Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

A unique model of care for youth in crisis: A pilot open trial.

Suicide is the second leading cause of death for those ages 10-24 years in the United States, and emergency department (ED) visits due to youth self-injurious thoughts and behaviors (SITB) and increased substantially between 2016 and 2021. Although ED services are essential for an effective system of care, the ED setting is typically not well-suited for the comprehensive, collaborative, and therapeutic evaluation of SITB; treatment planning; and care coordination that youth in a suicidal crisis need. As a result, an urgent care model for mental health designed to provide comprehensive crisis triage and intervention services is needed within outpatient psychiatry. This pilot trial examined the feasibility, acceptability, and preliminary clinical outcomes of a brief, urgent care model, the Behavioral Health Crisis Care Clinic (CCC), designed to provide comprehensive outpatient triage and intervention services aimed at reducing suicide risk for youth in crisis. Participants were 189 youth (ages 10-20; 62.4% females; 58% Caucasian) who had past-week suicidal ideation or behavior and their caregivers. The results demonstrated the CCC model exceeded feasibility and acceptability benchmarks based on the Service Satisfaction Scale (M score > 3.00). CCC care was associated with significant decreases in self-reported suicide risk based on the Collaborative Assessment and Management of Suicidality Suicide Status Form with low levels of ED usage during CCC care (7.7%) and 1-month posttreatment (11.8%). Over 88% of patients without established outpatient care at the time of referral were connected to care during CCC treatment, almost all of whom (95%) continued with ongoing mental health care 1 month after ending CCC care. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prospective randomised placebo-controlled trial assessing the efficacy of silver dressings to enhance healing of acute diabetes-related foot ulcers.

AIMS/HYPOTHESIS: Silver dressings are used for their antimicrobial properties but there is limited evidence of clinical benefit when managing diabetes-related foot ulcers (DFUs). We aimed to assess whether silver dressings in acute DFUs increased the proportion of ulcers healed compared with non-silver dressings. METHODS: In this open-labelled, randomised controlled trial, consecutive individuals who presented to a tertiary multidisciplinary diabetic foot service with a DFU without osteomyelitis or tendon on view of <6 weeks' duration were randomised 1:1 via a computer-generated randomisation process to receive Acticoat (Smith & Nephew, England) dressing (silver group) or dressing without silver (control group) in addition to standard care. Stratified randomisation was performed to ensure that the presence of peripheral arterial disease and infection were equally managed within the two groups. The primary outcome was the proportion of ulcers healed at 12 weeks. Secondary outcomes included time to heal and to 50% ulcer reduction, rates of osteomyelitis and amputation, and need for and duration of antibiotics. RESULTS: Seventy-six ulcers (55 participants) in the control group and 91 ulcers (63 participants) in the silver group were included. There was no difference in the proportion of ulcers healed by 12 weeks in the control vs silver group (75% vs 69%, p=0.49). After adjustment for presence of peripheral arterial disease, infection and initial ulcer size, silver dressing was not associated with odds of healing (OR 0.92; CI 0.26, 3.22; p=0.53). There was no difference in time to healing, progression to osteomyelitis, need for amputation, or duration of or need for antibiotic treatment. CONCLUSIONS/INTERPRETATION: In individuals with acute DFUs without osteomyelitis or tendon on view, Acticoat silver dressings did not improve wound healing or reduce need for antibiotics compared with non-silver dressings. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001234606 FUNDING: Australian Diabetes Society-unrestricted research award.

Survey of Lifestyle, Past Medical History and Complementary and Alternative Medicine Use Among Adult Patients Participating in the National Cancer Institute's Exceptional Responders Initiative.

