Excitons in CsPbBr3 Halide Perovskite.

Excitons in Bridgman grown halide perovskite CsPbBr3 single crystals were examined using photoluminescence (PL) spectroscopy to determine the nature of the electronic states. The photoluminescence intensity was strongly temperature-dependent and depended upon the specific exciton band. At low temperatures intrinsic disorder and its related shallow below bandgap tail states determine the emission properties. Photoluminescence at low temperature revealed the presence of several strong bands at the band edge that is attributed to free or trapped/bound excitons. This PL emission results from strong electron-phonon coupling with an average phonon energy Eph of 6.5 and 27.4 meV for the emissions, comparable to that observed in other perovskites. The Huang-Rhys parameter S was calculated to be 3.81 and 1.51, indicating strong electron-phonon coupling. The interactions between electrons and phonons produce small polarons that tend to bind charge carriers and result in trapped/bound excitons. The transient photoluminescence response of each specific band was studied, and the results indicated a multiphonon recombination process. Average PL lifetimes of ∼17 ns for free excitons and ∼38 ns for trapped/bound excitons were determined. The observed edge states could be associated with native defects such as vacancies and interstitials, as well as twinning due to the cubic-to-tetragonal phase transition in CsPbBr3. Elimination of the trapping sites for binding excitons could lead to improved charge transport mobilities, carrier lifetimes, and detector properties in this system.

Magnetoamplification in a bipolar magnetic junction transistor.

We have demonstrated the first bipolar magnetic junction transistor using a dilute magnetic semiconductor. For an InMnAs p-n-p transistor magnetoamplification is observed at room temperature. The observed magnetoamplification is attributed to the magnetoresistance of the magnetic semiconductor InMnAs heterojunction. The magnetic field dependence of the transistor characteristics confirm that the magnetoamplification results from the junction magnetoresistance. To describe the experimentally observed transistor characteristics, we propose a modified Ebers-Moll model that includes a series magnetoresistance attributed to spin-selective conduction. The capability of magnetic field control of the amplification in an all-semiconductor transistor at room temperature potentially enables the creation of new computer logic architecture where the spin of the carriers is utilized.

BaTiO3 thin-film waveguide modulator with a low voltage-length product at near-infrared wavelengths of 0.98 and 1.55 microm.

A BaTiO3 thin-film electro-optic waveguide modulator with a low half-wave voltage-length product has been demonstrated at near-infrared wavelengths of 1-1.6 microm. Half-wave voltage-length products as small as 0.25 and 0.5 V cm were measured for a 5-mm-long device at wavelengths of 973 and 1561 nm, respectively. The effective electro-optic coefficients were calculated as 420 pm/V at 973 nm and 360 pm/V at 1561 nm. Further improvements in device performance by optimizing the ferroelectric domain structure are anticipated.

Quality of coverage: conformity measures for stereotactic radiosurgery.

In radiosurgery, conformity indices are often used to compare competing plans, evaluate treatment techniques, and assess clinical complications. Several different indices have been reported to measure the conformity of the prescription isodose to the target volume. The PITV recommended in the Radiation Therapy Oncology Group (RTOG) radiosurgery guidelines, defined as the ratio of the prescription isodose volume (PI) over the target volume (TV), is probably the most frequently quoted. However, these currently used conformity indices depend on target size and shape complexity. The objectives of this study are to systematically investigate the influence of target size and shape complexity on existing conformity indices, and to propose a different conformity index-the conformity distance index (CDI). The CDI is defined as the average distance between the target and the prescription isodose line. This study examines five case groups with volumes of 0.3, 1.0, 3.0, 10.0, and 30.0 cm(3). Each case group includes four simulated shapes: a sphere, a moderate ellipsoid, an extreme ellipsoid, and a concave "C" shape. Prescription dose coverages are generated for three simplified clinical scenarios, i.e., the PI completely covers the TV with 1 and 2 mm margins, and the PI over-covers one half of the TV with a 1 mm margin and under-covers the other half with a 1 mm margin. Existing conformity indices and the CDI are calculated for these five case groups as well as seven clinical cases. When these values are compared, the RTOG PITV conformity index and other similar conformity measures have much higher values than the CDI for smaller and more complex shapes. With the same quality of prescription dose coverage, the CDI yields a consistent conformity measure. For the seven clinical cases, we also find that the same PITV values can be associated with very different conformity qualities while the CDI predicts the conformity quality accurately. In summary, the proposed CDI provides more consistent and accurate conformity measurements for all target sizes and shapes studied, and therefore will be a more useful conformity index for irregularly shaped targets.

