Summary Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including ...those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT01815840 , and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 94% of 114 in treatment group A and 109 97% of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four 4% patients in treatment group A vs 12 11% in treatment group B), increased blood creatine phosphokinase (one 1% vs four 4%), and hypophosphataemia (zero vs three 3%). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.
Summary
Background
Recent advances in biomedical optics have enabled dermal and epidermal components to be visualized at subcellular resolution and assessed noninvasively. Multiphoton microscopy ...(MPM) and reflectance confocal microscopy (RCM) are noninvasive imaging modalities that have demonstrated promising results in imaging skin micromorphology, and which provide complementary information regarding skin components. This study assesses whether combined MPM/RCM can visualize intracellular and extracellular melanin granules in the epidermis and dermis of normal human skin.
Methods
We perform MPM and RCM imaging of in vivo and ex vivo skin in the infrared domain. The inherent three‐dimensional optical sectioning capability of MPM/RCM is used to image high‐contrast granular features across skin depths ranging from 50 to 90 μm. The optical images thus obtained were correlated with conventional histologic examination including melanin‐specific staining of ex vivo specimens.
Results
MPM revealed highly fluorescent granular structures below the dermal–epidermal junction (DEJ) region. Histochemical staining also demonstrated melanin‐containing granules that correlate well in size and location with the granular fluorescent structures observed in MPM. Furthermore, the MPM fluorescence excitation wavelength and RCM reflectance of cell culture‐derived melanin were equivalent to those of the granules.
Conclusion
This study suggests that MPM can noninvasively visualize and quantify subepidermal melanin in situ.