INTRODUCTION: The Exceptional Responders Initiative (ERI) at the National Cancer Institute attempts to correlate unusually good outcomes in patients with cancer with genetic targets in tumors and the therapies the patients received. It is not known if other factors might contribute to exceptional responses or outcomes. We explored aspects of the medical history, lifestyle changes, complementary and alternative medicine (CAM) use and communication between health care practitioners and patients who experienced an exceptional response following cancer treatment. METHODS: All subjects whose case was submitted to the ERI were eligible to participate in the survey. A 121-question survey questionnaire was developed to assess aspects of the subject's past medical history, lifestyle (e.g., diet, exercise, spirituality) and use of CAM. RESULTS: Thirty subjects completed and returned the questionnaire from approximately 88 patients invited to participate (approximate response rate = 34%). Approximately 68% were female and 32% were male. Fifty percent of subjects changed their diet after their cancer diagnosis. Eighteen patients (60%) reported using a CAM therapy (not including oral vitamins/minerals or spiritual practices) during their Exceptional Response (ER). CONCLUSION: Multiple factors, including features of the tumor itself, the patient, or the environment, could affect tumor response or patient survival, either solely or in combination with the treatments received. Many patients use other medications, change their diet or physical activity or use CAM interventions after their cancer diagnosis. Investigators attempting to understand the exceptional response phenomenon should acquire rich data sets of their subjects that include information about these factors.

Benefit from adjuvant radiotherapy according to the number of risk factors in cutaneous squamous cell carcinoma.

INTRODUCTION: Indications of adjuvant radiotherapy (RT) for high-risk cutaneous squamous cell carcinoma (cSCC) are not clearly defined. We aimed to identify factors predicting relapse in cSCC patients treated with surgery or RT alone and to assess in which clinical setting adjuvant RT was beneficial in term of progression free survival (PFS). METHODS: This retrospective analysis included patients with resectable primary cSCC treated with surgery and/or RT in curative intent, managed at Centre Léon Bérard (Lyon, France) from April 2010 to September 2020. RESULTS: A total of 303 patients with 529 cSCC were included. 31 (5.9%) cSCC were treated with surgery and adjuvant RT. With a median follow-up of 54 (0.2-126) months, 103 (19.5%) cSCC relapsed. In multivariate analysis, the highest predictive factor of relapse in cSCC was the number of risk factors (HR = 15.110 [95% CI: 3.91-58.40] for ≥3 risk factors p < 0.001), followed by poor differentiation (HR = 4.930 [95% CI: 2.47-9.86], p < 0.001) and perineural invasion (HR = 2.442 [95% CI: 1.11-5.38], p = 0.027). For cSCC with ≥3 risk factors, PFS was significantly higher in cSCC treated with surgery and adjuvant RT compared to those treated with surgery or RT alone (the 36-month PFS was 74% [95% CI: 43-90%] and 31% [95% CI: 10-54%] respectively, p = 0.008). CONCLUSION: An increased number of risk factors was identified as being the highest predictive factor of relapse in cSCC. Adjuvant RT improved PFS for high-risk cSCC with ≥3 risk factors.

Strategies to identify individuals with monogenic diabetes: results of an economic evaluation.

OBJECTIVES: To evaluate and compare the lifetime costs associated with strategies to identify individuals with monogenic diabetes and change their treatment to more appropriate therapy. DESIGN: A decision analytical model from the perspective of the National Health Service (NHS) in England and Wales was developed and analysed. The model was informed by the literature, routinely collected data and a clinical study conducted in parallel with the modelling. SETTING: Secondary care in the UK. PARTICIPANTS: Simulations based on characteristics of patients diagnosed with diabetes <30 years old. INTERVENTIONS: Four test-treatment strategies to identify individuals with monogenic diabetes in a prevalent cohort of diabetics diagnosed under the age of 30 years were modelled: clinician-based genetic test referral, targeted genetic testing based on clinical prediction models, targeted genetic testing based on biomarkers, and blanket genetic testing. The results of the test-treatment strategies were compared with a strategy of no genetic testing. PRIMARY AND SECONDARY OUTCOME MEASURES: Discounted lifetime costs, proportion of cases of monogenic diabetes identified. RESULTS: Based on current evidence, strategies using clinical characteristics or biomarkers were estimated to save approximately £100-£200 per person with diabetes over a lifetime compared with no testing. Sensitivity analyses indicated that the prevalence of monogenic diabetes, the uptake of testing, and the frequency of home blood glucose monitoring had the largest impact on the results (ranging from savings of £400-£50 per person), but did not change the overall findings. The model is limited by many model inputs being based on very few individuals, and some long-term data informed by clinical opinion. CONCLUSIONS: Costs to the NHS could be saved with targeted genetic testing based on clinical characteristics or biomarkers. More research should focus on the economic case for the use of such strategies closer to the time of diabetes diagnosis. TRIAL REGISTRATION NUMBER: NCT01238380.

