Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study.

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10−20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1−2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1−2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1−2 adverse effects and Grade 1−2 immunotherapy-related adverse effects.

Real-time Feedback to Improve HIV Treatment Adherence in Pregnant and Postpartum Women in Uganda: A Randomized Controlled Trial.

We assessed an intervention aimed at improving adherence to antiretroviral therapy (ART) among pregnant and postpartum women living with HIV (PPWLH). We randomized 133 pregnant women initiating ART in Uganda to receive text reminders generated by real time-enabled electronic monitors and data-informed counseling through 3 months postpartum (PPM3) or standard care. Intention-to-treat analyses found low adherence levels and no intervention impact. Proportions achieving ≥95% adherence in PPM3 were 16.4% vs. 9.1% (t = -1.14, p = 0.26) in intervention vs. comparison groups, respectively; 30.9% vs. 29.1% achieved ≥80% adherence. Additional analyses found significant adherence declines after delivery, and no effect on disease progression (CD4-cell count, viral load), though treatment interruptions were significantly fewer in intervention participants. Per-protocol analyses encompassing participants who used adherence monitors as designed experienced better outcomes, suggesting potential benefit for some PPWLH. The study was registered on ClinicalTrials.Gov (NCT02396394).

Parents' Perspectives of Family Engagement with Early Childhood Education and Care During the COVID-19 Pandemic.

The COVID-19 pandemic has created significant challenges for Early Childhood Education and Care (ECEC) services and families, impacting family access to services and their communication and engagement with educators. This study aimed to examine parents' perspectives of family engagement with ECEC services during the pandemic. Primary caregivers in Victoria at the time of recruitment (September-November 2020) were invited to participate. Of the 66 participants who completed an online survey, 25 also took part in semi-structured video call or phone interviews; qualitative findings from these interviews are reported in this paper. Four key themes were conceptualised using a reflexive thematic approach: (1) disruptions to ECEC access and attendance impacting on family routines and relationships, and child development; (2) barriers to family engagement; (3) ECEC educators' support of families and children during the pandemic; and (4) increased parental appreciation of the ECEC profession. Findings revealed that disruptions to ECEC access and routines during the pandemic adversely impacted family engagement, and child learning and social-emotional wellbeing for some families. These were aggravated by other stressors, including increased parental responsibilities in the home, financial and health concerns, and changed work conditions. Findings also demonstrated successful methods used by educators to maintain communication and connections with families. Importantly, parents expressed increasing appreciation of the profession and an increased awareness of the value of family involvement in children's learning. Learnings regarding strategies for effective and alternative ways of engaging families are discussed.

Early Childhood Educators' Wellbeing During the COVID-19 Pandemic.

The importance of Early Childhood (EC) educators' wellbeing has been brought into sharp focus during the COVID-19 pandemic, as educators have navigated numerous additional stressors while providing education and care services for some children and ongoing support for many others learning at home. This study aimed to explore the impact of the pandemic on EC educators' wellbeing and educator-child relationships, as growing evidence shows the influence of these factors on children's developmental outcomes. In July 2020, members of a Research Network of EC Professionals-who previously identified educator wellbeing as a priority issue-were invited to participate in an online survey. The survey included two published, validated scales: the Early Childhood Professional Wellbeing scale (ECPW) and the Student-Teacher Relationship Scale (modified). Survey items about educators' experiences during the pandemic were also included. Two hundred and thirty-two EC educators from across Australia completed the survey, mostly from Victoria where lockdowns were most severe. Linear regression analysis demonstrated stronger professional wellbeing was associated with less conflict in educator-child relationships and lower risk of staff turnover. This was more likely to be experienced by senior or more experienced staff. Although a negative impact of COVID-19 was reported, ECPW scores were relatively high, and organizational structures supporting professional wellbeing were most strongly associated with lower risk of turnover (r = 0.63, p < 0.001). Findings highlight that supporting EC educators' wellbeing is essential for workforce retention, and for promoting quality educator-child relationships which are central to young children's learning and development.

Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells.

The therapeutic potential of stem cell-based therapies may be largely dependent on the ability of stem cells to modulate host cells rather than on their differentiation into host tissues. Within the last decade, there has been considerable interest in the intercellular communication mediated by the transfer of cytoplasmic material and organelles between cells. Numerous studies have shown that mitochondria and lysosomes are transported between cells by various mechanisms, such as tunneling nanotubes, microvesicles, and cellular fusion. This review will focus on the known instances of organelle transfer between stem cells and differentiated cells, what effects it has on recipient cells and how organelle transfer is regulated. Stem Cells 2019;37:14-25.

A feasibility trial of Acetic acid-targeted Biopsies versus nontargeted quadrantic biopsies during BArrett's surveillance: the ABBA trial.

BACKGROUND: The aims of this study were to compare neoplasia detection rates for nontargeted biopsies (Seattle protocol) versus acetic acid-targeted biopsies (Portsmouth protocol) during Barrett's surveillance and to explore feasibility, patient/clinician experience, acceptance, and barriers/enablers to study participation and implementation of the acetic acid technique. METHODS: This was a mixed-methods feasibility study including a pilot multicenter, randomized, crossover trial with qualitative interviews. Patients under Barrett's surveillance with no history of neoplasia were included. Patients underwent two endoscopies, one with each protocol, 8 weeks apart. Outcomes included recruitment and retention rates, neoplasia yield, and number of biopsies. RESULTS: 200 patients were recruited from 6 centers, and 174 (87.0 %) underwent both procedures. Neoplasia prevalence was 4.7 % (9/192). High grade dysplasia and cancer were detected with both protocols. Five low grade dysplasias were detected (two with acetic acid, four with nontargeted biopsies; one lesion was detected with both techniques). A total of 2139 biopsies were taken in the nontargeted arm and 226 in the acetic acid arm. Both patients and clinicians found the acetic acid technique acceptable. Based on these data, a noninferiority, tandem, crossover trial would require an estimated 2828 patients. CONCLUSIONS: We demonstrated the feasibility of performing a crossover endoscopy trial in Barrett's surveillance. Low neoplasia yield makes this design necessary and qualitative results demonstrated patient and clinician acceptance. The reduced numbers of biopsies suggest that the acetic acid technique could result in cost savings, providing the lack of missed pathology can be proven in a fully powered definitive trial.

A single-center experience using alemtuzumab, fludarabine, melphalan, and thiotepa as conditioning for transplantation in pediatric patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an immune deficiency characterized by defective neutrophil function and increased risk of life-threatening infections. Allogeneic hematopoietic cell transplantation is curative for CGD, and conditioning regimen impacts transplant-related outcomes. We report a single-center prospective study (NCT01821781) of four patients with CGD transplanted using a reduced-intensity conditioning regimen (RIC) containing alemtuzumab, fludarabine, melphalan, and thiotepa. Patients had early immune reconstitution with low incidence of infections. Disease-free survival was 75% at a median of five years after transplant. This RIC regimen presents an alternative approach for transplant of patients with CGD who may not tolerate busulfan-based conditioning.

Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days -21 to -19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with "early" alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.

Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.

Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection.

Long-Term Follow-Up after Reduced-Intensity Conditioning and Stem Cell Transplantation for Childhood Nonmalignant Disorders.

