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Purpose/Objective Total body irradiation (TBI) remains a key component of conditioning for allogeneic haemopoietic stem cell transplant (HSCT), with interstitial pneumonitis (IP) and chronic kidney disease (CKD) important late sequelae. We undertook a retrospective service evaluation of TBI patients treated with a forward-planned intensity modulated radiotherapy technique (FP IMRT). Material/Methods 74 adult patients were identified; all received step and shoot FP IMRT TBI, 14.4 Gy in 8 fractions over 4 days. Mean doses to the lungs and kidneys were 12–12.5 Gy. Toxicities were defined as per CTCAE v4.0: IP as multilobar infiltrates on CT with symptoms of dyspnoea, and renal dysfunction as an Estimated Glomerular Filtration rate (eGFR) 3 months. Secondary endpoints were overall survival (OS), progression free survival (PFS), cumulative incidence of non-relapse mortality (NRM), relapse risk and of acute and chronic GvHD. Results Patients received treatment for the following diagnosis: ALL/LBL (n = 37); AML (n = 33), CML-BC (n = 2) and High grade NHL (n = 2). The rate of IP due to any cause was 30%; positive microbiological evidence in 73% (16 /22). Idiopathic IP was seen in 8%, with only 4% (n = 3) having IP Grade ≥ 3. Two (4%) of 52 long term survivors developed CKD, one with thrombotic microangiopathy. 4 year NRM was 16% (CI 11–32%); no treatment related deaths in matched sibling or umbilical cord blood HSCT. Conclusion FP IMRT TBI, reducing dose to the lungs and kidneys, has lower rates of idiopathic IP and CKD compared to the literature. This technique is safe and effective conditioning for full intensity HSCT.

The low expression Met allele of the BDNF Val66Met polymorphism is associated with impaired fear extinction in healthy controls, and poorer response to exposure therapy in patients with Posttraumatic Stress Disorder (PTSD). Given that fear extinction underlies exposure therapy, this raises the question of the impact of BDNFVal66Met polymorphism on fear extinction in PTSD, yet this question has not yet been examined. One hundred and six participants (22 PTSD, 46 trauma-exposed controls (TC) and 38 non-trauma exposed controls (NTC)) completed a fear conditioning and extinction task and saliva samples were taken for DNA extraction and genotyped for the BDNF Val66Met polymorphism. Moderation analyses using PROCESS examined whether BDNF genotype (Val-Val vs Met carriers) moderated the relationship between PTSD symptom severity (and diagnostic status) and skin conductance response (SCR) amplitude during fear extinction. The PTSD group displayed significantly slower fear extinction learning compared to TC and NTC in the early extinction phase. The BDNF Val66Met polymorphism moderated the relationship between PTSD and fear extinction learning, such that poorer fear extinction learning was associated with greater PTSD symptom severity (and PTSD diagnostic status) in individuals with the low-expression Met allele, but no relationship was demonstrated in individuals with the Val-Val allele. This study reveals that impaired fear extinction learning is particularly evident in individuals with PTSD who carry the low-expression BDNF Met allele and importantly not in those with the Val-Val allele. This provides novel evidence of a link between BDNF and impaired fear extinction learning in PTSD, which may contribute to poorer response to exposure therapy.

