The distribution of breast density in women aged 18 years and older.

PURPOSE: Age and body mass index (BMI) are critical considerations when assessing individual breast cancer risk, particularly for women with dense breasts. However, age- and BMI-standardized estimates of breast density are not available for screen-aged women, and little is known about the distribution of breast density in women aged < 40. This cross-sectional study uses three different modalities: optical breast spectroscopy (OBS), dual-energy X-ray absorptiometry (DXA), and mammography, to describe the distributions of breast density across categories of age and BMI. METHODS: Breast density measures were estimated for 1,961 Australian women aged 18-97 years using OBS (%water and %water + %collagen). Of these, 935 women had DXA measures (percent and absolute fibroglandular dense volume, %FGV and FGV, respectively) and 354 had conventional mammographic measures (percent and absolute dense area). The distributions for each breast density measure were described across categories of age and BMI. RESULTS: The mean age was 38 years (standard deviation = 15). Median breast density measures decreased with age and BMI for all three modalities, except for DXA-FGV, which increased with BMI and decreased after age 30. The variation in breast density measures was largest for younger women and decreased with increasing age and BMI. CONCLUSION: This unique study describes the distribution of breast density measures for women aged 18-97 using alternative and conventional modalities of measurement. While this study is the largest of its kind, larger sample sizes are needed to provide clinically useful age-standardized measures to identify women with high breast density for their age or BMI.

Alternative methods to measure breast density in younger women.

BACKGROUND: Breast density is a strong and potentially modifiable breast cancer risk factor. Almost everything we know about breast density has been derived from mammography, and therefore, very little is known about breast density in younger women aged <40. This study examines the acceptability and performance of two alternative breast density measures, Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA), in women aged 18-40. METHODS: Breast tissue composition (percent water, collagen, and lipid content) was measured in 539 women aged 18-40 using OBS. For a subset of 169 women, breast density was also measured via DXA (percent fibroglandular dense volume (%FGV), absolute dense volume (FGV), and non-dense volume (NFGV)). Acceptability of the measurement procedures was assessed using an adapted validated questionnaire. Performance was assessed by examining the correlation and agreement between the measures and their associations with known determinants of mammographic breast density. RESULTS: Over 93% of participants deemed OBS and DXA to be acceptable. The correlation between OBS-%water + collagen and %FGV was 0.48. Age and BMI were inversely associated with OBS-%water + collagen and %FGV and positively associated with OBS-%lipid and NFGV. CONCLUSIONS: OBS and DXA provide acceptable and viable alternative methods to measure breast density in younger women aged 18-40 years.

Exposure to polycyclic aromatic hydrocarbons during pregnancy and breast tissue composition in adolescent daughters and their mothers: a prospective cohort study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers. METHODS: We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother-daughter dyads (recruited 1998-2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11-20 and 29-55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS. RESULTS: No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values < 0.05). Σ8 PAH exposure was associated with higher water content (ßdaughters = 0.42, 95% CI = 0.15-0.68; ßmothers = 0.32, 95% CI = 0.05-0.61) and higher optical index (ßdaughters = 0.38, 95% CI = 0.12-0.64; ßmothers = 0.38, 95% CI = 0.12-0.65) in those exposed to household tobacco smoke during pregnancy; no associations were found in non-smoking households (interaction p values < 0.05). CONCLUSIONS: Exposure to ambient Σ8 PAH and tobacco smoke during pregnancy might interact synergistically to impact BTC in mothers and daughters. If replicated in other cohorts, these findings might have important implications for breast cancer risk across generations.

Ru(II) CONTAINING PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY: A CRITIQUE ON REPORTING AND AN ATTEMPT TO COMPARE EFFICACY.

