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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 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.

Despite a clear link between ataxia-telangiectasia mutated (ATM)–dependent phosphorylation of p53 and cell cycle checkpoint control, the intracellular biology and subcellular localization of p53 phosphoforms during the initial sensing of DNA damage is poorly understood. Using G0-G1 confluent primary human diploid fibroblast cultures, we show that endogenous p53, phosphorylated at Ser15 (p53Ser15), accumulates as discrete, dose-dependent and chromatin-bound foci within 30 minutes following induction of DNA breaks or DNA base damage. This biologically distinct subpool of p53Ser15 is ATM dependent and resistant to 26S-proteasomal degradation. p53Ser15 colocalizes and coimmunoprecipitates with γ-H2AX with kinetics similar to that of biochemical DNA double-strand break (DNA-dsb) rejoining. Subnuclear microbeam irradiation studies confirm p53Ser15 is recruited to sites of DNA damage containing γ-H2AX, ATMSer1981, and DNA-PKcsThr2609 in vivo. Furthermore, studies using isogenic human and murine cells, which express Ser15 or Ser18 phosphomutant proteins, respectively, show defective nuclear foci formation, decreased induction of p21WAF, decreased γ-H2AX association, and altered DNA-dsb kinetics following DNA damage. Our results suggest a unique biology for this p53 phosphoform in the initial steps of DNA damage signaling and implicates ATM-p53 chromatin-based interactions as mediators of cell cycle checkpoint control and DNA repair to prevent carcinogenesis.

Supplementary Figures 1-3 from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

Supplementary Figure Legends from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

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.

Interstitial photodynamic therapy (iPDT) has shown promising results recently as a minimally invasive stand-alone or intra-operative cancer treatment. The development of non-toxic photosensitizing drugs with improved target selectivity has increased its efficacy. However, personalized treatment planning that determines the number of photon emitters, their positions and their input powers while taking into account tissue anatomy and treatment response is still lacking to further improve outcomes. Objective: To develop new algorithms that generate high-quality plans by optimizing over the light source positions, along with their powers, to minimize the damage to organs-at-risk while eradicating the tumor. The optimization algorithms should also accurately model the physics of light propagation through the use of Monte-Carlo simulators. Methods: We use simulated-annealing as a baseline algorithm to place the sources. We propose different source perturbations that are likely to provide better outcomes and study their impact. To minimize the number of moves attempted (and effectively runtime) without degrading result quality, we use a reinforcement learning-based method to decide which perturbation strategy to perform in each iteration. We simulate our algorithm on virtual brain tumors modeling real glioblastoma multiforme cases, assuming a 5-ALA PpIX induced photosensitizer that is activated at $\text{635 nm}$ wavelength. Results: The algorithm generates plans that achieve an average of 46% less damage to organs-as-risk compared to the manual placement used in current clinical studies. Significance: Having a general and high-quality planning system makes iPDT more effective and applicable to a wider variety of oncological indications. This paves the way for more clinical trials.

The editorial introduces the JBO Special Section Celebrating 30 Years of Open Source Monte Carlo Codes in Biomedical Optics for Volume 27, Issue 8.

Open-source software packages have been extensively used in the past three decades in medical imaging and diagnostics, aiming to study the feasibility of the application ex vivo. Unfortunately, most of the existing open-source tools require some software engineering background to install the prerequisite libraries, choose a suitable computational platform, and combine several software tools to address different applications.To facilitate the use of open-source software in medical applications, enabling computational studies of treatment outcomes prior to the complex in-vivo setting.FullMonteWeb, an open-source, user-friendly web-based software with a graphical user interface for interstitial photodynamic therapy (iPDT) modeling, visualization, and optimization, is introduced. The software can perform Monte Carlo simulations of light propagation in biological tissues, along with iPDT plan optimization. FullMonteWeb installs and runs the required software and libraries on Amazon Web Services (AWS), allowing scalable computing without complex set up.FullMonteWeb allows simulation of large and small problems on the most appropriate compute hardware, enabling cost improvements of 10 × versus always running on a single platform. Case studies in optical property estimation and diffuser placement optimization highlight FullMonteWeb's versatility.The FullMonte open source suite enables easier and more cost-effective in-silico studies for iPDT.