Purpose/Objective(s) Radiotherapy (RT) has potential synergistic effects with CD19 CAR-T but is not yet widely used as bridging therapy for lymphoma. Comprehensive outcome data of RT bridged patients are limited, and selection criteria for RT bridging and optimal dose / fractionation are unknown. We hypothesized that RT is a safe, well tolerated and effective bridging to CAR-T even in patients with advanced stage and high-risk features. We analyzed details of RT bridging in a prospective national CAR-T cohort, examining patient, disease and treatment factors which may affect outcome of RT bridging. Materials/Methods We analyzed consecutive patients with r/r high-grade lymphoma who had leukapheresis for axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between Dec 2018 - Nov 2020 in 10 UK centers and received RT bridging. Results Of 371 leukapheresed patients, 76 (21%) received RT bridging (61 RT alone, 15 combined modality treatment (CMT)). Median age was 58 years. 65% had de novo diffuse large B-cell lymphoma, 7% primary mediastinal B-cell, and 28% transformed lymphoma. 64 were infused (50 axi-cel, 14 tisa-cel), with a median turnaround time of 44 days from apheresis to infusion. 12/75 (16%) patients did not proceed to CAR-T infusion (6 progressive disease (PD), 4 deaths (not related to RT), 1 manufacturing failure, 1 CR after bridging). The dropout rates were 11%, 33% & 22% for RT, CMT and chemotherapy-bridged patients respectively (P = 0.086). Disease characteristics were similar in RT & CMT groups; the majority had advanced stage (71% and 86%), 34% & 43% bulky disease, 59% & 73% extranodal involvement, 55% & 57% were primary refractory to R-CHOP, 75% & 67% had SD/PD as best response to last treatment, 18% & 13% had prior autologous transplant, and 31% & 33% had double/triple hit or -expression. In-field response in 53 cases bridged with RT alone (doses 20 – 40Gy) was 85% (11/14) for early stage (3 CR) and 63% (22/35) for advanced stage. Details of the radiation techniques and RT-related toxicities will be provided at the meeting. The ongoing overall response rate at 3 months post infusion was 63% (50% CR). With a median follow-up of 11.5 months, the median time to progression has not been reached. The 6- & 12-months event-free survival was 60% (95% CI: 47-71) and 58% (95% CI: 45 -69), respectively, with no significant difference between RT and CMT. The median overall survival (OS) was 17.8 months (95% CI: 8.9-NR), with 6- & 12-months OS rates of 77% (95% CI: 64 – 86) and 65% (95% CI: 50-76). Post CAR-T toxicity was favorable, with 7/64 (11%) experiencing G3/4 cytokine release syndrome, 8/64 (13%) G3/4 neurotoxicity. Treatment-related mortality was 4.6%. Conclusion RT is a safe and effective bridging therapy prior to CD19 CART in lymphoma. In this large prospective real world national cohort with high proportion of advanced stage and high-risk features, RT bridging was given successfully with low dropout rate and excellent survival outcomes.

Brain-derived neurotropic factor (BDNF) is a potent regulator of memory processes and is believed to influence the consolidation of fear extinction memories. No previous human study has tested the effect of unstimulated BDNF on fear extinction recall, and no study has tested the association between plasma BDNF levels and psychophysiological responding during an extinction paradigm. We tested the association between fear responses during a 2-day differential conditioning, extinction and extinction recall paradigm and Val66Met genotype in a group of healthy participants (N = 191). There were no group differences during habituation or acquisition. Met allele carriers compared to Val homozygotes displayed higher responses to the CS + compared to the CS- during extinction learning and had higher responding to both the CS+ and CS- during extinction recall. Plasma levels of BDNF protein that were collected in a sub-sample of the group (n = 56) moderated the effect of Met allele presence, such that lower BDNF level was associated with higher skin conductance response in the Met but not Val group to the CS+ during extinction learning and to both the CS+ and CS- during extinction recall. The current results extend previous observations of a Val66Met effect during fear extinction learning to extinction recall and show for the first time that these effects are moderated by plasma BDNF level.

Background: Patients with cancer are at increased risk of severe outcomes from COVID-19. Understanding the impact of SARS-CoV-2 infection and vaccination induced-immunity is an area of unmet need. Methods: CAPTURE (NCT03226886) is a prospective longitudinal cohort study of COVID-19 vaccine or SARS-CoV-2 infection-induced immunity. SARS-CoV-2 infections were confirmed by RT-PCR and ELISA. Neutralising antibody titres (NAbT) against wild-type (WT) SARS-CoV-2 and variants of concern (VOC;Alpha, Beta, Delta) and SARS-CoV-2 specific T-cells (SsT-cells) were quantified. Results: 118 patients (89% solid malignancy, [SM]) were SARS-CoV-2-positive (median follow-up: 154 days). 85% patients were symptomatic;2 died of COVID-19. 82% had S1-reactive antibodies, of whom 89% had neutralising antibodies (NAbs);NAbT were lower against all VOCs. While S1-reactive antibody levels declined over time, NAbT remained stable up to 329 days. Most patients had detectable SsT-cells (76% CD4+, 52% CD8+). Haematological malignancy (HM) patients had impaired immune responses that were disease and treatment-specific (anti-CD20), but with evidence suggestive of compensation from T-cells. 585 patients were evaluated following 2 doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after 2 doses were 85% and 54% in patients with SM and HM, respectively. A lower proportion of patients had detectable NAbs against SARS-CoV-2 VOC (Alpha 62%, Beta 54%, Delta 49%) vs WT (84%), with corresponding significantly lower NAbT. Patients with HM were more likely to have an undetectable NAb and had lower NAbT vs solid malignancies to both WT and VOCs. Seroconversion showed poor concordance with NAbTs against VOCs. Prior SARS-CoV-2 infection boosted NAbT including against VOCs. Anti-CD20 treatment was associated with severely diminished NAbTs. Vaccine-induced T-cell responses were detected in 80% of patients, with no differences between vaccines or cancer types. Conclusions: Patients with HM had blunted humoural responses to infection and vaccination, particularly against VOCs, but preserved cellular responses might contribute to protection. Our results lend support to prioritisation of all cancer patients for further booster vaccination. Clinical trial identification: NCT03226886. Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust. Funding: The Royal Marsden Charity;The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute for Cancer Research (ICR). Disclosure: All authors have declared no conflicts of interest.

