The phenomenological diversity of auditory verbal hallucinations (AVH) is not currently accounted for by any model based around a single mechanism. This has led to the proposal that there may be distinct AVH subtypes, which each possess unique (as well as shared) underpinning mechanisms. This could have important implications both for research design and clinical interventions because different subtypes may be responsive to different types of treatment. This article explores how AVH subtypes may be identified at the levels of phenomenology, cognition, neurology, etiology, treatment response, diagnosis, and voice hearer’s own interpretations. Five subtypes are proposed; hypervigilance, autobiographical memory (subdivided into dissociative and nondissociative), inner speech (subdivided into obsessional, own thought, and novel), epileptic and deafferentation. We suggest other facets of AVH, including negative content and form (eg, commands), may be best treated as dimensional constructs that vary across subtypes. After considering the limitations and challenges of AVH subtyping, we highlight future research directions, including the need for a subtype assessment tool.

The reprogramming of a patient’s immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.

BackgroundFor children with cancer, the clinical integration of precision medicine to enable predictive biomarker–based therapeutic stratification is urgently needed.MethodsWe have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)–specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings.ResultsA total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma.ConclusionWe demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel–based approach can identify actionable genetic alterations in a high proportion of patients.

The present review aimed to 1) identify what sleep disturbances co-occur alongside psychotic-like, dissociative and hypomanic experiences; 2) assess the strength of potential associations between the severity of sleep disturbances and of the experiences studied; and 3) appraise evidence for a causal link. MedLine and PsycInfo were searched and 44 studies were deemed eligible. Results showed that insomnia was associated with all individual psychotic-like, dissociative and hypomanic experiences reviewed (effect size range: small-to-large). Parasomnias were associated with all psychotic-like experiences; however, there was evidence of variation in magnitude between individual experiences. An eveningness chronotype was associated with dissociative and hypomanic experiences, and circadian dysrhythmia was found alongside hypomania but not the other experiences reviewed. Finally, experimental sleep manipulation studies revealed a potential causal link between sleep loss and psychotic-like and dissociative experiences, although size and consistency of effects varied by specific experience. Future research, using experimental manipulations of sleep to address putative mechanisms, will enable questions of causality to be answered with more confidence.

Background: Treatment of high risk neuroblastoma remains challenging; current multimodal treatment regimens achieve long term survival in <50% of patients and are associated with significant morbidity. Ganglioside GD2 is abundantly expressed on almost all neuroblastomas whilst expression on normal tissue is highly limited, providing a suitable CAR target. Here, we report the preliminary results of a Phase I clinical study of GD2-CART for refractory/relapsed neuroblastoma (NCT02761915). Trial design: The therapeutic (1RG-CART) is autologous T-cells transduced with a gamma-retroviral vector encoding both an anti-GD2 CAR and the RQR8 suicide gene. The CAR comprises a humanized anti-GD2 single chain variable fragment derived from the K666 antibody and CD28/CD3ζ signalling domains. Both lymphodepletion and CART dose were escalated as follows: dose level (DL) 1 without lymphodepletion, DL2 with 1.2 g/m2 cyclophosphamide and DL3 and beyond 1.2 g/m2 cyclophosphamide and 125 mg/m2 fludarabine followed by administration of a single intravenous dose of 1x107/m2 (DL1-3) or 1x108/m2 (DL4) 1RG-CART. Primary objectives are to assess safety and tolerability. Results: To date, 12 patients have been enrolled. All had relapsed/refractory neuroblastoma with measurable disease in bone (n=11), bone marrow (n=7) and/or soft tissue sites (n=9). Cell products were successfully manufactured for all patients. Median transduction efficiency was 34.5% (range 16-54%). Nine patients have been treated on DL1 (n=4), DL2 (n=1), DL3 (n=1) and DL4 (n=3) respectively. No dose limiting toxicity (DLT) was seen. For patients treated on DL1-3 (1x107/m2), 1RG-CART could not be detected in peripheral blood, and no clinical responses were seen. In contrast, expansion of 1RG-CART cells as detected by flow cytometry and qPCR was seen in the 3 patients treated on DL4 (1x108/m2). In two DL4 patients, 1RG-CART expansion was still limited and transient (marking levels <10,000 copies/μg DNA). These patients had disease progression as measured at Day +28. In one DL4 patient however, 1RG-CART marking levels of >40,000 copies/μg DNA were achieved. This patient developed Grade 2 cytokine release syndrome (Day +5) and biochemical evidence of tumour lysis (Day +21). Disease reassessment on Day +28 showed response in many sites of bone/marrow disease as measured by mIBG scintigraphy, and near complete tumour clearance in bone marrow which at baseline was heavily infiltrated with neuroblastoma. Disease progression occurred on Day +45 at which time 1RG-CART were no longer detectable. In the absence of DLT this prompted us to continue with DL5 (1x109/m2). Conclusions: These preliminary results are the first to demonstrate on-target activity in bone and bone marrow of GD2-CART in this childhood solid tumour. Further 1RG-CART dose escalation is warranted, and under way. Citation Format: Karin Straathof, Barry Flutter, Rebecca Wallace, Simon Thomas, Gordon Cheung, Angela Collura, Talia Gileadi, Jack Barton, Gary Wright, Sarah Inglott, David Edwards, Claire Barton, Karen Dyer, Nigel Westwood, Thalia Loka, Sarita Depani, Karen Howe, Giuseppe Barone, Martin Pule, John Anderson. A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT145.