Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Imaging patterns of intraductal papillary mucinous neoplasms of the pancreas: an illustrated discussion of the International Consensus Guidelines for the Management of IPMN.

Intraductal papillary mucinous neoplasms (IPMN) are being diagnosed with increasing frequency, necessitating an algorithm to help stratify patients into low- and high-risk groups, for follow-up versus more invasive evaluation. New evidence concerning their natural history and overall risk of malignancy has emerged since the 2006 International Association of Pancreatology consensus guidelines, prompting an update in 2012, that distinguishes radiologic 'worrisome features' from 'high-risk stigmata'. The aim of this article is to illustrate, with case examples, the variable imaging patterns of IPMN and how their radiologic features, such as cyst size and mural nodules, are interpreted in the context of the new 2012 guidelines. The 2012 and 2006 guidelines will be compared and discussed with reference to additional studies that have since been published. Despite these guidelines, lingering uncertainty remains about the natural history of IPMN, a source of unease to both radiologists and referring clinicians alike, mandating further refinement of clinical and radiologic parameters predictive of malignancy. Emerging data regarding the risk of extrapancreatic malignancy, as well as synchronous or metachronous pancreatic ductal adenocarcinoma remote in location from a branch duct IPMN are also reviewed. With the expanding research and evolving understanding of this clinicopathologic entity across the globe, radiologists will continue to play an important role in the management of patients with IPMN.

MRI for evaluation of treatment response in rectal cancer.

MRI plays an increasingly pivotal role in the clinical staging of rectal cancer in the baseline and post-treatment settings. An accurate evaluation of response to neoadjuvant treatment is crucial because of its major influence on patient management and quality of life. However, evaluation of treatment response is challenging for both imaging and clinical assessments owing to treatment-related inflammation and fibrosis. At one end of the spectrum are clinical yT4 rectal cancers, wherein precise post-treatment MRI evaluation of tumour spread is particularly important for avoiding unnecessary exenterative surgery. At the other extreme, for tumours with clinical near-complete response or clinical complete response to neoadjuvant treatment, less invasive treatment may be suitable instead of the standard surgical approach such as, for example, a "Watch and Wait" approach or perhaps local excision. Ideally, the goal of post-treatment MRI evaluation would be to identify these subgroups of patients so that they might be spared unnecessary surgical intervention. It is known that post-chemoradiation therapy restaging using conventional MR sequences is less accurate than baseline staging, particularly in confirming T0 disease, largely owing to the difficulty in distinguishing fibrosis, oedema and normal mucosa from small foci of residual tumour. However, there is a growing utilization of multiparametric MRI, which has superseded other types of evaluations and requires review and periodic re-evaluation. This commentary discusses the current status of multiparametric MRI in the post-treatment setting and the challenges facing imaging in general in the accurate determination of treatment response.