Consumers lived experiences and satisfaction with sub-acute mental health residential services.

PURPOSE: Sub-acute recovery-oriented facilities offer short-term residential support for people living with mental illness. They are generally highly regarded by consumers, with emerging evidence indicating that these services may support recovery. The aim of the current study was to explore the relationship between personal recovery and consumers' satisfaction with sub-acute residential services, and consumers' views about service features that aid recovery. METHODS: Consumers at 19 adult Prevention and Recovery Care Services in Victoria, Australia, were invited to complete measures containing sociodemographic information and measures on personal recovery and wellbeing. After going home, participants were invited to complete measures on service satisfaction and experience. RESULTS: Total and intrapersonal scores on the personal recovery measure increased significantly between Time 1 and Time 2, indicating marked improvement. Personal recovery and satisfaction measures were moderately to strongly correlated. Thematically analysed open-ended responses revealed themes of feeling connected, finding meaning and purpose, and self-empowerment as important aspects of these services, with some recommendations for improvements. CONCLUSION: Sub-acute residential mental health care may support individuals' personal recovery; consumer satisfaction indicates these services also offer an acceptable and supportive environment for the provision of recovery-oriented care. Further exploring consumers' experiences of sub-acute residential services is essential to understand their effectiveness, opportunities for improvement and intended impacts on personal recovery.

Low avascular necrosis rates in femoral neck fractures: efficacy of cannulated screw fixation.

PURPOSE: Cannulated screw fixation for femoral neck fractures is often limited by concerns of avascular necrosis (AVN) occurring, historically seen in 5-40% of fixed intracapsular fractures. This study aims to assess the outcomes, particularly the AVN rate, associated with current surgical techniques within our unit. METHODS: We conducted a single-center cross-sectional study, manually searching operative records between July 14, 2014, and December 1, 2018, identifying patients with intracapsular fractured neck of femur fixed with cannulated screws, with a minimum of two years follow-up. Patient records and radiographs were reviewed for clinical and radiographic diagnoses of AVN, non-union, post-operative metalwork infection, and screw penetration of the head. Additionally, fracture pattern and displacement, screw configuration, reduction techniques, and adequacy of reduction were recorded, with radiographs independently analyzed by four orthopedic surgeons. RESULTS: Fifty-six patients were included; average age of 67 years (range 30-100). Forty-two patients (75%) sustained displaced fractures and 14 patients (25%) had undisplaced fractures. Two (4%) patients developed AVN, with no cases of non-union, post-operative metalwork infection or screw penetration of the head. Eight patients (14%) sustained a high-energy injury, though none of these patients developed AVN. All fractures required closed reduction; no open reductions performed. Twenty-seven (64%) of reductions were adequate. CONCLUSION: Our observed AVN rate is notably lower than the widely reported figures, even among a significant proportion of displaced fractures that were fixed. This study underscores that with adequate fixation, cannulated screws represent an excellent option for treating intracapsular neck of femur fractures, even in cases of displaced fracture patterns with imperfect reduction.

Patterns of host plant use do not explain mushroom body expansion in Heliconiini butterflies.

The selective pressures leading to the elaboration of downstream, integrative processing centres, such as the mammalian neocortex or insect mushroom bodies, are often unclear. In Heliconius butterflies, the mushroom bodies are two to four times larger than those of their Heliconiini relatives, and the largest known in Lepidoptera. Heliconiini lay almost exclusively on Passiflora, which exhibit a remarkable diversity of leaf shape, and it has been suggested that the mushroom body expansion of Heliconius may have been driven by the cognitive demands of recognizing and learning leaf shapes of local host plants. We test this hypothesis using two complementary methods: (i) phylogenetic comparative analyses to test whether variation in mushroom body size is associated with the morphological diversity of host plants exploited across the Heliconiini; and (ii) shape-learning experiments using six Heliconiini species. We found that variation in the range of leaf morphologies used by Heliconiini was not associated with mushroom body volume. Similarly, we find interspecific differences in shape-learning ability, but Heliconius are not overall better shape learners than other Heliconiini. Together these results suggest that the visual recognition and learning of host plants was not a main factor driving the diversity of mushroom body size in this tribe.