Ruthenium(II)-based coordination complexes have emerged as photosensitizers (PSs) for photodynamic therapy (PDT) in oncology as well as antimicrobial indications and have great potential. Their modular architectures that integrate multiple ligands can be exploited to tune cellular uptake and subcellular targeting, solubility, light absorption, and other photophysical properties. A wide range of Ru(II) containing compounds have been reported as PSs for PDT or as photochemotherapy (PCT) agents. Many studies employ a common scaffold that is subject to systematic variation in one or two ligands to elucidate the impact of these modifications on the photophysical and photobiological performance. Studies that probe the excited state energies and dynamics within these molecules are of fundamental interest and are used to design next-generation systems. However, a comparison of the PDT efficacy between Ru(II) containing PSs and 1st or 2nd generation PSs, already in clinical use or preclinical/clinical studies, is rare. Even comparisons between Ru(II) containing molecular structures are difficult, given the wide range of excitation wavelengths, power densities, and cell lines utilized. Despite this gap, PDT dose metrics quantifying a PS's efficacy are available to perform qualitative comparisons. Such models are independent of excitation wavelength and are based on common outcome parameters, such as the photon density absorbed by the Ru(II) compound to cause 50% cell kill (LD50) based on the previously established threshold model. In this focused photophysical review, we identified all published studies on Ru(II) containing PSs since 2005 that reported the required photophysical, light treatment, and in vitro outcome data to permit the application of the Photodynamic Threshold Model to quantify their potential efficacy. The resulting LD50 values range from less than 1013 to above 1020 [hν cm-3], indicating a wide range in PDT efficacy and required optical energy density for ultimate clinical translation.

Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433.

Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochemical and photophysical properties derive from a variety of excited-state electronic configurations accessible with visible and near-infrared light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiological activity. Selected examples highlight the use of rational design in coordination chemistry to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clinical trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chemical and photophysical solutions that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clinical trial.

Photobiomodulation therapy can change actin filaments of 3T3 mouse fibroblast.

The purpose of this study was to investigate the effects that photobiomodulation therapy might produce in cells, in particular, related to their structure. Thus, this paper presents the results of morphological changes in fibroblasts following low-intensity light illumination. Mouse fibroblasts were grown on glass coverslips on either 4 kPa or 16 kPa gels, to mimic normal tissue conditions. Cells were photo-irradiated with laser light at either 625 nm or 808 nm (total energies ranging from 34 to 47 J). Cells were fixed at 5 min, 1 h, or 24 h after photo-irradiation, stained for both actin filaments and the cell nucleus, and imaged by confocal microscopy. A non-light exposed group was also imaged. A detailed analysis of the images demonstrated that the total polymerized actin and number of actin filaments decrease, while the nucleus area increases in treated cells shortly after photo-irradiation, regardless of substrate and wavelength. This experiment indicated that photobiomodulation therapy could change the morphological properties of cells and affect their cytoskeleton. Further investigations are required to determine the specific mechanisms involved and how this phenomenon is related to the photobiomodulation therapy mechanisms of action.

Skin color and tissue thickness effects on transmittance, reflectance, and skin temperature when using 635 and 808 nm lasers in low intensity therapeutics.

OBJECTIVE: To examine the role of skin color and tissue thickness on transmittance, reflectance, and skin heating using red and infrared laser light. METHODS: Forty volunteers were measured for skin color and skin-fold thickness at a standardized site near the elbow. Transmittance, reflectance and skin temperature were recorded for energy doses of 2, 6, 9, and 12 Joules using 635 nm (36 mW) and 808 nm (40 mW) wavelength laser diodes with irradiances within American National Standards Institute safety guidelines (4.88 mm diameter, 0.192 W/cm2 and 4.88 mm diameter, 0.214 W/cm2 , respectively). RESULTS: The key factors affecting reflectance to an important degree were skin color and wavelength. However, the skin color effects were different for the two wavelengths: reflectance decreased for darker skin with a greater decrease for red light than near infrared light. Transmittance was greater using 808 nm compared with 635 nm. However, the effect was partly lost when the skin was dark rather than light, and was increasingly lost as tissue thickness increased. Dose had an increasing effect on temperature (0.7-1.6°C across the 6, 9, and 12 J doses); any effects of wavelength, skin color, and tissue thickness were insignificant compared to dose effects. Subjects themselves were not aware of the increased skin temperature. Transmittance and reflectance changes as a function of energy were very small and likely of no clinical significance. Absorption did not change with higher energy doses and increasing temperature. CONCLUSION: Skin color and skin thickness affect transmittance and reflectance of laser light and must be accounted for when selecting energy dose to ensure therapeutic effectiveness at the target tissue. Skin heating appears not to be a concern when using 635 and 808 nm lasers at energy doses of up to 12 J and irradiance within American National Standards Institute standards. Photobiomodulation therapy should never exceed the American National Standards Institute recommendation for the maximum permissible exposure to the skin. Lasers Surg. Med. 50:291-301, 2018. © 2017 Wiley Periodicals, Inc.

