Biomedical subjects
Clifton Ling
Publications and source records attributed to Clifton Ling.
Animal-specific positioning molds for registration of repeat imaging studies: comparative microPET imaging of F18-labeled fluoro-deoxyglucose and fluoro-misonidazole in rodent tumors.
INTRODUCTION: Comparative imaging of multiple radiotracers in the same animal can be invaluable in elucidating and validating their respective mechanisms of localization. Comparative imaging of PET tracers, particularly in small animals, is problematic, however: such tracers must be administered and imaged separately because simultaneously imaged positron emitters cannot be separated based on energy discrimination. OBJECTIVE: As part of our ongoing development of hypoxia imaging radiotracers, the intratumoral distributions of sequentially administered F18-fluoro-deoxyglucose (FDG) and the hypoxia tracer F18-fluoromisonidazole (FMiso) were compared in rats by registered microPET imaging with positioning of each animal in a custom-fabricated whole-body mold. METHODS: Nude rats with a hindlimb R3327-AT anaplastic rat prostate tumor xenograft and a hindlimb FaDu human squamous cell carcinoma (each up to 20 x 20 x 30 mm in size) were studied. Rapid-Foam (Soule Medical, Lutz, FL) was used to fabricate animal-specific molds for immobilization and reproducible positioning. Each rat was injected via the tail vein with approximately 33 MBq (900 microCi) of FDG and imaged in its mold at 1 h postinjection (pi) on the microPET. The next day, each rat was injected with approximately 22 MBq (600 microCi) of FMiso and positioned and imaged in its mold at approximately 2 h pi. Custom-manufactured germanium-68 rods (10 microCi each, 1 x 10 mm) were reproducibly positioned in the mold as fiduciary markers. RESULTS: The registered microPET images unambiguously demonstrated grossly similar though not identical distributions of FDG and FMiso in the tumors - a high-activity rim surrounding a lower-activity core. There were subtle but possibly significant differences in the intratumoral distributions of FDG and FMiso, however. These may not have been discerned without careful image registration. CONCLUSION: Animal-specific molds are inexpensive and straightforward to fabricate and use for registration (+/-1 to 2 mm) of sequential PET images and may aid image interpretation.
Comparison of end normal inspiration and expiration for gated intensity modulated radiation therapy (IMRT) of lung cancer.
BACKGROUND AND PURPOSE: Gated delivery of radiation during part of the respiration cycle may improve the treatment of lung cancer with intensity modulated radiation therapy (IMRT). In terms of the respiration phase for gated treatment, normal end-expiration (EE) is more stable but normal end-inspiration (EI) increases lung volume. We compare the relative merit of using EI and EE in gated IMRT for sparing normal lung tissue. PATIENTS AND METHODS: Ten patients received EI and EE respiration-triggered CT scans in the treatment position. An IMRT plan for a prescription dose of 70 Gy was generated for each patient and at each respiration phase. The optimization constraints included target dose uniformity, less than 35% of the total lung receiving 20 Gy or more and maximum cord dose <or=45 Gy. We compared planning target volume (PTV) coverage, mean lung dose, percentage of total lung receiving 20 Gy or more (V(20)) and lung normal tissue complication probability (NTCP). RESULTS: For 9 of the 10 patients, cord and lung doses were acceptable and PTV coverage was similar for EE and EI, with lung sparing was equal to or slightly better at EI than at EE. For the 10th patient, lung sparing at EI was significantly better. Patient averaged mean lung dose was 15.4 Gy (range: 7.1-20.4) at EI and 16.3 Gy (range: 6.9-21.9) at EE. The average V(20) was 23.8% (range: 13-36.4) at EI and 25.3% (range: 13-37.3) at EE. The average NTCP at EI was 8 versus 12% at EE. CONCLUSIONS: Dosimetric indices of lung protection for IMRT plans at EI are better than at EE. For 9 out of the 10 patients in our study, this difference is small. Thus other factors such as reproducibility, reliability and duty cycle at normal end expiration may be more critical for selecting treatment breathing phase.
Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning.
