British Journal of Dermatology最新文献

Background: Patients with Gorlin (basal cell nevus) syndrome (GS) have numerous phenotypic abnormalities due to over-activity of the hedgehog (HH) signaling pathway, most commonly due to a heritable mutation in the PTCH1 gene, which encodes a major inhibitor of this pathway. HH inhibitors (HHi) taken orally can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit:risk ratio, we have developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop treatment with oral HHis.

Objectives: This study attempts to determine whether or not Patidegib Topical Gel, 2% or 4%, can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects that are typical of oral HHi treatment.

Methods: We conducted a small, randomized, double blinded Phase 2A trial at two sites in the United Kingdom to assess the clinical and molecular efficacy and adverse effects of 6 months of twice daily application of Patidegib Topical Gel to the entire face as well as to treatment-targeted surgically-eligible BCCs at other anatomical sites.

Results: Post hoc analyses suggested that Patidegib Topical Gel reduced the number of new surgically-eligible BCCs and the level of HH signaling with minimal adverse effects.

Conclusions: Patidegib Topical Gel warrants further clinical development.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.