Current perspective on actinic keratosis: a review.

Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun-damaged skin. Yearly AK to SCC progression rates of 0·6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5-fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management.

Formaldehyde in residences: long-term indoor concentrations and influencing factors.

UNLABELLED: Chronic human exposure to formaldehyde is significantly increased by indoor sources. However, information is lacking on why these exposures appear to persist in older homes with aging sources. We use data from the Relationships of Indoor, Outdoor, and Personal Air study to evaluate 179 residences, most of which were older than 5 years. We assess the dependence of indoor formaldehyde concentrations (C(in)) on building type and age, whole-house air exchange rate, indoor temperature, and seasonal changes. Indoor formaldehyde had mean and median concentrations of 17 ppb, and primarily originated from indoor sources. The factors we analyzed did not explain much of the variance in C(in), probably because of their limited influence on mechanisms that control the long-term release of formaldehyde from aging pressed-wood products bound with urea-formaldehyde (UF) resins. We confirmed that the mitigating effects of ventilation on C(in) decrease with time through the analysis of data for new homes available in the literature, and through models. We also explored source control strategies and conclude that source removal is the most effective way to decrease chronic exposures to formaldehyde in existing homes. For new homes, reducing indoor sources and using pressed-wood with lower UF content are likely the best solutions. PRACTICAL IMPLICATIONS: Formaldehyde concentrations in homes due to indoor sources appear to persist throughout the lifetime of residences. Increases in ventilation rates are most effective in decreasing indoor concentrations in new homes where formaldehyde levels are high or when homes are tight. Consequently, other alternatives need to be promoted such as decreasing the amount of pressed-wood products with urea-formaldehyde (UF) resins in homes or reducing the UF content in these materials.

Outpatient treatment with (131)I-anti-B1 antibody: radiation exposure to family members.

UNLABELLED: The Nuclear Regulatory Commission (NRC) regulations that govern release of patients administered radioactive material have been revised to include dose-based criteria in addition to the conventional activity-based criteria. A licensee may now release a patient if the total effective dose equivalent to another individual from exposure to the released patient is not likely to exceed 5 mSv (500 mrem). The result of this dose-based release limit is that now many patients given therapeutic amounts of radioactive material no longer require hospitalization. This article presents measured dose data for 26 family members exposed to 22 patients treated for non-Hodgkin's lymphoma with (131)I-anti-B1 antibody after their release according to the new NRC dose-based regulations. METHODS: The patients received administered activities ranging from 0.94 to 4.77 GBq (25--129 mCi). Family members were provided with radiation monitoring devices (film badges, thermoluminescent or optically stimulated luminescent dosimeters, or electronic digital dosimeters). Radiation safety personnel instructed the family members on the proper wearing and use of the devices. Instruction was also provided on actions recommended to maintain doses to potentially exposed individuals as low as is reasonably achievable. RESULTS: Family members wore the dosimeters for 2--17 d, with the range of measured dose values extending from 0.17 to 4.09 mSv (17--409 mrem). The average dose for infinite time based on dosimeter readings was 32% of the predicted doses projected to be received by the family members using the NRC method provided in regulatory guide 8.39. CONCLUSION: Therapy with (131)I-anti-B1 antibody can be conducted on an outpatient basis using the established recommended protocol. The patients can be released immediately with confidence that doses to other individuals will be below the 5-mSv (500 mrem) limit.

Contribution to red marrow absorbed dose from total body activity: a correction to the MIRD method.

UNLABELLED: The contribution to red marrow absorbed dose from beta-emitting radionuclides distributed uniformly in the total body can be overestimated using either MIRD 11 or MIRDOSE3. The S value assigned to the red marrow target region from activity distributed in the remainder of the body is of particular concern. The assumption that the specific absorbed fraction for total body irradiating red marrow and other skeletal tissues is the inverse of the total-body mass can result in an inappropriate remainder-of-body contribution to marrow dose. We evaluated differences in the calculation of marrow dose using MIRD 11 and MIRDOSE3 formulations and developed methods to correct the results from either to remove inappropriate contributions. When bone takes up significantly less activity than is predicted from an apportionment of remainder-tissue activity based on mass, the standard remainder-of-body correction may substantially overestimate the electron component of the S value from remainder tissues to red marrow using either MIRD 11 or MIRDOSE3. If bone takes up activity, this contribution is negligible using MIRD 11 S values but remains with MIRDOSE3 S values. This overestimate can be significant, particularly when the residence time of activity in the remainder of the body is much higher than in the red marrow and a different correction is needed. As the ratio of the remainder of body to marrow residence time is lowered, the overestimate becomes less significant. CONCLUSION: In this article, we show the magnitude of this overestimate (which is most important for nuclides with large "nonpenetrating" emission components and for pharmaceuticals that have a large ratio of remainder of body to marrow residence times), show the appropriate corrections to be made in each case, and propose a new method for calculating marrow dose contributions that will avoid this complication in future applications. Because all models give approximate doses for real patients, with uncertainties within those involved in these corrections, we do not suggest that changes be made to existing marrow dose estimates. We suggest only that future calculations be as accurate as possible.