Non-invasive optical spectroscopic monitoring of breast development during puberty.

BACKGROUND: Tanner staging (TS), a five-stage classification indicating no breast tissue (TS1) to full breast development (TS5), is used both in health research and clinical care to assess the onset of breast development (TS2) and duration in each stage. Currently, TS is measured both visually and through palpation but non-invasive methods will improve comparisons across settings. METHODS: We used optical spectroscopy (OS) measures from 102 girls at the Ontario site of the LEGACY girls study (average age 12 years, range 10.0-15.4 years) to determine whether breast tissue optical properties map to each TS. We further examined whether these properties differed by age, body mass index (BMI), and breast cancer risk score (BCRS) by examining the major principal components (PC). RESULTS: Age and BMI increased linearly with increasing TS. Eight PCs explained 99.9% of the variation in OS data. Unlike the linear increase with age and BMI, OS components had distinct patterns by TS: the onset of breast development (TS1 to TS2) was marked by elevation of PC3 scores indicating an increase in adipose tissue and decrease in signal from the pectoral muscle; transition to TS3 was marked by elevation of PC6 and PC7 and decline of PC2 scores indicating an increase in glandular or dense tissue; and transition to TS4+ by decline of PC2 scores representing a further increase in glandular tissue relative to adipose tissue. Of the eight PCs, three component scores (PC4, PC5, and PC8) remained in the best-fitting model of BCRS, suggesting different levels of collagen in the breast tissue by BCRS. CONCLUSIONS: Our results suggest that serial measures of OS, a non-invasive assessment of breast tissue characteristics, can be used as an objective outcome that does not rely on visual inspection or palpation, for studying drivers of breast development.

Low-intensity laser therapy efficacy evaluation in FVB mice subjected to acute and chronic arthritis.

Rheumatoid arthritis, an autoimmune inflammation, has a high prevalence in the population, and while therapy is available, it required often injection of drugs causing discomfort to patients. This study evaluates the clinical and histological effect of low-intensity laser therapy (LILT) as an alternative treatment, in a murine model of acute and chronic inflammation. FVB mice received either a Zymosan A injection into one knee joint inducing acute inflammation, followed after 15 min or 24 h by LILT or a collagen bovine type II injection emulsified in "Freund's Complete Adjuvant" to induce chronic arthritis, followed at 4 weeks with multiple LILT sessions. LILT mediated by either 660, 808, or 905 nm and tissue response was evaluated based on clinical symptoms and histological analysis of inflammatory infiltrate and damage to the articular surfaces. LILT can be effective in elevating clinical symptoms, so Kruskal-Wallis testing indicated no significant differences between knees affected by acute arthritis and treated once with LILT and an injured knee without treatment (p > 0.05) for 660 and 808 nm with some improvements for the 905-nm LILT. Mice receiving two treatments for acute arthritis showed exacerbation of inflammation and articular resorption following therapy with a 660-nm continuous laser (p < 0.05). For chronic inflammation, differences were not noted between LILT treated and untreated injured knee joints (p > 0.05). Among the lasers, the 905 nm tends to show better results for anti-inflammatory effect in acute arthritis, and the 660 nm showed better results in chronic arthritis. In conclusion, LILT wavelength selection depends on the arthritis condition and can demonstrate anti-inflammatory effects for chronic arthritis and reduced resorption area in this murine model.

The LEGACY Girls Study: Growth and Development in the Context of Breast Cancer Family History.