Soluble syndecan-3 binds chemokines, reduces leukocyte migration in vitro and ameliorates disease severity in models of rheumatoid arthritis.

BACKGROUND: Syndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms. Syndecan-3, the least well-characterised of the syndecan family, is highly expressed on synovial endothelial cells in rheumatoid arthritis patients. Here, it binds pro-inflammatory chemokines with evidence for a role in chemokine presentation and leukocyte trafficking into the joint, promoting the inflammatory response. In this study, we explored the role of soluble syndecan-3 as a binder of chemokines and as an anti-inflammatory and therapeutic molecule. METHODS: A human monocytic cell line and CD14+ PBMCs were utilised in both Boyden chamber and trans-endothelial migration assays. Soluble syndecan-3 was tested in antigen-induced and collagen-induced in vivo arthritis models in mice. ELISA and isothermal fluorescence titration assays assessed the binding affinities. Syndecan-3 expression was identified by flow cytometry and PCR, and levels of shedding by ELISA. RESULTS: Using in vitro and in vivo models, soluble syndecan-3 inhibited leukocyte migration in vitro in response to CCL7 and its administration in murine models of rheumatoid arthritis reduced histological disease severity. Using isothermal fluorescence titration, the binding affinity of soluble syndecan-3 to inflammatory chemokines CCL2, CCL7 and CXCL8 was determined, revealing little difference, with Kds in the low nM range. TNFα increased cell surface expression and shedding of syndecan-3 from cultured human endothelial cells. Furthermore, soluble syndecan-3 occurred naturally in the sera of patients with rheumatoid arthritis and periodontitis, and its levels correlated with syndecan-1. CONCLUSIONS: This study shows that the addition of soluble syndecan-3 may represent an alternative therapeutic approach in inflammatory disease.

Novel Anti-Inflammatory Peptides Based on Chemokine-Glycosaminoglycan Interactions Reduce Leukocyte Migration and Disease Severity in a Model of Rheumatoid Arthritis.

Inflammation is characterized by the infiltration of leukocytes from the circulation and into the inflamed area. Leukocytes are guided throughout this process by chemokines. These are basic proteins that interact with leukocytes to initiate their activation and extravasation via chemokine receptors. This is enabled through chemokine immobilization by glycosaminoglycans (GAGs) at the luminal endothelial surface of blood vessels. A specific stretch of basic amino acids on the chemokine, often at the C terminus, interacts with the negatively charged GAGs, which is considered an essential interaction for the chemokine function. Short-chain peptides based on this GAG-binding region of the chemokines CCL5, CXCL8, and CXCL12γ were synthesized using standard Fmoc chemistry. These peptides were found to bind to GAGs with high affinity, which translated into a reduction of leukocyte migration across a cultured human endothelial monolayer in response to chemokines. The leukocyte migration was inhibited upon removal of heparan sulfate from the endothelial surface and was found to reduce the ability of the chemokine and peptide to bind to endothelial cells in binding assays and to human rheumatoid arthritis tissue. The data suggest that the peptide competes with the wild-type chemokine for binding to GAGs such as HS and thereby reduces chemokine presentation and subsequent leukocyte migration. Furthermore, the lead peptide based on CXCL8 could reduce the disease severity and serum levels of the proinflammatory cytokine TNF-α in a murine Ag-induced arthritis model. Taken together, evidence is provided for interfering with the chemokine-GAG interaction as a relevant therapeutic approach.

