Evaluation of an 131I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers.

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[131I]iodobenzoate (iso-[131I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [131I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[131I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[131I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc2-iso-[131I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[131I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[131I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted.

A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance.

In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration.

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine.

BACKGROUND: Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation. OBJECTIVE: The purpose of this study was to synthesize and characterize a novel 18F labeled leucine analog, 5-[18F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET. METHODS: 5-fluoroleucine was synthesized and characterized, and its 18F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3H- or 14C-labeled L-leucine and other essential amino acids. Both L-leucine and 5- [18F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18F]fluoroleucine tumor uptake. RESULTS: Breast cancer cell lines showed increasing high net accumulation of L-[14C]leucine. Both L-leucine and 5-[18F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5- [18F]fluoroleucine in the tumor, which progressively increased over time. CONCLUSION: 5-[18F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

Lifetime Attributable Risk of Cancer From Radiation Exposure During Parathyroid Imaging: Comparison of 4D CT and Parathyroid Scintigraphy.

OBJECTIVE: The purpose of this study is to measure the organ doses and effective dose (ED) for parathyroid 4D CT and scintigraphy and to estimate the lifetime attributable risk of cancer incidence associated with imaging. MATERIALS AND METHODS: Organ radiation doses for 4D CT and scintigraphy were measured on the basis of imaging with our institution's protocols. An anthropomorphic phantom with metal oxide semiconductor field effect transistor detectors was scanned to measure CT organ dose. Organ doses from the radionuclide were based on International Commission for Radiological Protection report 80. ED was calculated for 4D CT and scintigraphy and was used to estimate the lifetime attributable risk of cancer incidence for patients differing in age and sex with the approach established by the Biologic Effects of Ionizing Radiation VII report. A 55-year-old woman was selected as the standard patient according to the demographics of patients with primary hyperparathyroidism. RESULTS: Organs receiving the highest radiation dose from 4D CT were the thyroid (150.6 mGy) and salivary glands (137.8 mGy). For scintigraphy, the highest organ doses were to the colon (41.5 mGy), gallbladder (39.8 mGy), and kidneys (32.3 mGy). The ED was 28 mSv for 4D CT, compared with 12 mSv for scintigraphy. In the exposed standard patient, the lifetime attributable risk for cancer incidence was 193 cancers/100,000 patients for 4D CT and 68 cancers/100,000 patients for scintigraphy. Given a baseline lifetime incidence of cancer of 46,300 cancers/100,000 patients, imaging results in an increase in lifetime incidence of cancer over baseline of 0.52% for 4D CT and 0.19% for scintigraphy. CONCLUSION: The ED of 4D CT is more than double that of scintigraphy, but both studies cause negligible increases in lifetime risk of cancer. Clinicians should not allow concern for radiation-induced cancer to influence decisions regarding workup in older patients.

Cumulative radiation exposure and cancer risk estimation in children with heart disease.

BACKGROUND: Children with heart disease are frequently exposed to imaging examinations that use ionizing radiation. Although radiation exposure is potentially carcinogenic, there are limited data on cumulative exposure and the associated cancer risk. We evaluated the cumulative effective dose of radiation from all radiation examinations to estimate the lifetime attributable risk of cancer in children with heart disease. METHODS AND RESULTS: Children ≤6 years of age who had previously undergone 1 of 7 primary surgical procedures for heart disease at a single institution between 2005 and 2010 were eligible for the study. Exposure to radiation-producing examinations was tabulated, and cumulative effective dose was calculated in millisieverts. These data were used to estimate lifetime attributable risk of cancer above baseline using the approach of the Committee on Biological Effects of Ionizing Radiation VII. The cohort included 337 children exposed to 13 932 radiation examinations. Conventional radiographs represented 92% of examinations, whereas cardiac catheterization and computed tomography accounted for 81% of cumulative exposure. Overall median cumulative effective dose was 2.7 mSv (range, 0.1-76.9 mSv), and the associated lifetime attributable risk of cancer was 0.07% (range, 0.001%-6.5%). Median lifetime attributable risk of cancer ranged widely depending on surgical complexity (0.006%-1.6% for the 7 surgical cohorts) and was twice as high in females per unit exposure (0.04% versus 0.02% per 1-mSv effective dose for females versus males, respectively; P<0.001). CONCLUSIONS: Overall radiation exposures in children with heart disease are relatively low; however, select cohorts receive significant exposure. Cancer risk estimation highlights the need to limit radiation dose, particularly for high-exposure modalities.

Informed consent in human research: what to say and how to say it.

To ensure that the possibility of harm to human research subjects is minimized, clinical trials and other research protocols are subject to oversight by Institutional Review Boards (IRBs). IRBs require that subjects be fully informed about the real or potential risks of participation in a research study. The use of radiological examinations in research protocols subjects the participants to exposure to ionizing radiation, which in theory carries a risk of stochastic effects such as radiation-induced cancer, and in practice may lead to deterministic effects such as skin injury. Because IRB members and clinical study coordinators may have little knowledge of radiation effects or how best to communicate the risk to the research subjects, they will consult with institutional Radiation Safety Committees and radiation protection professionals regarding how to integrate radiation risk information into the informed consent process. Elements of radiation informed consent include: (1) comparison of the radiation dose to some benchmark that enables the study subjects to make a value judgment regarding the acceptability of the risk; (2) a quantitative expression of the absolute risk of stochastic effects; (3) an expression of uncertainty in the risk; and (4) understandability. Standardized risk statement templates may be created for specific radiological examinations. These standardized risk statements may be deployed as paper forms or electronically in the form of internet-based applications. The technical nature of creating useful radiation risk statements represents an opportunity for radiation protection professionals to participate productively in the clinical research process.