Quasi-planar InGaAsSb p-B-n photodiodes for spectroscopic sensing.

An InGaAsSb p-B-n structure has been designed and characterized for zero bias low power detection applications. Devices were grown by molecular beam epitaxy and fabricated into quasi-planar photodiodes with a 2.25 µm cut-off wavelength. Maximum responsivity was measured to be 1.05 A/W at 2.0 µm, achieved at zero bias. D* of 9.4 × 1010 Jones was determined from room temperature spectra of noise power measurements with calculated D* remaining >1 × 1010 Jones up to 380 K. With a view to simple miniaturized detection and measurement of low concentration biomarkers, optical powers down to 40 pW were detected, without temperature stabilization or phase-sensitive detection, indicating the photodiode's potential.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD. METHODS: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system. RESULTS: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed. CONCLUSIONS: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Dimethyl fumarate modulates the Treg-Th17 cell axis in patients with psoriasis.

BACKGROUND: Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively. Various immunomodulatory mechanisms of action have been identified for DMF; however, it is still unclear what effects DMF exerts in vivo in patients with psoriasis. OBJECTIVES: In this study we examined the effects of DMF, both in vivo and in vitro, on T cells, which play a key role in the pathogenesis of psoriasis. METHODS: The frequency of T-cell subsets was examined by flow cytometry in untreated patients with psoriasis or those treated with DMF. The effects of DMF in vitro on T-cell survival, activation and proliferation, and cell-surface thiols were assessed by flow cytometry. RESULTS: In patients with psoriasis treated with DMF we observed an increase in the frequency of T regulatory (Treg) cells and a decrease in T helper (Th)17 lineage cells and the associated cytokines interleukin-17, interleukin-22 and granulocyte-macrophage colony-stimulating factor. T cells cultured in vitro with DMF exhibited reduced viability, and inhibition of activation and proliferation in response to stimulation due to the oxidative effects of DMF. However, the frequency of Treg cells increased in the presence of DMF due to their heightened ability to resist DMF-induced oxidative stress. CONCLUSIONS: DMF enhanced the ratio of Treg cells to Th17 cells in patients with psoriasis, in patients with multiple sclerosis and in vitro. Furthermore, our data suggest that this is at least in part as a result of the differential effects of DMF on Treg cells compared with conventional T cells.

Engagement in HIV Care Among New York City Transgender Women of Color: Findings from the Peer-Led, TWEET Intervention, a SPNS Trans Women of Color Initiative.

Transgender women (TW) have higher HIV prevalence rates than cisgender (i.e., non-transgender) women. However, utilization of healthcare for transgender people in the U.S. is low. As part of a multisite initiative to facilitate entry and retention in HIV care for TW of color, we compared health outcomes between participants who became Peer Leaders and those who did not. From 2013 to 2016, 163 New York City, mostly Latina, TW enrolled in the Transgender Women Engagement and Entry to Care Project (TWEET). The TWEET intervention included peer-led, group-based educational sessions called Transgender Leader-Teach Back; 39% completed Peer Leadership requirements. Comparing pre-post change by Peer Leader status, Peer Leaders had a significant decrease in viral load and significant increase in CD4 at the last HIV care visit compared to the first. In multivariable logistic regression, predictors associated with Peer Leadership included having at least some college education, being in a relationship, stable housing, receiving legal assistance for political asylum, and having two or more HIV care visits during the intervention. Findings suggest that, for trans women who have completed at least secondary school education, participating in a peer-led intervention can lead to improved HIV care engagement. Understanding which program components lead to becoming a Peer Leader, and how to better engage non-Peer Leaders, are important next steps.

Getting the most out of MRI in perianal fistula: update on surgical techniques and radiological features that define surgical options.