Reduced-intensity conditioning (RIC) before hematopoietic stem cell transplantation (HCT) in children could result in fewer complications during follow-up compared with myeloablative regimens. Hence, many RIC regimens are under investigation, but long-term follow-up is essential. We describe late follow-up beyond 2 years post-HCT in 43 children with nonmalignant disorders who underwent related or unrelated donor (56%) HCT on a multicenter study using a RIC regimen (alemtuzumab, fludarabine, and melphalan) followed by bone marrow (n = 30), peripheral blood (n = 3), or umbilical cord blood (n = 10) HCT for immune dysfunction, bone marrow failure, metabolic disorders, or hemoglobinopathy. Recipients (median age, 7.5 years; range, 3 to 26) underwent HCT 2 to 8 years (median, 3.1 years) before this report. Full donor (67%) or stable mixed chimerism (33%) was noted without late graft rejection. Five patients (12%) required systemic immunosuppression therapy (IST) beyond 2 years post-HCT for graft-versus-host disease (GVHD); 2 patients died 38 and 79 months later, whereas the others improved, enabling an IST wean. Overall, 17 complications were documented in 10 patients (23%). Complications not related to GVHD included hypothyroidism (n = 2), low grade neoplasms (n = 2), and delayed puberty (n = 1). One patient with GVHD had ovarian failure; all other postpubertal females resumed normal ovarian function. Twenty-seven of 28 school-age recipients were functioning at grade level. RIC HCT recipients thus had few regimen-related toxicities during long-term follow-up. However, objective long-term follow-up is still necessary to identify complications so timely intervention may be planned.

Innovative in vitro methodologies for establishing therapeutic equivalence.

To improve the quality of pharmaceutical products in their markets, several Latin American countries have begun to require that new generic products demonstrate bioequivalence against innovator or reference products. However, given the number of products involved, it is not feasible to rely on clinical studies to comply with this requirement. Instead, it makes sense to adopt or develop strategies that are appropriate to the characteristics of the region. To streamline drug development and accelerate patients' access to quality drug products, 15 years ago the United States Food and Drug Administration (FDA) decided to grant exemptions from clinical bioequivalence studies (i.e., biowaivers) for certain types of drug products based on the Biopharmaceutics Classification System (BCS). Biowaivers can significantly reduce development time and cost and can also prevent unnecessary human exposure to potentially dangerous drugs while providing a robust, consistent standard for therapeutic equivalence of generic drug products. In addition, the limited success of translating in vitro dissolution data into in vivo performance can be enhanced using innovative tools such as the in vitro dissolution and absorption systems (IDAS). By integrating in vitro dissolution and permeability tests, these systems can provide useful insights for formulation development. A thorough assessment of the potential of in vitro techniques, along with formalization of their use through regulatory science initiatives when appropriate, may lead to cost-effective tools to help address some of the quality and regulatory challenges faced in the Latin American and Caribbean region.

Hematopoietic Cell Transplantation Using Reduced-Intensity Conditioning Is Successful in Children with Hematologic Cytopenias of Genetic Origin.

Genetically derived hematologic cytopenias are a rare heterogeneous group of disorders. Allogeneic hematopoietic cell transplantation (HCT) is curative but offset by organ toxicities from the preparative regimen, graft rejection, graft-versus-host disease (GVHD), or mortality. Because of these possibilities, consideration of HCT can be delayed, especially in the unrelated donor setting. We report a prospective multicenter trial of reduced-intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan and HCT in 11 children with marrow failure of genetic origin (excluding Fanconi anemia) using the best available donor source (82% from unrelated donors). The median age at transplantation was 23 months (range, 2 months to 14 years). The median times to neutrophil (>500 × 10(6)/L) and platelet (>50 × 10(9)/L) engraftment were 13 (range, 12 to 24) and 30 (range, 7 to 55) days, respectively. The day +100 probability of grade II to IV acute GVHD and the 1-year probability of limited and extensive GVHD were 9% and 27%, respectively. The probability of 5-year overall and event-free survival was 82%; 9 patients were alive with normal blood counts at last follow-up and all were successfully off systemic immunosuppression. In patients with genetically derived severe hematologic cytopenias, allogeneic HCT with this RIC regimen was successful in achieving a cure. This experience supports consideration of HCT early in such patients even in the absence of suitable related donors.

Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies.

Fifty-two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion-dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan-Meier probabilities of overall and event-free survival at a median of 3.42 (range, 0.75-11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment-related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17-18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901).

Alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia.