Social environment may influence breast tissue composition and breast cancer risk through shaping risk factors operating in early life, adolescence, and adulthood. Socioeconomic status (SES) has been positively associated with breast cancer risk, and mammography studies in women in middle to late adulthood suggest the association might be mediated by the positive relationship between higher SES and higher breast density. Yet, the impact of SES on breast tissue composition earlier in the lifecourse has not been examined, thus limiting the ability to elucidate lifecourse social influences and pathways in the development of breast cancer. In this study, we examined if SES is associated with breast tissue composition in a New York City cohort of 216 Black and Hispanic adolescent girls (aged 11-20 years) and their mothers (aged 29-55 years). We used optical spectroscopy to measure breast tissue chromophores including water content, lipid content, and collagen content, as well as a combined optical index measure. Previous studies have shown that these measures positively (water, collagen, optical index) or negatively (lipid) correlate with mammographic breast density. Questionnaires captured SES indicators at different timepoints across generations: grandparents’ highest level of education; mother’s highest level of education at daughter’s birth; mother’s highest level of education at breast measurement; household income at daughter’s birth; and public assistance at daughter’s birth. We evaluated associations using multivariable linear regression models adjusted for age at breast measurement, percent body fat at breast measurement, race/ethnicity, and mother’s birth country. We tested for additive effect modification by age at breast measurement. In daughters, higher mother’s education at birth was associated with lower lipid content (≥ bachelor’s degree vs. < high school degree, β: -6.96, 95% CI: -13.64, -0.27), and higher grandmother’s education was associated with higher water content (≥ some college vs. < elementary school, β: 3.77, 95% CI: 0.58, 6.97). In mothers, higher household income was associated with lower lipid content ($20,000-80,000 vs. < $10,000, β: -4.26, 95% CI: -7.93, -0.59) and higher optical index (β: 0.30, 95% CI: 0.01, 0.58), while not being on public assistance was associated with higher collagen content (β: 2.54, 95% CI: 0.74, 4.34). Mothers with some college education vs. high school degree or lower at daughter’s birth had higher water content (β: 3.81, 95% CI: 1.07, 6.54), but no association was found comparing mothers with bachelor’s degree or higher vs. high school degree or lower. Associations were not modified by age at breast measurement. This study provides novel data linking intergenerational and early life SES to breast tissue composition in adolescent girls independent of body fat and provides evidence consistent with previous mammography studies of a positive relationship between SES and breast density in adult women. Further studies are needed to explore the downstream factors mediating these relationships. Citation Format: Rebecca D. Kehm, Parisa Tehranifar, E. Jane Walter, Melissa L. White, Sabine Oskar, Julie B. Herbstman, Frederica Perera, Lothar Lilge, Rachel L. Miller, Mary Beth Terry. Multigenerational socioeconomic status and breast tissue composition in mothers and their adolescent daughters: Findings from a multiethnic cohort in New York City [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B102.

With the continued development of non-toxic photosensitizer drugs, interstitial photodynamic therapy (iPDT) is showing more favorable outcomes in recent clinical trials. IPDT planning is crucial to further increase the treatment efficacy. However, it remains a major challenge to generate a high-quality, patient-specific plan due to uncertainty in tissue optical properties (OPs), µ a and µ s . These parameters govern how light propagates inside tissues, and any deviation from the planning-assumed values during treatment could significantly affect the treatment outcome. In this work, we increase the robustness of iPDT against OP variations by using machine learning models to recover the patient-specific OPs from light dosimetry measurements and then re-optimizing the diffusers’ optical powers to adapt to these OPs in real time. Simulations on virtual brain tumor models show that reoptimizing the power allocation with the recovered OPs significantly reduces uncertainty in the predicted light dosimetry for all tissues involved.

