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Spinal metastases often occur in the advanced stages of breast, lung or prostate cancer, resulting in a significant impact on the patient’s quality of life. Current treatment modalities for spinal metastases include both systemic and localized treatments that aim to decrease pain, improve mobility and structural stability, and control tumour growth. With the development of non-toxic photosensitizer drugs, photodynamic therapy (PDT) has shown promise as a minimally invasive non-thermal alternative in oncology, including for spinal metastases. To apply PDT to spinal metastases, predictive algorithms that optimize tumour treatment and minimize the risk of spinal cord damage are needed to assess the feasibility of the treatment and encourage a broad acceptance of PDT in clinical trials. This work presents a framework for PDT modelling and planning, and simulates the feasibility of using a BPD-MA mediated PDT to treat bone metastases at two different wavelengths (690 nm and 565 nm). An open-source software for PDT planning, PDT-SPACE, is used to evaluate different configurations of light diffusers (cut-end and cylindrical) fibres with optimized power allocation in order to minimize the damage to spinal cord or maximize tumour destruction. The work is simulated on three CT images of metastatically involved vertebrae acquired from three patients with spinal metastases secondary to colorectal or lung cancer. Simulation results show that PDT at a 565 nm wavelength has the ability to treat 90% of the metastatic lesion with less than 17% damage to the spinal cord. However, the energy required, and hence treatment time, to achieve this outcome with the 565 nm is infeasible. The energy required and treatment time for the longer wavelength of 690 nm is feasible ($${\sim }\,40$$ ∼ 40 min), but treatment aimed at 90% of the metastatic lesion would severely damage the proximal spinal cord. PDT-SPACE provides a simulation platform that can be used to optimize PDT delivery in the metastatic spine. While this work serves as a prospective methodology to analyze the feasibility of PDT for tumour ablation in the spine, preclinical studies in an animal model are ongoing to elucidate the spinal cord damage extent as a function of PDT dose, and the resulting short and long term functional impairments. These will be required before there can be any consideration of clinical trials.

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.

As oncological treatments aim to move towards personalize medicine, increase tissue response monitoring has become the focus of research. In particular, spatially resolved in vivo information of hypoxia and its relationship to cell survival is required to maximize the patient's benefit. At the same time, several preclinical imaging approaches were developed in the past years, including Photoacoustic, Bioluminescence imaging (BLI) to quantify blood flow/volume. Here Photo acoustic Imaging (PAl) is used to study tumor hypoxia for Photodynamic Therapy (PDT) monitoring to predict cell survival. The Photoacoustic and Bioluminescence signals' temporal dynamic are used to detect vascular changes during and post-PDT.

Background Isolated lung metastases in sarcoma and colorectal cancer patients are inadequately treated with current standard therapies. In Vivo Lung Perfusion, a novel platform, could overcome limitations to photodynamic therapy treatment volumes by using low cellular perfusate, removing blood, theoretically allowing greater light penetration. To develop personalized photodynamic therapy protocols requires in silico light propagation simulations based on optical properties and maximal permissible photodynamic threshold dose of lung tissue. This study presents quantification of optical properties for two perfusates and the photodynamic threshold for 5-ALA and Chlorin e6. Methods Porcine and human lungs were placed on Ex Vivo Lung Perfusion, and perfused with acellular solution or blood. Isotropic diffusers were placed within bronchi and on lung surface for light transmission measurements, from which absorption and light scattering properties were calculated at multiple wavelengths. Separately, pigs were injected with 5-ALA or Chlorin e6, and lung tissue was irradiated at increasing doses. Resultant lesion sizes were measured by CT and histology to quantify the photodynamic threshold. Results Low cellular perfusate reduced the tissue absorption coefficient significantly, increasing penetration depth of light by 3.3 mm and treatment volumes 3-fold. The photodynamic threshold for lung exposed to 5-ALA was consistent with other malignancies. Chlorin e6 levels were undetectable in lung tissue and did not demonstrate photodynamic-induced necrosis. Conclusions Light penetration with low cellular perfusate is significantly greater and could enable treatments for diffuse disease. This data aids photodynamic treatment planning and will guide clinical translation of photodynamic therapy protocols in the lung, especially during lung perfusion.

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

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.