Feasibility and safety of outpatient Bexxar therapy (tositumomab and iodine I 131 tositumomab) for non-Hodgkin's lymphoma based on radiation doses to family members.

Radioimmunotherapy with anti-CD20 antibodies is a promising treatment approach for relapsed low-grade non-Hodgkin's lymphoma. Under revised Nuclear Regulatory Commission regulations (May 1997), patients may be released following treatment provided the maximum dose to any individual is not likely to exceed 500 mrem. Non-Hodgkin's lymphoma patients have been studied to evaluate radiation exposure to caregivers/family members after outpatient treatment with tositumomab and iodine I 131 tositumomab (Bexxar therapy). Estimates of total radiation doses to individuals expected to be maximally exposed to patients posttreatment have revealed that the doses should be within revised guidelines. In a University of Nebraska Medical Center study, the predicted total radiation doses (based on patient dose rate at 1 meter) ranged from 95-423 mrem. Family members were provided radiation-monitoring devices to directly monitor radiation exposure. Measured doses ranged from 10-409 mrem. In this and other studies, estimated and measured dose equivalents to maximally exposed individuals were below 500 mrem. Measured doses were, in most instances, lower than those predicted by patient-specific calculations, thus confirming the validity of the calculated dose predictions. Therefore, radioimmunotherapy with tositumomab and iodine I 131 tositumomab can be safely conducted on an outpatient basis.

A generalized algorithm for determining the time of release and the duration of post-release radiation precautions following radionuclide therapy.

The Nuclear Regulatory Commission has recently amended its regulation concerning patients who have received therapeutic amounts of radioactivity. The amended regulation allows patient release based on a total effective dose equivalent (TEDE) limit of 5 mSv (500 mrem) instead of the activity administered or retained [1,110 MBq (30 mCi)] or the dose rate [0.05 mSv h(-1) (5 mrem h(-1)) at 1 m]. Record-keeping and written post-release radiation safety precautions are required, however. A general algorithm, combining patient-specific kinetics and dose rate measurements, has been developed to systematically determine the actual duration of post-release radiation precautions as well as the time of release post-treatment. This algorithm is based on the maximum permissible effective dose equivalents (MPEDEs) of the respective cohorts exposed, 5 mSv (500 mrem) to non-pregnant adult family members and 1 mSv (100 mrem) to pregnant women, children, and members of the general public. Operational equations to determine the times post-radionuclide treatment of release from medical confinement, of not working, of avoiding pregnant women and children, of limiting holding of children, and of sleeping partners not sleeping together have been derived and illustrated with a hypothetical example. TEDE-based release criteria should be less restrictive than the previous activity-based or dose rate-based release criteria. However, post-release radiation precautions may be more intrusive and longer in duration than those to which most practitioners have grown accustomed. Up to now, however, the duration (typically 1-2 d) of advised post-release precautions had not been rigorously derived from MPEDEs and were generally inappropriately short. Even so, dose-based release criteria should prove more cost-effective overall than hospitalization of patients commonly imposed by activity-based and dose rate-based release criteria.

Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease.