BACKGROUND: Although the timing of pubertal milestones has been associated with breast cancer risk, few studies of girls' development include girls at increased breast cancer risk due to their family history. METHODS: The Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study was initiated in 2011 in the USA and Canada to assess the relation between early life exposures and intermediate markers of breast cancer risk (e.g., pubertal development, breast tissue characteristics) and to investigate psychosocial well being and health behaviors in the context of family history. We describe the methods used to establish and follow a cohort of 1,040 girls ages 6-13 years at baseline, half with a breast cancer family history, and the collection of questionnaire data (family history, early life exposures, growth and development, psychosocial and behavioral), anthropometry, biospecimens, and breast tissue characteristics using optical spectroscopy. RESULTS: During this initial 5-year phase of the study, follow-up visits are conducted every 6 months for repeated data and biospecimen collection. Participation in baseline components was high (98% for urine, 97.5% for blood or saliva, and 98% for anthropometry). At enrollment, 77% of girls were premenarcheal and 49% were at breast Tanner stage T1. CONCLUSIONS: This study design allows thorough examination of events affecting girls' growth and development and how they differ across the spectrum of breast cancer risk. A better understanding of early life breast cancer risk factors will be essential to enhance prevention across the lifespan for those with and without a family history of the disease.

A ruthenium(ii) based photosensitizer and transferrin complexes enhance photo-physical properties, cell uptake, and photodynamic therapy safety and efficacy.

Metal-based photosensitizers are of interest as their absorption and chemical binding properties can be modified via the use of different ligands. Ru(2+) based photosensitizers are known to be effective photodynamic therapy (PDT) agents against bacteria, whereas use for oncological indications in vivo has not been demonstrated with the same level of evidence. We present data showing that premixing the Ru(2+)-complex TLD1433 with transferrin increases the molar extinction coefficient, including longer activation wavelengths, reduces photobleaching rates, and reduces the toxicity of the complex improving overall PDT efficacy. As the transferrin receptor is upregulated in most malignancies, premixing the Ru(2+) complex with transferrin converts the active pharmaceutical ingredient TLD1433 into a drug of potentially considerable clinical utility.

A novel class of ruthenium-based photosensitizers effectively kills in vitro cancer cells and in vivo tumors.

The photo-physical and photo-biological properties of two small (<2 kDa), novel Ru(ii) photosensitizers (PSs) referred to as TLD1411 and TLD1433 are presented. Both PSs are highly water-soluble, provide only very limited luminescence emission at 580-680 nm following excitation at 530 nm, and demonstrate high photostability with less than 50% photobleaching at radiant exposures H = 275 J cm(-2) (530 nm irradiation). It was previously shown that these two photosensitizers exhibit a large singlet oxygen ((1)O2) quantum yield (Φ (Δ) ∼0.99 in acetonitrile). Their photon-mediated efficacy to cause cell death (λ = 530 nm, H = 45 J cm(-2)) was tested in vitro in colon and glioma cancer cell lines (CT26.WT, CT26.CL25, F98, and U87) and demonstrated a strong photodynamic effect with complete cell death at concentrations as low as 4 and 1 µM for TLD1411 and TLD1433, respectively. Notably, dark toxicity was negligible at concentrations less than 25 and 10 µM for TLD1411 and TLD1433, respectively. The ability of the PSs to initiate Type I photoreactions was tested by exposing PS-treated U87 cells to light under hypoxic conditions (pO2 < 0.5%), which resulted in a complete loss of the PDT effect. In vivo, the maximum tolerated doses 50 (MTD50) were determined to be 36 mg kg(-1) (TLD1411) and 103 mg kg(-1) (TLD1433) using the BALB/c murine model. In vivo growth delay studies in the subcutaneous colon adenocarcinoma CT26.WT murine model were conducted at a photosensitizer dose equal to 0.5 and 0.2 MTD50 for TLD1411 and TLD1433, respectively. 4 hours post PS injection, tumours were irradiated with continuous wave or pulsed light sources (λ = 525-530 nm, H = 192 J cm(-2)). Overall, treatment with continuous wave light demonstrated a higher tumour destruction efficacy when compared to pulsed light. TLD1433 mediated PDT resulted in statistically significant longer animal survival compared to TLD1411. Two-thirds of TLD1433-treated mice survived more than 100 days (p < 0.01) whereas TLD1411-treated mice did not survive longer than 20 days. Here we present evidence that two novel PSs have very potent photo-biological properties and are able to cause PDT-mediated cell death in both in vitro cell culture models and in vivo tumour regression.