Tumor hypoxia, present in many human cancers, can lead to resistance to radiation and chemotherapy, is associated with a more aggressive tumor phenotype and is an independent prognostic factor of clinical outcome. It is therefore important to identify and localize tumor hypoxia in cancer patients. In the current study, serial microPET imaging was used to evaluate iodine-124-labeled iodo-azomycin-galactoside ((124)I-IAZG) (4.2-day physical half-life) as a hypoxia imaging agent in 17 MCa breast tumors and six FSaII fibrosarcomas implanted in mice. For comparison, another promising hypoxic-cell PET radiotracer, fluorine-18-labeled fluoro-misonidazole ((18)F-FMISO), was also imaged in the same tumor-bearing animals. Twelve animals were also imaged with (18)F-labeled fluoro-deoxyglucose ((18)F-FDG). In addition, histological examination was performed, and direct measurement of tumor oxygenation status carried out with the Oxylite probe system. Two size groups were used, relatively well-oxygenated tumors in the range of 80-180 mg were designated as small, and those >300 mg and highly hypoxic, as large. Based on the data from 11 MCa and six FSaII tumors, both (124)I-IAZG and (18)F-FMISO images showed high tracer uptake in the large tumors. In (18)F-FMISO images at 1, 3-4, and 6-8 h post-injection (p.i.), there was considerable whole-body background activity. In contrast, (124)I-IAZG imaging was optimal when performed at 24-48 h p.i., when the whole-body background had dissipated considerably. As a result, the (124)I-IAZG images at 24-48 h p.i. had higher tumor to whole-body activity contrast than the (18)F-FMISO images at 3-6 h p.i. Region-of-interest analysis was performed as a function of time p.i. and indicated a tumor uptake of 5-10% (of total-body activity) for FMISO at 3-6 h p.i., and of ~17% for IAZG at 48 h p.i. This was corroborated by biodistribution data in that the tumor-to-normal tissue (T/N, normal tissues of blood, heart, lung, liver, spleen, kidney, intestine, and muscle) activity ratios of IAZG at 24 h p.i. was 1.5-2 times higher than those of FMISO at 3 h p.i., with the exception of stomach. Statistical analysis indicated that these differences in T/N ratios were significant. The small tumors were visualized in the (18)F-FDG images, but not in the (124)I-IAZG or (18)F-FMISO images. This was perhaps due to the combined effect of a smaller tumor volume and a lower hypoxic fraction. Oxylite probe measurement indicated a lesser proportion of regions with pO(2)<2.5 mmHg in the small tumors (e.g., pO(2) was <2.5 mmHg in 28% and 67% of the data in small and large FSaII tumors, respectively), and the biodistribution data showed lower uptake of the tracers in the small tumors than in the large tumors. In the first study of its kind, using serial microPET imaging in conjunction with biodistribution analysis and direct probe measurements of local pO(2) to evaluate tumor hypoxia markers, we have provided data showing the potential of (124)I-IAZG for hypoxia imaging.
IMRT of large fields: whole-abdomen irradiation.