Acute arthritis is an inflammation that affects many joints. The principal treatment options comprise drugs (corticosteroids), invasive and painful surgery. The objective of this study was to evaluate the efficacy of low intensity laser therapy (LILT), a non-invasive treatment, in a murine model of acute inflammation model. 48 mice received a synovial injection of Zymosan A into one knee. Mice were treated with LILT by three different wavelengths, either as a single (S) or dual (D) application immediately after the injury or after 24h following initiation of an inflammatory response. The histological analysis aimed at identifying inflammatory infiltrate and the structure of the articular surfaces as an indicator of a long-term damage due to inflammation. Statistical analysis (Kruskal-Wallis test), did not allow to reject the null hypothesis. However, LILT promoted histological alterations in some treatment groups. Histological evidence (Median and confidence interval) of anti-inflammatory effects was especially noticeable in knees of mice irradiated with lasers emitting moderate intensity and continuous 660nm (S=18.5 (11.4; 27.6); D=16.0 (6.93; 27.0)) and high intensity and pulsed 905nm (S=17.5 (10.2; 24.79), with decrease of the resorbed region. However, the 905nm pulsed laser was responsible for exacerbation of inflammation for multiple LILT sessions with a short delay (D=45.0 (22.84; 63.83)), tending to aggravate the resorption of the articular surface (p

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

The simulation of light propagation through tissues is important for medical applications, such as photodynamic therapy (PDT) for cancer treatment. To optimize PDT an inverse problem, which works backwards from a desired distribution of light to the parameters that caused it, must be solved. These problems have no closed-form solution and therefore must be solved numerically using an iterative method. This involves running many forward light propagation simulations which is time-consuming and computationally intensive. Currently, the fastest general software solver for this problem is FulMonteSW. It models complex 3D geometries with tetrahedral meshes and uses Monte Carlo techniques to model photon interactions with tissues. This work presents FullMonteFPGACL: an FPGA-accelerated version of FullMonteSW using an Intel Stratix 10 FPGA and the Intel FPGA SDK for OpenCL. FullMonteFPGACL has been validated and benchmarked using several models and achieves improvements in performance (4x) and energy-efficiency (11x) over the optimized and multi-threaded FullMonteSW implementation. We discuss methods for extending the design to improve the performance and energy-efficiency ratios to 16x and 17x, respectively. We achieved these gains by developing in an agile fashion using OpenCL to facilitate quick prototyping and hardware-software partitioning. However, achieving competitive area and performance required careful design of the hardware pipeline and expression of its structure in OpenCL. This led to a hybrid design style that can improve productivity when developing complex applications on an FPGA.

We present an optimized light diffuser placement algorithm for high-quality interstitial photodynamic therapy planning. We simulate the algorithm on modeled glioblas-toma multiforme cases. Results show damage to organs-at-risk is reduced by 46%-77% on average.

Glioblastoma is a highly aggressive and common brain cancer in adults with a grave prognosis, and aggressive radio and chemotherapy provide only a 15 months median survival. We evaluated the tolerability, and efficacy of the Ruthenium-based photosensitizer TLD-1433 in the formulation with apo-Transferrin (Rutheriin®) in the RG2, rat glioblastoma model. The specific tumour uptake ratio, PDT threshold, of the RG2 rat glioblastoma models and normal brain in vivo were determined as well as the survival post-PDT and the extent of CD8+T cell infiltration post-PDT. Results were compared with those obtained by 5-ALA-induced PpIX mediated PDT in the same animal model. As both photosensitizers have different photophysical properties, the number of absorbed photons required to achieve an equal cell kill is compared during in-vitro and in vivo studies. A significantly lower absorbed energy was enough to achieve LD50 with Rutherrin® versus -PpIX mediated PDT. Rutherrin® provides higher selective uptake ratio (SUR>20) in RG2 tumours compared to normal brain, whereas the SUR for ALA-induced PpIX was 10.6 in the same tumour model. To evaluate the short-term tissue response in vivo enhanced T2-weighted MR images provided the spatial extent of edema, which is twice post PpIX-PDT versus Rutherrin®-PDT suggesting reduced non-specific damage typically associated with a secondary wave of neuronal damage. A significant survival increase was observed in Rutherrin® treated rats bearing RG2 versus PpIX-PDT for the selected treatment conditions, associated with an increased CD8+T cell infiltration in the tumours. Rutherrin®-PDT was well tolerated providing safe and effective treatment of RG2 -induced glioblastoma.

While the prevalence of central bronchial tumours is declining, that of peripheral lung tumours is increasing. Peripheral lung tumours present either as individual index lesion or as field cancerization, requiring for the former targeting of particular confined volumes of lung tissue versus a therapy for an entire lung or particular lobes thereof. Using FullMonte, a Monte Carlo code; the ability to achieve a tumour selective PDT by transbronchial light source placement was simulated for 525, 665 and 808 nm wavelength. Simulations were executed utilizing in silica models with up to 10 generations of the bronchial tree, tissue photosensitizer concentrations taken from literature or measure in preclinical model systems and tissue optical properties measured with alive ex vivo pig and human lungs perfused with either blood or a transparent low cellular (STEEN) fluid. The measured effective attenuation coefficients [cm-1] at the three wavelengths for ventilated lungs with either blood 1.26±1.07, 1.93±0.534, 1.09±0.93 or STEEN fluid 1.01±0.873, 0.901±0.318, 0.641±0.31 used as perfusate. When modelling the PDT dose distribution in the lung’s the bronchial air ducts up to the eight generations perturb the fluence considerably. In all simulations, a dose sufficient to cause necrosis in 98% of the target volume placement of 3 source fibres albeit with various extent of normal lung tumour damage. Full coverage of an entire lung lobe with only three source fibres placed does not provide for effective coverage of the diffuse disease unless a very high selective uptake of the photosensitizer in malignant tissues can be achieved.