The study presented a Monte Carlo simulation of light transport in eight commonly used filtered facepiece respirators (FFRs) to assess the efficacy of UV at 254 nm for the inactivation of SARS‐CoV‐2. The results showed different fluence rates across the thickness of the eight different FFRs, implying that some FFR models may be more treatable than others, with the following order being (from most to least treatable): models 1512, 9105s, 1805, 9210, 1870+, 8210, 8110s and 1860, for single side illumination. The model predictions did not coincide well with some previously reported experimental data on virus inactivation when applied to FFR surfaces. The simulations predicted that FFRs should experience higher log reductions (>>6‐log) than those observed experimentally (often limited to ~5‐log). Possible explanations are virus shielding by aggregation or soiling, and a lack of the Monte Carlo simulations considering near‐field scattering effects that can create small, localized regions of low UV photon probability on the surface of the fiber material. If the latter is the main cause in limiting practical UV viral decontamination, improvement might be achieved by exposing the FFR to UV isotropically from all directions, such as by varying the UV source to the FFR surface angle during treatment., The study presented a Monte Carlo simulation of light transport in eight commonly used filtered facepiece respirators (FFRs) to assess the efficacy of UV at 254 nm for the inactivation of SARS‐CoV‐2. The results showed different fluence rates across the thickness of the eight different FFRs, implying that some FFR models may be more treatable than others.

The authors wish to acknowledge the funding support from NSERC and CIHR as well as the contributions of David Han and Erik Alerstam to code development. Research infrastructure support was provided by the Ontario Ministry of Health and Long Term Care (OMHLTC). The views expressed do not necessarily reflect those of OMHLTC.

This study presents numerical simulations of UVC light propagation through seven different filtered face respirators (FFR) to determine their suitability for UV germicidal inactivation (UVGI). UV propagation was modelled using the FullMonte program for two external light illuminations. The optical properties of the dominant three layers were determined using the inverse adding doubling method.The resulting fluence rate volume histograms and the lowest fluence rate recorded in the modelled volume, sometimes in the nW cm-2, provide feedback on a respirator’s suitability for UVGI and the required exposure time for a given light source. While UVGI can present an economical approach to extend an FFR’s useable lifetime, it requires careful optimization of the illumination setup and selection of appropriate respirators.Abstract Figure

Background: The Pakistani Salt Range has a rich floral diversity including Withania coagulans from the Solanaceae family. Methods: The crude methanolic extracts of the root, leaf, leaf stalk, and fruit of this plant were screened for their cytotoxic activity against human (HeLa, MCF-7, RD) and rat (RG2 and INS-1) cancer cell lines at 20 μg/mL and compared to methotrexate. The IC50 values indicated that leaf stalk and fruit extracts exert an 80% or higher cytotoxic activity against all cell lines at 24 hours. Results: The leaf stalk extract showed the highest cytotoxic efficacy against all tested cell lines, with IC50 values ranging from 0.96 ± 0.01 μg/mL to 4.73 ± 0.05 μg/mL followed by the fruit extract with IC50 values of 0.69 ± 0.01–6.69 ± 0.06 μg/mL after 48–72 hours incubation. The leaf stalk and seed extracts were analyzed for polyphenols and flavonoids using RP-HPLC. The total flavonoid content (TFC) was calculated for all tested samples, and the highest TFC was recorded for the root extract (394.34 ± 1.26 μg/g). The total phenolic content (TPC) was found in the seed extract (307.86 ± 9.42 μg/g) of W. coagulans. The highest contents of myricetin (358.46 ± 2.91 μg/g) were noted in the leaf extract, and highest quercetin was recorded in the seed extract (21.43 ± 0.13 μg/g). The highest gallic acid concentration (83.62 ± 0.71 μg/g) was recorded in leaf stalk extract and p-hydroxybenzoic acid in the seed extract (157.46 ± 1.43 μg/g). Conclusion: The present study gives a scientific insight and comparative analysis of various plant parts in this medicinally important plant species from the Salt Range of Pakistan against both human and rat cancer cells. Keywords: Anticancer, Presto Blue cell metabolic assay, Total phenolic contents, Total flavonoid contents

Made available in DSpace on 2018-11-28T16:42:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-08-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Ontario Ministry of Health and Long-Term Care Princess Margaret Cancer Centre 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. Univ Sao Paulo, Sch Dent Ribeirao Preto, Sao Paulo, Brazil Univ Hlth Network, Princess Margaret Canc Ctr, 101 Coll St, Toronto, ON M5G 1L7, Canada Univ Estadual Paulista, Aracatuba, SP, Brazil Univ Toronto, Dept Med Biophys, Toronto, ON, Canada Univ Estadual Paulista, Aracatuba, SP, Brazil

Significance: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient. Aim: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall. Approach: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer’s specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram. Results: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties. Conclusions: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer’s specific uptake ratio.