BACKGROUND: Metastatic disease of the acetabulum can be painful and disabling. Operative intervention is indicated for patients who fail to respond adequately to nonoperative treatment. We evaluated the functional and oncological outcome of acetabular reconstruction after curettage for the treatment of refractory symptomatic acetabular metastases. METHODS: Fifty-five patients with metastatic disease of the acetabulum were treated with operative acetabular reconstruction combined with a total hip replacement. The most common primary tumor was carcinoma of the breast (eighteen patients), followed by carcinoma of the kidney (seven patients) and carcinoma of the prostate (seven patients). Forty (73 percent) of the patients presented with multiple skeletal metastases, and eighteen (33 percent) had associated visceral metastases. Twenty-eight (51 percent) had severe pain requiring continuous use of narcotics, twenty-four (44 percent) had moderate pain requiring periodic use of narcotics, and the remaining three (5 percent) had mild pain requiring use of non-narcotic analgesics. Eighteen (33 percent) of the patients could not walk, twenty-three (42 percent) needed a walker or crutches, twelve (22 percent) used a single cane, and two (4 percent) walked without assistive devices. Intralesional curettage of the tumor was performed in all of the patients. Fifty-four of the hips were reconstructed with a protrusio cup and one, with a hemipelvis endoprosthesis. Large defects were reinforced with cement and pin or screw fixation (the modified Harrington technique), which allowed transmission of weight-bearing forces to the remaining intact pelvis. Thirty-six acetabular reconstructions were performed with antegrade pins or cannulated screws; fifteen, with long retrograde screws; and four, with cement. RESULTS: The median period of survival was nine months. Patients with visceral metastases had a median period of survival of three months compared with twelve months for patients without visceral metastases (p < 0.001). Patients with breast cancer presented later in the disease process (p < 0.004) and lived longer than did those with other carcinomas (p < 0.004). Forty-five patients were evaluated three months after reconstruction. Thirty-four (76 percent) of them had relief of pain as determined by decreased use of narcotics. Nine of the eighteen patients who could not walk preoperatively regained the ability to walk. Fourteen of the seventeen patients who originally were able to walk in the community retained that ability. Thirty-three patients were available for evaluation at six months. Twenty-five (76 percent) still had relief of pain, and nineteen (58 percent) were able to walk and function in the community. Overall, fourteen (25 percent) of the fifty-five patients had moderate local progression of the disease, and five of these patients had failure of the fixation. Fourteen early complications developed in twelve (22 percent) of the patients. One patient (2 percent) died perioperatively. CONCLUSIONS: Patients who have acetabular metastases that are refractory to radiation and chemotherapy have a short life expectancy. The early, gratifying results of reconstruction validate the role of operative treatment as a short-term palliative procedure. Protrusio acetabular cups presumably compensate for deficiencies of the medial wall, while cement and pin fixation can be used effectively to reconstruct large defects in the acetabular column and dome. The low rate of fixation failure supports the biomechanical principles of the reconstruction. Generally, the reconstructions are sufficiently durable to exceed the life expectancy of the patients.

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.

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.

Absolute organ activity estimated by five different methods of background correction.

UNLABELLED: Accurate absorbed dose estimates in radionuclide therapy require patient-specific dosimetry. In patient-based dosimetry, estimation of absolute organ uptake is essential. The methods used should be reasonably accurate as well as easy to perform in routine clinical practice. One of the major sources of uncertainty in quantification of organ or tumor activity from planar images is the activity present in the tissue surrounding the source. METHODS: To estimate organ activity as a function of organ-to-background activity concentration ratio, a cylindrical phantom, filled with 5.6 liters of water was used to simulate the abdomen of a patient. Two other cylinders of 150 ml each, representing the kidneys, were each filled with 19 MBq 99mTC and were positioned in the abdomen phantom. The phantom was imaged with a dual-head gamma camera with the kidneys placed at posterior depths of 1-, 5- and 10-cm at kidney-to-background activity concentration ratios of infinity, 10:1, 5:1 and 2:1. The conjugate view geometric mean counting method was used to quantify activity. Five methods for background correction were applied: (1) no correction; (2) conventional background correction (simple subtraction of the background counting rate from the source region counting rate); (3) Kojima method (background corrected for organ thickness and depth); (4) Thomas method (analytical solution); and (5) Buijs method (background corrected for organ and total-body thickness). RESULTS: Since the results were identical for both kidneys, only the left kidney activity measurements are presented. The accuracy of the five background correction methods is given as the percentage difference between the actual and measured activity in the left kidney. For Method 1, the percentage difference ranged from 2% with an infinite kidney-to-background activity concentration ratio to +413% with a 2:1 ratio. For Method 2, these values ranged from -1% to -80%, for Method 3 from +11% to -18%, for Method 4 from -2% to +120% and for Method 5 from -4% to +39%. CONCLUSION: Even though quantitative SPECT is the most rigorous method for activity quantification in conditions of low organ-to-background activity concentration ratio, planar scintigraphy can be applied accurately if appropriate attention is paid to background correction. Using relatively simple background subtraction methods, the quantitative planar imaging technique can result in reasonably accurate activity estimates (Methods 3 and 5). The use of Kojima's method is preferable, especially at very low source-to-background activity concentration ratios.