Even though a patient has a good immune system, tumors are shielded from it, because tumors grow by suppressing the host’s immune-response by various mechanisms. They are keeping their local microenvironment immune suppressed by producing immune suppressive cytokines like IL-10 and TGF-b, express immune checkpoint ligands like Programmed Death Ligand 1 (PDL1), and harbor immune suppressive cells like Tregs and MDSCs. To overcome these barriers a stronger anti-tumour immune-response is essential. We evaluated a whole cell vaccine with extracorporeal Rutherrin®-PDT treated cancer cells (RuVaCareTM) to break the suppressive barrier in the RG2-glioblastoma model. Rutherrin®-PDT induced strong immunogenic cell death (ICD) in glioblastoma cells in-vitro. RuVaCareTM supernatants showed significantly higher level of extracellular ATP, which is known to induce recruitment of antigen presenting cells (APCs) and their activation by eliciting an effective anti-tumour immune-response. Extracellular calreticulin (CRT) is one of the hallmarks of ICD; its expression went up in more than 85% cells undergoing Rutherrin®-PDT mediated cell death. There was a close to 10 times increase in expression of HSP 70 in RuVaCareTM. Immunostimulatory cytokines IFNa, IL-1b and GMCSF expression is high in the RuVaCareTM. In-vivo efficacy of the RuVaCare™ was evaluated in orthotopic RG2 rat glioblastoma model. There was a significant increase (~43% with 2-time vaccine and 87% in the 6-time vaccine) in survival in the RuVaCare™ vaccinated groups compared to unvaccinated controls. Increased intratumoral CD8+T-cell numbers are shown to be correlated with increased survival in glioblastoma rats, with RuVaCare™ there was a significant increase in the number of CD8+T-cells.

For patients failing standard Bacillus Calmette-Guerin based immunotherapy for Non-Muscle Invasive Bladder Cancer (NMIBC), PDT may delay or prevent cystectomy. A Phase IB clinical trial evaluated the feasibility and safety of TLD1433, a novel Ruthenium coordination-complex as photosensitizer (PS) for PDT. The clinical trial combined PS instillation for one hour and the use of strongly attenuated green (525nm) light to reduce PDT caused damage to the bladder wall. The low and high PS doses were defined as 0.35mg and 0.7mg TLD1433 per cm^2 bladder surface (N=3 each) and 90+/-9J/cm^2 as target radiant exposure on the bladder wall. The PS concentration in the urine and blood at 24hrs post instillation was below 1ng/ml indicating rapid drug clearing. In all patients, the average target radiant exposure was attained as verified by irradiance sensors in the bladder. The average measured irradiance was ~ 15mW/cm^2, never exceeding 35mW/cm2 at the sensor positions. At 30 days post-treatment, all patients receiving the low PS dose tolerated the procedure well with no grade 3, 4 or 5 AEs. Three patients were then treated at the Therapeutic Dose, again with no grade 3, 4 or 5 AEs, and an identical pharmacokinetic profile to the half dose. At half dose, all patients had recurrent, but no progressive NMIBC noted at the 180-day cystoscopy. At therapeutic dose, 2 of 3 patients were tumour-free at the 180-day cystoscopy. Moderate bladder irritability was reported at full dose which primarily resolved within 90 days.

Determining the light propagation in heterogeneous media is a challenging task which can only be approximated by solving the Boltzmann transport equation via diffusion theory. However, diffusion theory becomes very inaccurate at interfaces, boundaries, sources, and sinks, which are present in heterogeneous media. Monte Carlo methods are able to converge to the correct solution by simulating a sufficiently high number of photons, at the cost of increased runtime. Therefore, it is important to optimize the Monte Carlo simulator, thereby allowing more photons to be simulated and a more accurate solution within a given runtime. FullMonte is a full-featured simulator that uses processor-optimized operations to achieve the highest performance of any 3D tetrahedral Monte Carlo light propagation software to date. This paper presents two medical use cases which benefit from FullMonte, highlights new features and explains the optimizations that lead to its high performance.

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.

Spinal bone metastases often present as a diffuse combination of osteolytic and osteoblastic disease. Photodynamic therapy (PDT) is a minimally invasive therapy that has been shown to locally ablate cancer cells within the bony spine. To optimize patient-specific treatment protocols and ensure safety of critical neural structures, the responsivities of the heterogenous tissues to PDT must be known. This work derives a PDT threshold value for the spinal cord using a benzoporphyrin derivative monoacid (BPD-MA) photosensitizer.

