Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Dietary intervention in gestational diabetes: a qualitative study of the acceptability and feasibility of a novel whole-diet intervention in healthcare professionals.

Gestational diabetes is treated with medical nutrition therapy, delivered by healthcare professionals; however, the optimal diet for affected women is unknown. Randomised controlled trials, such as the DiGest (Dietary Intervention in Gestational Diabetes) trial, will address this knowledge gap, but the acceptability of whole-diet interventions in pregnancy is unclear. Whole-diet approaches reduce bias but require high levels of participant commitment and long intervention periods to generate meaningful clinical outcomes. We aimed to assess healthcare professionals' views on the acceptability of the DiGest dietbox intervention for women with gestational diabetes and to identify any barriers to adherence which could be addressed to support good recruitment and retention to the DiGest trial. Female healthcare professionals (n 16) were randomly allocated to receive a DiGest dietbox containing 1200 or 2000 kcal/d including at least one weeks' food. A semi-structured interview was conducted to explore participants' experience of the intervention. Interviews were audio-recorded, transcribed verbatim and analysed thematically using NVivo software. Based on the findings of qualitative interviews, modifications were made to the dietboxes. Participants found the dietboxes convenient and enjoyed the variety and taste of the meals. Factors which facilitated adherence included participants having a good understanding of study aims and sufficient organisational skills to facilitate weekly meal planning in advance. Barriers to adherence included peer pressure during social occasions and feelings of deprivation or hunger (affecting both standard and reduced calorie groups). Healthcare professionals considered random allocation to a whole-diet replacement intervention to be acceptable and feasible in a clinical environment and offered benefits to participants including convenience.

Experiences of emotional eating in an Acceptance and Commitment Therapy based weight management intervention (SWiM): A qualitative study.

BACKGROUND: Emotional eating is a barrier to weight management. Interventions based on Acceptance and Commitment Therapy (ACT) promote the acceptance of uncomfortable feelings, which can reduce the urge to use food as a coping mechanism. We aimed to explore how participants of an ACT-based weight management intervention (WMI) experience emotional eating and relevant intervention content. METHODS: We conducted semi-structured telephone interviews with participants of a digital ACT-based guided self-help WMI. Fifteen participants were purposefully selected to represent a range of demographic characteristics and emotional eating scores. We used reflexive thematic analysis to explore experiences of emotional eating. RESULTS: We generated five themes. Participants improved emotional eating by disconnecting emotions from behaviours though increased self-awareness (theme 1) and by implementing alternative coping strategies, including preparation, substitution, and acceptance (theme 2). Most participants maintained improvements in emotional eating over time but wished for more opportunities to re-engage with intervention content, including more immediate support in triggering situations (theme 3). Participants who struggled to engage with emotional eating related intervention content often displayed an external locus of control over emotional eating triggers (theme 4). The perceived usefulness of the intervention depended on participants' prior experiences of emotional eating, and was thought insufficient for participants with complex emotional experiences (theme 5). DISCUSSION: This ACT-based WMI helped participants with emotional eating by improving self-awareness and teaching alternative coping strategies. Intervention developers may consider adding ongoing forms of intervention that provide both real-time and long-term support. Additionally, a better understanding of how to support people with an external locus of control and people with complex experiences of emotional eating is needed. Future research may explore ways of personalising WMIs based on participants' emotional needs.

Supporting Weight Management during COVID-19 (SWiM-C): twelve-month follow-up of a randomised controlled trial of a web-based, ACT-based, guided self-help intervention.

