Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond.

Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling-related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm. Some of these pathways could be regulated by noncoding microRNA. Altered microRNA expression profile is recognized with the progression of these lesions. Stopping treatment with Smoothened (SMO) inhibitors often leads to tumor reoccurrence in the patients with basal cell nevus syndrome, who develop 10-100 of BCCs. In addition, the initial effectiveness of these SMO inhibitors is impaired due to the onset of mutations in the drug-binding domain of SMO. These data point to a need to develop strategies to overcome tumor recurrence and resistance and to enhance efficacy by developing novel single agent-based or multiple agents-based combinatorial approaches. Immunotherapy and photodynamic therapy could be additional successful approaches particularly if developed in combination with chemotherapy for inoperable and metastatic BCCs.

Patient satisfaction and reported outcomes on the management of actinic keratosis.

Actinic keratosis (AK) is a common dermatologic condition in which hyperplastic epidermal lesions develop in response to excessive and chronic exposure to ultraviolet (UV) radiation. If left untreated, AK can progress to squamous cell carcinomas of the skin. Incidence is rising worldwide as a result of the progressive aging of populations and an increase in lifetime cumulative exposure to UV radiation. Currently, various treatment options exist, which range from topical medications to light-based therapies and procedural modalities. In this article, we will review the treatment options for AK with a focus on assessments of patient satisfaction with treatment.

Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members.

Importance: Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS). Objective: To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS. Design, Setting, and Participants: The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015. Main Outcomes and Measures: Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography. Results: This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population. Conclusions and Relevance: Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals. Trial Registration: clinicaltrials.gov Identifier: NCT01353547.

Assessing Cutaneous Psoriasis Activity Using FDG-PET: Nonattenuation Corrected Versus Attenuation Corrected PET Images.

Psoriasis is a chronic inflammatory skin condition characterized by well-circumscribed erythematous plaques with thick silvery scale. Infiltration of inflammatory cells such as lymphocytes, neutrophils, and macrophages and epidermal cell proliferation within psoriatic lesions may result in selective FDG accumulation. We present a 55-year-old patient with a 30-year history of psoriasis. Nonattenuation corrected PET/CT images demonstrated significant cutaneous FDG uptake corresponding to clinically apparent psoriatic lesions. However, in attenuation corrected (AC) FDG-PET images, the signal was substantially diminished and minimally detectable. Nonattenuation corrected FDG-PET images may be useful and preferable to AC images in assessing skin inflammation in psoriasis.

In vivo imaging of spinal cord atrophy in neuroinflammatory diseases.

OBJECTIVE: Spinal cord atrophy is prominent in chronic progressive neurologic diseases such as human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Here we compared the spinal cord cross-sectional area (SCCSA) in HAM/TSP and MS patients to that of healthy volunteers (HVs). METHODS: SCCSA and clinical disability scores were measured in 18 HAM/TSP patients, 4 asymptomatic carriers (ACs) of HTLV-1, 18 MS patients, and 10 HVs from a 3T magnetic resonance imaging. SCCSA measured in patients and ACs were compared to that of HVs and correlated with disability scores. RESULTS: The entire spinal cord in HAM/TSP patients was thin compared to HVs, whereas only the cervical cord in MS patients was thinner than in HVs (p < 0.0001). In HAM/TSP patients, SCCSA extensively correlated with Ambulation Index, whereas only the cervical cord correlated with disease duration (p < 0.05). In MS patients, the SCCSA extensively correlated with Scripps Neurologic Rating Score and the Expanded Disability Status Scale (p < 0.05). One of the 4 ACs showed atrophy in a pattern similar to HAM/TSP. INTERPRETATION: These results are in accordance with the findings that whereas over half of all lesions in an MS cord are seen in the upper cervical cord, most of the pathology in HAM/TSP is seen in the thoracolumbar cord, which in turn may be responsible for the more extensive cord atrophy seen in HAM/TSP. An imaging marker such as SCCSA might serve as a surrogate endpoint in clinical trials, especially to assess the neuroprotective impact of various therapies.

Rapid semi-automatic segmentation of the spinal cord from magnetic resonance images: application in multiple sclerosis.

A new semi-automatic method for segmenting the spinal cord from MR images is presented. The method is based on an active surface (AS) model of the cord surface, with intrinsic smoothness constraints. The model is initialized by the user marking the approximate cord center-line on a few representative slices, and the compact surface parametrization results in a rapid segmentation, taking on the order of 1 min. Using 3-D acquired T(1)-weighted images of the cervical spine from human controls and patients with multiple sclerosis, the intra- and inter-observer reproducibilities were evaluated, and compared favorably with an existing cord segmentation method. While the AS method overestimated the cord area by approximately 14% compared to manual outlining, correlations between cord cross-sectional area and clinical disability scores confirmed the relevance of the new method in measuring cord atrophy in multiple sclerosis. Segmentation of the cord from 2-D multi-slice T(2)-weighted images is also demonstrated over the cervical and thoracic region. Since the cord center-line is an intrinsic parameter extracted as part of the segmentation process, the image can be resampled such that the center-line forms one coordinate axis of a new image, allowing simple visualization of the cord structure and pathology; this could find wider application in standard radiological practice.