Median survival for Glioblastoma patients remains at around 15 months after surgery, radiation, and chemotherapy but varies widely between surgeons and centres. Interstitial Photodynamic Therapy (iPDT) mediated by ALA induced PpIX or other photosensitizers is investigated at various clinics. To enable iPDT treatment planning, photosensitizer transport characteristics needs to be known in order to optimize photoactivation. A method using contrast enhanced, functional magnetic resonance imaging, compartment modelling, spatial frequency domain imaging (SFDI) and inductively coupled plasma mass spectrometry (ICP-MS) is proposed to predict and validate the localization characteristics of two photosensitizers in murine Glioblastoma models.

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...

Optical Breast Spectroscopy (OBS) has been shown to predict mammographic breast density, a strong breast cancer risk factor. OBS is a low-cost technique applicable at any age. OBS information may be useful for personalizing breast cancer screening programs based on risk to improve consensus on and adherence to screening guidelines. To facilitate the use of OBS in population-wide studies, a research prototype OBS device was modified to make it portable and cheaper and to require less operator interaction. Two major changes were made: (1) the broadband light source was replaced with a laser module with 13 individual wavelengths turned on sequentially, enabling the use of photodiode detectors instead of a spectrometer, and (2) the light sources and detectors were placed in fixed positions within 4 sizes of cup, eliminating the need for placement by the operator. Wavelengths were selected using data from two previous studies. The reduction in spectral content did not significantly reduce the ability to distinguish between different risk groups. Positions for the light sources and detectors were chosen based on Monte Carlo simulations to match the optically interrogated volumes of the original device. Two light sources and six detectors per cup were used in the final design.

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.

While Photofrin mediated PDT for bladder cancer was the first approved indication for this technique, it failed to attract the confidence of urologists as a treatment option, primarily due to the high incidence of incontinence linked to PDT damage to the bladder muscle. To mitigate this hazard a phase I clinical trial using instillation of the Ru(II) coordination complex TLD1433 and 530 nm activation light was initiated. To achieve the intended drug doses of 0.35 and 0.7 mg/cm2 and a radiant exposure of 90 J/cm2 the concentration of the instillation was adjusted to each patients' bladder volume and the irradiance was measured at up to 12 positions in the bladder. Irradiance monitoring proved helpful in adjusting the irradiation time to the bladder wall albedo and also for increased light scattering and absorption due to turbidity built up in the bladder void. The initial multiplication factors of the bladders (n=6) ranged from 1.1 to 2.8. Monte Carlo simulations based on CT-scans from all 6 participants approximate the range of irradiances observed during these studies. Nevertheless, a fraction of the surface can see a multiple of the average irradiance whereas other regions (typically less than 5% of the surface area) see significantly less than the average irradiance. These variations are due to the actual bladder shape and are somewhat independent of the position of the spherical emitter. Fitting of the measured surface irradiance to the simulated dose surface histograms enables extraction of the bladder wall and bladder void’s optical properties.

Non-muscle invasive bladder cancer remains one of the costliest cancer to treat, and while a cystectomy will reduce a patient’s risk of developing metastatic disease it reduced the patient’s quality of life. While Photofrin mediate Photodynamic Therapy was approved already in 1993, poor control over the photon density and drug accumulation in of target tissue resulted in overdosing the bladder muscle layers, causing permanent volume shrinkage and incontinence. For an ongoing Phase Ib clinical trial, evaluating the safety of TLD1433 ([Ru(II)(4,4'-dimethyl-2,2'-bipyridine(dmb))2(2-(2',2'':5'',2'''-terthiophene)-imidazo[4,5-f][1,10]phenanthroline)]2+) a Ru(II) coordination complex, significant deviations from the previous studies are implemented. The photosensitizer is instilled, to reduce the sensitization of the muscle layer, 525 nm light is used to limit the light penetration into the bladder and the photon density is measured in each patient at up to 12 positions. Improved tumour selectivity is provided by this photosensitizer as it is block by the Urothelium from entering healthy tissue, whereas it enters tumour cells, supposing via the transferrin receptor, as demonstrated in in-vitro and in vivo studies. The Ru(II) coordination complex stains tissues where the urothelium is damaged very strongly in an orange-rust colour, visible under white light illumination. Preclinical in vivo studies showed the destruction of tumours up to 1 mm in depth following 1 hr of drug instillation, followed by 3 washes and the delivery of 90 Jcm-2 of 525nm light in the wistar rat Ay-27 tumour model. Histology showed very limited muscle damage and in general intact urothelium layers, with a moderate infiltration of macrophages. To achieve the prescribed target radiant exposure of 90 Jcm-2, independent of the bladder tissue diffuse reflectivity and shape, an optical dosimetry system was developed which can be deployed via a cystoscope. The optical dose monitoring device allows the treating physician to adjust the source position to achieve the target optical dose for the 12 sensor positions. The optical radiation was delivered via a 0.8 mm diameter spherical diffuser at up to 2.5 W power. The attainable photon density and the anticipated PDT dose are simulated for each patient using a photon propagation engine and the patient’s anatomical information. During these simulations, a range of tissue optical properties is simulated and compared to the initial photon density measurements to advise the physician further about the ability to achieve a homogenous illumination in each patient. The multiplication factor of the irradiance inside the bladder, calculated based on the spherical volume equivalent size of the bladder, the delivered power and measured irradiance, varied between patients (from 1.1 to 2.5) and also over the course of the treatment. The changes over the course of the treatment were predominantly due to light diffusing proteinaceous material floating in the bladder. Expanding prior work by the Rotterdam group on light propagation in the bladder we determined that the tissue albedo varied from 0.87 to 0.92 for 525 nm in this patient population. The estimated average effective attenuation coefficient for this population was approximately 1 mm adequate for the treatment of non-muscle invasive bladder cancer after transurethral resection of the large tumours. Monte Carlo modelling demonstrated that the fluence as function of depth into the tissue is determined by the exposure of bladder wall elements to the remaining bladder surface and can vary by factor of more than 2 even when assuming homogenous tissue optical properties across the bladder wall surface. These studies and analysis demonstrate the need for accurate light dosimetry in hollow organs when variations in the tissue albedo and the shape of the organ can influence the photodynamic dose significantly.