BACKGROUND: Hematopoietic cell transplantation (HCT) is curative in patients with severe aplastic anemia (SAA). HCT is considered at presentation when a HLA-matched related donor (MRD) is available and has a high success rate. Unrelated donor (URD) transplants are typically undertaken if immunosuppressive therapy fails. Increased toxicity and graft rejection are often encountered in this setting. PROCEDURE: We report a prospective multi-center trial of HCT in 17 children with SAA following novel reduced intensity conditioning with alemtuzumab, fludarabine and melphalan, and the best available donor. Nine were URD transplants matched at 7-8/8 loci, and performed following failure of immune suppression. Median follow up was 61 months (range 6-128). RESULTS: All patients engrafted. Estimated 5 year event-free and overall-survival was 88% (95%CI 65.7-96.7). Five year overall survival for MRD and URD transplants was 100% and 78% (95%CI 45-93.6) respectively. Median times to neutrophil and platelet engraftment was 14 (range 10-27) and 23.5 (range 11-65) days respectively. Treatment related mortality was 12%. The incidence of grade II-IV and III-IV acute graft-versus-host disease was 29% and 18% respectively. At two years, all but one patient discontinued immunosuppression successfully. Laboratory measures of immune reconstitution normalized at one year and infection rates were low in the latter part of the first year. CONCLUSIONS: HCT using this RIC approach was well tolerated and successful in achieving donor engraftment and early immune reconstitution with good quality of life free of immune suppression. Children with SAA can be successfully transplanted using alemtuzumab based conditioning.

Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns.

Chronic lymphocytic leukemia is characterized by relapse after treatment and chemotherapy resistance. Similarly, in other malignancies leukemia cells accumulate mutations during growth, forming heterogeneous cell populations that are subject to Darwinian selection and may respond differentially to treatment. There is therefore a clinical need to monitor changes in the subclonal composition of cancers during disease progression. Here, we use whole-genome sequencing to track subclonal heterogeneity in 3 chronic lymphocytic leukemia patients subjected to repeated cycles of therapy. We reveal different somatic mutation profiles in each patient and use these to establish probable hierarchical patterns of subclonal evolution, to identify subclones that decline or expand over time, and to detect founder mutations. We show that clonal evolution patterns are heterogeneous in individual patients. We conclude that genome sequencing is a powerful and sensitive approach to monitor disease progression repeatedly at the molecular level. If applied to future clinical trials, this approach might eventually influence treatment strategies as a tool to individualize and direct cancer treatment.

Accurate whole human genome sequencing using reversible terminator chemistry.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.

Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs.

MOTIVATION: Whole genome and exome sequencing of matched tumor-normal sample pairs is becoming routine in cancer research. The consequent increased demand for somatic variant analysis of paired samples requires methods specialized to model this problem so as to sensitively call variants at any practical level of tumor impurity. RESULTS: We describe Strelka, a method for somatic SNV and small indel detection from sequencing data of matched tumor-normal samples. The method uses a novel Bayesian approach which represents continuous allele frequencies for both tumor and normal samples, while leveraging the expected genotype structure of the normal. This is achieved by representing the normal sample as a mixture of germline variation with noise, and representing the tumor sample as a mixture of the normal sample with somatic variation. A natural consequence of the model structure is that sensitivity can be maintained at high tumor impurity without requiring purity estimates. We demonstrate that the method has superior accuracy and sensitivity on impure samples compared with approaches based on either diploid genotype likelihoods or general allele-frequency tests. AVAILABILITY: The Strelka workflow source code is available at ftp://strelka@ftp.illumina.com/. CONTACT: csaunders@illumina.com

Immunotherapy-related adverse events in real-world patients with advanced non-small cell lung cancer on chemoimmunotherapy: a Spinnaker study sub-analysis.

