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

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

High quantum efficiency ruthenium coordination complex photosensitizer for improved radiation-activated Photodynamic Therapy.

Traditional external light-based Photodynamic Therapy (PDT)'s application is limited to the surface and minimal thickness tumors because of the inefficiency of light in penetrating deep-seated tumors. To address this, the emerging field of radiation-activated PDT (radioPDT) uses X-rays to trigger photosensitizer-containing nanoparticles (NPs). A key consideration in radioPDT is the energy transfer efficiency from X-rays to the photosensitizer for ultimately generating the phototoxic reactive oxygen species (ROS). In this study, we developed a new variant of pegylated poly-lactic-co-glycolic (PEG-PLGA) encapsulated nanoscintillators (NSCs) along with a new, highly efficient ruthenium-based photosensitizer (Ru/radioPDT). Characterization of this NP via transmission electron microscopy, dynamic light scattering, UV-Vis spectroscopy, and inductively coupled plasma mass-spectroscopy showed an NP size of 120 nm, polydispersity index (PDI) of less than 0.25, high NSCs loading efficiency over 90% and in vitro accumulation within the cytosolic structure of endoplasmic reticulum and lysosome. The therapeutic efficacy of Ru/radioPDT was determined using PC3 cell viability and clonogenic assays. Ru/radioPDT exhibited minimal cell toxicity until activated by radiation to induce significant cancer cell kill over radiation alone. Compared to protoporphyrin IX-mediated radioPDT (PPIX/radioPDT), Ru/radioPDT showed higher capacity for singlet oxygen generation, maintaining a comparable cytotoxic effect on PC3 cells.

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

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

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

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

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

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

Alternative methods to measure breast density in younger women.

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

A comparison of various methods for measuring breast density and breast tissue composition in adolescent girls and women.

This study compared different approaches to measuring breast density and breast tissue composition (BTC) in adolescent girls (n = 42, aged 14-16 years) and their mothers (n = 39, aged 36-61 years) from a cohort in Santiago, Chile. Optical spectroscopy (OS) was used to measure collagen, water, and lipid concentrations, which were combined into a percent breast density index (%BDI). A clinical dual-energy X-ray absorptiometry (DXA) system calibrated to measure breast density provided percent fibroglandular volume (%FGV) from manually delineated images. After digitizing mammogram films, the percent mammographic breast density (%MBD) was measured using computer-assisted software. Partial correlation coefficients (rpartial) were used to evaluate associations between breast density measures and BTC from these three different measurement approaches, adjusting for age and body mass index. %BDI from OS was associated with %FGV from DXA in adolescent girls (rpartial = 0.46, p-value = 0.003), but not in mothers (rpartial = 0.17, p-value = 0.32). In mothers, %FGV from DXA was associated with %MBD from mammograms (rpartial = 0.60, p-value < 0.001). These findings suggest that data from OS, DXA, and mammograms provide related but distinct information about breast density and BTC. Future studies should explore how the information provided by these different devices can be used for breast cancer risk prediction in cohorts of adolescent girls and women.

A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients with Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer.

Background: A phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design setting and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

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

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

Assessment of repeated reference measurements to inform the validity of optical breast spectroscopy.

Mammographic breast density is a strong breast cancer risk factor, and its routine clinical measurement could potentially be used to identify women at higher risk of breast cancer and/or monitor primary prevention strategies. Previous reports of optical breast spectroscopy (OBS), a novel approach to measuring breast density, demonstrated that it is safe (no ionizing radiation), portable, low-cost, and does not require image interpretation but have been limited to small, single-center studies. Reference measurements taken on a phantom breast prior to and after each woman's OBS assessment are required for the calibration of the system transfer function as a part of processing participant data. To inform the validity of participant data, a detailed description of the reference measurements and a repeatability analysis of these measurements taken before and after participant assessment is presented. Reference measurements for OBS from 539 women aged 18-40 years were obtained as a part of a high-throughput epidemiological pilot study. Of these, measurements from 20 women with no useable data due to device failure (3.7%) were excluded and from another 12 women due to user error. The intra-class correlation (ICC) within complete pairs of reference data (taken before and after assessment) was high (all ICC > 0.84). The analysis presented here confirms the OBS participant data as valid for use in ongoing epidemiological research, providing further supporting evidence of OBS as a measure of breast density. A novel method of measuring breast density is needed to bridge large gaps in the knowledge of breast density in younger women and its relation to later-life breast cancer risk.

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

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

Machine learning for real-time optical property recovery in interstitial photodynamic therapy: a stimulation-based study.

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.

Photodynamic therapy outcome modelling for patients with spinal metastases: a simulation-based study.

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 ([Formula: see text] 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.

Determination of Optical Properties and Photodynamic Threshold of Lung Tissue for Treatment Planning of In Vivo Lung Perfusion Assisted Photodynamic Therapy.

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.

Optimizing Interstitial Photodynamic Therapy Planning With Reinforcement Learning-Based Diffuser Placement.

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 [Formula: see text] 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.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer.

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.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer (Erratum).

The erratum corrects a misspelled author surname.

Liposomal Lapatinib in Combination with Low-Dose Photodynamic Therapy for the Treatment of Glioma.

BACKGROUND: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan®, 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 3-5 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 < 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 < 0.05). Furthermore, PDT leads to enhanced survival in rats following treatment with lapatinib compared to lapatinib alone and PDT alone (p < 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.

Efficacy of ruthenium coordination complex-based Rutherrin in a preclinical rat glioblastoma model.

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.

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

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