Background: The majority of cancers upregulate their transferrin receptor (Tf-R) to satisfy their higher Fe3+ requirements for proliferation. TLD-1433 can bind to transferrin to form Rutherrin, which is a promising photosensitizer with stable chemical structure and higher tissue selectivity. Methods: To investigate the effect of Rutherrin®-mediated photodynamic treatment (PDT), we used non-small lung cancer cell lines H2170, A549, and H460. Subcutaneous tumors were treated with Rutherrin-mediated PDT, 4hrs post intravenous administration. The treatment parameters10 mg/kg Rutherrin and 600 Jcm-2 808 nm radiation. In an orthotopic A549 tumor model, the presence of tumor after inoculation in lungs was confirmed by microCT. Tissue samples were collected for Inductively Coupled Mass Spectrometry to quantify the Rutherrin concentrations via a Ru isotope in tumor and normal lung tissue. Results: Evaluation of TfR expression by flow cytometric and western blotting showed that almost all cancer cells express TfR. In in-vitro cytotoxicity assay, all cancer cell lines showed high cell kill by PDT at 100nM Rutherrin concentrations. In the subcutaneous tumor model, PDT after Rutherrin injection significantly inhibited the tumor growth and histopathology showed extensive necrosis at 24 hrs, which was confirmed with lowered Ki67 staining. In an orthotopic model, the lung lobe with tumor retained more Rutherrin than the contralateral lung, showing specific tumor uptake. Conclusion: These results support the hypothesis that safe and efficient Rutherrin-mediated PDT is feasible due to improved photosensitizer localization to lung tumors tissue. Selective irradiation of the cancer lesions by strategic placement of the light source remains a requirement.

Ultrafast `pulsetrain-burst' machining has proven to deliver qualitative advantages for the processing of hard materials. This approach to tailoring the delivery of radiant exposure uses microsecond bursts of picosecond or femtosecond pulses. The mixed-timescale mode reaps the rewards of providing laser-material interactions at ultrashort timescales, while allowing for some control of heat and stress dissipation over longer timescales. As a result, our group has been able to ablate hard materials such as aluminum [1], as well as optically transparent materials like fused silica [2,3] beyond the capabilities of more conventional methods that employ slower repetition rates. It is well known that gross differences in the end results of materials-processing are the result of the manner in which the laser fluence is delivered - wavelength, continuous-wave vs. pulsed, pulse shape, and the pulse duration itself all have significant impact, and each parameter-value has significant advantages. For brittle materials, where limited tolerance to heat and tensile stress sets limits on the etch-depth possible for multi-kHz repetition rates, 'pulsetrain-burst' machining has enabled us to drill deeper and more cleanly, while eliminating damage due to thermal cycling and over-pressure shocks.

Background: The majority of de novo cancers are diagnosed in low and middle-income countries, which often lack the resources to provide adequate therapeutic options. None or minimally invasive therapies such as Photodynamic Therapy (PDT) or photothermal therapies could become part of the overall treatment options in these countries. However, widespread acceptance is hindered by the current empirical training of surgeons in these optical techniques and a lack of easily usable treatment optimizing tools. Methods: Based on image processing programs, ITK-SNAP, and the publicly available FullMonte light propagation software, a work plan is proposed that allows for personalized PDT treatment planning. Starting with, contoured clinical CT or MRI images, the generation of 3D tetrahedral models in silico, execution of the Monte Carlo simulation and presentation of the 3D fluence rate, Φ, [mWcm -2 ] distribution a treatment plan optimizing photon source placement is developed. Results: Permitting 1-2 days for the installation of the required programs, novices can generate their first fluence, H [Jcm -2 ] or Φ distribution in a matter of hours. This is reduced to 10th of minutes with some training. Executing the photon simulation calculations is rapid and not the performance limiting process. Largest sources of errors are uncertainties in the contouring and unknown tissue optical properties. Conclusions: The presented FullMonte simulation is the fastest tetrahedral based photon propagation program and provides the basis for PDT treatment planning processes, enabling a faster proliferation of low cost, minimal invasive personalized cancer therapies.