OBJECTIVES: We developed a guided self-help intervention (Supporting Weight Management during COVID-19, "SWiM-C") to support adults with overweight or obesity in their weight management during the COVID-19 pandemic. This parallel, two-group trial (ISRCTN12107048) evaluated the effect of SWiM-C on weight and determinants of weight management over twelve months. METHODS: Participants (≥18 years, body-mass-index ≥25 kg/m2) were randomised to the SWiM-C intervention or to a standard advice group (unblinded). Participants completed online questionnaires at baseline, four months, and twelve months. The primary outcome was change in self-reported weight from baseline to twelve months; secondary outcomes were eating behaviour (uncontrolled eating, emotional eating, cognitive restraint of food intake), experiential avoidance, depression, anxiety, stress, wellbeing and physical activity. INTERVENTIONS: SWiM-C is based on acceptance and commitment therapy (ACT). Participants had access to an online web platform with 12 weekly modules and email and telephone contact with a trained, non-specialist coach. Standard advice was a leaflet on managing weight and mood during the COVID-19 pandemic. RESULTS: 388 participants were randomised (SWiM-C: n = 192, standard advice: n = 196). The baseline-adjusted difference in weight change between SWiM-C (n = 119) and standard advice (n = 147) was -0.81 kg (95% CI: -2.24 to 0.61 kg). SWiM-C participants reported a reduction in experiential avoidance (-2.45 [scale:10-70], 95% CI: -4.75 to -0.15), uncontrolled eating (-3.36 [scale: 0-100], 95% CI: -5.66 to -1.06), and emotional eating (-4.14 [scale:0-100], 95% CI: -7.25 to -1.02) and an increase in physical activity (8.96 [MET-min/week], 95% CI: 0.29 to 17.62) compared to standard advice participants. We found no evidence of an effect on remaining outcomes. No adverse events/side effects were reported. CONCLUSIONS: Whilst we were unable to conclude that the intervention had an effect on weight, SWiM-C improved eating behaviours, experiential avoidance and physical activity. Further refinement of the intervention is necessary to ensure meaningful effects on weight prior to implementation in practice. TRIAL REGISTRATION NUMBER: ISRCTN 12107048.

Perceived weight-related stigma, loneliness, and mental wellbeing during COVID-19 in people with obesity: A cross-sectional study from ten European countries.

BACKGROUND: Increased weight-related stigma during the COVID-19 pandemic has amplified the need to minimise the impacts on mental wellbeing. We investigated the relationship between the perceived changes in the representation of obesity in the media and mental wellbeing during the pandemic in a sample of people with obesity across 10 European countries. We also investigated the potential moderating effect of loneliness. METHODS: Between September to December 2020 during the COVID-19 pandemic, participants reported data on demographics, mental wellbeing (measured by World Health Organisation Five Wellbeing Index and Patient Health Questionaire-4), loneliness (measured by De Jong Gierveld short scale), and perceived change in the representation of obesity in media (measured by a study-specific question) using the online, cross-sectional EURopean Obesity PatiEnt pANdemic Survey (EUROPEANS). Data were analysed using linear mixed-effects models, controlling for age, gender, body mass index, and shielding status, with random incept for country. RESULTS: The survey was completed by 2882 respondents. Most identified as female (56%) and reported their ethnicity as White or White-mix (92%). The total sample had a mean age of 41 years and a BMI of 35.4 kg/m2. During the peak of the pandemic, compared to pre-pandemic, perceiving more negative representation of people with obesity on social media was associated with worse psychological distress, depression, and wellbeing. Perceiving more positive representation, compared to no change in representation, of people with obesity on television was associated with greater wellbeing, yet also higher psychological distress and anxiety. Loneliness, as a moderator, explained ≤0.3% of the variance in outcomes in any of the models. CONCLUSIONS: Perceiving negative representation of obesity on social media was associated with poorer mental wellbeing outcomes during the pandemic; positive representation on television was associated with both positive and negative mental wellbeing outcomes. We encourage greater media accountability when representing people with obesity.

Breaking habits or breaking habitual behaviours? Old habits as a neglected factor in weight loss maintenance.