The feasibility and effectiveness of Catch It, an innovative CBT smartphone app.

BACKGROUND: The widespread use of smartphones makes effective therapies such as cognitive-behavioural therapy (CBT) potentially accessible to large numbers of people. AIMS: This paper reports the usage data of the first trial of Catch It, a new CBT smartphone app. METHOD: Uptake and usage rates, fidelity of user responses to CBT principles, and impact on reported negative and positive moods were assessed. RESULTS: A relatively modest proportion of people chose to download the app. Once used, the app tended to be used more than once, and 84% of the user-generated content was consistent with the basic concepts of CBT. There were statistically significant reductions in negative mood intensity and increases in positive mood intensity. CONCLUSIONS: Smartphone apps have potential beneficial effects in mental health through the application of basic CBT principles. More research with randomised controlled trial designs should be conducted. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Practical Classification Guidelines for Diabetes in patients treated with insulin: a cross-sectional study of the accuracy of diabetes diagnosis.

BACKGROUND: Differentiating between type 1 and type 2 diabetes is fundamental to ensuring appropriate management of patients, but can be challenging, especially when treating with insulin. The 2010 UK Practical Classification Guidelines for Diabetes were developed to help make the differentiation. AIM: To assess diagnostic accuracy of the UK guidelines against 'gold standard' definitions of type 1 and type 2 diabetes based on measured C-peptide levels. DESIGN AND SETTING: In total, 601 adults with insulin-treated diabetes and diabetes duration ≥5 years were recruited in Devon, Northamptonshire, and Leicestershire. METHOD: Baseline information and home urine sample were collected. Urinary C-peptide creatinine ratio (UCPCR) measures endogenous insulin production. Gold standard type 1 diabetes was defined as continuous insulin treatment within 3 years of diagnosis and absolute insulin deficiency (UCPCR<0.2 nmol/mmol ≥5 years post-diagnosis); all others classed as having type 2 diabetes. Diagnostic performance of the clinical criteria was assessed and other criteria explored using receiver operating characteristic (ROC) curves. RESULTS: UK guidelines correctly classified 86% of participants. Most misclassifications occurred in patients classed as having type 1 diabetes who had significant endogenous insulin levels (57 out of 601; 9%); most in those diagnosed ≥35 years and treated with insulin from diagnosis, where 37 out of 66 (56%) were misclassified. Time to insulin and age at diagnosis performed best in predicting long-term endogenous insulin production (ROC AUC = 0.904 and 0.871); BMI was a less strong predictor of diabetes type (AUC = 0.824). CONCLUSION: Current UK guidelines provide a pragmatic clinical approach to classification reflecting long-term endogenous insulin production; caution is needed in older patients commencing insulin from diagnosis, where misclassification rates are increased.

Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice.

INTRODUCTION: Syndecans are heparan sulphate proteoglycans expressed by endothelial cells. Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. The objective of the current study was to examine the function of syndecan-3 in joint inflammation by genetic deletion in mice and compare with other tissues. METHODS: Chemokine C-X-C ligand 1 (CXCL1) was injected in the joints of syndecan-3-/-and wild-type mice and antigen-induced arthritis performed. For comparison chemokine was administered in the skin and cremaster muscle. Intravital microscopy was performed in the cremaster muscle. RESULTS: Administration of CXCL1 in knee joints of syndecan-3-/-mice resulted in reduced neutrophil accumulation compared to wild type. This was associated with diminished presence of CXCL1 at the luminal surface of synovial endothelial cells where this chemokine clustered and bound to heparan sulphate. Furthermore, in the arthritis model syndecan-3 deletion led to reduced joint swelling, leukocyte accumulation, cartilage degradation and overall disease severity. Conversely, CXCL1 administration in the skin of syndecan-3 null mice provoked increased neutrophil recruitment and was associated with elevated luminal expression of E-selectin by dermal endothelial cells. Similarly in the cremaster, intravital microscopy showed increased numbers of leukocytes adhering and rolling in venules in syndecan-3-/-mice in response to CXCL1 or tumour necrosis factor alpha. CONCLUSIONS: This study shows a novel role for syndecan-3 in inflammation. In the joint it is selectively pro-inflammatory, functioning in endothelial chemokine presentation and leukocyte recruitment and cartilage damage in an RA model. Conversely, in skin and cremaster it is anti-inflammatory.

