Abstract
.More people die from melanoma after a stage I diagnosis than after a stage IV diagnosis, because the tools available to clinicians do not readily identify which early-stage cancers will be aggressive. Near-infrared pump-probe microscopy detects fundamental differences in melanin structure between benign human moles and melanoma and also correlates with metastatic potential. However, the biological mechanisms of these changes have been difficult to quantify, as many different mechanisms can contribute to the pump-probe signal. We use model systems (sepia, squid, and synthetic eumelanin), cellular uptake studies, and a range of pump and probe wavelengths to demonstrate that the clinically observed effects come from alterations of the aggregated mode from “thick oligomer stacks” to “thin oligomer stacks” (due to changes in monomer composition) and (predominantly) deaggregation of the assembled melanin structure. This provides the opportunity to use pump-probe microscopy for the detection and study of melanin-associated diseases.
Highlights
In the past several years, advances in nonlinear laser microscopy have provided a new and important approach for diagnosing and grading melanoma by visualizing molecular details of melanin in pigmented skin lesions
The one-sentence, oversimplified version of our results is that dissociation of the eumelanin assembly structure, induced by metabolic activity of cancers, is the dominant molecular mechanism behind the clinically important feature, chemical heterogeneity of the pump-probe signals in metastatic melanoma
This connection among cellular chemistry, clinical outcome, and straightforward imaging methods implies that pump-probe microscopy has great potential to improve patient outcomes
Summary
In the past several years, advances in nonlinear laser microscopy have provided a new and important approach for diagnosing and grading melanoma by visualizing molecular details of melanin in pigmented skin lesions This is exceptionally important because of the challenges in detecting aggressive cancers at an early stage.[1,2] The problem is that the standard diagnostic protocol (excision, staining, pathological evaluation) does not identify the most dangerous early lesions. Stage I melanomas make up 78% of all newly diagnosed cutaneous melanomas reported in the U.S National Cancer Institute SEER database, and of these, 81% are thin lesions (Breslow thickness of ≤1.0 mm).[3] For these thin lesions, the standard of care is usually a therapeutic 1-cm margin excision and watchful waiting. This presents a critical challenge: how do you fix a bad diagnostic gold standard for a bad disease?
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