The benefit of early-stage diagnosis: A registry-based survey evaluating the quality of life in patients with melanoma.

Background: The morbidity associated with advanced stage melanoma is an important consideration in the dialog surrounding early detection and overdiagnosis. Few studies have stratified melanoma patient quality of life (QoL) by stage at diagnosis. Objective: We sought to investigate if melanoma stage is independently associated with changes in QoL within a large, community-based melanoma registry. Secondarily, we investigated whether demographic factors such as age, geographic location or level of education are associated with changes in QoL in the same population. Methods: 1108 melanoma patients were surveyed over a three-month period using the QoL in Adult Cancer Survivors Survey, consisting of 47 items on a 7-point frequency scale. Data were analysed using both descriptive statistical models and adjusted multivariate logistic regression. Results: There were 677 respondents generating a 61% response rate. Overall, higher stage at diagnosis correlated with the largest decreases in QoL as it pertained to both general (p = 0.001) and Cancer-Specific stressors (p < 0.001). Education level (p = 0.020), age (p < 0.001), rural area code designation (p = 0.020) and family history of melanoma (p = 0.017) were also independently associated with changes in QoL. Conclusion: Earlier stage at melanoma diagnosis is associated with better QoL and thus represents a crucial intervention in patient care. Given our findings and the growing body of evidence surrounding morbidity in late-stage melanoma, it is essential that QoL be included in assessing the benefits of early detection.

Mammary collagen is under reproductive control with implications for breast cancer.

Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.

MoleMapper: an application for crowdsourcing mole images to advance melanoma early-detection research.

Advancements in smartphone technologies and the use of specialized health care applications offer an exciting new era to promote melanoma awareness to the public and improve education and prevention strategies. These applications also afford an opportunity to power meaningful research aimed at improving image diagnostics and early melanoma detection. Here, we summarize our experience associated with developing and managing the implementation of MoleMapper™, a research-based application that not only provides an efficient way for users to digitally track images of moles and facilitate skin self-examinations but also provides a platform to crowdsource research participants and the curation of mole images in efforts to advance melanoma research. Obtaining electronic consent, safeguarding participant data, and employing a framework to ensure collection of meaningful data represent a few of the inherent difficulties associated with orchestrating such a wide-scale research enterprise. In this review, we discuss strategies to overcome these and other challenges leading to the implementation of MoleMapper™.

Melanoma Early Detection: Big Data, Bigger Picture.

Innovative technologies, including novel communication and imaging tools, are affecting dermatology in profound ways. A burning question for the field is whether we will retrospectively react to innovations or proactively leverage them to benefit precision medicine. Early detection of melanoma is a dermatologic area particularly poised to benefit from such innovation. This session of the Montagna Symposium on Biology of Skin focused on provocative, potentially disruptive advances, including crowdsourcing of patient advocacy efforts, rigorous experimental design of public education campaigns, research with mobile phone applications, advanced skin imaging technologies, and the emergence of artificial intelligence as a diagnostic supplement.

Noninvasive in vivo optical characterization of blood flow and oxygen consumption in the superficial plexus of skin.

Assessing the metabolic activity of a tissue, whether normal, damaged, aged, or pathologic, is useful for diagnosis and evaluating the effects of drugs. This report describes a handheld optical fiber probe that contacts the skin, applies pressure to blanch the superficial vascular plexus of the skin, then releases the pressure to allow refill of the plexus. The optical probe uses white light spectroscopy to record the time dynamics of blanching and refilling. The magnitude and dynamics of changes in blood content and hemoglobin oxygen saturation yield an estimate of the oxygen consumption rate (OCR) in units of attomoles per cell per second. The average value of OCR on nine forearm sites on five subjects was 10±5 (amol/cell/s). This low-cost, portable, rapid, noninvasive optical probe can characterize the OCR of a skin site to assess the metabolic activity of the epidermis or a superficial lesion.

Polarized light imaging specifies the anisotropy of light scattering in the superficial layer of a tissue.

This report describes how optical images acquired using linearly polarized light can specify the anisotropy of scattering (g) and the ratio of reduced scattering [µs'=µs(1−g)] to absorption (µa), i.e., N'=µs'/µa. A camera acquired copolarized (HH) and crosspolarized (HV) reflectance images of a tissue (skin), which yielded images based on the intensity (I=HH+HV) and difference (Q=HH−HV) of reflectance images. Monte Carlo simulations generated an analysis grid (or lookup table), which mapped Q and I into a grid of g versus N', i.e., g(Q,I) and N'(Q,I). The anisotropy g is interesting because it is sensitive to the submicrometer structure of biological tissues. Hence, polarized light imaging can monitor shifts in the submicrometer (50 to 1000 nm) structure of tissues. The Q values for forearm skin on two subjects (one Caucasian, one pigmented) were in the range of 0.046±0.007 (24), which is the mean±SD for 24 measurements on 8 skin sites×3 visible wavelengths, 470, 524, and 625 nm, which indicated g values of 0.67±0.07 (24).

