of clinical decision-making for cardiorespiratory physiotherapy. This conceptual model can be used to inform future educational strategies to prepare physiotherapists and nurses for working in acute respiratory care.

The need to demonstrate clinical effectiveness and value in orthopaedic spinal practice is unprecedented. Previously in this journal, Professor Haddad has led a call to arms to enter more patients into prospective randomised studies, warning that Orthopaedic Surgery “undoubtedly lags behind other

Case management has become a popular model for providing home care services to nursing home-eligible older adults. To maximize collaborative decision making and patient outcomes, members of the case management team must engage in ongoing, open communication. However, little is known about the quality of communication between home care case managers and their clients’ physicians. This study examined geriatric home care case managers’ perceptions of their communication with their clients’ physicians. Participating case managers were employed at two large home care agencies located in the South Florida region. The findings suggest that communication between home care case managers and physicians is limited and inefficient. Implication for policy and practice are provided. Finally, we propose ways to leverage Information Technology to bridge this communication gap.

IntroductionEmploying allied health professionals in extended scope roles has developed relatively recently in health-care. Within physiotherapy, the extended role has provided clinicians with autonomy to use knowledge and clinical acumen to request investigations such as Magnetic Resonance Imaging (MRI) and X-ray as part of the diagnostic process, a practice beyond the traditional scope of physiotherapy. In these advancing roles, little is written about the clinical reasoning processes that clinicians use in managing patients with musculoskeletal pain and knowledge of these processes would advance training for new recruits to this arena.StudyThis qualitative study has explored the processes by which extended scope physiotherapists (ESPs) clinically reason their decisions regarding patients reporting low back pain in a musculoskeletal outpatient setting. The study used a multiple case study design informed by grounded theory methodology, using focus groups (involving ESPs and non-ESPs/musculoskeletal physiotherapists) and semi-structured interviews with a think-aloud method (ESPs only) to investigate these processes.ConclusionsThe themes identified include: prior thinking; patient interaction; formal testing; time; safety and accountability; external and internal factors; and gut-feeling (which challenges current physiotherapy models of reasoning). Extended scope physiotherapists reported experiencing greater stress due to higher levels of perceived accountability, safety requirements and internal drivers for competence than non-ESPs. Further research is indicated to explore the role of gut-feeling in musculoskeletal physiotherapy clinical reasoning.

More than 5.4 million people in the U.S. are affected by Alzheimer’s disease and other dementias (AD), most of whom receive care and support from family caregivers and are medically managed by their primary care provider (PCP). However, there are a number of barriers to providing care to those with AD: PCPs report difficulty in communicating with AD patients, their caregivers, and their in-home providers; in addition, caregivers experience compromised health and psychiatric and physical consequences to the burden associated with caregiving. AD caregivers in rural settings experience additional unique challenges, given local limitations in services, significant distance of services, and limited availability of information regarding AD and available services. To address these issues, a multi-disciplinary team, along with community partners, has developed CareHeroes, a bilingual (English/Spanish), internet and Android-based App that has multiple functions aimedto: improve disease management; provide case managers, caregivers, and PCPs with the ability to share critical health-related information in real time; and increase access to caregiving information and resources. This presentation will summarize pilot data from several studies of CareHeroes to highlight: perceptions about usability and satisfaction among users (caregivers, home care case managers, PCPs) and lessons learned about developing health information technology for a diverse population of dementia caregivers. Then, it will discuss specific policy, practice, and technical considerations that present opportunities and challenges for extending CareHeroes to rural AD caregivers as a cost-effective, sustainable mechanism for providing them with ongoing support, caregiving information and ability to communicate with healthcare providers.

2033Background: Depatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic ...