Perianal fistulas affect approximately 2 in 10,000 people, causing symptoms such as pain and discharge, which can have a debilitating effect on a patient's quality of life. Surgical treatment, which can offer a potential cure or palliation of symptoms, must be considered carefully in cases with extensive sphincter involvement. In complex cases, the use of preoperative magnetic resonance imaging (MRI) can help to determine the best course of operative action. This review describes common and contemporary surgical procedures for perianal fistula, highlighting technical features, as well as important surgical considerations associated with each method and how these can be assessed radiologically. We focus on the anatomical features and MRI findings that take procedural elements into account and help determine the most appropriate method of treatment. The aim of this article is to provide a basis for informed and focused discussion between surgeons and radiologists to ensure the most appropriate procedure is selected for each case, with the ultimate aim of obtaining the most favourable outcomes for patients.

Changes in pain catastrophization and neuropathic pain following operative stabilisation for patellofemoral instability: a prospective study with twelve month follow-up.

PURPOSE: To determine the prevalence and change in neuropathic pain or pain catastrophizing before and 12 months following patellar stabilisation surgery for patellofemoral instability. METHODS: We conducted a prospective clinical audit within a UK NHS orthopaedic surgical centre. Data from 84 patients with patellofemoral instability requiring stabilisation were analysed. Fifty percent (42/84) underwent MPFL reconstruction alone, and 16% (13/84) had both trochleoplasty and MPFL reconstruction. Neuropathic pain was assessed using painDETECT score. Pain catastrophizing was assessed using the Pain Catastrophizing Score. The Norwich Patellar Instability (NPI) Score and Kujala Patellofemoral Disorder Score were also routinely collected pre-operatively and one year post-operatively. RESULTS: At 12 months post-operatively there was a statistically significant reduction in mean Pain Catastrophizing Scores (18.9-15.7; p < 0.02), but no change in mean painDETECT scores (7.3-7.8; p = 0.72). There was a statistically significant improvement in NPI scores (90.2-61.9; p < 0.01) and Kujala Patellofemoral Disorder Scores (48.7-58.1; p = 0.01). The prevalence of pain catastrophizing decreased from 31% pre-operatively to 24% post-operatively, whereas the prevalence of neuropathic pain remained consisted (10-11%). CONCLUSIONS: Neuropathic pain and catastrophizing symptoms are not commonly reported and did not significantly change following patellofemoral stabilisation surgery. Whilst low, for those affected, there remains a need to intervene to improve outcomes following PFI surgery.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Pollen feeding in Heliconius butterflies: the singular evolution of an adaptive suite.

Major evolutionary transitions can be triggered by behavioural novelty, and are often associated with 'adaptive suites', which involve shifts in multiple co-adapted traits subject to complex interactions. Heliconius butterflies represent one such example, actively feeding on pollen, a behaviour unique among butterflies. Pollen feeding permits a prolonged reproductive lifespan, and co-occurs with a constellation of behavioural, neuroanatomical, life history, morphological and physiological traits that are absent in closely related, non-pollen-feeding genera. As a highly tractable system, supported by considerable ecological and genomic data, Heliconius are an excellent model for investigating how behavioural innovation can trigger a cascade of adaptive shifts in multiple diverse, but interrelated, traits. Here, we synthesize current knowledge of pollen feeding in Heliconius, and explore potential interactions between associated, putatively adaptive, traits. Currently, no physiological, morphological or molecular innovation has been explicitly linked to the origin of pollen feeding, and several hypothesized links between different aspects of Heliconius biology remain poorly tested. However, resolving these uncertainties will contribute to our understanding of how behavioural innovations evolve and subsequently alter the evolutionary trajectories of diverse traits impacting resource acquisition, life history, senescence and cognition.

IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa.

