Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkA splice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.

Background Psoriasis (Ps) is a chronic systemic autoimmune disease associated with pruritus in 64–98% of patients. However, few modestly sized studies assess factors associated with psoriatic pruritus. Objective To investigate factors associated with Ps pruritus intensity. Methods Psoriasis patients 18 years or older seen in one of 155 centres in Italy between September 2005 and 2009 were identified from the Italian PsoCare registry. Patients without cutaneous psoriasis and those with missed information on pruritus were excluded. Results We identified 10 802 patients, with a mean age 48.8 ± 14.3 years. Mild itch was present in 33.2% of patients, moderate in 34.4%, severe in 18.7% and very severe in 13.7%. Higher itch intensity was associated with female gender, lower educational attainment compared to university degree, pustular psoriasis, psoriasis on the head, face, palmoplantar areas, folds and genitalia, more severe disease, disease duration <15 years, and no or few prior systemic treatments. Limitations Effects of specific medication on itch were not assessed. Conclusions Pruritus should be evaluated during psoriasis visits, and physicians should be aware of patients at higher risk for itch. Further studies are needed to assess the effects of medications on itch, and establish therapy for psoriasis patients with persistent itch.

The most likely causes of these associations are the clustering of lifestyle risk factors in the same subgroups of population, mainly on a sociocultural basis and surveillance bias. This raises important questions about how to best follow cancer survivors by avoiding an inefficient use of resources and an excessive medicalization of these patients' lives.

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18). In addition, TCR engagecharacteristic of 'memory' T lymphocytes. 1-5 A high percentment results in Zap70 activation after its binding to the tyrosylage of the malignant cells constitutively express BE2, a late phosphorylated immunoreceptor tyrosine-based activation activation marker of 78 kDa, that appears on cloned normal motifs (ITAMs) of the chains and the CD3 complex 23,24 (for T cells only after stimulation with specific antigen, and on review see Ref. 25) and in rapid tyrosine phosphorylation and freshly isolated normal T cells in response to mitogens, 6,7 sugactivation of Syk. 26 The signaling initiated by TCR activation gesting that CTCL cells have been activated by their surroundis transmitted from the cell membrane through the cytoplasm ing dermal environment. Since CTCL lymphocytes can proto the nucleus and induces quiescent T cells to undergo cell liferate in the cutaneous compartment but are extremely division and maturation, processes critical for clonal expandifficult to cultivate in vitro, their neoplastic growth appears sion and initiation of the immune responses. to reflect in vivo stimulation, possibly through their TCR, orWe selected for investigation several immediate key reacantigen-independent pathways or cytokines. IL-7 might be one tions essential for T cell receptor-mediated signal transducof the required growth factors for CTCL cells in the skin since tion, proliferation and effector functions. Our results, based transgenic mice constitutively producing IL-7 developed on analysis of a limited sample of CTCL cells (from four extensive dermal infiltration followed by dermotropic lympatients), show nevertheless, common characteristics, ie phoma. 8,9 However, although IL-7 is produced by keradeficiencies in critical immediate functions associated with tinocytes, it is a weak in vitro CTCL mitogen, 10 and purified TCR activation. These include molecules participating in populations of CTCL cells were sustained in culture for only events proximal and distal to the TCR such as: (1) reduced a short period (such as a week) by mixtures of cytokines that levels of basal and stimulated tyrosyl-phosphorylated proteins include IL-7 and IL-2. 11,12 belonging to a wide range of signaling molecules; The preferential expression of CD45RO and the clonal TCR (2) suppressed specific activity of membrane-bound Csk and rearrangement suggest that CTCL clones have encountered a Lck; (3) failure to activate membrane-bound PTPase; (4) failure to activate Zap70 and to induce its association with the TCR chain; and (5) reduced expression and activity of Syk. LimitedCorrespondence: R Halaban, Department of Dermatology, Yale Unicomparative analysis with the CD4 + /CD45RO + subpopulation