Physical and chemical properties of radionuclide therapy.

As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it becomes increasingly important for the labeling chemistry to produce consistently a stable radiopharmaceutical that remains intact under the challenge of human catabolism. Similarly, once proof of principle is established to bring a radionuclide conjugate into clinical therapy trials, dosimetric estimates should be made to select the appropriate radionuclide properties, which are based on animal-specific or patient-specific pharmacokinetics and match a set of specific clinical endpoints. These properties may include the radionuclide physical half-life, radiolabeled conjugate biological uptake and clearance, product-specific activity, range and type of emissions, and resultant effects on tumor and normal tissue cellular survival. The immunologist and labeling chemist have now produced a variety of strategies that have potential to increase the therapeutic ratio (tumor-to-normal tissue dose ratio). The advent of normal tissue clearing agents, fragmented or chimerized carriers to improve targeting, and the method of bispecific or two-step and three-step targeting agents has increased the need for realistic modeling of the carrier in vivo to guide prospectively the competitive development of these radiopharmaceuticals. In this article, examples have been taken from the literature to elucidate the benchmark of success that careful experimental design has fostered to bring these agents into clinical practice by creative and logical methodologies.

131I-Lym-1 in mice implanted with human Burkitt's lymphoma (Raji) tumors: loss of tumor specificity due to radiolysis.

UNLABELLED: Preliminary evaluations of 125I-labeled Lym-1, an anti-lymphoma mouse IgG2a monoclonal antibody, demonstrated favorable tumor uptake in mice bearing human Burkitt's lymphoma (Raji) tumors. In this study, the pharmacokinetics of 125I- and 131I-Lym-1, and the dosimetry, efficacy, and toxicity of 131I-Lym-1 in Raji-tumored mice were evaluated. METHODS: Lym-1 was radioiodinated by the chloramine-T method and analyzed for monomeric fraction and immunoreactivity (antigen cell binding, relative to unmodified Lym-1). Nude mice bearing Raji tumors (20-500 mm3) received 1.5 MBq (40 microCi) 125I-Lym-1, or 1.5, 7.4, 14.8, or 18.5 MBq (40, 200, 400, or 500 microCi) 131I-Lym-1. Pharmacokinetic data (total body and blood clearance and biodistribution) were used to estimate radiation dosimetry. Mini-thermoluminescent dosimetry (TLD) was also used to measure radiation dosimetry directly for 7 days after injection of 131I-Lym-1. Tumor size, survival, body weight, and blood counts were monitored for 60 days to evaluate therapeutic efficacy and toxicity of 131I-Lym-1. RESULTS: At the time of injection, the mean quality assurance (QA) values for 125I-Lym-1 were 100% monomer and 100% relative immunoreactivity; the corresponding values for 131I-Lym-1 were 73% and 66%, indicating that radiolysis had occurred during the interval between radiolabeling and injection. 125I-Lym-1 exhibited high and sustained concentration in tumors relative to normal organs, whereas 131I-Lym-1 did not. Assuming identical pharmacokinetic behavior to 125I-Lym-1, 131I-Lym-1 would deliver radiation doses of 3.45, 0.83, 1.03, 0.34, and 0.56 Gy per MBq injected (12.8, 3.1, 3.8, 1.3, and 2.1 rad/microCi), to tumor, liver, lungs, total body, and marrow, respectively. When the actual pharmacokinetic data for 131I-Lym-1 (1.5 MBq) were used to estimate dosimetry, corresponding values of 0.51, 0.72, 0.49, 0.31, and 0.41 Gy/MBq (1.9, 2.7, 1.8, 1.1, and 1.5 rad/microCi) were obtained. Similar values were obtained for mice receiving 7.4 or 14.8 MBq of 131I-Lym-1. Similarly, TLD data indicated little preferential radiation dosimetry to tumor. Response rates (cure + CR + PR) for mice receiving 0, 7.4, 14.8, and 18.5 MBq of 131I-Lym-1 were 8%, 7%, 21%, and 45%, respectively. The LD50/30 dose of 131I-Lym-1 was 12.7 MBq (343 microCi). CONCLUSIONS: 125I-Lym-1 exhibited high and sustained concentration in Raji tumors in mice, indicating excellent therapeutic potential for 131I-Lym-1. However, in vitro QA results for 131I-Lym-1 indicated that radiolysis had occurred, and 131I-Lym-1 demonstrated little accumulation in tumor, or preferential radiation dosimetry to tumor in the same model.

