Timothy M. Baran

Factors influencing tumor response to photodynamic therapy sensitized by intratumor administration of methylene blue.

We examined tumor response to methylene blue (MB)‐mediated photodynamic therapy (PDT) in a murine tumor model. The goal was to investigate the effects of drug–light interval (DLI), injection vehicle, and fluence on tumor destruction. Fluorescence and reflectance spectroscopy informed our understanding.

Determination of optical properties by interstitial white light spectroscopy using a custom fiber optic probe.

Abstract. We demonstrate interstitial recovery of absorption and scattering coefficients using a custom optical probe and a Monte Carlo (MC)–based recovery algorithm. The probe consists of six side-firing spectroscopy fibers contained in a 1.1-mm outer diameter cladding, with each fiber having a different axial and angular position on the probe. Broadband white light is delivered by one of the fibers and is detected steady-state by the remaining fibers. These spatially and spectrally resolved data are analyzed using a MC-based fitting algorithm in order to extract the local optical properties. The technique was verified in tissue-simulating phantoms consisting of Intralipid-20% as a scatterer and either manganese meso-tetra (4-sulfanatophenyl) porphine or intact human erythrocytes as an absorber. Absorption coefficients were recovered with a mean error of 9% and scattering coefficients were recovered with a mean error of 19%, whereas the hemoglobin oxygen saturation was recovered with a mean error of 12%. These results demonstrate the feasibility of optical property recovery for situations in which surface-contact spectroscopy is not a possibility, and where only a single probe can be inserted into the tissue.

Comparison of flat cleaved and cylindrical diffusing fibers as treatment sources for interstitial photodynamic therapy.

PURPOSE For interstitial photodynamic therapy (iPDT) of bulky tumors, careful treatment planning is required in order to ensure that a therapeutic dose is delivered to the tumor, while minimizing damage to surrounding normal tissue. In clinical contexts, iPDT has typically been performed with either flat cleaved or cylindrical diffusing optical fibers as light sources. Here, the authors directly compare these two source geometries in terms of the number of fibers and duration of treatment required to deliver a prescribed light dose to a tumor volume. METHODS Treatment planning software for iPDT was developed based on graphics processing unit enhanced Monte Carlo simulations. This software was used to optimize the number of fibers, total energy delivered by each fiber, and the position of individual fibers in order to deliver a target light dose (D90) to 90% of the tumor volume. Treatment plans were developed using both flat cleaved and cylindrical diffusing fibers, based on tissue volumes derived from CT data from a head and neck cancer patient. Plans were created for four cases: fixed energy per fiber, fixed number of fibers, and in cases where both or neither of these factors were fixed. RESULTS When the number of source fibers was fixed at eight, treatment plans based on flat cleaved fibers required each to deliver 7180-8080 J in order to deposit 90 J/cm(2) in 90% of the tumor volume. For diffusers, each fiber was required to deliver 2270-2350 J (333-1178 J/cm) in order to achieve this same result. For the case of fibers delivering a fixed 900 J, 13 diffusers or 19 flat cleaved fibers at a spacing of 1 cm were required to deliver the desired dose. With energy per fiber fixed at 2400 J and the number of fibers fixed at eight, diffuser fibers delivered the desired dose to 93% of the tumor volume, while flat cleaved fibers delivered this dose to 79%. With both energy and number of fibers allowed to vary, six diffusers delivering 3485-3600 J were required, compared to ten flat cleaved fibers delivering 2780-3600 J. CONCLUSIONS For the same number of fibers, cylindrical diffusers allow for a shorter treatment duration compared to flat cleaved fibers. For the same energy delivered per fiber, diffusers allow for the insertion of fewer fibers in order to deliver the same light dose to a target volume.

Fluence rate-dependent photobleaching of intratumorally administered Pc 4 does not predict tumor growth delay.

We examined effects of fluence rate on the photobleaching of the photosensitizer Pc 4 during photodynamic therapy (PDT) and the relationship between photobleaching and tumor response to PDT. BALB/c mice with intradermal EMT6 tumors were given 0.03 mg kg−1 Pc 4 by intratumor injection and irradiated at 667 nm with an irradiance of 50 or 150 mW cm−2 to a fluence of 100 J cm−2. While no cures were attained, significant tumor growth delay was demonstrated at both irradiances compared with drug‐only controls. There was no significant difference in tumor responses to these two irradiances (P = 0.857). Fluorescence spectroscopy was used to monitor the bleaching of Pc 4 during irradiation, with more rapid bleaching with respect to fluence shown at the higher irradiance. No significant correlation was found between fluorescence photobleaching and tumor regrowth for the data interpreted as a whole. Within each treatment group, weak associations between photobleaching and outcome were observed. In the 50 mW cm−2 group, enhanced photobleaching was associated with prolonged growth delay (P = 0.188), while at 150 mW cm−2 this trend was reversed (P = 0.308). Thus, it appears that Pc 4 photobleaching is not a strong predictor of individual tumor response to Pc 4‐PDT under these treatment conditions.