Background: In excess of 60% of all cancers are detected in low and middle-income countries, with breast cancer (BC) the dominant malignancy for women. Incidence rates continue to climb, most noticeably in the less than 50-year-old population. Expansion of mammography infrastructure and resources is lacking, resulting in over 60% of women diagnosed with stage III/IV BC in the majority of these countries. Optical Breast Spectroscopy (OBS) was shown to correlate well with mammographic breast density (MBD). OBS could aid breast screening programs in low- and middle-income countries by lowering the number of mammographs required for complete population coverage. However, its performance needs to be tested in large population trails to ensure high sensitivity and acceptable specificity. Methods: For the planned studies in low- and middle-income countries in different continents, online methods need to be implemented to monitor the performance and data collection by these devices, operated by trained nurses. Based on existing datasets, procedures were developed to validate an individual woman's data integrity and to identify operator errors versus system malfunctions. Results: Using a dataset comprising spectra from 360 women collected by 2 instruments in different locations and with 3 different trained operators, automated methods were developed to identify 100% of the source or photodetector malfunctions as well as incorrect calibrations and 96% of instances of insufficient tissue contact. Conclusions: Implementing the dataset validation locally in each instrument and tethered to a cloud database will allow the planned clinical trials to proceed.

Brain tumors are characterized with morphological changes at cellular level such as enlarged, non-spherical nuclei, microcalcifications, cysts, etc., and are highly vascularized. In this study, two research-grade optical coherence tomography (OCT) systems operating at ~800 nm and ~1060 nm with axial resolution of 0.95 µm and 3.5 µm in biological tissue respectively, were used to image in vivo and ex vivo the structure of brain tumours in rats. Female Fischer 344 rats were used for this study, which has received ethics clearance by the Animal Research Ethics Committees of the University of Waterloo and the University Health Network, Toronto. Brain tumours were induced by injection of rat brain cancer cell line (RG2 glioma) through a small craniotomy. Presence of brain tumours was verified by MRI imaging on day 7 post tumour cells injection. The in vivo OCT imaging session was conducted on day 14 of the study with the 1060 nm OCT system and both morphological OCT, Doppler OCT and OMAG images were acquired from the brain tumour and the surrounding healthy brain tissue. After completion of the imaging procedure, the brains were harvested, fixed in formalin and reimaged after 2 weeks with the 800 nm OCT system. The in vivo and ex vivo OCT morphological images were correlated with H and E histology. Results from this study demonstrate that UHR-OCT can distinguish between healthy and cancerous brain tissue based on differences in structural and vascular pattern.

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.

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. Lasers Surg. Med. 45:460–468, 2013. © 2013 Wiley Periodicals, Inc.

A 12-laser-wavelength, fixed source-detector position, cup-based optical breast spectroscopy (OBS) device was developed for use in large-scale, multicenter trials as a mammographic breast density (MBD) quantification and breast cancer (BC) risk prescreening tool. In this study, the device was evaluated in comparison with a spectrometer-based device used in previous studies. The devices were compared on their ability to predict mammographic percent density (MPD) and to identify women with high MBD from optical spectra. OBS measurements were made on 60 women, (age 29-73), using both devices. Recent mammograms were collected for all women and MPD quantified from the mammograms. Principal components (PCs) analysis was performed on both sets of OBS spectra, and multivariate logistic regression analysis of the resulting PC scores was used to identify women with high MBD. Both devices are able to identify high MBD with very high sensitivity and specificity. Partial least-squares regression of the spectra was used to predict MPD. Both devices show a strong correlation between OBS-predicted MPD and MPD read from mammograms, however, the correlation is stronger for the continuous-spectrum device (r = 0.74, P = .001) than for the 12-wavelength device (r = 0.62, P = .004). Improvements to the cup-based device to reduce detector saturation should improve the prediction of MPD from the spectra.