PURPOSE: To assess the feasibility of inverse planning for whole-abdomen intensity-modulated radiation therapy (IMRT) with bone marrow and kidney sparing and to develop approaches to circumventing field size restrictions in the application of whole-abdomen IMRT using dynamic multileaf collimators (DMLC). METHODS AND MATERIALS: The entire peritoneal cavity as derived from serial computerized tomography scans was defined as the gross target volume, whereas the planning target volume (PTV) was defined as the gross target volume plus a 5-mm margin extending 1 cm superiorly and inferiorly. In 10 randomly selected patients, the PTV ranged from 5629 to 12578 cc (median 7935 cc), and the superior-inferior, lateral, and anterior-posterior dimensions of the PTV ranged from 37 to 46 cm (median 42.5 cm), 27 to 33 cm (median 29 cm), and 18 to 23 cm (median 20 cm), respectively. A single isocenter was defined for patients with field length <40 cm. For patients with fields >40 cm, two isocenters were defined: one in the abdominal region, and the other in the pelvis. For IMRT planning, five 15-MV intensity-modulated beams at gantry angles of 180 degrees, 105 degrees, 35 degrees, 325 degrees, and 255 degrees were used. Optimization was designed to spare kidneys and bones. To fully account for the significant scattered dose contributions, an iterative process for dose calculations was implemented in the optimization. To overcome the 15-cm field width limit of our DMLC delivery system, fields with a width >15 cm were split into two or more subfields. To minimize field match errors, adjacent subfields overlapped by at least 2 cm, with intensity "feathering" in the overlap region. For patients with two isocenters, fields were overlapped and feathered in the cephalad-caudad direction by at least 3 cm. For comparison, conventional anterior-posterior/posterior-anterior 6-MV photon beams with posterior kidney blocks at extended distance were also generated for each patient. RESULTS: Treatment plan optimization calculations required 20-80 min on a 500-MHz DEC alpha workstation. Including beam splitting, an average of 16 DMLC beams was used per patient. Delivery of 150 cGy required, on average, 1442 monitor units. For the same dose constraints on the kidneys, whole-abdomen IMRT resulted in significant dose reduction to the bones and improved PTV coverage as compared to conventional treatment. For a prescription dose of 30 Gy, the volume of the pelvic bones receiving more than 21 Gy was reduced on average by almost 60% with IMRT, and the mean dose to all bones was reduced from 24.0 +/- 1.5 Gy to 18.5 +/- 1.0 Gy (p = 0.002). PTV coverage, as measured by V95 (the volume receiving 95% of the prescription dose), improved from 71.7 +/- 4.8% with conventional treatment to 83.5 +/- 3.9% with IMRT (p = 0.002), although small regions of underdose in areas near the kidneys could not be avoided completely. The high-dose regions within the PTV, as measured by D05 (the dose covering 5% of PTV volume), increased slightly from 31.2 +/- 0.6 Gy with conventional treatment to 32.8 +/- 0.2 Gy with IMRT. CONCLUSION: We have developed a process to plan and deliver whole-abdomen IMRT using standard linear accelerators and DMLC. IMRT can achieve better PTV coverage with the same level of kidney sparing and improved sparing of the bone marrow. These methods may be applicable also to other sites requiring large-field irradiation.
Measurements of tumor tissue oxygen tension using a time-resolved luminescence-based optical oxylite probe: comparison with a paired survival assay.
Recently, a system that measures tissue oxygen tension using time-resolved luminescence-based optical sensors has become available commercially (Oxford Optronix, Oxford, England). Two experiments were conducted using this system. First, the oxygen tension distribution was measured in two tumor lines: a spontaneous mouse fibrosarcoma, FSa-II, and a human squamous cell carcinoma xenograft, FaDu. The area in which the pO(2) was equal to or lower than 2.5 mmHg was defined as the hypoxic lesion, and the hypoxic cell fraction was taken as the fraction of these measurements in a tumor. The measured hypoxic cell fractions were compared with those determined by the paired cell survival assay for tumors of various sizes. Second, the tumor tissue pO(2) was measured continuously after administration of two different anesthetics to evaluate the effect of these drugs on tissue pO(2). Results indicated a good agreement between the hypoxic cell fractions measured by this system and those determined by the paired cell survival curve assay for tumors smaller than approximately 500 mm(3). For tumors larger than approximately 500 mm(3), the hypoxic cell fractions measured by the oxygen probe system were higher than those measured by the paired cell survival assay. This may suggest that the hypoxic cell fraction measured by the oxygen probes included both hypoxic and necrotic areas in large tumors where necrotic lesions occupied a significant portion of the tumor. Continuous measurements of pO(2) after anesthesia (Nembutal, or ketamine plus xylazine) showed a consistent rise in the pO(2) during the first 20-30 min of measurement. Subsequently, the pO(2) values became constant or continued to rise slowly. For comparison, the tumor cell survivals were assayed after a dose of 20 Gy given in air at 5, 20 and 60 min after anesthesia. The result showed a decrease in cell survival only in tumors irradiated 20 min after an injection of Nembutal.