Assessing and managing hallucinations in children and adolescents

Children and young people who disclose sensory experiences suggestive of hallucinations do pose a diagnostic and therapeutic challenge to mental health clinicians in their daily practice. Hallucinations, defined as erroneous percepts in the absence of identifiable stimuli, are a key feature of psychotic states, but they had also long been known to present in children with non-psychotic psychiatric disorders. The recent upsurge of interest in childhood hallucinations has arisen out of epidemiological studies of child populations, where comprehensive symptom enquiry has included screening questions on abnormal perceptions. This has resulted in what seemed surprisingly high rates of hallucinatory experiences among other psychotic-like symptoms. Children and ado lescents show a prevalence rate of self-reported hallucinatory experiences of about 10% and are reported as more common in childhood than in adolescence. These hallucinatory phenomena are most likely to occur in the absence of any psychiatric disorder and would be expected more often than not to be simpler, less elaborate and distressing than those observed in clinical samples of children with psychiatric disorders. Longitudinal studies have in fact shown that only a small proportion of children in the general population with hallucinations (less than 10%) will suffer from a psychotic disorder later in life. In clinical settings, presentations with hallucinations can be an expression of a psychotic state, or alternatively of a symptom constellation co-occurr ing along other psychiatric conditions. Associations have been found between hallucinations and traumatic stressors (i.e. bullying and sexual assault), severity of psychopathology and suicidal symptoms. These associations could be mediated by individual vulnerability, involving neurodevelopmental anomalies and a tendency to mental dissociation and mood dysregulation. This review details the clinical assessment of hallucinations in children and adolescents taking into account developmental considerations and paediatric organic associations. It describes hallucinations in young people with psychoses (schizophrenic spectrum and mood disorders) and other non-psychotic psychiatric disorders (emotional and behavioural disorders), and it addresses therapeutic aspects

The use of routine outcome measures in two child and adolescent mental health services: a completed audit cycle

Background: Routine outcome measurement (ROM) is important for assessing the clinical effectiveness of health services and for monitoring patient outcomes. Within Child and Adolescent Mental Health Services (CAMHS) in the UK the adoption of ROM in CAMHS has been supported by both national and local initiatives (such as government strategies, local commissioning policy, and research). Methods: With the aim of assessing how these policies and initiatives may have influenced the uptake of ROM within two different CAMHS we report the findings of two case-note audits: a baseline audit conducted in January 2011 and a re-audit conducted two years later in December 2012-February 2013. Results: The findings show an increase in both the single and repeated use of outcome measures from the time of the original audit, with repeated use (baseline and follow-up) of the Health of the Nation Outcome Scale for Children and Adolescents (HoNOSCA) scale increasing from 10% to 50% of cases. Re-audited case-notes contained more combined use of different outcome measures, with greater consensus on which measures to use. Outcome measures that were applicable across a wide range of clinical conditions were more likely to be used than symptom-specific measures, and measures that were completed by the clinician were found more often than measures completed by the service user. Conclusions: The findings show a substantial improvement in the use of outcome measures within CAMHS. These increases in use were found across different service organisations which were subject to different types of local service priorities and drivers

Implementation of routine outcome measurement in child and adolescent mental health services in the United Kingdom: a critical perspective

The aim of this commentary is to provide an overview of clinical outcome measures that are currently recommended for use in UK Child and Adolescent Mental Health Services (CAMHS), focusing on measures that are applicable across a wide range of conditions with established validity and reliability, or innovative in their design. We also provide an overview of the barriers and drivers to the use of Routine Outcome Measurement (ROM) in clinical practice

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET inhibition; Pralsetinib; Targeted therapyInhibición de RET; Pralsetinib; Terapia dirigidaInhibició de RET; Pralsetinib; Teràpia dirigidaBackground RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. Patients and methods ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Results Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Conclusions Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.This work was supported by Blueprint Medicines Corporation and F. Hoffmann-La Roche, Ltd, Switzerland (no grant number)

Exploring the physical channel of diffusion-based molecular communication by simulation

Diffusion-based molecular communication is a promising bio-inspired paradigm to implement nanonetworks, i.e., the interconnection of nanomachines. The peculiarities of the physical channel in diffusion-based molecular communication require the development of novel models, architectures and protocols for this new scenario, which need to be validated by simulation. With this purpose, we present N3Sim, a simulation framework for diffusion-based molecular communication. N3Sim allows to simulate scenarios where transmitters encode the information by releasing molecules into the medium, thus varying their local concentration. N3Sim models the movement of these molecules according to Brownian dynamics, and it also takes into account their inertia and the interactions among them. Receivers decode the information by sensing the particle concentration in their neighborhood. The benefits of N3Sim are multiple: the validation of channel models for molecular communication and the evaluation of novel modulation schemes are just a few examples.Peer ReviewedPostprint (author’s final draft

Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors

Colorectal cancer; Lung cancer; Monoclonal antibodyCáncer colorrectal; Cáncer de pulmón; Anticuerpo monoclonalCàncer colorectal; Càncer de pulmó; Anticòs monoclonalBackground The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors. Patients and methods Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab. Results A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival. Conclusions Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.This work was supported by Glycotope GmbH (no grant number)

Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

Leukemia inhibitory factor; Safety; Solid tumorsFactor inhibidor de la leucemia; Seguridad; Tumores sólidosFactor inhibidor de la leucèmia; Seguretat; Tumors sòlidsBackground Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors. Materials and methods Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers. Results Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action. Conclusions MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.This work was supported by Northern Biologics (no grant number). Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Carole Mongin-Bulewski, PhD, of Ashfield MedComms (Manchester, UK), an Ashfield Health company, and was funded by AstraZeneca (no grant number)