Optimizing light delivery for photodynamic therapy, quantifying tissue optical properties or reconstructing 3D distributions of sources in bioluminescence imaging and absorbers in diffuse optical imaging all involve solving an inverse problem. This can require thousands of forward light propagation simulations to determine the parameters to optimize treatment, image tissue or quantify tissue optical properties, which is time-consuming and computationally expensive. Addressing this problem requires a light propagation simulator that produces results quickly given modelling parameters. In previous work, we developed FullMonteSW: currently the fastest, tetrahedral-mesh, Monte Carlo light propagation simulator written in software. Additional software optimizations showed diminishing performance improvements, so we investigated hardware acceleration methods. This work focuses on FullMonteCUDA: a GPU-accelerated version of FullMonteSW which targets NVIDIA GPUs. FullMonteCUDA has been validated across several benchmark models and, through various GPU-specific optimizations, achieves a 288-936x speedup over the single-threaded, non-vectorized version of FullMonteSW and a 4-13x speedup over the highly optimized, hand-vectorized and multi-threaded version. The increase in performance allows inverse problems to be solved more efficiently and effectively.

Background Glioblastoma is an aggressive brain cancer in adults with a grave prognosis, aggressive radio and chemotherapy provide only a 15 months median survival. Methods We evaluated the tolerability and efficacy of the Ruthenium-based photosensitizer TLD-1433 with apo-Transferrin (Rutherrin) in the rat glioma 2 (RG-2) model. The specific tumor uptake ratio and photodynamic therapy (PDT) threshold of the rat glioblastoma and normal brain were determined, survival and CD8+T-cell infiltration post-therapy were analyzed. Results were compared with those obtained for 5-aminolevulinic acid (ALA)-induced Protoporphyrin IX (PpIX)-mediated photodynamic therapy in the same animal model. As both photosensitizers have different photophysical properties, the number of absorbed photons required to achieve an equal cell kill was determined for in vitro and in vivo studies. Results A significantly lower absorbed energy was sufficient to achieve LD50 with Rutherrin versus PpIX-mediated PDT. Rutherrin provides a higher specific uptake ratio (SUR) >20 in tumors versus normal brain, whereas the SUR for ALA-induced PpIX was 10.6. To evaluate the short-term tissue response in vivo, enhanced T2-weighted magnetic resonance imaging (MRI) provided the spatial extent of edema, post PpIX-PDT at twice the cross-section versus Rutherrin-PDT suggesting reduced nonspecific damage, typically associated with a secondary wave of neuronal damage. Following a single therapy, a significant survival increase was observed in rats bearing glioma for PDT mediated by Rutherrin versus PpIX for the selected treatment conditions. Rutherrin-PDT also demonstrated an increased CD8+T-cell infiltration in the tumors. Conclusion Rutherrin-PDT was well tolerated providing a safe and effective treatment of RG-2 glioma.

INTRODUCTION AND OBJECTIVES:To achieve a pre-defined photosensitizer dose and photon irradiance for PDT of NMIBC, independent of a patient’s bladder volume, shape and bladder wall optical propertie...

Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that result from incomplete combustion of biomass and fossil fuels. PAH have endocrine-disrupting properties and are known animal carcinogens. Evidence from case-control studies suggests an association between PAH and breast cancer risk, but longitudinal research on PAH exposure during critical windows of susceptibility, such as prenatally and in early life, is limited. The purpose of this study was to prospectively examine whether prenatal exposure to PAH is associated with breast tissue composition, an intermediate marker of breast cancer risk, in adolescent girls. We studied 105 adolescent girls in the Columbia Center for Children’s Environmental Health (CCCEH) birth cohort, which recruited nonsmoking African American and Dominican American pregnant women living in three low-income neighborhoods in New York City from 1998-2006. Women wore a small backpack holding a personal air monitor for 2 consecutive days during the 3rd trimester of pregnancy, which measured concentrations of pyrene and 8 other carcinogenic PAH (summed and categorized into tertiles for analysis). Girls completed a follow-up clinic visit in adolescence (ages 11.2-19.6 years, median=15.8), at which time breast tissue composition was measured by optical spectroscopy (OS). OS is a novel and noninvasive tool that provides a broad compositional view of the breast by capturing variation in the amount of water, lipid, oxy-hemoglobin, deoxy-hemoglobin, and collagen, as well as overall cellular and connective tissue density. OS measured red and near-infrared light transmission of 7 wavelengths (650-1060 nm) at 4 source-detector distances in each breast quadrant, resulting in 16 overlapping tissue volumes. Principal component analysis was used to reduce spectral data and generate principal component (PC) scores for each participant, which were averaged over both breasts. We used multivariable linear regression to examine associations of prenatal PAH measures (pyrene and Σ8 PAH) with each of the first 4 OS PCs, which explained >99% of the spectral variation in the sample. Models were adjusted for age, ethnicity, body mass index (BMI) at time of OS measurement, age at breast development, and mothers’ prepregnancy BMI. After adjusting for covariates, PC1 scores were significantly lower on average in the highest compared to lowest tertile of prenatal ambient Σ8 PAH (β = -0.42, 95% CI = -0.81 to -0.02, p = 0.04). PC1 covered 91.8% of the spectral variations and represents overall light attenuation from higher scattering due to higher cellularity and connective tissues. PC1 also mapped to multiple chromophores including hemoglobin and collagen. No associations were found between prenatal ambient Σ8 PAH and PCs 2-4, and no associations with OS PCs were found for pyrene. To conclude, we found evidence suggesting that prenatal exposure to PAH is associated with breast tissue composition in adolescent girls. Citation Format: Rebecca D. Kehm, Lothar Lilge, E. Jane Walter, Nur Zeinomar, Jasmine A. McDonald, Parisa Tehranifar, Julie B. Herbstman, Rachel L. Miller, Mary Beth Terry. Prenatal exposure to polycyclic aromatic hydrocarbons and breast tissue composition in adolescent girls [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A15.

Significance: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient. Aim: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall. Approach: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer’s specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram. Results: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties. Conclusions: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer’s specific uptake ratio.

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.

Date of Conference: 5–10 May 2019 Conference name: 2019 Conference on Lasers and Electro-Optics (CLEO) Plasma-mediated ablation by ultrafast pulses is generally considered to be a material-independent process. We show that, in certain circumstances, this assumption may be invalid. Physical processes involved and the impact on applications are discussed.

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 the most widely studied 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 included the light component and the protocol for treating nonmuscle 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.

Background Malignant gliomas are highly invasive, difficult to treat, and account for 2% of cancer deaths worldwide. Glioblastoma Multiforme (GBM) comprises the most common and aggressive intracranial tumor. The study hypothesis is to investigate the modification of Photodynamic Therapy (PDT) efficacy by mild hypothermia leads to increased glioma cell kill while protecting normal neuronal structures. Methods Photosensitizer accumulation and PDT efficacy in vitro were quantified in various glioma cell lines, primary rat neurons, and astrocytes. In vivo studies were carried out in healthy brain and RG2 glioma of naive Fischer rats. Hypothermia was induced at 1 hour pre- to 2 hours post-PDT, with ALA-PpIX accumulation and PDT treatments effects on tumor and normal brain PDT quantified using optical spectroscopy, histology, immunohistochemistry, MRI, and survival studies, respectively. Findings In vitro studies demonstrated significantly improved post-PDT survival in primary rat neuronal cells. Rat in vivo studies confirmed a neuroprotective effect to hypothermia following PpIX mediated PDT by T2 mapping at day 10, reflecting edema/inflammation volume reduction. Mild hypothermia increased PpIX fluorescence in tumors five-fold, and the median post-PDT rat survival time (8.5 days normothermia; 14 days hypothermia). Histology and immunohistochemistry show close to complete cellular protection in normal brain structures under hypothermia. Conclusions The benefits of hypothermia on both normal neuronal tissue as well as increased PpIX fluorescence and RG2 induced rat survival strongly suggest a role for hypothermia in photonics-based surgical techniques, and that a hypothermic intervention could lead to considerable patient outcome improvements.