Maintaining weight loss requires long-term behaviour change. Theory and evidence around habitual behaviour - i.e., action triggered by impulses that are automatically activated upon exposure to cues, due to learned cue-action associations - can aid development of interventions to support weight loss maintenance. Specifically, weight loss is more likely to be sustained where people develop new habits that support weight management, and break old habits that may undermine such efforts. Interventions seeking to break 'bad' weight-related habits have focused on inhibiting unwanted impulses or avoiding cues. This paper draws attention to the possibility that while such approaches may discontinue habitual behaviour, underlying habit associations may remain. We use evidence from existing qualitative studies to demonstrate that, left unchecked, unwanted habit associations can render people prone to lapsing into old patterns of unhealthy behaviours when motivation or willpower is momentarily weakened, or when returning to familiar settings following temporarily discontinued exposure. We highlight six behaviour change techniques especially suited to disrupting habit associations, but show that these techniques have been underused in weight loss maintenance interventions to date. We call for intervention developers and practitioners to adopt techniques conducive to forming new habit associations to directly override old habits, and to use the persistence of unwanted habit associations as a potential indicator of long-term weight loss intervention effectiveness.

Validation of a next generation sequencing assay for BRCA1, BRCA2, CHEK2 and PALB2 genetic testing.

BRCA1, BRCA2, CHEK2 and PALB2 genes are associated with hereditary breast and ovarian cancer syndrome. Genetic testing of these genes is of increasing importance to guide therapeutic and management decisions. In this study, we evaluated the performance of a next generation sequencing (NGS) assay for the complete analysis of BRCA1, BRCA2, CHEK2 and PALB2 genes using Agilent's SureMASTR BRCA Screen that enabled the detection of single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variations (CNVs) in a single-tube PCR based library preparation. The results showed 100% sensitivity and specificity on a set of 52 known samples from de-identified patients and external quality assessment program. A concordance rate of 87.5% was achieved in the comparison of variant classification with the external laboratories. The high accuracy of the assay supports the use of SureMASTR BRCA Screen in clinical diagnostic laboratories (SureMASTR BRCA Screen is for research use only, not for use in diagnostic procedures).

Multi-centre evaluation of a comprehensive preimplantation genetic test through haplotyping-by-sequencing.