A chemokine self-presentation mechanism involving formation of endothelial surface microstructures.

Endothelial surface microstructures have been described previously under inflammatory conditions; however, they remain ill-characterized. In this study, CXCL8, an inflammatory chemokine, was shown to induce the formation of filopodia-like protrusions on endothelial cells; the same effects were observed with CXCL10 and CCL5. Chemokines stimulated filopodia formation by both microvascular (from bone marrow and skin) and macrovascular (from human umbilical vein) endothelial cells. Use of blocking Abs and degradative enzymes demonstrated that CXCL8-stimulated filopodia formation was mediated by CXCR1 and CXCR2, Duffy Ag/receptor for chemokines, heparan sulfate (HS), and syndecans. HS was present on filopodial protrusions appearing as a meshwork on the cell surface, which colocalized with CXCL8, and this glycosaminoglycan was 2,6-O- and 3-O-sulfated. Transmission electron microscopy revealed that CXCL8-stimulated filopodial and microvilli-like protrusions that interacted with leukocytes before transendothelial migration and removal of HS reduced this migration. iTRAQ mass spectrometry showed that changes in the levels of cytoskeletal, signaling, and extracellular matrix proteins were associated with CXCL8-stimulated filopodia/microvilli formation; these included tropomyosin, fascin, and Rab7. This study suggests that chemokines stimulate endothelial filopodia and microvilli formation, leading to their presentation to leukocytes and leukocyte transendothelial migration.

Babies born at the threshold of viability: changes in survival and workload over 20 years.

OBJECTIVE: To assess the care given to the babies born at the threshold of viability over the last 20 years using regional and national data. DESIGN: Population-based retrospective study. SETTING: Former 'Trent' health region. PARTICIPANTS: Babies born between 1 January 1991 and 31 December 2010 at 22(+0) to 25(+6) weeks gestational age. MAIN OUTCOME MEASURE: Survival and use of respiratory support. METHODS: Data of all babies born between 1 January 1991 and 31 December 2010 with a gestational age of 22(+0) to 25(+6) weeks and admitted to a neonatal unit were extracted from The Neonatal Survey. Use of respiratory support in terms of ventilation and continuous positive airway pressure (CPAP) for this group of babies was calculated as a proportion of the total used by the whole neonatal intensive care population within the defined study area. RESULTS: The proportion of babies surviving to discharge increased significantly over time in those born at 24 and 25 weeks (p<0.01) but failed to achieve statistical significance for those at 23 weeks (p=0.08). No babies born at 22 weeks survived. The babies born at 22-25 weeks accounted for 26.3% of all ventilation and 21.5% of CPAP given. CONCLUSION: Our work concurs with the current UK guidelines. There could be advantages in focusing the care of babies born at 23 weeks to a small number of intensive care units to allow specialist expertise to develop in all aspects of the management of these babies. However, focusing care will not necessarily improve survival or reduce morbidity.

HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates.

The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics.

Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.

The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis and literature precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 open reading frame 2 induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human LINE-1 open reading frame 2 (96% identity with macaque), as well as simian endogenous retrovirus-K Gag and Env, induced polyfunctional T cell responses to all Ags, and Ab responses to simian endogenous retrovirus-K Env. There were no adverse safety or pathological findings related to vaccination. These studies provide the first evidence, to our knowledge, that immune responses can be induced safely against this class of self-antigens and pave the way for investigation of them as HIV- or tumor-associated targets.