Background: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan&reg, has been studied previously with partial success in treating these tumours and extending lifetime. We aim to determine whether combining PDT using ALA-protoporphyrin IX (PpIX) with a liposomal formulation of the clinical epidermal growth factor receptor (EGFR) inhibitor, lapatinib, would increase the anti-tumour PDT efficacy. Methods: Lapatinib was given in vitro and in vivo 24 h prior to PDT and for 3&ndash, 5 days following PDT to elicit whether the combination provided any benefits to PDT therapy. Live-cell imaging, in vitro PDT, and in vivo studies were performed to elucidate the effect lapatinib had on PDT for a variety of glioma cell lines and as well as GSC-30 neurospheres in vivo. Results: PDT combined with lapatinib led to a significant increase in PpIX accumulation, and reductions in the LD50 of PpIX mediated PDT in two EGFR-driven cell lines, U87 and U87vIII, tested (p &lt, 0.05). PDT + lapatinib elicited stronger MRI-quantified glioma responses following PDT for two human glioma-derived tumours (U87 and GSC-30) in vivo (p &lt, 0.05). Furthermore, PDT leads to enhanced survival in rats following treatment with lapatinib compared to lapatinib alone and PDT alone (p &lt, 0.05). Conclusions: As lapatinib is approved for other oncological indications, a realization of its potential combination with PDT and in fluorescence-guided resection could be readily tested clinically. Furthermore, as its use would only be in acute settings, long-term resistance should not pose an issue as compared to its use as monotherapy.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0805-x) contains supplementary material, which is available to authorized users.

Tumor heterogeneity can be elucidated by mapping subregions of the lesion with differential imaging characteristics, called habitats. Dynamic Contrast Enhanced (DCE-)MRI can depict the tumor microenvironments by identifying areas with variable perfusion and vascular permeability, since individual tumor habitats vary in the rate and magnitude of the contrast uptake and washout. Of particular interest is identifying areas of hypoxia, characterized by inadequate perfusion and hyper-permeable vasculature. An automatic procedure for delineation of tumor habitats from DCE-MRI was developed as a two-part process involving: (1) statistical testing in order to determine the number of the underlying habitats; and (2) an unsupervised pattern recognition technique to recover the temporal contrast patterns and locations of the associated habitats. The technique is examined on simulated data and DCE-MRI, obtained from prostate and brain pre-clinical cancer models, as well as clinical data from sarcoma and prostate cancer patients. The procedure successfully identified habitats previously associated with well-perfused, hypoxic and/or necrotic tumor compartments. Given the association of tumor hypoxia with more aggressive tumor phenotypes, the obtained in vivo information could impact management of cancer patients considerably.

We introduce the FullMonte tetrahedral 3-D Monte Carlo (MC) software package for simulation, visualization, and analysis of light propagation in heterogeneous turbid media including tissue. It provides the highest computational performance and richest set of input, output, and analysis facilities of any open-source tetrahedral-mesh MC light simulator. It also provides a robust framework for statistical verification. A scripting interface makes set-up of simulation runs simple, including parameter sweeps, while simultaneously providing customization options. Data formats shared with class-leading visualization tools, VTK and Paraview, facilitate interactive generation of publication-quality fluence and irradiance maps. The simulator can read and write file formats supported by other similar simulators, such as TIM-OS, MMC, COMSOL (finite-element simulations), and MCML to support comparison. Where simulator features permit, FullMonte can take a single test case, run it in multiple software packages, and load the results together for comparison. Example meshes, optical properties, set-up scripts, and output files are provided for user convenience. We demonstrate its use in several test cases, including photodynamic therapy of the brain, bioluminescence imaging (BLI) in a mouse phantom, and a comparison against MCML for layered geometries. Application domains that can benefit from use of FullMonte include photodynamic, photothermal, and photobiomodulation therapies, BLI, diffuse optical tomography, MC software development, and biophotonics education. Since MC results may be used for preclinical or even clinical experiments, a robust and rigorous verification process is essential. Being a stochastic numerical method, MC simulation has unique challenges associated with verification of output results since observed differences may be due simply to output variance or actual differences in expected output. We describe and have implemented a rigorous and statistically justified framework for comparing between simulators of the same class and for performing regression testing.