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect.

Acceptance and Commitment Therapy (ACT) utilizes cognitive defusion strategies to alter the function of unwanted, distressing thoughts so as to reduce their impact and foster greater psychological flexibility. Though defusion is linked to several positive outcomes (e.g., reduced thought believability, improved pain tolerance), it remains unclear whether such effects are associated with the behavioral process of defusion itself; namely, behavior that is relatively broad and flexible compared with behavior that is narrow and inflexible. To address this issue, the present study assessed the impact of a defusion intervention on behavior, as measured by the Implicit Relational Assessment Procedure (IRAP). Undergraduates high in spider fear ( N =65) were randomly assigned to one of two interventions targeting phobic thoughts of spiders: a defusion intervention or a thought distraction intervention. A control condition (reading an article) was used to evaluate the relative impact of both interventions. Participants completed the IRAP and rating scales of believability and distress of target thoughts pre- and post-intervention. Consistent with expectation, defusion produced significantly greater pre- to post-intervention reductions in IRAP effects and thought believability relative to comparison conditions. The practical and scientific implications of the present findings, suggesting that defused behavior is broad and flexible relative to narrow and inflexible, are discussed.

Recent evidence suggests that an interaction of noradrenaline (NE) and cortisol (CORT) during encoding leads to greater consolidation of emotional memories. Convergent models of posttraumatic stress disorder (PTSD) suggest the release of CORT and NE lead to greater intrusive memories in PTSD. This study examined the effect of NE and CORT during encoding on recall and intrusive memories in PTSD. Fifty-eight participants (18 participants with PTSD, 20 trauma-exposed controls, and 20 non-trauma exposed controls) provided saliva samples of NE (indexed by salivary alpha amylase; sAA) and CORT at (a) baseline and (b) after viewing negative emotional stimuli. Delayed memory recall and number of intrusive memories of negative, neutral and positive stimuli were recorded two days after this initial testing session. The PTSD group had greater NE levels to negative stimuli and reported greater numbers of intrusive memories of negative stimuli than controls. Regression analyses revealed that the interaction of CORT and NE significantly predicted negative intrusive memories in the PTSD group. The trauma-exposed group reported significantly greater recall of negative images compared to controls, but did not differ significantly from the PTSD group. The PTSD group reported greater levels of suppression of negative images during encoding compared to the other groups. Our results confirm that the interaction of NE and CORT significantly predicts greater negative intrusive memories, but this occurs specifically in the PTSD group. This suggests that a level of heightened arousal is required for the relationship between stress hormones and emotional memory to manifest in PTSD.

Computer misuse, and in particular computer hacking, has gripped the public imagination of late. A rash of US media reports crossed the Atlantic late last Autumn and gained briefer reprints in the British national press alongside tantalisingly short excerpts from European Community national dailies commenting on and reporting incidents in Belgium, France and Scandinavia. At the same time The Sunday Times identified computer pornography and children as an area of social concern while the computer security trade journals continued to highlight in some detail industrial and commercial vulnerability from disaffected computer staff or malicious or naive Outsiders. As winter wore on stories of computer hacking surfaced, with The Observer's Victor Smart taking the lead in charting the largeness of the threat that hackers posed not just to industry and the financial world but to the Government (and to any Government irrespective of Party colouring) and to the private citizen whose visage, warts and all, is now so finely-documented on a variety of computer systems. I wrote an article in The Times giving examples without company or individual names, and a riposte in The Guardian to a challenger supporting hacking. The television and radio came alive in April and subsequently, with Channel 4~and ITN leading 'The Money Programme' by a nose. The 'Today' programme, 'The World Tonight' and BBC World Service each treated the topic with ingenuity and responsibility. Channel 4 and three days later 'The Money Programme' took hacking in the round, talking to mainframe manufacturers, users and to hackers while ITN boldly eavesdropped electronically, tO the dismay of their legal advisers. As a commentator, I pointed out their action was wholly within the law, but even knowing this did not make the scrutiny of others' personal data seem a healthy or a socially acceptable pastime.