Faculty Bibliography

Ultrasound-guided wire localization of impalpable lesions is a well-recognized technique in the management of breast pathology, but its use in the head and neck is not well described. Performed under local anesthesia, high-resolution ultrasound provides real-time imaging for accurate placement of the wire resulting in fewer complications. Wire localization can focus the surgical approach, which reduces operating time and minimizes trauma to surrounding tissues. In this technical note, we describe two cases of pre-operative ultrasound-guided wire localization to facilitate the surgical excision of impalpable neck lesions.

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.

The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.

Probability and risk are important factors for value-based decision making and optimal foraging. In order to survive in an unpredictable world, organisms must be able to assess the probability and risk attached to future events and use this information to generate adaptive behavior. Recent studies in non-human primates and rats have shown that both probability and risk are processed in a distributed fashion throughout the brain at the level of single neurons. Reward probability has mainly been shown to be coded by phasic increases and decreases in firing rates in neurons in the basal ganglia, midbrain, parietal, and frontal cortex. Reward variance is represented in orbitofrontal and posterior cingulate cortex and through a sustained response of dopaminergic midbrain neurons.

This article reviews the role of imaging in the management of trauma patients. First the trauma series is reviewed, principally the chest, pelvis and cervical spine radiographs along with an approach to their interpretation. The role of computed tomography in trauma imaging is then discussed.

The importance of cranial computed tomography in the diagnosis and follow up of intracranial pathology cannot be underestimated. Clinicians at every level should have a basic understanding of this technique. This second part discusses the practical use of computed tomography in the clinical setting.

Individuals can learn by interacting with the environment and experiencing a difference between predicted and obtained outcomes (prediction error). However, many species also learn by observing the actions and outcomes of others. In contrast to individual learning, observational learning cannot be based on directly experienced outcome prediction errors. Accordingly, the behavioral and neural mechanisms of learning through observation remain elusive. Here we propose that human observational learning can be explained by two previously uncharacterized forms of prediction error, observational action prediction errors (the actual minus the predicted choice of others) and observational outcome prediction errors (the actual minus predicted outcome received by others). In a functional MRI experiment, we found that brain activity in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex respectively corresponded to these two distinct observational learning signals.

The importance of cranial computed tomography in the diagnosis and follow up of intracranial pathology cannot be underestimated. Clinicians at every level should have a basic understanding of this technique. This first of two articles looks at the technical strengths and weaknesses of cranial computed tomography, and cranial anatomy.

Non-fatal stroke has significant social and financial implications, and the use of appropriate imaging is essential for early diagnosis and treatment to prevent permanent disability. This article discusses the pivotal role radiological imaging plays in the management of stroke and transient ischaemic attack.

Preoperative positron emission tomography (PET) scanning of three patients with lung cancer revealed increased unilateral focal activity in a parotid gland. Further investigation with ultrasound and core biopsy confirmed benign parotid neoplasm in all three cases. The phenomenon of imaging-related incidentaloma is increasingly recognized and further investigation of these lesions remains controversial. This article discusses PET incidentaloma in the parotid, why tracer uptake may occur and how these lesions may be managed with changes in patient management that ensue.