Sarah McGuire

Improving interstitial transport of macromolecules through reduction in cell volume fraction in tumor tissues

UNLABELLED Interstitial transport of large molecules and nanoparticles is an important concern in nanomedicine-mediated cancer treatment. To that end, the current study was proposed to improve the transport through enlargement of extracellular space by treating tumors with hypertonic solution of mannitol and cytotoxic agents (e.g., ethacrynic acid [ECA]), which could effectively shrink and kill cells, respectively. In the study, the improvement in interstitial penetration of dextran was investigated ex vivo using rat fibrosarcoma tissues sectioned into 600 μm slices. Experimental data showed that the hypertonic solution was more effective than ECA for improving interstitial penetration of dextran with molecular weights ranging from 4000 to 2,000,000. The extent of improvement depended on the size of dextran molecules and the time when the treatment was applied. Results from the study suggested that increases in both size and connectedness of interstitial pathways were important for improvement of interstitial transport of large molecules and nanoparticles. FROM THE CLINICAL EDITOR This study reports on the optimization of interstitial transport both for large molecules and nanoparticles in nanomedicine-mediated cancer treatment. The study demonstrates that hypertonic solutions could efficiently lead to cancer cell shrinkage and more so than the applied cytotoxic agent thereby improving transport of chemotherapeutic entities.

TH‐E‐M100E‐03: Optimizing the Methodology for Incorporating SPECT‐Guidance to Reduce Intensity Modulated Radiation Therapy (IMRT) Dose to Functioning Lung

Purpose:Single photon emission computed tomography(SPECT) provides a spatial distribution map of lung perfusion. Previously, an algorithmic methodology was developed using IMRT and SPECT guidance to deliberately divert dose away from higher functioning (perfused) lung, thereby potentially reducing lung toxicity. This work aims to refine this methodology by determining the optimal number and segmentation method for incorporating different levels of functionality. Method and Materials: The lowest 15% of SPECT numbers were discarded as background noise. The remaining values were then divided equally so that each segment had the same range. IMRT treatment plans incorporating functional information were generated with the lung subdivided into varying numbers of SPECT segments. The segments ranged from 2 to the number beyond which there was no improvement in the Dose Functional Histogram (DFH) or function‐weighted lung volume above 20/30 Gy (F20 / F30). The thresholds of 20/30 Gy were chosen for their significance in predicting radiation‐induced pneumonitis. The plans generated using SPECT guidance were compared against “conventional” plans, generated with the assumption that lung function was spatially homogeneous. Results: Of all the SPECT plans generated, those created with four segments produced the most favorable results overall. The results were variable, with the four segment SPECT‐guided plans showing marginal to large improvement over conventional plans. One patient had a 42.9% and 61.7% reduction in F20 and F30 values, respectively, when compared to the conventional plan. For all patients, on average, the F20 and F30 values were reduced by 16.5% ± 18.3% and 21.1% ± 26.0%, respectively. Conclusion: A standardized intensity‐based segmentation procedure is crucial for routine use of SPECT‐guidance in IMRTlungtreatment planning. The simple procedure outlined here is valid for a range of patients. Segmenting lungSPECT into four intensity regions appears to provide the greatest benefit in reducing radiotherapy‐induced functional lung damage.

TH‐C‐224C‐09: Using SPECT‐Guidance to Reduce Intensity Modulated Radiation Therapy (IMRT) Dose to Functioning Lung

Purpose:Single photon emission computed tomography(SPECT) provides a map of the spatial distribution of lung perfusion. Thus, SPECT guidance can be used to deliberately divert dose away from higher functioning lung, thereby potentially reducing lung toxicity. This work presents an algorithmic methodology for achieving this aim, and tests it in intensity modulated radiotherapy(IMRT)treatment planning of five randomly selected lungcancer patients. Method and Materials:IMRTtreatment plans were generated with and without SPECT guidance and compared. Both sets of plans were made to adhere to the same dose‐volume constraints. The SPECT‐guided process works by segmenting healthy lung into four regions on the basis of SPECT intensity, and sequentially allowing dose to the target via regions of increasing SPECT intensity. This process results in reduction of dose to functional lung, reflected in the dose‐function histogram (DFH). DFHs quantify the percentage of total function above dose levels. The plans were compared using DFHs and F20 / F30 values (Fx is the functional lung receiving dose above x Gy; 20/30 Gy are significant thresholds for radiation pneumonitis). Results: In all cases, the SPECT‐guided plan produced a more favorable DFH compared to the non‐SPECT guided plan. Additionally, the F20 and F30 values were reduced for all patients by an average of 13.6% ± 5.2% and 10.5% ± 5.8%, respectively. In all patients, for the SPECT‐guided plans, DFHs of the two highest functioning SPECT regions were reduced while DFHs of the two lower functioning regions were increased, illustrating the dose “give‐take” between SPECT regions that is inherent to the redistribution process. Conclusion: SPECT‐guided IMRT shows potential for reducing the dose delivered to highly functional lung regions. This dose reduction could reduce the number of high grade pneumonitis cases that develop after radiation treatment and improve patient quality of life.

Effects of tissue stretching or cell shrinkage on penetration depth of macromolecules in a rat fibrosarcoma

Interstitial penetration is critical for drug delivery in tumor tissues. To experimentally determine the penetration depth of macromolecules at the steady state, rat fibrosarcoma tissues were sectioned into 600 /spl mu/m slices and incubated in solutions of dextrans with molecular weights of 10 kDa, 70 kDa, and 2000 kDa, respectively. After incubation, 10 /spl mu/m cross-sections were taken and imaged to determine normalized steady-state concentration profiles as a function of molecular size. 10 kDa dextran had a relatively uniform concentration distribution. However, the concentration profile was nonuniform for 70 kDa dextran and the least uniform for 2000 kDa dextran. Stretching or incubation of tissues in 1 M mannitol solution improved the penetration of macromolecules in tissues. These results indicate that creating more interstitial space by either stretching or reducing cell size improves macromolecule distribution in tissues.