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.

ALA-PpIX mediated photodynamic therapy of malignant gliomas augmented by hypothermia.

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.

Early biomarker for radiation-induced wounds: day one post-irradiation assessment using hemoglobin concentration measured from diffuse optical reflectance spectroscopy.

Normal tissue radiation toxicities are evaluated subjectively and cannot predict the development of severe side-effects. Using a hand-held diffuse reflectance optical spectroscopy probe, we measured optical parameters in mouse skin 1-4 days after irradiation. Using a radiation toxicity model and a therapeutic mitigator described previously [BMC Cancer14, 614 (2014)], we found that hemoglobin (Hb) levels increased sharply 24 h after irradiation only in the irradiated group without the mitigator.

Diffuse Optical Spectroscopy for the Quantitative Assessment of Acute Ionizing Radiation Induced Skin Toxicity Using a Mouse Model.

Acute skin toxicities from ionizing radiation (IR) are a common side effect from therapeutic courses of external beam radiation therapy (RT) and negatively impact patient quality of life and long term survival. Advances in the understanding of the biological pathways associated with normal tissue toxicities have allowed for the development of interventional drugs, however, current response studies are limited by a lack of quantitative metrics for assessing the severity of skin reactions. Here we present a diffuse optical spectroscopic (DOS) approach that provides quantitative optical biomarkers of skin response to radiation.

Polyacrylamide gel substrates that simulate the mechanical stiffness of normal and malignant neuronal tissues increase protoporphyin IX synthesis in glioma cells.

Protoporphyrin IX (PPIX) produced following the administration of exogenous 5d-aminolevulinic acid is clinically approved for photodynamic therapy and fluorescence-guided resection in various jurisdictions around the world. For both applications, quantification of PPIX forms the basis for accurate therapeutic dose calculation and identification of malignant tissues for resection. While it is well established that the PPIX synthesis and accumulation rates are subject to the cell’s biochemical microenvironment, the effect of the physical microenvironment, such as matrix stiffness, has received little attention to date.

Characterization of collagen in non-small cell lung carcinoma with second harmonic polarization microscopy.

Polarization second harmonic microscopy was used for collagen imaging in human non-small cell lung carcinoma and normal lung tissues ex vivo and revealed significant differences in the nonlinear susceptibility component ratio, demonstrating potential use in cancer diagnosis.

Quantitative monitoring of radiation induced skin toxicities in nude mice using optical biomarkers measured from diffuse optical reflectance spectroscopy.

Monitoring the onset of erythema following external beam radiation therapy has the potential to offer a means of managing skin toxicities via biological targeted agents - prior to full progression. However, current skin toxicity scoring systems are subjective and provide at best a qualitative evaluation. Here, we investigate the potential of diffuse optical spectroscopy (DOS) to provide quantitative metrics for scoring skin toxicity.

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

Effective therapies for malignant gliomas are still elusive and limited survival improvements are provided only by Temozolomide or fluorescence guided resection. The efficacy of photodynamic therapy (PDT) in this indication is limited by the higher sensitivity of normal brain structures compared to glioma necessitating a modulation of its sensitivity. We evaluate the influence of hypothermia and the tyrosine kinase inhibitor Erlotinib on cell's ability to synthesize PPIX following the administration of ALA which was not previously investigated.

Effect of tissue optics on wavelength optimization for quantum dot-based surface and subsurface fluorescence imaging.

Optimization is an important but relatively unexplored aspect of contrast-enhanced fluorescence imaging, since minimizing contrast agent usage reduces the associated cost and potential toxicity. In a previous study, the authors developed a quantitative experimental approach to optimize quantum dot (QD)-based imaging using homogenized liver as a model tissue. In this follow-up study, the authors further extend and validate the approach using eight different tissues and five QDs emission wavelengths, and introduce quantitative imaging performance metrics, namely the threshold QD concentration and wavelength optimization gain.

Estimation of minimum doses for optimized quantum dot contrast-enhanced vascular imaging in vivo.

Quantum dot (QD) contrast-enhanced molecular imaging has potential for early cancer detection and image guided treatment, but there is a lack of quantitative image contrast data to determine optimum QD administered doses, affecting the feasibility, risk and cost of such procedures, especially in vivo. Vascular fluorescence contrast-enhanced imaging is performed on nude mice bearing dorsal skinfold window chambers, injected with 4 different QD solutions emitting in the visible and near infrared. Linear relationships are observed among the vascular contrast, injected contrast agent volume, and QD concentration in blood.

A novel technique to enable experimental validation of deformable dose accumulation.

Purpose: To propose a novel technique to experimentally validate deformable dose algorithms by measuring 3D dose distributions under the condition of deformation using deformable gel dosimeters produced by a novel gel fabrication method.

Method: Five gel dosimeters, two rigid control gels and three deformable gels, were manufactured and treated with the same conformal plan that prescribed 400 cGy to the isocenter. The control gels were treated statically; the deformable gels were treated while being compressed by an actuation device to simulate breathing motion (amplitude of compression  = 1, 1.

Quasi-static magnetic resonance elastography at 7 T to measure the effect of pathology before and after fixation on tissue biomechanical properties.

Evaluation of imaging for cancer detection and localization can be achieved by correlation of gold-standard histopathology with imaging data. Usage of a 3D biomechanical-based deformable registration for correlation of the histopathology of whole-tissue specimens with ex vivo imaging necessitates measurement of the distribution of biomechanical properties in the ex vivo tissue specimen and changes that occur during pathology fixation. To measure high-resolution 3D distributions of Young's modulus (E) prefixation and postfixation, a quasi-static magnetic resonance elastography method was developed at 7 T.

δ-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy.

Extent of resection is a major goal and prognostic factor in the treatment of gliomas. In this study we evaluate whether quantitative ex vivo tissue measurements of δ-aminolevulinic acid-induced protoporphyrin IX (PpIX) identify regions of increasing malignancy in low- and high-grade gliomas beyond the capabilities of current fluorescence imaging in patients undergoing fluorescence-guided resection (FGR). Surgical specimens were collected from 133 biopsies in 23 patients and processed for ex vivo neuropathological analysis: PpIX fluorimetry to measure PpIX concentrations (C(PpIX)) and Ki-67 immunohistochemistry to assess tissue proliferation.