Antimicrobial photodynamic therapy with fulleropyrrolidine: photoinactivation mechanism of Staphylococcus aureus, in vitro and in vivo studies.

A family of N-methylpyrrolidinium fullerene iodide salts has been intensively studied to determine their applicability in antimicrobial photodynamic therapy (APDT). This study examined in vitro the efficacy of a C60 fullerene functionalized with one methylpyrrolidinium group to kill upon irradiation with white light gram-negative and gram-positive bacteria, as well as fungal cells, and the corresponding mechanism of the fullerene bactericidal action. The in vitro studies revealed that the high antistaphylococcal efficacy of functionalized fullerene could be linked to their ability to photogenerate singlet oxygen and superoxide anion. Following Staphylococcus aureus photoinactivation, no modifications of its genomic DNA were detected. In contrast, photodamage of the cell envelope seemed to be a dominant mechanism of bactericidal action. In in vivo studies, a 2 log10 reduction in the average bioluminescent radiance between treated and non-treated mice was reached. One day post APDT treatment, moist and abundant growth of bacteria could be observed on wounds of non-fulleropyrrolidine and dark control mice. APDT-treated wounds stayed visibly clear up to the third day. Moreover, cytotoxicity test on human dermal keratinocytes revealed great safety of using the sensitizer toward eukaryotic cells. These data indicate potential application of functionalized fullerene as antistaphylococcal sensitizer for superficial infections.

The Prospective Association between Early Life Growth and Breast Density in Young Adult Women.

Breast density is a strong intermediate endpoint to investigate the association between early-life exposures and breast cancer risk. This study investigates the association between early-life growth and breast density in young adult women measured using Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA). OBS measurements were obtained for 536 female Raine Cohort Study participants at ages 27-28, with 268 completing DXA measurements. Participants with three or more height and weight measurements from ages 8 to 22 were used to generate linear growth curves for height, weight and body mass index (BMI) using SITAR modelling. Three growth parameters (size, velocity and timing) were examined for association with breast density measures, adjusting for potential confounders. Women who reached their peak height rapidly (velocity) and later in adolescence (timing) had lower OBS-breast density. Overall, women who were taller (size) had higher OBS-breast density. For weight, women who grew quickly (velocity) and later in adolescence (timing) had higher absolute DXA-breast density. Overall, weight (size) was also inversely associated with absolute DXA-breast density, as was BMI. These findings provide new evidence that adolescent growth is associated with breast density measures in young adult women, suggesting potential mediation pathways for breast cancer risk in later life.

Modulation of PPIX synthesis and accumulation in various normal and glioma cell lines by modification of the cellular signaling and temperature.

Effective therapies for malignant gliomas are still elusive and limited survival improvements are provided only by Temozolomide or fluorescence guided resection. The efficacy of photodynamic therapy (PDT) in this indication is limited by the higher sensitivity of normal brain structures compared to glioma necessitating a modulation of its sensitivity. We evaluate the influence of hypothermia and the tyrosine kinase inhibitor Erlotinib on cell's ability to synthesize PPIX following the administration of ALA which was not previously investigated. We demonstrate that both hypothermia and Erlotinib are favorable in PPIX selectivity as only glioma cell lines demonstrate an increased PPIX synthesis, whereas the neuronal and astrocytic synthesis is remaining unaffected. The results are encouraging to consider hypothermia and Erlotinib as adjuvant therapies to increase the PDT therapeutic index between GBM and normal intracranial tissues, as well as to improve contrast in fluorescence guided resection.

An observational study of personal ultraviolet dosimetry and acute diffuse reflectance skin changes at extreme altitude.