Reflectance confocal microscopy of optical phantoms.

A reflectance confocal scanning laser microscope (rCSLM) operating at 488-nm wavelength imaged three types of optical phantoms: (1) 100-nm-dia. polystyrene microspheres in gel at 2% volume fraction, (2) solid polyurethane phantoms (INO Biomimic(TM)), and (3) common reflectance standards (Spectralon(TM)). The noninvasive method measured the exponential decay of reflected signal as the focus (z(f)) moved deeper into the material. The two experimental values, the attenuation coefficient µ and the pre-exponential factor ρ, were mapped into the material optical scattering properties, the scattering coefficient µ(s) and the anisotropy of scattering g. Results show that µ(s) varies as 58, 8-24, and 130-200 cm(-1) for phantom types (1), (2) and (3), respectively. The g varies as 0.112, 0.53-0.67, and 0.003-0.26, respectively.

In vivo measurement of epidermal thickness changes associated with tumor promotion in murine models.

The characterization of tissue morphology in murine models of pathogenesis has traditionally been carried out by excision of affected tissues with subsequent immunohistological examination. Excision-based histology provides a limited two-dimensional presentation of tissue morphology at the cost of halting disease progression at a single time point and sacrifice of the animal. We investigate the use of noninvasive reflectance mode confocal scanning laser microscopy (rCSLM) as an alternative tool to biopsy in documenting epidermal hyperplasia in murine models exposed to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). An automated technique utilizing average axial rCSLM reflectance profiles is used to extract epidermal thickness values from rCSLM data cubes. In comparisons to epidermal thicknesses determined from hematoxylin and eosin (H&E) stained tissue sections, we find no significant correlation to rCSLM-derived thickness values. This results from method-specific artifacts: physical alterations of tissue during H&E preparation in standard histology and specimen-induced abberations in rCSLM imaging. Despite their disagreement, both histology and rCSLM methods reliably measure statistically significant thickness changes in response to TPA exposure. Our results demonstrate that in vivo rCSLM imaging provides epithelial biologists an accurate noninvasive means to monitor cutaneous pathogenesis.

Rapid spectral analysis for spectral imaging.

Spectral imaging requires rapid analysis of spectra associated with each pixel. A rapid algorithm has been developed that uses iterative matrix inversions to solve for the absorption spectra of a tissue using a lookup table for photon pathlength based on numerical simulations. The algorithm uses tissue water content as an internal standard to specify the strength of optical scattering. An experimental example is presented on the spectroscopy of portwine stain lesions. When implemented in MATLAB, the method is ~100-fold faster than using fminsearch().

Optical properties of mutant versus wild-type mouse skin measured by reflectance-mode confocal scanning laser microscopy (rCSLM).

Separation of the two optical scattering properties, the scattering coefficient (mu(s)) and the anisotropy of scattering (g), has been experimentally difficult in tissues. A new method for measuring these properties in tissues uses reflectance-mode confocal scanning laser microscopy (rCSLM). Experimentally, the focus at depth z is scanned down into the tissue. The measured data is the exponential decay of the confocal reflectance signal as a function of the depth of the focal volume, R(z)=rho exp(-muz), summarized as a local reflectivity (rho) and an exponential decay constant (mu). The rho and mu map uniquely into the mu(s) and g of the tissue. The method was applied to three mouse skin tissues: one wild-type (wt/wt), one heterozygous mutant (oim/wt), and one homozygous mutant (oim/oim), where oim indicates the mutation for osteogenesis imperfecta, a bone disease that affects type I collagen structure. The mutation affects the collagen fibrils of the skin and the assembly of collagen fiber bundles. The anisotropy of scattering (g) at 488 nm wavelength decreased from 0.81 to 0.46 with the added mutant allele. There was a slight increase in the scattering coefficient (mu(s)) with the mutation from 74 to 94 cm(-1). The decrease in g (toward more isotropic scattering) is likely due to the failure of the mutant fibrils to assemble into the larger collagen fiber bundles that yield forward scattering.