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.

nude mice. Once tumors had developed (average volume 70 mm), they were treated with 8 intravesical injections of miR-145. Synthetic miR-145 (100 nM) complexed with 100 ml of LipofectamineTM RNAiMAX reagent was added to 50 ml of PBS and delivered 8 times intravesically every other day. Induction of sub-cellular pathways was assessed by Western blot analyses in in Vitro and in Vivo. RESULTS: The expression level of miR-145 in 253J B-V cells was markedly down-regulated compared with that in normal human urothelial cells. Transfection of human 253J B-V cells with miR-145 resulted in a pronounced growth suppression that occurred in a dosedependent fashion. Western blotting analysis showed that the expression levels of all FSCN1, E-cadherin, b-catenin, and catenin d-1 were significantly down-regulated in the miR-145-treated 253J B-V cells. Also, cleaved form of PARP and down-regulation of c-Myc and socs7 were observed. Hoechst33342 nuclear staining indicated a typical apoptotic appearance such as condensed chromatin and nuclear fragmentation in the miR-145-treated 253J B-V cells. The ectopic expression of miR-145 significantly decreased cell migration of 253J BV cells approximately 30%. preparing Kaplan-Maier plots, with the survival duration analyzed for significance by performing log-rank survival analysis. The intravesical treatment with miR-145 significantly prolonged animal survival in mice bearing orthotopic 253J B-V xenografts when compared with that for the controls (Log rank p 1⁄4 0.018). CONCLUSIONS: The present findings for the first time showed that miR-145 was an effective tumor suppressor miRNA against bladder cancer and that its intravesical delivery effectively inhibited the tumorigenic phenotypes without any adverse effects. Thus we propose that the use of miR-145 by the intravesical approach can become a successful therapeutic strategy for bladder cancer.

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.

Purpose: Variations during breast tissue development can influence later breast cancer risk. In particular, prolonged nulliparity increases risk. The authors used optical spectroscopy to compare breast tissue in 115 nulliparous women aged 31–40 (group 2) to 140 nulliparous women aged 18–21 (group 1), and also to 36 parous women aged 31–40 (group 3), and to evaluate the relationship between IGF-1 and optical breast tissue properties. IGF-1 has been linked in particular to premenopausal breast cancer. Methods: The authors measured the transmission spectra from 625 to 1050 nm wavelengths in each breast and determined regions of interindividual variation using principal components analysis. Spectral differences represent variation in lipid, water, oxyhemoglobin, deoxyhemoglobin, and collagen content. Group differences and the relationship with IGF-1 were estimated by linear regression after adjustment for multiple factors including height, weight, ethnicity, hormonal contraceptive use, and days since last menstrual period. Results: Principal component 3 scores were more negative in the older nulliparous women compared to either younger nulliparous women or to parous women of the same age ( β = − 0.16 , p = 0.008 for group 2 vs group 1 and β = 0.51 , p = 0.03 for group 3 vs group 2). These differences appear to indicate increased deoxyhemoglobin relative to oxyhemoglobin content in the tissue of the older, nulliparous premenopausal women compared to the other groups, which may be an indicator of proportionally increased proliferative tissue. Principal component 4 also differed between older and younger nulliparous women ( β = 0.08 , p = 0.02 for group 2 vs group 1) and was negatively associated with IGF-1 in younger women ( β = − 0.0004 , p = 0.03 ) and positively associated with IGF-1 in older women ( β = 0.001 , p = 0.004 ). Conclusions: Optical spectroscopy may be useful to identify breast tissue at increased risk of cancer development and track changes over time, particularly in young women where exposure to radiation is of particular concern. Additional work is needed to confirm the observed breast tissue differences and to determine the specific tissue chromophore changes with age and parity.

Objective To determine whether laser light can improve healing of skin wounds by killing wound bacteria while simultaneously accelerating host tissue activity. Materials and Methods Wounds on the rat dorsum were irradiated or sham-irradiated three times weekly from days 1 to 19 using 635 or 808 nm diode lasers at 1 or 20 J/cm2. Wound area and bacterial growth were evaluated three times weekly. Histological analysis was performed on days 8 and 19. Immunohistochemical analysis was performed on day 19. Results Wounds that were irradiated using 635 nm light at 1 J/cm2 healed similarly to controls. Wounds that were irradiated using 808 nm (1 and 20 J/cm2, P≤0.05) and 635 nm light (20 J/cm2, P≤0.05) were worse in wound maximum area at day 3 compared with controls. Further, 635 nm light at 20 J/cm2 delayed wound closure at day 19 (ASL = 0.0127). Bacterial colonization of wounds was altered using 635 nm (20 J/cm2, P

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.

The efficacy of photodynamic therapy (PDT) for the treatment of primary and recurrent gliomas has been evaluated in a fair number of clinical trials over the past two decades. While some studies showed an effect, it is evident that PDT as a standalone or adjuvant to standard therapy has highly variable efficacy and bears morbidity risks for some patients, preventing its broader adoption in the clinic. Cofactors as causes for the observed efficacy variance and strategies to improve PDT efficacy need to be determined in preclinical models, and the same applies to dosimetry concepts and response monitoring strategies. However, the use of small murine models poses in itself challenges for PDT research, such as the intracranial dimensions between the tumor and eloquent areas of the brain being small compared to the light and hence PDT dose gradient. Here, we present current work pertaining to the use of preclinical models for the PDT-mediated destruction of gliomas, including the biological relevance of commonly used glioma cell lines, the means to modify protoporphyrin IX (PpIX) synthesis in vivo and the tissue responsivity to PpIX-mediated intracranial PDT, as well as novel magnetic resonance imaging-based approaches for predicting tissue response. Employing the appropriate preclinical models has the potential for rapid hypothesis generation and testing in order to design improved clinical studies in the future that will be needed for demonstrating improved efficacy in the vast majority of patient if PDT is to become a first-line therapy in neurosurgery.