Validation of an analytical expression for the absorbed dose from a spherical beta source geometry and its application to micrometastatic radionuclide therapy.

The purpose of this study was to validate an analytical expression for the absorbed-dose calculation from the spherical source of beta-emitting radionuclides and to apply it to micrometastases treated with radiolabeled monoclonal antibodies. The self-absorbed fractions from I-131 and P-32 uniform spherical sources were calculated using the analytical expression introduced by P. K. Leichner (J. Nucl. Med., 35: 1721-1729, 1994). The calculated absorbed fractions were compared with previously reported values and were found to be in reasonable agreement, with a maximum difference of 15% for smaller masses and a long-range beta emitter. The expression was subsequently applied to estimate the absorbed dose within spheroid models with nonuniform penetration of radiolabeled antibody. The corresponding absorbed dose for I-131 was compared with reported micro-thermoluminescence dosimeter measurements and found to be in good agreement. This work has independently substantiated the methodology outlined by Leichner and may be reliably incorporated into new software developments for radionuclide dosimetry treatment planning.

Can current models explain the lack of liver complications in Y-90 microsphere therapy?

Normal liver complications have not been observed in Y-90 microsphere therapy of hepatic tumors [selective internal radiation (SIR)], despite clinical studies reporting estimated absorbed doses to normal liver between 100 and 150 Gy. The purpose of the study was to see whether predictions of normal tissue complication probability (NTCP) models for liver based on clinical data from external beam therapy are consistent with clinical results of SIR. Liver NTCP was calculated using a parallel architecture model and normal liver dose-volume histograms that have been proposed for SIR. A parallel model including internal functional subunit structure is also proposed. Dose rate effects are incorporated. A criterion for comparing model calculations with clinical data is presented. For the parallel architecture model, the predicted NTCP is sensitive to the dose distribution in normal liver and to the model parameters, particularly the repair time. With reasonable assumptions about the microsphere distribution, the parallel model with parameters deduced from external beam therapy outcome analysis is consistent with the observed lack of liver complications. Inclusion of FSU structure widens the range of assumptions under which consistency is found. The parallel model can be consistent with the clinically observed lack of liver complications in SIR. More information about the activity distribution and the radiobiology of normal liver under conditions typical of microsphere therapy should be sought.

The MIRD perspective 1999. Medical Internal Radiation Dose Committee.

The MIRD schema is a general approach for medical internal radiation dosimetry. Although the schema has traditionally been used for organ dosimetry, it is also applicable to dosimetry at the suborgan, voxel, multicellular and cellular levels. The MIRD pamphlets that follow in this issue and in coming issues, as well as the recent monograph on cellular dosimetry, demonstrate the flexibility of this approach. Furthermore, these pamphlets provide new tools for radionuclide dosimetry applications, including the dynamic bladder model, S values for small structures within the brain (i.e., suborgan dosimetry), voxel S values for constructing three-dimensional dose distributions and dose-volume histograms and techniques for acquiring quantitative distribution and pharmacokinetic data.

MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee.

The availability of quantitative three-dimensional in vivo data on radionuclide distributions within the body makes it possible to calculate the corresponding nonuniform distribution of radiation absorbed dose in body organs and tissues. This pamphlet emphasizes the utility of the MIRD schema for such calculations through the use of radionuclide S values defined at the voxel level. The use of both dose point-kernels and Monte Carlo simulation methods is also discussed. PET and SPECT imaging can provide quantitative activity data in voxels of several millimeters on edge. For smaller voxel sizes, accurate data cannot be obtained using present imaging technology. For submillimeter dimensions, autoradiographic methods may be used when tissues are obtained through biopsy or autopsy. Sample S value tabulations for five radionuclides within cubical voxels of 3 mm and 6 mm on edge are given in the appendices to this pamphlet. These S values may be used to construct three-dimensional dose profiles for nonuniform distributions of radioactivity encountered in therapeutic and diagnostic nuclear medicine. Data are also tabulated for 131I in 0.1-mm voxels for use in autoradiography. Two examples illustrating the use of voxel S values are given, followed by a discussion of the use of three-dimensional dose distributions in understanding and predicting biologic response.

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Use of the fast Hartley transform for three-dimensional dose calculation in radionuclide therapy.