Dosimetric analysis of chimeric monoclonal antibody cMOv18 IgG in ovarian carcinoma patients after intraperitoneal and intravenous administration.

In this study the potential of intraperitoneal (i.p.) and intravenous (i.v.) administration of chimeric iodine-131-labelled MOv18 IgG for radioimmunotherapy was determined. The dosimetry associated with both routes of administration of cMOv18 IgG was studied in patients. Eight patients suspected of having ovarian carcinoma received 150 MBq 131I-cMOv18 IgG i.p. Blood and urine were collected and serial gamma camera images were acquired. Another group of four patients received 7.5 MBq 131I-cMOv18 IgG i.v. For all patients, tissue biopsies were obtained at surgery. Activity in the blood after i.p. administration was described by a bi-exponential curve with a mean uptake and elimination half-life of 6.9+/-3.2 h and 160+/-45 h, respectively. For i.v. infusion the mean half-life for the elimination phase was 103+/-12 h. Cumulative excretion in the urine was 17%+/-3% ID and 21%+/-7% ID in 96 h for i.p. and i.v. administration, respectively. Scintigraphic images after i.p. administration showed accumulation in ovarian cancer lesions, while all other tissues showed decreasing activity with time. Tumour uptake determined in the ovarian cancer tissue specimens ranged from 3.4% to 12.3% ID/kg for i.p. administration and from 3.6% to 5.4% ID/kg for i.v. administration. Dosimetric analysis of the data indicated that 1.7-4.3 mGy/MBq and 1.7-2.2 mGy/MBq can be guided to solid or ascites cells after i.p. and i.v. administration, respectively. Assuming that an absorbed dose to the bone marrow of 2 Gy will be dose limiting, a total activity of 4.1 GBq 131I-cMOv18 IgG can be administered safely via the i.p. route and 3.5 GBq via the i.v. route. At this maximal tolerated dose, a maximum absorbed dose to 1-g tumours in the peritoneal cavity of 18 and 8 Gy can be reached after i.p. and i.v. administration, respectively. For the i. p. route of administration, dose estimates for the tumour are even higher when the electron dose of the peritoneal activity is also taken into account: total doses to the tumour of 30 Gy and 22 Gy will be absorbed at the tumour surface and at 0.2 mm depth, respectively. In conclusion, therapeutic tumour doses can be achieved with 131I-cMOv18 IgG in patients with intraperitoneal ovarian cancer lesions with no normal organ toxicity. The i.p. route of administration seems to be preferable to i.v. administration.

The need for better methods to determine release criteria for patients administered radioactive material.

In current NRC regulations, three options exist that may be used to determine release criteria for patients administered radioactive materials. Absorbed dose estimates may be based on administered activity, measured dose rate, or on patient-specific calculations. All of these methods proposed by the NRC can lead to overestimation of the dose equivalent to others due to their oversimplified nature. The primary oversimplifications are the use of a point source methodology and using the measured surface entrance dose rate to determine whole body dose. In order to show the inaccuracy of these oversimplifications for 131I, results using Monte Carlo radiation transport analysis with simplified anthropomorphic mathematical phantoms were determined. These results were then compared to actual patient measurements and the results of point source analysis. The measurement data were taken from 49 131I radioimmunotherapy patients. The point source calculations were performed using well established methodologies and using the same assumptions as in the NRC regulations for patient release criteria. Monte Carlo results were obtained by implementing two simplified 70 kg anthropomorphic phantoms and performing radiation transport simulation. The activity in the "patient" phantom was assumed to be localized in the abdominal region to correspond to the activity localization seen in the radioimmunotherapy patients who were measured. Dose equivalents per unit cumulated activities were determined for 131I using the various methods. The relationship between measured dose equivalent per unit cumulated activity and whole body dose equivalent per unit cumulated activity was also investigated using Monte Carlo analysis. The point source method as implemented by the NRC yields an estimated dose equivalent per unit cumulated activity of 1.6 x 10(-8) mSv MBq(-1) s(-1) at 1 m (2.2 x 10(-4) rem mCi(-1) h(-1) at 1 m), and the Monte Carlo based method yielded a whole body dose equivalent per unit cumulated activity in the target phantom of 6.8 x 10(-9) mSv MBq(-1) s(-1)(9.0 x 10(-5) rem mCi(-1) h(-1)) for abdominal localization of activity in the source phantom. The measurements of the radioimmunotherapy patients yielded an average result of 1.0 x 10(-8) mSv MBq(-1) s(-1) (13 x 10(-4) rem mCi(-1) h(-1)). When corrected for the difference between measured surface dose equivalent and whole body dose equivalent as determined by Monte Carlo analysis, these measurements represent a whole body dose equivalent per unit cumulated activity of about 6.2 x 10(-9) mSv MBq(-1) s(-1) (8.1 x 10(-5) rem mCi(-1) h(-1)). Based on these results, the current NRC dose-based methodology for the release of patients administered radioactive materials significantly overestimates the dose equivalent to others from 131I therapy patients.