Background: The Spinnaker study evaluated survival outcomes and prognostic factors in patients with advanced non-small-cell lung cancer receiving first-line chemoimmunotherapy in the real world. This sub-analysis assessed the immunotherapy-related adverse effects (irAEs) seen in this cohort, their impact on overall survival (OS) and progression-free survival (PFS), and related clinical factors. Methods: The Spinnaker study was a retrospective multicentre observational cohort study of patients treated with first-line pembrolizumab plus platinum-based chemotherapy in six United Kingdom and one Swiss oncology centres. Data were collected on patient characteristics, survival outcomes, frequency and severity of irAEs, and peripheral immune-inflammatory blood markers, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII). Results: A total of 308 patients were included; 132 (43%) experienced any grade irAE, 100 (32%) Grade 1-2, and 49 (16%) Grade 3-4 irAEs. The median OS in patients with any grade irAES was significantly longer (17.5 months [95% CI, 13.4-21.6 months]) than those without (10.1 months [95% CI, 8.3-12.0 months]) (p<0.001), either if Grade 1-2 (p=0.003) or Grade 3-4 irAEs (p=0.042). The median PFS in patients with any grade irAEs was significantly longer (10.1 months [95% CI, 9.0-11.2 months]) than those without (6.1 months [95% CI, 5.2-7.1 months]) (p<0.001), either if Grade 1-2 (p=0.011) or Grade 3-4 irAEs (p=0.036). A higher rate of irAEs of any grade and specifically Grade 1-2 irAEs correlated with NLR <4 (p=0.013 and p=0.018), SII <1,440 (p=0.029 ad p=0.039), response to treatment (p=0.001 and p=0.034), a higher rate of treatment discontinuation (p<0.00001 and p=0.041), and the NHS-Lung prognostic classes (p=0.002 and p=0.008). Conclusions: These results confirm survival outcome benefits in patients with irAEs and suggest a higher likelihood of Grade 1-2 irAEs in patients with lower NLR or SII values or according to the NHS-Lung score.

SafeSpace: what is the feasibility and acceptability of a codesigned virtual reality intervention, incorporating compassionate mind training, to support people undergoing cancer treatment in a clinical setting?

OBJECTIVES: The SafeSpace study codesigned and tested a virtual reality (VR) intervention, incorporating relaxation and compassionate mind training to determine acceptability/feasibility in an oncology setting and evaluate impact on physical/psychological well-being and quality of life. DESIGN: A two-phase study. Phase I determined key characteristics using an experienced-based codesign approach. Phase II evaluated the intervention using various measures and qualitative interviews in a mixed methods approach. Descriptive statistics were used to analyse measures data and framework analysis to analyse interviews. SETTING: A specialist cancer centre, UK. PARTICIPANTS: 11 in phase I and 21 in phase II. Participants were in cancer treatment, recovery or palliative care. PRIMARY AND SECONDARY OUTCOME: Primary outcome: acceptability of the intervention, assessed by >60% uptake of three sessions. SECONDARY OUTCOMES: impact on psychological well-being using EQ-5D/QLQ-C30, Profile of Mood Scale, Warwick and Edinburgh Mental Well-being Scale, Depression and Anxiety Severity Scale 21, Self-Compassion Scale, Acceptance and Action Questionnaire and a locally developed questionnaire to capture self-compassion post use. Physiological impact was assessed by change in heart rate (HR)/HR variability and electrodermal activity (EDA). RESULTS: Twenty participants (mean age=48.7 years; SD=16.87); 65% (n=13) completed three sessions. Mental well-being improved following each use and from baseline to after session 3 (VR 1-z=2.846, p≤0.01; VR 2-z=2.501, p≤0.01; VR 3-z=2.492, p≤0.01). There was statistically significant difference in mean scores for EDA at mid-session and post session compared with pre session (F (1.658, 4.973)=13.364, p<0.05). There was statistically significant reduction in stress levels from baseline to post session 3. Participants found the intervention acceptable and highlighted areas for development. CONCLUSION: The intervention is acceptable and feasible and has shown positive effects on mental well-being/stress in the oncology setting. Larger studies are needed to confirm findings.