Background: Aberrant EGFR plays a vital role in the oncogenesis of multiple tumor types. ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR, based on the 1st-generation ADC depatuxizumab mafodotin (depatux-m, formerly ABT-414). Depatux-m demonstrates efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the microtubule toxin monomethylauristatin E. ABBV-221 has higher affinity for EGFR than depatux-m, potentially allowing it to target a broader range of tumor types. To understand the population most suitable for ABBV-221, molecular assays characterizing EGFR pathway status, including EGFR protein, EGFR mRNA, and EGFR ligand mRNA expression, were evaluated from available tumor tissue of enrolled patients. The results of each assay were correlated with patient outcome to determine which marker may be best associated with prognosis. Methods: In this phase 1, multicenter study of ABBV-221, eligible pts have solid tumors that are likely to overexpress EGFR. EGFR protein expression in tumor tissue samples was analyzed with immunohistochemistry (IHC) using the Dako pharmDx IHC assay. EGFR and mRNA expression from the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) were measured using next-generation RNA sequencing (RNAseq). Results: As of 29 March 2017, 42 pts were treated (13 colon, 5 head & neck [H&N] cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. The most common adverse events were infusion reactions in 19/42 pts (45%) and fatigue in 17/42 pts (41%). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. All markers are expressed in a wide range across enrolled pts. The pts with response had high EGFR and EGFR ligand. One pt with head and neck cancer who received 5 cycles of ABBV-221 had a partial response and elevated levels of both EGFR (3-fold higher than median for all pts) and EGFR ligand (8-fold higher AREG and 19-fold higher EREG than median for all pts). One colorectal cancer pt with durable SD >6 months had high levels of ligand (EREG) but not receptor, and one H&N pt with SD >6 months had high levels of EGFR receptor but not ligand. Conclusions: Multiple EGFR pathway status biomarkers were evaluated and correlated with clinical outcomes observed in this phase 1 trial of ABBV-221. Patients who observed clinical benefit had high levels of EGFR pathway markers. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662 Citation Format: Emiliano Calvo, James M. Cleary, Victor Moreno, Maryella Gifford, Lisa Roberts-Rapp, Peter J. Ansell, Ho-Jin Lee, Beibei Hu, David Barch, Christopher Ocampo, Anthony W. Tolcher. Biomarker analysis in a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to overexpress the epidermal growth factor receptor (EGFR) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A028.

Fraser S, Roberts L, Murphy E. Cauda equina syndrome: a literature review of its definition and clinical presentation. Objective To review the current evidence for the signs and symptoms of cauda equina syndrome (CES). Data Sources Relevant literature sourced through Medline, Embase, and CINAHL using the key search words "cauda equina syndrome" combined with "definition," "clinical presentation," "signs and symptoms," "pathology," and "etiology." Study Selection Not applicable. Data Extraction Not applicable. Data Synthesis Three reviewers independently extracted data on CES from the literature specific to its definition, clinical presentation, and etiology. Of 111 articles, 105 were included for review, and relevant information on CES was synthesized into a framework structured as per a clinical consultation. A content analysis was then conducted using the method adopted by the Chartered Society of Physiotherapy whereby the level of consensus for each sign and symptom of CES was determined by its percentage coverage within the literature: 100% coverage equals unanimity, 75% to 99% equals consensus, 51% to 74% equals majority view, and 0% to 50% equals no consensus. This enabled the frequency of each reported sign and symptom to be ranked. Articles that included specific definitions for CES were divided into 3 categories: those that (1) included generalized statements, (2) stated a pathomechanical basis, and (3) defined the syndrome by its clinical presentation. Throughout this review, the frequencies of specific etiologies and pathologies were noted. Together with details of clinical presentation, this enabled a comprehensive review of CES. No single aspect of CES within the literature achieved unanimity or consensus; however, a majority view indicated that there would be bladder and sensory disturbance (74% and 66% of all articles, respectively). The most commonly cited pathology resulting in CES was identified as the disk (45% of all articles reviewed). Conclusions There are marked inconsistencies in the current evidence base surrounding the etiology and clinical presentation of CES, with 17 definitions identified. Subclassifications of the definition of CES are ambiguous and should be avoided. From reviewing 105 articles, a single definition of CES is proposed. For a diagnosis of CES, one or more of the following must be present: (1) bladder and/or bowel dysfunction, (2) reduced sensation in the saddle area, and (3) sexual dysfunction, with possible neurologic deficit in the lower limb (motor/sensory loss, reflex change).