OBJECTIVE: To determine the level of UV radiation at extreme altitude and to assess the effect it has on the skin. METHODS: Fifteen expeditioners and 10 Sherpas were assessed during a climbing expedition on the north side of Mt Everest (8848 m). UV exposure measurement and diffuse skin reflectance spectrophotometry were performed at the beginning and end of the expedition. RESULTS: Over the course of the expedition, the expeditioners and Sherpas received a median dose of 93.6 (interquartile range [IQR], 61.0-102.8) and 102.5 (IQR, 72.2-117.8) minimal erythemal doses (MEDs) of UV radiation. The maximum dosage exceeded 106 ± 1.4 MEDs. Using reflectance spectrophotometry, expeditioner and Sherpa melanin-hemoglobin increased by 83.6% (IQR, -1.5 to 89.8%) and 24.7% (IQR, -22.4 to 61.5%) for exposed skin, respectively. The amount of subcutaneous lipid-water decreased by a factor of 196.6 (IQR, 52.1-308.4) and 46.7 (IQR, 1.8-1156.5), for expeditioners and Sherpas, respectively. CONCLUSIONS: This expedition's participants received massive doses of UV radiation during their time at high altitude. In many individuals this was similar to the annual exposure of northern European office-workers (100 MEDs). Diffuse skin reflectance spectroscopy revealed considerable subcutaneous lipid loss, skin dehydration, and increased melanin in keeping with these levels of exposure.

Spatial analysis of polarimetric images to enhance near-surface sampling sensitivity: feasibility in demineralized teeth and other tissue-like media.

Significance: Early tooth demineralization may be detectable through spatial analysis of polarized light images as demonstrated in this study. This may also prove useful in the early detection of epithelial tumors that comprise the majority of the cancer burden worldwide. Aim: The spatial properties of polarized light images have not been greatly exploited in biomedicine to improve sensitivity to superficial tissue regions; therefore, we investigate the optical sampling depth effects as a function of location in the backscattered polarimetric images. Approach: Backscattered linear polarization intensity distributions exhibit four-lobed patterns arising through single-scattering, multiple-scattering, and geometrical effects. These photon pathway dynamics are investigated through experimental imaging of microsphere suspensions along with corroborative computational polarization-sensitive Monte Carlo modeling. The studied sampling depth effects of linear and circular polarization images (explored in a previous study) are then evaluated on normal and demineralized human teeth, which are known to differ in their surface and sub-surface structures. Results: Backscattered linear polarization images exhibit enhanced sensitivity to near-surface properties of media (for example, surface roughness and turbidity) at specific locations within the four-lobed patterns. This yields improved differentiation of two tooth types when spatially selecting image regions in the direction perpendicular to the incident linear polarization vector. Circular polarimetric imaging also yields improved differentiation through spatial selection of regions close to the site of illumination. Improved sensitivity to superficial tissues is achieved through a combination of these linear and circular polarimetric imaging approaches. Conclusions: Heightened sampling sensitivity to tissue microstructure in the surface/near-surface region of turbid tissue-like media and dental tissue is achieved through a judicious spatial selection of specific regions in the resultant co-linear and cross-circular backscattered polarimetric images.

Integrating clinical access limitations into iPDT treatment planning with PDT-SPACE.

PDT-SPACE is an open-source software tool that automates interstitial photodynamic therapy treatment planning by providing patient-specific placement of light sources to destroy a tumor while minimizing healthy tissue damage. This work extends PDT-SPACE in two ways. The first enhancement allows specification of clinical access constraints on light source insertion to avoid penetrating critical structures and to minimize surgical complexity. Constraining fiber access to a single burr hole of adequate size increases healthy tissue damage by 10%. The second enhancement generates an initial placement of light sources as a starting point for refinement, rather than requiring entry of a starting solution by the clinician. This feature improves productivity and also leads to solutions with 4.5% less healthy tissue damage. The two features are used in concert to perform simulations of various surgery options of virtual glioblastoma multiforme brain tumors.

On the need for standardized reporting of photophysical parameters of in vitro photodynamic therapy studies.