STUDY QUESTION: Can reduced representation genome sequencing offer an alternative to single nucleotide polymorphism (SNP) arrays as a generic and genome-wide approach for comprehensive preimplantation genetic testing for monogenic disorders (PGT-M), aneuploidy (PGT-A) and structural rearrangements (PGT-SR) in human embryo biopsy samples? SUMMARY ANSWER: Reduced representation genome sequencing, with OnePGT, offers a generic, next-generation sequencing-based approach for automated haplotyping and copy-number assessment, both combined or independently, in human single blastomere and trophectoderm samples. WHAT IS KNOWN ALREADY: Genome-wide haplotyping strategies, such as karyomapping and haplarithmisis, have paved the way for comprehensive PGT, i.e. leveraging PGT-M, PGT-A and PGT-SR in a single workflow. These methods are based upon SNP array technology. STUDY DESIGN, SIZE, DURATION: This multi-centre verification study evaluated the concordance of PGT results for a total of 225 embryos, including 189 originally tested for a monogenic disorder and 36 tested for a translocation. Concordance for whole chromosome aneuploidies was also evaluated where whole genome copy-number reference data were available. Data analysts were kept blind to the results from the reference PGT method. PARTICIPANTS/MATERIALS, SETTING, METHODS: Leftover blastomere/trophectoderm whole genome amplified (WGA) material was used, or secondary trophectoderm biopsies were WGA. A reduced representation library from WGA DNA together with bulk DNA from phasing references was processed across two study sites with the Agilent OnePGT solution. Libraries were sequenced on an Illumina NextSeq500 system, and data were analysed with Agilent Alissa OnePGT software. The embedded PGT-M pipeline utilises the principles of haplarithmisis to deduce haplotype inheritance whereas both the PGT-A and PGT-SR pipelines are based upon read-count analysis in order to evaluate embryonic ploidy. Concordance analysis was performed for both analysis strategies against the reference PGT method. MAIN RESULTS AND THE ROLE OF CHANCE: PGT-M analysis was performed on 189 samples. For nine samples, the data quality was too poor to analyse further, and for 20 samples, no result could be obtained mainly due to biological limitations of the haplotyping approach, such as co-localisation of meiotic crossover events and nullisomy for the chromosome of interest. For the remaining 160 samples, 100% concordance was obtained between OnePGT and the reference PGT-M method. Equally for PGT-SR, 100% concordance for all 36 embryos tested was demonstrated. Moreover, with embryos originally analysed for PGT-M or PGT-SR for which genome-wide copy-number reference data were available, 100% concordance was shown for whole chromosome copy-number calls (PGT-A). LIMITATIONS, REASONS FOR CAUTION: Inherent to haplotyping methodologies, processing of additional family members is still required. Biological limitations caused inconclusive results in 10% of cases. WIDER IMPLICATIONS OF THE FINDINGS: Employment of OnePGT for PGT-M, PGT-SR, PGT-A or combined as comprehensive PGT offers a scalable platform, which is inherently generic and thereby, eliminates the need for family-specific design and optimisation. It can be considered as both an improvement and complement to the current methodologies for PGT. STUDY FUNDING/COMPETING INTEREST(S): Agilent Technologies, the KU Leuven (C1/018 to J.R.V. and T.V.) and the Horizon 2020 WIDENLIFE (692065 to J.R.V. and T.V). H.M. is supported by the Research Foundation Flanders (FWO, 11A7119N). M.Z.E, J.R.V. and T.V. are co-inventors on patent applications: ZL910050-PCT/EP2011/060211- WO/2011/157846 'Methods for haplotyping single cells' and ZL913096-PCT/EP2014/068315 'Haplotyping and copy-number typing using polymorphic variant allelic frequencies'. T.V. and J.R.V. are co-inventors on patent application: ZL912076-PCT/EP2013/070858 'High-throughput genotyping by sequencing'. Haplarithmisis ('Haplotyping and copy-number typing using polymorphic variant allelic frequencies') has been licensed to Agilent Technologies. The following patents are pending for OnePGT: US2016275239, AU2014345516, CA2928013, CN105874081, EP3066213 and WO2015067796. OnePGT is a registered trademark. D.L., J.T. and R.L.R. report personal fees during the conduct of the study and outside the submitted work from Agilent Technologies. S.H. and K.O.F. report personal fees and other during the conduct of the study and outside the submitted work from Agilent Technologies. J.A. reports personal fees and other during the conduct of the study from Agilent Technologies and personal fees from Agilent Technologies and UZ Leuven outside the submitted work. B.D. reports grants from IWT/VLAIO, personal fees during the conduct of the study from Agilent Technologies and personal fees and other outside the submitted work from Agilent Technologies. In addition, B.D. has a patent 20160275239 - Genetic Analysis Method pending. The remaining authors have no conflicts of interest.

Evaluation of massively parallel sequencing for forensic DNA methylation profiling.

Epigenetics is an emerging area of interest in forensic science. DNA methylation, a type of epigenetic modification, can be applied to chronological age estimation, identical twin differentiation and body fluid identification. However, there is not yet an agreed, established methodology for targeted detection and analysis of DNA methylation markers in forensic research. Recently, a massively parallel sequencing-based approach has been suggested. The use of massively parallel sequencing is well established in clinical epigenetics and is emerging as a new technology in the forensic field. This review investigates the potential benefits, limitations, and considerations of this technique for the analysis of DNA methylation in a forensic context. The importance of a robust protocol, regardless of the methodology used, which minimizes potential sources of bias is highlighted.

Influences of cancer symptom knowledge, beliefs and barriers on cancer symptom presentation in relation to socioeconomic deprivation: a systematic review.