Revised Nuclear Regulatory Commission regulations for release of patients administered radioactive materials: outpatient iodine-131 anti-B1 therapy.

UNLABELLED: The Nuclear Regulatory Commission regulations for the release of patients administered radioactive material have been revised to include dose-based or activity-based criteria. METHODS: The revised 10 CFR 35.75 regulations and the formula that can be used to determine when an individual patient administered radioactivity is releasable are reviewed. The implications of these new regulations on patient release after 131I anti-B1 therapy for the treatment of non-Hodgkin's lymphoma are also discussed. RESULTS: A licensee may now release patients if the total effective dose equivalent to another individual from exposure to a released patient is <500 mrem. Compliance with this dose limit is demonstrated by licensees either by using a default table for activity or dose rate provided in Regulatory Guide 8.39 or by performing a patient-specific dose calculation. Licensees may also demonstrate compliance by basing patient release on the patient-specific measured dose rate at 1 m instead of administered activity. Data on more than 50 patients receiving 131I anti-B1 therapy, an investigational therapy for non-Hodgkin's lymphoma, indicate that all patients would have been releasable under the new regulations. CONCLUSION: The new regulations will permit 131I anti-B1 therapy to be conducted on an outpatient basis.

Nonmyeloablative iodine-131 anti-B1 radioimmunotherapy as outpatient therapy.

UNLABELLED: The expected effective dose equivalent to an individual from contact with 131I anti-B1 radioimmunotherapy (RIT) patients released immediately after therapeutic infusion was estimated. METHODS: Effective dose equivalents were calculated retrospectively using data acquired on 46 patients treated with 1311 anti-B1 RIT as inpatients. Effective dose equivalents to members of the public were estimated using the method published in the Nuclear Regulatory Commission (NRC) Regulatory Guide 8.39, assuming the administered activity, the patient-specific effective half-life, the 0.25 occupancy factor, and no photon attenuation. Effective dose equivalents also were estimated using ionization chamber dose rates, measured immediately after therapeutic infusion and integrated to total decay based on the measured effective half-life. RESULTS: For the whole-body treatment absorbed dose limit of 75 cGy (75 rad), the administered 131I activity ranged from 2.1 to 6.5 GBq (56 to 175 mCi), and the measured dose rate at 1 m ranged from 70 to 190 microSv/hr (7 to 19 mrem/hr). The total-body effective half-life for these patients ranged from approximately 40 to 88 hr. Using the NRC method and not accounting for the attenuation of photons, the mean dose equivalent to the public exposed to an 131I anti-B1 patient discharged without hospitalization was 4.9 +/- 0.9 mSv (490 +/- 90 mrem). The range was 3.2-6.6 mSv (320 to 660 mrem), where 48% of patients would deliver a dose to another individual that is <5 mSv (500 mrem) (i.e., 48% of the patients would be allowed to return home immediately following the infusion). Using the measured dose rate method, the mean dose equivalent to an individual exposed to the same RIT patients was 2.9 +/- 0.4 mSv (290 +/- 40 mrem). The range was 2.0-3.7 mSv (200-370 mrem), where 100% of the estimated effective dose equivalents were <5 mSv (500 mrem). CONCLUSION: Based on calculated and patient-specific exposure data, outpatient RIT with nonmyeloablative doses of 131I should be feasible for all patients under current NRC regulations. Implementing outpatient RIT should make the therapy more widely available and more convenient and should lower patient care costs without exceeding accepted limits for public exposure to radiation.

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.