Photodynamic therapy has been successfully applied to numerous cancers. Its potential to treat cancer metastases in the spine has been demonstrated previously in a preclinical animal model. The aim of this study was to test two photosensitizers, benzoporphyrin-derivative monoacid ring A (BPD-MA) and by 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), for their potential use to treat bony metastases. The difference in photosensitizer concentration in the spinal cord and the surrounding tumor-bearing vertebrae was of particular interest to assess the risk of potential collateral damage to the spinal cord. Vertebral metastases in a rat model were generated by intracardiac injection of human breast cancer cells. When tumor growth was confirmed, photosensitizers were injected systemically and the animals were euthanized at different time points. The following tissues were harvested: liver, kidney, ovaries, appendicular bone, spinal cord and lumbar vertebrae. Photosensitizer tissue concentration of BPD-MA or PpIX was determined by fluorescence spectrophotometry. In contrast to BPD-MA, ALA-PpIX did not demonstrate an appreciable difference in the uptake ratio in tumor-bearing vertebrae compared to spinal cord. The highest ratio for BPD-MA concentration was found 15 min after injection, which can be recommended for therapy in this model.

Risk assessment by parenchymal density pattern, a strong physical indicator of future breast cancer risk, is available with the onset of mammographic screening programmes. However, due to the use of ionizing radiation, mammography is not recommended for use in younger women, thereby rendering risk assessment unattainable at an earlier age. Visible and near infrared light was used on 292 women with radiologically normal mammograms to determine whether transillumination breast spectroscopy (TIBS) can identify women with a high parenchymal density pattern as an intermediate indicator of breast cancer risk. Principal component analysis (PCA) was used to reduce the spectral data and generate density scores for each woman. To assess the accuracy of TIBS, logistic regression was used to calculate crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for each score. Receiver operator characteristic (ROC) curves and area under the curve (AUC) were also calculated for the crude and adjusted logistic models. Optical information relating to tissue chromophores, such as water, lipid and haemoglobin content, was sufficient to identify women with high parenchymal density. The resulting AUC for the final and most parsimonious multivariate logistic model was 0.922 (95% CI 0.878-0.967). TIBS provides information correlating to high parenchymal density and is a promising tool for risk assessment, particularly for younger women.

The laser induced forward transfer (LIFT) process was used to create conductive lines and pads for rapid prototyping and repairing microdevices. Single 0.1–10 μJ pulses from a 120 fs 800 nm titanium:sapphire laser were used to transfer films consisting of 40–80 nm thick gold to create the lines. Experiments were conducted in air ambient. The laser was focused using 4× and 10× microscope objectives and produced 5–20 μm diameter metal spots which were overlapped to produce conductive lines. Electrodes with widths between 10 and 50 μm have been produced and their resistances have been measured. The resistivities of these LIFT produced Au electrodes were found to be approximately (1–4) × 10−6 Ω m. It has also been shown that the conductivity of the lines can be further improved by electrical curing. The LIFT process was used to repair heaters for microfluidic applications and preliminarily create electrodes for control of electro-osmotic flow in microfluidic devices.

A portable, spatially resolved diffuse reflectance (SRDR) lensless imaging technique based on the charge coupled device (CCD), or complementary metal-oxide semiconductor (CMOS) sensor directly coupled with fiber optic bundle can be proposed for visualization of subsurface structures such as intrapapillary capillary loops (IPCLs). In this article, we discuss an experimental method for emulating a lensless imaging setup via raster scanning a single fiberoptic cable (where image is relayed onto the sensor surface through a fiber-optic cable equivalent to coupling a fiber optic conduit directly onto the sensor surface without any lenses) over a microfluidic phantom containing periodic hemoglobin absorption contrast. For mimicking scattering properties of turbid media, a diffusive layer formed of polydimethylsiloxane (PDMS) and titanium dioxide (TiO2) was placed atop of the microfluidic phantom. Thickness of the layers ranged from 0.2‒0.7mm, and the µs value of the layers were in the range of 0.85 mm-1 ‒ 4.25mm-1. The results demonstrate that a fiber-optic bundle/plate coupled lensless imaging setup has a high potential to recover intensity modulations from the subsurface patterns. Decreasing of the interrogation volumes leads to enhanced spatial resolution of diffuse reflectance imaging, and hence, can potentially overcome the scattering caused blurring.