BACKGROUND: People from lower socioeconomic groups have worse survival outcomes for cancer, which in part reflects later-stage disease at diagnosis. The mechanisms underlying delayed cancer symptom presentation in lower socioeconomic groups are not well understood. METHODS: Systematic review of studies of actual or anticipated symptom presentation across all tumour sites. Included studies measured socioeconomic group, symptom presentation and one or more of the following variables: cancer symptom knowledge, beliefs about cancer, barriers/facilitators to symptom presentation. RESULTS: A total of 60 studies was included. Symptom knowledge overall was lowest and actual presentation time was longest in lower socioeconomic groups. Knowledge for specific symptoms such as lumps and bleeding was good and encouraged timely symptom presentation, in contrast to non-specific symptoms which were not well recognised. The combination of fearful and fatalistic beliefs was typically associated with later presentation, especially in lower socioeconomic groups. Emotional barriers such as 'worry what the doctor might find' were more frequently reported in lower socioeconomic groups, and there was evidence to suggest that disclosing symptoms to family/friends could help or hinder early presentation. CONCLUSIONS: Poor symptom knowledge, fearful and fatalistic beliefs about cancer, and emotional barriers combine to prolong symptom presentation among lower socioeconomic groups. Targeted interventions should utilise social networks to improve knowledge of non-specific symptoms, challenge negative beliefs and encourage help-seeking, in order to reduce avoidable delays and minimise socioeconomic group inequalities.

Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization.

Phase variation of surface structures occurs in diverse bacterial species due to stochastic, high frequency, reversible mutations. Multiple genes of Campylobacter jejuni are subject to phase variable gene expression due to mutations in polyC/G tracts. A modal length of nine repeats was detected for polyC/G tracts within C. jejuni genomes. Switching rates for these tracts were measured using chromosomally-located reporter constructs and high rates were observed for cj1139 (G8) and cj0031 (G9). Alteration of the cj1139 tract from G8 to G11 increased mutability 10-fold and changed the mutational pattern from predominantly insertions to mainly deletions. Using a multiplex PCR, major changes were detected in 'on/off' status for some phase variable genes during passage of C. jejuni in chickens. Utilization of observed switching rates in a stochastic, theoretical model of phase variation demonstrated links between mutability and genetic diversity but could not replicate observed population diversity. We propose that modal repeat numbers have evolved in C. jejuni genomes due to molecular drivers associated with the mutational patterns of these polyC/G repeats, rather than by selection for particular switching rates, and that factors other than mutational drift are responsible for generating genetic diversity during host colonization by this bacterial pathogen.

The Potential of a Digital Weight Management Program to Support Specialist Weight Management Services in the UK National Health Service: Retrospective Analysis.

BACKGROUND: Digital weight management interventions (DWMIs) have the potential to support existing specialist weight management services (SWMS) in the National Health Service (NHS) to increase access to treatment for people living with obesity and type 2 diabetes. At present, there is limited real-world evidence and long-term outcomes on the potential effectiveness of DWMIs to support such services. OBJECTIVE: This study aimed to examine real-world data to evaluate the impact of Second Nature's 12-month DWMI for patients living with obesity with or without type 2 diabetes, referred from NHS primary care services, on sustained weight loss over a 2-year period. METHODS: Retrospective data were extracted in August 2023 for participants who participated in the program between January 1, 2017, and January 8, 2021. Eligible participants were adults with a BMI ≥35 kg/m2, with or without type 2 diabetes. The primary outcomes were weight change in kilograms and percentage weight change at 2 years. Secondary outcomes were weight loss at 1 year, program engagement, and the proportion of participants who achieved >5% and >10% weight loss. Differences in weight loss between baseline and the 1- and 2-year follow-up points were compared using paired 2-tailed t tests. Linear regression models were used to examine whether participants' ethnicity, indices of multiple deprivation, presence of type 2 diabetes, or program engagement were associated with weight loss at 1 year or 2 years. RESULTS: A total of 1130 participants with a mean baseline BMI of 46.3 (SD 31.6) kg/m2 were included in the analysis. Of these participants, 65% (740/1130) were female (mean age 49.9, SD 12.0 years), 18.1% (205/339) were from Black, Asian, mixed, or other ethnicities, and 78.2% (884/1130) had type 2 diabetes. A total of 281 (24.9%) participants recorded weight readings at 2 years from baseline, with a mean weight loss of 13.8 kg (SD 14.2 kg; P<.001) or 11.8% (SD 10.9%; P<.001). A total of 204 (18.1%) participants achieved ≥5% weight loss, and 130 (11.5%) participants reached ≥10% weight loss. Weight loss did not significantly differ by ethnicity, indices of multiple deprivation, presence of type 2 diabetes, or engagement in the program. CONCLUSIONS: The findings suggested that Second Nature's DWMI has the potential to support people living with obesity and type 2 diabetes remotely to achieve clinically significant and sustained weight loss at 2 years from baseline. Further research is needed to compare the intervention to standard care and assess integration with multidisciplinary clinical teams and pharmacotherapy in order to support this study's findings.

Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer.

PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

A Remotely Delivered, Semaglutide-Supported Specialist Weight Management Program: Preliminary Findings From a Retrospective Service Evaluation.

BACKGROUND: Digital weight management interventions have the potential to increase access to novel pharmacotherapy for people living with obesity. At present, there is limited real-world evidence on the effectiveness, feasibility, and acceptability of this type of intervention. OBJECTIVE: This retrospective service evaluation examines real-world data to evaluate the preliminary impact of Second Nature's 24-month, remotely delivered, semaglutide-supported weight management intervention for adults living with obesity at 12 weeks. METHODS: Retrospective data were extracted in October 2023 for participants who started the intervention between June 8, 2023, and July 22, 2023. The primary outcomes were weight change (kg) and percentage of weight change at 12 weeks. The secondary outcomes were the proportion of participants who achieved ≥5% and ≥10% weight loss and the feasibility and acceptability of this type of intervention. Descriptive statistics were used to evaluate the baseline characteristics, retention, engagement, prevalence of side effects, and weight change. A paired 2-tailed t test was used to determine the significance of weight change. Content analysis was used to analyze the free-text questionnaire responses. RESULTS: A total of 113 participants with a mean baseline BMI of 38.4 kg/m2 (SD 7.3) were included in the analysis (n=102, 90.4% women, mean age 46.6, SD 11.1 years). Over 12 weeks, 23% (n=26) of participants withdrew from the intervention. A total of 70.8% (n=80) of participants provided weight data at 12 weeks. The average weight loss observed over this 12-week period was 6.5 (SD 4.4) kg (P<.001) or 6.4% (SD 4.2%) of their starting weight (P<.001). Of the 80 participants who recorded weight readings, 62.5% (n=50) achieved ≥5% weight loss, and 11.3% (n=9) achieved ≥10% weight loss. Engagement with the app-based program declined from a mean of 131 (SD 142.6) home screen views in week 0 to 35 (SD 57.1) in week 11. Common side effects reported over 12 weeks included feeling more tired than usual, constipation, and feeling sick. However, a significant proportion of participants reported no side effects. Most participants (n=106, 93.8%) did not experience any difficulties in medication administration. Qualitative data showed that most participants had a positive or neutral experience of the intervention, with some reporting perceived benefits as early as 4 weeks. Most participants did not feel that improvements in the intervention were needed; however, some participants faced issues with medication shipping or logistics. CONCLUSIONS: This retrospective preliminary service evaluation suggests that a remotely delivered semaglutide-supported weight management intervention has the potential to be effective, feasible, and acceptable for self-paying consumer adults with obesity in the United Kingdom. Areas for further improvement were highlighted, including user engagement in an app-based program. A full-service evaluation at the end of the 24-month intervention with a larger sample size is required to support these early findings.

SARS-CoV-2 infections in pediatric and young adult recipients of chimeric antigen receptor T-cell therapy: an international registry report.

BACKGROUND: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%-40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited. METHODS: We created an international retrospective registry of CAR T recipients aged 0-30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed. RESULTS: Nine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15-30 days. CONCLUSIONS: In a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease.

Tumor inflammation-associated neurotoxicity.

Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.