Effective radioimmunotherapy may depend on a priori knowledge of the radiation absorbed dose distribution obtained by trace imaging activities administered to a patient before treatment. A new, fast, and effective treatment planning approach is developed to deal with a heterogeneous activity distribution. Calculation of the three-dimensional absorbed dose distribution requires convolution of a cumulated activity distribution matrix with a point-source kernel; both are represented by large matrices (64 x 64 x 64). To reduce the computation time required for these calculations, an implementation of convolution using three-dimensional (3-D) fast Hartley transform (FHT) is realized. Using the 3-D FHT convolution, absorbed dose calculation time was reduced over 1000 times. With this system, fast and accurate absorbed dose calculations are possible in radioimmunotherapy. This approach was validated in simple geometries and then was used to calculate the absorbed dose distribution for a patient's tumor and a bone marrow sample.

Marrow toxicity and radiation absorbed dose estimates from rhenium-186-labeled monoclonal antibody.

UNLABELLED: Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody. METHODS: White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered. RESULTS: Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates. CONCLUSION: Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.

Dosimetry overview: keeping score on the scorekeepers.

BACKGROUND: As a direct result of the use of the absorbed dose unit the 'Gray' as the gold standard for predicting response in external beam radiotherapy, the physicist role has been essential to clinical practice for many decades. However, although the dosimetry for internal emitters has proven useful in managing health physics concerns and diagnostic nuclear medicine, the relative success of correlating absorbed dose with response from radionuclide therapy has been limited. METHODS: This overview presents the relative success and/or failure of model-based dosimetry for radionuclide therapy in comparison to results quoted for external beam therapy dosimetry. RESULTS: Using the standard MIRD formalism for macroscopic dosimetry, the marked non-uniform distribution of radionuclide in both tumor and normal tissue has resulted in limited correlation between computed absorbed dose and biological response in clinical trials. Several efforts are underway aimed at improving this dose-response correlation which include individualized patient specific dosimetry and selected biological parameters. CONCLUSIONS: The physicist role in helping the clinician determining which patients will succeed on given radionuclide therapy has been improved with simplified methods such as the assessment of tracer whole body absorbed dose on a per patient basis. The dose-response correlations are now in the moderate range of significance when individualized patient dosimetry is included. These correlations are expected to improve as unified treatment planning programs are instituted and standard methods of clinically based dosimetry are widely accepted and practiced universally.

Radiobiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts.