Optical property measurements establish the feasibility of photodynamic therapy as a minimally invasive intervention for tumors of the kidney

Abstract. We measured the optical properties of freshly excised kidneys with renal parenchymal tumors to assess the feasibility of photodynamic therapy (PDT) in these patients. Kidneys were collected from 16 patients during surgical nephrectomies. Spatially resolved, white light, steady-state diffuse reflectance measurements were performed on normal and neoplastic tissue identified by a pathologist. Reflectance data were fit using a radiative transport model to obtain absorption (μa) and transport scattering coefficients (μs′), which define a characteristic light propagation distance, δ. Monte Carlo (MC) simulations of light propagation from cylindrical diffusing fibers were run using the optical properties extracted from each of the kidneys. Interpretable spectra were obtained from 14 kidneys. Optical properties of human renal cancers exhibit significant inter-lesion heterogeneity. For all diagnoses, however, there is a trend toward increased light penetration at longer wavelengths. For renal cell carcinomas (RCC), mean values of δ increase from 1.28 to 2.78 mm as the PDT treatment wavelength is increased from 630 to 780 nm. MC simulations of light propagation from interstitial optical fibers show that fluence distribution in tumors is significantly improved at 780 versus 630 nm. Our results support the feasibility of PDT in selected renal cancer patients, especially with photosensitizers activated at longer wavelengths.

Recovery of intrinsic fluorescence from single-point interstitial measurements for quantification of doxorubicin concentration

We developed a method for the recovery of intrinsic fluorescence from single‐point measurements in highly scattering and absorbing samples without a priori knowledge of the sample optical properties. The goal of the study was to demonstrate accurate recovery of fluorophore concentration in samples with widely varying background optical properties, while simultaneously recovering the optical properties.

Insula and Inferior Frontal Gyrus' Activities Protect Memory Performance Against Alzheimer's Disease Pathology in Old Age.

Apolipoprotein E (APOE) ɛ4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimers disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

Cylindrical diffuser axial detection profile is dependent on fiber design.

The axial emission and detection profiles of 1- and 2-cm cylindrical diffusing fibers based on concentration gradients of scatterers were measured. Based on these measurements, we describe a method for determination of the scatterer concentration gradient within the diffusers. Using a Monte Carlo model incorporating these concentrations, detection was simulated and found to agree with measurements. The measured and simulated detection profiles for these diffusers were found to be drastically different from those previously measured in an alternative diffuser design incorporating an end reflector. When using cylindrical diffusers as detection fibers, it is, therefore, important to understand the design of the fiber and characterize the detection behavior.

Image-Guided Treatment Planning and Dosimetry for Interstitial Photodynamic Therapy

The treatment scenario for photodynamic therapy (PDT) can vary between patients. We present a method that combines clinical images, radiation therapy planning contours, and Monte Carlo simulation in order to design individualized PDT treatment plans.

Recovery of optical properties using interstitial cylindrical diffusers as source and detector fibers

Abstract. We demonstrate recovery of optical properties using arrays of interstitial cylindrical diffusing fibers as sources and detectors. A single 1-cm diffuser delivered laser illumination at 665 nm, while seven 1- and 2-cm diffusers at 1-cm grid spacing acted as detectors. Extraction of optical properties from these measurements was based upon a diffusion model of emission and detection distributions for these diffuser fibers, informed by previous measurements of heterogeneous axial detection. Verification of the technique was performed in 15 liquid tissue-simulating phantoms consisting of deionized water, India ink as absorber, and Intralipid 20% as scatterer. For the range of optical properties tested, mean errors were 4.4% for effective attenuation coefficient, 12.6% for absorption coefficient, and 7.6% for reduced scattering coefficient. Error in recovery tended to increase with decreasing transport albedo. For therapeutic techniques involving the delivery of light to locations deep within the body, such as interstitial photodynamic and photothermal therapies, the methods described here would allow the treatment diffuser fibers also to be used as sources and detectors for recovery of optical properties. This would eliminate the need for separately inserted fibers for spectroscopy, reducing clinical complexity and improving the accuracy of treatment planning.