Overcoming the nephrotoxicity of radiometal-labeled immunoconjugates: improved cancer therapy administered to a nude mouse model in relation to the internal radiation dosimetry.

BACKGROUND: Elevated renal uptake and extended retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. However, cationic amino acids have been shown to reduce renal accretion. The aims of the current study were to evaluate whether this methodology would benefit therapy with yttrium 90 (90Y)-labeled antibody fragments (Fab, F(ab)2), to establish the relationship between radiation dosimetry and observed biologic effects, and to compare the antitumor efficacy of antibody fragments with that of whole immunoglobulin (Ig)G. METHODS: The maximum tolerated dose (MTD) and the dose-limiting organ toxicity of 90Y-labeled anti-carcinoembryonic antigen (CEA) MN-14 monoclonal antibodies (Fab, F(ab)2, and IgG) were determined in nude mice bearing GW-39 human colon carcinoma xenografts. The mice were treated with or without kidney protection by administration of D-lysine, with or without bone marrow transplantation (BMT), or with combinations of each. Toxicity and tumor growth were monitored at weekly intervals after radioimmunotherapy. Dosimetry was calculated from biodistribution studies using 88Y-labeled antibody. Three different dosimetric models were examined: 1) taking solely self-to-self doses into account, using S factors for 90Y in spheroids from 0.1 to 1 g; 2) correcting for cross-organ radiation; and 3) using actual mouse anatomy as represented by nuclear magnetic resonance imaging with a three-dimensional internal dosimetry package (3D-ID). RESULTS: The kidney was the first dose-limiting organ with the use of Fab fragments. Acute radiation nephritis occurred at injected activities > or = 325 microCi, and chronic nephrosis at doses > or = 250 microCi. Activities of 200 microCi were tolerated by 100% of the animals (i.e., the MTD). Application of lysine decreased the renal dose by approximately fivefold, facilitating a 25% increase in the MTD (to 250 microCi), because myelotoxicity became dose-limiting despite red marrow doses of less than 5 gray (Gy). By using BMT and lysine, the MTD could be doubled from 200 to 400 microCi, where no biochemical or histologic evidence of renal damage was observed (kidney dose, < or = 40 Gy). With injected activities of > or = 325 microCi without kidney protection, and with a hepatic self-to-self dose of only 4 Gy, rising liver enzymes were observed, which could be explained only by cross-organ radiation from radioactivity in the kidneys (in the immediate neighborhood of the right kidney up to > or = 150 Gy). The MTD of F(ab)2 fragments could be elevated only by a combination of BMT and lysine. With IgG, the bone marrow alone was dose-limiting. Tumor dosimetry correlated well with antitumor effects; Fab was more effective than F(ab)2, which was consistent with its more favorable dosimetry, and it may also be more effective than IgG due to its higher dose rate and more homogenous distribution. Dosimetry Model 1 was insufficient for predicting biologic effects. Model 2 seemed to be more accurate, accounting for interorgan crossfire. However, Model 3 showed an additional substantial contribution to the red bone marrow dose due to crossfire from the abdominal organs. CONCLUSIONS: These data show that radiation nephrotoxicity is an important effect of cancer therapy with radiometal-conjugated antibody fragments or peptides. However, this effect can be overcome successfully with the application of cationic amino acids, which substantially increase the anti-tumor efficacy of radiometal-labeled immunoconjugates. For understanding the biologic effects (e.g., liver toxicity) of 90Y in a mouse model, accounting for cross-organ radiation is essential. Further studies with radiometal-conjugated monoclonal antibody fragments and peptides are necessary to determine the MTD, dose-limiting organs, antitumor effectiveness, and nephroprotective effects of cationic amino acids in humans.

Medical management of coronary artery disease revisited: the endothelial factor.

Coronary artery disease mortality can be reduced by aggressive lipid lowering. The reduction in cardiovascular events observed in the recent major lipid lowering trials is dramatically better than that seen in the classic studies of medically or surgically managed CAD from the 1970s. One postulated mechanism for this improvement is restoration of normal endothelial function through cholesterol lowering. By restoring endothelial dependent vasodilation, cardiovascular events and ischemia can be reduced. PTCA has variable effects on endothelial function. Lipid lowering is beneficial in combination with invasive CAD interventions. The appropriate management of coronary artery disease should consider the advance in medically managed outcomes provided by HMG CoA reductase inhibitors (statins).

Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG.

UNLABELLED: The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.