Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study.

Schizophrenia is a common, severe, and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell-free DNA (cfDNA) fragments are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129), and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area under the curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier, or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.

Liquid biopsy reveals collateral tissue damage in cancer.

Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type-specific cfDNA methylation markers enabled the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.

Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study.

Anecdotal evidence of successful cannabis treatment in autism spectrum disorder (ASD) are accumulating but clinical studies are lacking. This retrospective study assessed tolerability and efficacy of cannabidiol-rich cannabis, in 60 children with ASD and severe behavioral problems (age = 11.8 ± 3.5, range 5.0-17.5; 77% low functioning; 83% boys). Efficacy was assessed using the Caregiver Global Impression of Change scale. Adverse events included sleep disturbances (14%) irritability (9%) and loss of appetite (9%). One girl who used higher tetrahydrocannabinol had a transient serious psychotic event which required treatment with an antipsychotic. Following the cannabis treatment, behavioral outbreaks were much improved or very much improved in 61% of patients. This preliminary study supports feasibility of CBD-based cannabis trials in children with ASD.

[THE PLACEBO EFFECT - NEUROBIOLOGICAL ASPECTS].

INTRODUCTION: Any medical treatment, whether it be medication, behavioral therapy or medical procedure, can affect the patient in a very complex way. Each of these forms of medical treatment have both psychobiological and physiological effects on the patient, with interactions between those levels. When considering the specific efficacy of a new treatment, there is therefore a need to neutralize the psychobiological effect by comparing the effect of the treatment to the effect of a placebo - a treatment involving similar characteristics which does not produce that physiological effect. We may term the non-specific effect (the psychobiological effect) the 'placebo effect'. However, the placebo effect itself involves physiological elements, elements of which our understanding has improved greatly in recent years. In this review we will discuss the neurobiological aspects of the placebo effect. We now know that the influence of the placebo effect on medical treatment and on the interaction between therapist and patient is enormous and may contribute up to 50% of the treatment's effect, making it very important for every therapist to become aware of these aspects.

Osteomyelitis of the Odontoid Process in Children: Two Cases and Review of the Literature.

OBJECTIVE: To report clinical, laboratory and radiologic manifestations in 2 infants with osteomyelitis of the odontoid process (dens). BACKGROUND: Vertebral osteomyelitis is uncommon, and osteomyelitis of the dens has rarely been reported in the pediatric population. METHODS: The medical records of 2 infants diagnosed with dens osteomyelitis were reviewed. RESULTS: Both infants had fever, which resolved spontaneously before admission. Both were nontoxic appearing with persistent neck stiffness and torticollis. White blood count and C-reactive protein were only mildly elevated in both cases. Blood cultures were sterile. Magnetic resonance imaging revealed the diagnosis. They both fully recovered. CONCLUSIONS: We report 2 cases of dens osteomyelitis. These cases emphasize the need to consider C1-C2 osteomyelitis in the differential diagnosis of neck stiffness and torticollis.