The skin is one of the most important organs in the body, providing integrity and acting as a barrier to exclude microbes, allergens and chemicals. However, chronic skin inflammation can result when barrier function is defective and immune responses are dysregulated or misdirected against harmless or self-antigens. During the last 15 years interleukin (IL)-17 cytokines have emerged as key players in multiple inflammatory disorders, and they appear to be especially prominent in skin inflammation. IL-17 cytokines produced by T cells and other cell types potently activate keratinocytes to promote inflammation in a feed-forward loop. Given this key pathogenic role of the IL-17 pathway in autoimmune and inflammatory disease, it has been the focus of intense efforts to target therapeutically. The inflammatory effects of IL-17 can be targeted directly by blocking the cytokine or its receptor, or indirectly by blocking cytokines upstream of IL-17-producing cells. Psoriasis has been the major success story for anti-IL-17 drugs, where they have proven more effective than in other indications. Hidradenitis suppurativa (HS) is another inflammatory skin disease which, despite carrying a higher burden than psoriasis, is poorly recognized and under-diagnosed, and current treatment options are inadequate. Recently, a key role for the IL-17 pathway in the pathogenesis of HS has emerged, prompting clinical trials with a variety of IL-17 inhibitors. In this review, we discuss the roles of IL-17A, IL-17F and IL-17C in psoriasis and HS and the strategies taken to target the IL-17 pathway therapeutically.

Heliconiini butterflies can learn time-dependent reward associations.

For many pollinators, flowers provide predictable temporal schedules of resource availability, meaning an ability to learn time-dependent information could be widely beneficial. However, this ability has only been demonstrated in a handful of species. Observations of Heliconius butterflies suggest that they may have an ability to form time-dependent foraging preferences. Heliconius are unique among butterflies in actively collecting pollen, a dietary behaviour linked to spatio-temporally faithful 'trap-line' foraging. Time dependency of foraging preferences is hypothesized to allow Heliconius to exploit temporal predictability in alternative pollen resources. Here, we provide the first experimental evidence in support of this hypothesis, demonstrating that Heliconius hecale can learn opposing colour preferences in two time periods. This shift in preference is robust to the order of presentation, suggesting that preference is tied to the time of day and not due to ordinal or interval learning. However, this ability is not limited to Heliconius, as previously hypothesized, but also present in a related genus of non-pollen feeding butterflies. This demonstrates time learning likely pre-dates the origin of pollen feeding and may be prevalent across butterflies with less specialized foraging behaviours.

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis.

Rheumatoid arthritis is characterized by synovial proliferation, neovascularization and leucocyte extravasation leading to joint destruction and functional disability. The blood vessels in the inflamed synovium are highly dysregulated, resulting in poor delivery of oxygen; this, along with the increased metabolic demand of infiltrating immune cells and inflamed resident cells, results in the lack of key nutrients at the site of inflammation. In these adverse conditions synovial cells must adapt to generate sufficient energy to support their proliferation and activation status, and thus switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This alters redox-sensitive signalling pathways and also results in the accumulation of metabolic intermediates which, in turn, can act as signalling molecules that further exacerbate the inflammatory response. The RA synovium is a multi-cellular tissue, and while many cell types interact to promote the inflammatory response, their metabolic requirements differ. Thus, understanding the complex interplay between hypoxia-induced signalling pathways, metabolic pathways and the inflammatory response will provide better insight into the underlying mechanisms of disease pathogenesis.

Do we know how scabies outbreaks in residential and nursing care homes for the elderly should be managed? A systematic review of interventions using a novel approach to assess evidence quality.

Currently no national guidelines exist for the management of scabies outbreaks in residential or nursing care homes for the elderly in the United Kingdom. In this setting, diagnosis and treatment of scabies outbreaks is often delayed and optimal drug treatment, environmental control measures and even outcome measures are unclear. We undertook a systematic review to establish the efficacy of outbreak management interventions and determine evidence-based recommendations. Four electronic databases were searched for relevant studies, which were assessed using a quality assessment tool drawing on STROBE guidelines to describe the quality of observational data. Nineteen outbreak reports were identified, describing both drug treatment and environmental management measures. The quality of data was poor; none reported all outcome measures and only four described symptom relief measures. We were unable to make definitive evidence-based recommendations. We draw on the results to propose a framework for data collection in future observational studies of scabies outbreaks. While high-quality randomised controlled trials are needed to determine optimal drug treatment, evidence on environmental measures will need augmentation through other literature studies. The quality assessment tool designed is a useful resource for reporting of outcome measures including patient-reported measures in future outbreaks.