BACKGROUND: Previous studies suggest that the radiobiologic characteristics of in vitro survival curves are important determinants of the response of tumors to both conventional radiotherapy and radioimmunotherapy (RIT). The purpose of this study was to elucidate the relationship between in vitro radiation survival curve parameters and the relative sensitivity of tumor to RIT, exponentially decreasing low dose rate (ED LDR) irradiation and conventional high dose rate (HDR) fractionated external beam radiotherapy. METHODS: Two human renal cell carcinoma cell lines, Caki-1 and A498, were used in vitro and nude mouse xenograft studies. HDR external beam gamma irradiation (dose rate, 430 centigray [cGy]/minute) and ED LDR irradiation (initial dose rate, 22-25 cGy/hour) were performed with a cesium-137 (137Cs) gamma irradiator. RIT was carried out with yttrium-90 (90Y-labeled monoclonal antibody NR-LU-10, and the absorbed radiation doses were calculated by medical internal radiation dose methodology. A clonogenic assay was used to generate radiation survival curves, and a computer FIT program was used to calculate the radiobiologic parameters. The antitumor efficacy of the different treatments was compared in vivo using a tumor regrowth delay assay in these two tumor xenograft models. RESULTS: The radiation survival curves showed that the Caki-1 cell line was more sensitive to both HDR and ED LDR irradiation than A498 in vitro. The Caki-1 cell line, compared with A498, had a larger alpha (0.39 vs. 0.15 Gy following HDR and 0.32 vs. 0.21 Gy following ED LDR) and alpha-to-beta ratio (6.92 vs. 2.60 Gy for HDR and 40.0 vs. 19.2 Gy for ED LDR), a smaller n number (5.13 vs. 23 for HDR and 1.16 vs. 3.53 for ED LDR), a lower quasi-threshold dose (Dq) (1.60 vs. 3.15 Gy for HDR and 0.35 vs. 1.76 Gy for ED LDR), and a lower surviving fraction at 2 Gy (SF2) (0.37 vs. 0.60 for HDR and 0.51 vs. 0.61 for ED LDR), suggesting that Caki-1, compared with A498, had a steep initial slope and a small shoulder. The final slope represented by the beta value and D0 dose (the dose (Gy) required to reduce the fraction of surviving cells of 37% of its previous value in the exponential region of the survival curves) did not vary significantly between these two cell lines at either HDR or ED LDR irradiation. Tumor volume doubling times were 4.0 +/- 1.5 days for Caki-1 and 4.2 +/- 1.8 days for A498 tumor xenografts. One hundred microCi/50 microg of 90Y-labeled, isotype-matched irrelevant monoclonal antibody CCOO16-3 produced a tumor growth delay time (TGD) of 2.1 days in Caki-1 tumors but had no effect on A498 tumors (P < 0.05). RIT with 100 microCi of 90Y-NR-LU-10 resulted in a TGD of 4.8 days for Caki-1 tumors, whereas 100 microCi and 150 microCi of 90Y-NR-LU-10 produced a TGD of 1.9 and 2.7 days for A498 tumors, respectively. Estimated absorbed doses were 21.9 Gy in Caki-1 tumors treated with 100 microCi of 90Y-NR-LU-10 and 14.5 Gy and 21.8 Gy in A498 tumors treated with 100 microCi and 150 microCi of 90Y-NR-LU-10, respectively. The weighted normal tissue absorbed doses were 7.4 Gy for Caki-1 tumor-bearing mice and 9.0 Gy for A498 tumor-bearing mice (P > 0.05). To compare the responses of Caki-1 and A498 xenografts to RIT with external beam ED LDR and HDR irradiation, tumor-bearing mice were treated with equivalent doses (20-22 Gy) of 1) RIT with 90Y-NR-LU-10 (100 microCi for Caki-1 and 150 microCi for A498), 2) continuous ED LDR 137Cs irradiation with a initial dose rate of 22 cGy/hour, or 3) HDR X-irradiation (2 Gy x 10 fractions in 2 weeks). The TGDs produced by RIT, ED LDR, and HDR were 5.3, 9.7, and 8.3 days for Caki-1 and 2.7, 5.1, and 5.8 days for A498. The relative efficacy of RIT in these xenograft models correlated well with the radiobiologic parameters (i.e., the size of the initial slope and shoulder) of in vitro survival curves following HDR and ED LDR irradiation in these cell lines. (ABSTRACT TRUNCATED)

Treatment planning for radio-immunotherapy.

To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have 'favorable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose-volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.

Application of the linear-quadratic model to myelotoxicity associated with radioimmunotherapy.

The purposes of this study were: (1) to use the linear-quadratic model to determine time-dependent biologically effective doses (BEDs) that were delivered to the bone marrow by multiple infusions of radiolabeled antibodies, and (2) to determine whether granulocyte and platelet counts correlate better with BED than administered radioactivity, which does not take stem cell repopulation, i.e., time, into consideration. Twenty patients with B-cell malignancies that had progressed despite intensive chemotherapy and who had a significant number of malignant cells in their bone marrow were treated with multiple 0.7-3.7 GBq/m2 (18-100 mCi/m2) intravenous infusions of Lym-1, a murine monoclonal antibody that binds to a tumour-associated antigen, labeled with iodine-131. Granulocyte and platelet counts were measured in order to assess bone marrow toxicity. BEDs were calculated according to the formula: BED=D(1+gD/(alpha/beta))-0.693(Tn-Tk)/alphaTp, where D represents the absorbed dose of radiation delivered to the red marrow by penetrating emissions of 131I throughout the whole body and nonpenetrating emissions of 131I in the blood and bone marrow, g is a factor that depends on the duration of irradiation relative to the repair half-life of human bone marrow, alpha is the coefficient of nonrepairable damage per Gy, beta is the coefficient of repairable damage per Gy2, Tn is the time required to reach the granulocyte or platelet count nadir after an 131I-Lym-1 infusion, Tk is the time at which bone marrow proliferation begins after the start of treatment and Tp is the doubling time of the bone marrow after the granulocyte or platelet count nadir has been reached. The cumulative 131I-Lym-1 radioactivity administered to each patient was calculated. Biologically effective doses from multiple 131I-Lym-1 infusions were summated in order to arrive at a total BED for each patient. There was a weak association between granulocyte and platelet counts and radioactivity (the correlation coefficients were -0.23 and -0.60, respectively). Likewise, there was a weak association between granulocyte and platelet counts and BED (the correlation coefficients were -0.27 and -0.40, respectively). The attempt to take bone marrow absorbed doses and overall treatment time into consideration with the linear-quadratic model did not produce a stronger association than was observed between peripheral blood counts and administered radioactivity. The association between granulocyte and platelet counts and BED may have been weakened by several factors, including variable bone marrow reserve at the start of 131I-Lym-1 therapy and the delivery of heterogeneous absorbed doses of radiation to the bone marrow.