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2 positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.

Objectives To assess the effect of sample size, methodological quality and statistical rigour on outcomes of randomised controlled trials (RCTs) on manual therapy (i.e. manipulation, mobilisation and/or massage) for non-specific low back pain (LBP) of at least 6 weeks duration, and to report results from RCTs with adequate sample size, methodological quality and statistical rigour. Data sources MedLine, EMBASE, CINAHL, AMED, Cochrane, PEDro and the library collection of the Chartered Society of Physiotherapy. Review methods RCTs were identified that compared manual therapy with a control or alternative intervention in adults with non-specific LBP of at least 6 weeks duration. The sample size, methodological quality (adapted 10-point van Tulder scale) and statistical rigour were then assessed. RCTs were regarded as higher quality if they fulfilled the following three criteria: (a) >40 subjects in the manual therapy group; (b) scoring >5/10 on the Van Tulder scale; and (c) reporting statistical tests that compared the change in the intervention group with the change in the control group. Results Ten RCTs were included in the review but only two qualified as higher quality RCTs. Results from smaller trials and lower quality RCTs showed more variation in differences between the intervention and control groups than larger or higher quality trials. Evidence from large, high-quality RCTs with adequate statistical analyses showed that, for improvement in pain and function, a mobilisation/manipulation package is an effective intervention [compared with general practitioner (GP) care], whilst manipulation used in isolation showed no real benefits over sham manipulation or an alternative intervention. No higher quality evidence considering massage was identified. Conclusions Many RCTs in the area of manual therapy for LBP have shortcomings in sample size, methodological quality and/or statistical rigour, but there remains evidence from higher quality RCTs to support the use of a manual therapy package, compared with GP care, for non-specific LBP of at least 6 weeks duration.

Background and Purpose Communication is the most important aspect of practice that health care professionals have to master. The purpose of this study was to measure the content and prevalence of verbal and nonverbal communications between physical therapists and patients with back pain. Subjects Seven physical therapists and 21 patients with back pain participated in this study. Methods The first interaction following the initial assessment was recorded with a video camera. The outcome measures were the Medical Communications Behavior System (verbal communication) and frequencies of nonverbal behaviors (affirmative head nodding, smiling, eye gaze, forward leaning, and touch). Semistructured interviews were undertaken with the physical therapists to determine the perceived influence of the video camera. Results A total of 2,055 verbal statements were made. Physical therapists spent approximately twice as much time talking as patients, with content behaviors (such as taking history and giving advice) comprising 52% of verbal communications. The most prevalent nonverbal behaviors were touch by physical therapists (54%) and eye gaze by patients (84%). Discussion and Conclusion The prevalence and content of communication can be measured with video analysis and validated tools. Communication is an extremely important but underexplored dimension of the patient-therapist relationship, and the methods described here could provide a useful model for further research and reflective practice.

IntroductionLow back pain (LBP) is a prevalent and costly condition. The majority of patients experiencing LBP are managed in primary care, where first-line care recommendations consist of advice to self-manage and remain active. Internet interventions present a potential means of providing patients with tailored self-management advice and evidence-based support for increasing physical activity.Methods/analysisThis protocol describes a single-blind, randomised controlled feasibility trial of an internet intervention developed to support the self-management of LBP in primary care. Patients are being randomised to 1 of 3 groups receiving either usual primary care, usual primary care with the addition of an internet intervention or an internet intervention with physiotherapist telephone support. Patients are followed up at 3?months. Primary outcomes are the feasibility of (1) the trial design/methods, (2) the delivery of the internet intervention and (3) the provision of telephone support by physiotherapists. Secondary outcomes will include exploratory analysis of estimates and variation in clinical outcomes of pain and disability, in order to inform a future main trial.Ethics/disseminationThis feasibility trial has undergone ethical scrutiny and been approved by the National Health Service (NHS) Research Ethics Committee, REC Reference 13/SC/0202. The feasibility findings will be disseminated to the research community through presentations at conferences and publication in peer review journals. Broader dissemination will come following a definitive trial.Trial registration number ISRCTN 31034004.