LO-Phonon Emission Rate of Hot Electrons from an On-Demand Single-Electron Source in a GaAs/AlGaAs Heterostructure.

Using a recent time-of-flight measurement technique with 1 ps time resolution and electron-energy spectroscopy, we develop a method to measure the longitudinal-optical-phonon emission rate of hot electrons traveling along a depleted edge of a quantum Hall bar. Comparison to a single-particle model implies the scattering mechanism involves a two-step process via an intra-Landau-level transition. We show that this can be suppressed by control of the edge potential profile, and a scattering length >1 mm can be achieved, allowing the use of this system for scalable single-electron device applications.

The pathogenic role of dendritic cells in non-infectious anterior uveitis.

BACKGROUND: Anterior uveitis (AU) is characterised by infiltration of immune cells into the anterior chamber of the eye. Dendritic cells (DC) are professional antigen presenting cells that initiate and promote inflammation. This study aims to characterise DC in AU and to examine the effects of aqueous humor (AqH) on DC maturation and function. METHODS: The frequency and phenotype of AU and healthy control (HC) circulating DC was examined. AU and HC AqH was immunostained and assessed by flow cytometry. The effect of AU and HC AqH on DC activation and maturation was examined and subsequent effects on CD4+ T cell proliferation assessed. RESULTS: AU peripheral blood demonstrated decreased circulating myeloid and plasmacytoid DC. Within AU AqH, three populations of CD45+ cells were significantly enriched compared to HC; DCs (CD11c+ HLA-DR+), neutrophils (CD15+ CD11c+) and T cells (CD4+ and CD8+). A significant increase in IFNγ, IL8 and IL6 was observed in the AU AqH, which was also significantly higher than that of paired serum. AU AqH induced expression of CD40 and CD80 on DC, which resulted in increased T cell proliferation and the production of GM-CSF, IFNγ and TNFα. CONCLUSION: DC are enriched at the site of inflammation in AU. Our data demonstrate an increase in inflammatory mediators in the AU inflamed microenvironment. AU AqH can activate DC, leading to subsequent proliferation and activation of effector T cells. Thus, the AU microenvironment contributes to immune cell responses and intraocular inflammation.

Neonatal Acute Kidney Injury: A Survey of Neonatologists' and Nephrologists' Perceptions and Practice Management.

BACKGROUND: Neonatal acute kidney injury (AKI) occurs in 40 to 70% of critically ill neonatal intensive care admissions. This study explored the differences in perceptions and practice variations among neonatologists and pediatric nephrologists in diagnostic criteria, management, and follow-up of neonatal AKI. METHODS: A survey weblink was emailed to nephrologists and neonatologists in Australia, Canada, New Zealand, India, and the United States. Questions consisted of demographic and unit practices, three clinical scenarios assessing awareness of definitions of neonatal AKI, knowledge, management, and follow-up practices. RESULTS: Many knowledge gaps among neonatologists, and to a lesser extent, pediatric nephrologists were identified. Neonatologists were less likely to use categorical definitions of neonatal AKI (p < 0.00001) or diagnose stage 1 AKI (p < 0.00001) than pediatric nephrologists. Guidelines for creatinine monitoring for nephrotoxic medications were reported by 34% (aminoglycosides) and 62% (indomethacin) of respondents. Nephrologists were more likely to consider follow-up after AKI than neonatologists (p < 0.00001). Also, 92 and 86% of neonatologists and nephrologists, respectively, reported no standardization or infrastructure for long-term renal follow-up. CONCLUSION: Neonatal AKI is underappreciated, particularly among neonatologists. A lack of evidence on neonatal AKI contributes to this variation in response. Therefore, dissemination of current knowledge and areas for research should be the priority.

Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. RESULTS: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. CONCLUSIONS: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. CLINICAL TRIAL NUMBER: NCT01068769.