Threshold estimation in single photon emission computed tomography and planar imaging for clinical radioimmunotherapy.

Thresholding is the most widely used organ or tumor segmentation technique used in single photon emission computed tomography (SPECT) and planar imaging for monoclonal antibodies. Selecting the optimal threshold requires a priori knowledge (volumes from CT or magnetic resonance) for the size and contrast level of the organ in question. Failure to select an optimal threshold leads to overestimation or underestimation of the volume and, subsequently, the organ-absorbed dose value in radio-immunotherapy. To investigate this threshold selection problem, we performed a phantom experiment using six lucite spheres ranging from 1 to 117 ml and filled with a uniform activity of 1 microCi/ml Tc-99m. These spheres were placed at the center and off-center locations of a Jasczsak phantom and scanned with a three-headed gamma camera in SPECT and planar modes. Target-nontarget (T:NT) ratios were changed by adding the appropriate activity to the background. A threshold search algorithm with an interpolative background correction was applied to sphere images. This algorithm selects a threshold that minimizes the difference between the true and measured volumes (SPECT) or areas (planar). It was found that for spheres equal to or larger than 20 ml [diameter (D) > 38 mm] and T:NT ratios higher than 5:1, mean thresholds at 42% for SPECT and 38% for planar imaging yielded minimum image segmentation errors, which is in agreement with current literature. However, for small T:NT ratios (< 5:1), the threshold values as high as 71% for SPECT and 85% for planar imaging were substantially different than those fixed thresholds for large spheres (D > 38 mm). Hence, the use of fixed thresholds in low contrasts and with tumor and organ sizes of clinical interest (25 < or = D < or = 50 mm) may result in limited volume estimation accuracy. Therefore, we have provided the investigator a method to obtain the threshold values in which the proper threshold can be selected based on the organ and tumor size and image contrast. By measuring and calibrating the proper threshold value derived through machine-specific phantom measurements, a more accurate volume and activity quantitation can be performed. This, in turn, will provide tumor-absorbed dose optimization and greater accuracy in the measurement of potentially subacute, toxic absorbed doses to normal organs for patients undergoing radioimmunotherapy.

A new fiducial alignment system to overlay abdominal computed tomography or magnetic resonance anatomical images with radiolabeled antibody single-photon emission computed tomographic scans.

BACKGROUND: The use of computed tomography (CT) or magnetic resonance (MR) to overlay or register uptake patterns displayed by single-photon emission computed tomography (SPECT) with specific underlying anatomy has the potential to improve image interpretation and decrease diagnostic reading errors. The authors have developed a method that will allow the selection of a region of interest on MR or CT images that correlates with SPECT antibody images from the same patient. This method was validated first in phantom studies and subsequently was used on three patients with suspected colorectal carcinoma. METHODS: Two patients were injected with the technetium-99m-labeled 88BV59 immunoglobulin G human antibody, and the third patient was injected with the iodine-131-labeled 16.88 immunoglobulin M human antibody. CT or MR scans were obtained before antibody infusion, and subsequent SPECT scans were obtained on the first or fourth day after infusion. A customized body cast with landmarks was used for each patient during the CT, MR, and SPECT scans to match slice positions for all scanning modalities. Corresponding fiducial landmarks were identified on axial images. A computer graphics program was written to match and overlay corresponding landmarks for each imaging modality. The image registration accuracy was measured by comparing fiducial marker separations (center to center) on the registered scans. This separation uncertainty was 1-2 mm for CT-MR and 3-4 mm for CT-SPECT phantom studies. RESULTS: For patient studies, the fiducial alignment uncertainty was 3-4 mm for axial CT-SPECT and MR-SPECT images, and 6-8 mm for sagittal CT-SPECT and MR-SPECT images. The accuracy of the anatomic alignment of the patient and image registration system was +/- 1 cm in the medial-lateral axis and +/- 2 cm in the cranial-caudal direction. CONCLUSIONS: This type of image analysis may resolve uncertainties with the anatomic correlation of SPECT images that otherwise may be regarded as questionable when SPECT is used alone for radioimmunodiagnosis.