A 3-chip CCD imaging system has been developed for quantitative in vivo fluorescence imaging. This incorporates a ratiometric algorithm to correct for the effects of tissue optical absorption and scattering, imaging “geometry” and tissue autofluorescence background. The performance was characterized, and the algorithm was validated in tissue-simulating optical phantoms for quantitative measurement of the fluorescent molecule protoporphyrin IX (PpIX). The technical feasibility to use this system for fluorescence-guided surgical resection of malignant brain tumor tissue was assessed in an animal model in which PpIX was induced exogenously in the tumor cells by systemic administration of aminolevulinic acid (ALA).

Transillumination breast spectroscopy (TiBS) uses nonionizing optical radiation to gain information about tissue properties directly from the breast. TiBS measurements were obtained from 225 women with normal mammograms. Principal component analysis was used to reduce the spectral data set into four principal components and to generate four TiBS scores (t1-t4) for each woman. These components and scores represent light scattering, water, lipid, and hemoglobin content. Percent density, dense area, and nondense area were measured using Cumulus. The association between TiBS scores and quantitative mammographic features was analyzed using linear regression stratified by menopausal status and adjusted for body mass index. Among premenopausal women, t1 and t3 were significantly associated with percent density (βt1 = −0.14, P = 0.04; βt3 = −2.43, P < 0.0001), whereas t2 and t3 were significantly associated with dense area (βt2 = −1.57, P < 0.0001; βt3 = −2.54, P < 0.0001). Among postmenopausal women, t1, t3, and t4 were significantly associated with percent density (βt1 = −0.30, P < 0.0001; βt3 = −2.51, P < 0.0001; βt4 = 4.75, P < 0.0001) and dense area (βt1 = −0.19, P = 0.004; βt3 = −2.13, P = 0.002; βt4 = 5.02, P < 0.0001). Scores t2 and t4 were also significantly correlated with age among postmenopausal women (rt2 = 0.41 and rt4 = −0.36). Given the association with quantitative mammographic features and tissue changes related to age and menopause, TiBS scores may prove useful as intermediate markers in studies of breast cancer etiology and prevention. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1043–50)

Interstitial photodynamic therapy (PDT) has seen a rebirth, partially prompted by the development of photosensitizers with longer absorption wavelengths that enable the treatment of larger tissue volumes. Here, we study whether using diffusers with customizable longitudinal emission profiles, rather than conventional ones with flat emission profiles, improves our ability to conform the light dose to the prostate. We present a modified Cimmino linear feasibility algorithm to solve the treatment planning problem, which improves upon previous algorithms by (1) correctly minimizing the cost function that penalizes deviations from the prescribed light dose, and (2) regularizing the inverse problem. Based on this algorithm, treatment plans were obtained under a variety of light delivery scenarios using 5-15 standard or tailored diffusers. The sensitivity of the resulting light dose distributions to uncertainties in the optical properties, and the placement of diffusers was also studied. We find that tailored diffusers only marginally outperform conventional ones in terms of prostate coverage and rectal sparing. Furthermore, it is shown that small perturbations in optical properties can lead to large changes in the light dose distribution, but that those changes can be largely corrected with a simple light dose re-normalization. Finally, we find that prostate coverage is only minimally affected by small changes in diffuser placement. Our results suggest that prostate PDT is not likely to benefit from the use of tailored diffusers. Other locations with more complex geometries might see a better improvement.