In vitro dose escalation experiments are one of the first gatekeepers in therapeutic evaluation and development. This also holds for evaluating novel photosensitizers (PS) and Photodynamic Therapy (PDT) co-therapies as needed to provide dose response guidelines before engaging in further pre-clinical studies. The dose needed to achieve 50% cell kill (LD50) is a standard metric to report the potency of a therapeutic agents that is widely accepted for single-drug therapies. In reporting results of PDT experiments, which involve delivery of both drug and light, it is inherently more complicated to identify such a convenient dose response metric that actually captures the larger space of treatment parameters. In addition to ubiquitous sources of biological variability that apply broadly in biomedical research, PDT treatment efficacy is determined by multiple key parameters that may or may not have been documented, including PS concentration and light fluence, where the latter is itself a function of the spectral properties of the light source used (often not described), not to mention dose rate, fractionation and other parameters that potentially vary between individual studies. It is impossible to compare results between two study when, for example one reports LD50 PS concentration without providing essential light dosimetry details. Motivated by this challenge in comparing outcomes and establishing reproducibility of in vitro PDT studies, we endeavored to perform a meta-analysis of the reporting of PDT results by converting, where possible, the disparately reported experimental details into a consistent metric that could be used to compare across studies. In this context we adopt here the number of photons absorbed by photosensitizers per unit volume to affect a 50% decline in cell survival as a standardized metric. By choosing this metric one can acknowledge the quantum-based generation of cytotoxins. While this metric does not cover every possible source of variability between any two studies, for a PS with known optical properties, this does encapsulate PS concentration as well as irradiance and spectral properties of light delivered. For the sake of focus we adopt this approach for study of reported results with two photosensitizers, Protoporphyrin IX, either synthesized in the cells by aminolevulinic acid or administered exogenously, and Chlorin e6. A literature search was performed to identify in vitro studies with these two photosensitizers and collect necessary information to calculate the absorbed photon LD50 threshold for each study. Only approximately 1/10 of the manuscripts reporting on in vitro studies provide the minimum required information to calculate the threshold values. While the majority of the determined threshold values are within a factor of 10, the range of threshold values spanned close to 7 orders of magnitude for both photosensitizers. To contrast with single-agent therapies, a similar exercise was performed for chemotherapeutic drugs targeting cellular mitosis or tyrosine kinase inhibitors resulted in an LD50 or IC50 range of 1-2 orders of magnitude, with LD50 or IC50 values for a single cell line being within a factor of 5. This review underscores challenges in the reporting of in vitro PDT efficacy. In many cases it takes considerable effort to extract the necessary methodology information to make meaningful comparison between PDT studies. Only when results between studies can be compared is it possible to begin to assess reproducibility which, as shown here, can be a major issue. Hence, guidelines need to be developed and enforced through the peer review process for meaningful reporting of preclinical PDT results in order for the most promising sensitizers and co-therapies to be identified and translated into the clinic.

Socioeconomic Status at Birth and Breast Tissue Composition in Adolescence and Adulthood.

BACKGROUND: Socioeconomic status (SES) at birth is associated with breast cancer risk. Whether this association is driven by changes in breast tissue composition (BTC) prior to adulthood remains unclear. METHODS: We used multivariable linear regression models to examine whether SES at birth is associated with BTC in adolescence and adulthood using data from a New York City cohort of daughters (n = 165, 11-20 years) and mothers (n = 160, 29-55 years). We used maternal-reported data on daughters' household income and maternal education at birth, analyzed individually and in combination (SES index). Women also reported their own mothers' education at birth. We used optical spectroscopy to evaluate BTC measures that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized breast cancer risk factor. RESULTS: Being in the highest versus lowest category of the SES index was associated with lower lipid content [ßadjusted (ßadj) = -0.80; 95% confidence interval (CI), -1.30 to -0.31] and higher collagen content (ßadj = 0.54; 95% CI, 0.09-0.99) in adolescence. In women with a body mass index (BMI) <30 kg/m2, higher maternal education at birth (≥ vs. < high school degree) was associated with lower lipid content (ßadj = -0.57; 95% CI, -0.97 to -0.17), higher water content (ßadj = 0.70; 95% CI, 0.26-1.14), and higher optical index (ßadj = 0.53; 95% CI, 0.10-0.95). CONCLUSIONS: This study supports that SES at birth is associated with BTC in adolescence and adulthood, although the latter association may depend on adult BMI. IMPACT: Further research is needed to identify the socially patterned early life factors influencing BTC.