Comparison of current and past surgical smoke control practices.

In 2010, we teamed with AORN to repeat a simple web-based survey on surgical smoke control practices first conducted in 2007. This survey of AORN members assessed the level of compliance with established surgical smoke control measures (ie, use of wall suction with an in-line particulate filter, use of a smoke evacuator, use of an N95 or other National Institute for Occupational Safety and Health-approved respirator) in various medical specialties and facilities throughout North America, as well as the extent to which compliance rates may have changed since 2007. Survey responses indicate that while the use of wall suction as a control measure has increased for nearly all procedures, progress in the adoption of other control measures has been mixed, with improvement for some procedures, no change for most procedures, and a decrease in compliance for a few procedures.

Results of a survey on current surgical smoke control practices.

Researchers at Duke University Medical Center, Durham, NC, conducted a simple, web-based survey of AORN members to evaluate surgical smoke control practices. Survey respondents from various medical specialties and facilities throughout North America indicated their facilities' level of compliance with established surgical smoke control measures. Survey results indicate that many facilities have not implemented best practices for protecting patients and health care workers from surgical smoke hazards, especially smoke created during electrosurgical, electrocautery, and diathermy procedures.

Radiation dose from contemporary cardiothoracic multidetector CT protocols with an anthropomorphic female phantom: implications for cancer induction.

PURPOSE: To measure prospectively and directly both organ dose and effective dose (ED) for adult cardiac and pulmonary computed tomographic (CT) angiography by using current clinical protocols for 64-detector CT in an anthropomorphic female phantom and to estimate lifetime attributable risk of breast and lung cancer incidence on the basis of measured ED and organ dose. MATERIALS AND METHODS: Cardiac and pulmonary 64-detector CT angiography was performed by using current clinical protocols to evaluate the pulmonary veins (electrocardiographically [ECG] gated, 64 sections at 0.625-mm collimation, 120 kVp, 300 mA, 0.35-second tube rotation), native coronary arteries (ECG gated; 64 sections at 0.625 mm; 120 kVp; maximum current, 500-750 mA; minimum, 100-350 mA; 0.35-second tube rotation) and pulmonary embolus (64 sections at 1.25 mm, 140 kVp, 645 mA, 0.5-second tube rotation). Absorbed organ doses were measured by using an anthropomorphic female phantom and metal oxide semiconductor field effect transistor detectors. ED was calculated from measured organ doses and the dose-length product. RESULTS: ED for current adult cardiac and pulmonary 64-detector CT angiography protocols were 12.4-31.8 mSv. Overall, skin, breast, and esophagus and heart had the highest recorded absorbed organ doses. Relative risk for breast cancer incidence for girls and women was 1.004-1.042 for a single examination. Relative risk for lung cancer incidence for men and women was 1.005-1.076 from a single examination. CONCLUSION: EDs and organ doses from 64-detector CT are higher than those previously reported for adult cardiac and pulmonary CT angiography protocols. Risk for breast and lung cancer induction from these studies is greatest for the younger patient population.

Radiation dose to the female breast from 16-MDCT body protocols.

OBJECTIVE: The objective of our study was to determine the radiation dose to the female breast from current 16-MDCT body examinations. MATERIALS AND METHODS: Metal oxide semiconductor field effect transistor (MOSFET) detectors were placed in four quadrants of the breast of a female-configured anthropomorphic phantom to determine radiation dose to the breast. Imaging was performed on a 16-MDCT scanner (LightSpeed, GE Healthcare) using current clinical protocols designed to assess pulmonary embolus (PE) (140 kVp, 380 mA, 0.8-sec rotation, 16 x 1.25 mm collimation), appendicitis (140 kVp, 340 mA, 0.5-sec rotation, 16 x 0.625 mm collimation), and renal calculus (140 kVp, 160 mA, 0.5-sec rotation, 16 x 0.625 mm collimation). RESULTS: Radiation dose to the breast ranged from 4 to 6 cGy for the PE protocol and up to 1-2 cGy in the inferior aspect of the right breast and lateral aspect of the left breast for the appendicitis protocol. The renal calculus protocol yielded less than 150 microGy absorbed breast dose. CONCLUSION: Current clinical chest and abdomen protocols result in vairable radiation doses to the breast. The magnitude of exposure may have implications for imaging strategies.

Radiation dose to the fetus from body MDCT during early gestation.

OBJECTIVE: The purpose of our study was to determine radiation dose to the fetus at early gestation when contemporary MDCT scanners are used for common clinical indications. MATERIALS AND METHODS: Anthropomorphic phantoms were constructed to reflect a pregnant woman. Thermoluminescence dosimeters (TLDs) and metal oxide semiconductor field effect transistor (MOSFET) detectors were placed in appropriate locations to determine real-time radiation exposure to the fetus at 0 and 3 months' gestation. Imaging was performed on a 16-MDCT scanner using current institutional CT protocols: renal stone (140 kVp, 160 mA, rotation time of 0.5 sec, 16 x 0.625 mm), appendix (140 kVp, 340 mA, rotation time of 0.5 sec, 16 x 0.625 mm), and pulmonary embolus (140 kVp, 380 mA, rotation time of 0.8 sec, 16 x 1.25 mm). RESULTS: The radiation dose to the fetus at 0 and 3 months, respectively, was as follows: renal stone protocol, 0.8-1.2 and 0.4-0.7 cGy; appendix protocol, 1.52-1.68 and 2-4 cGy; and pulmonary embolus protocol, 0.024-0.047 and 0.061-0.066 cGy. CONCLUSION: Radiation doses to the fetus from institutional MDCT protocols that may be used during pregnancy (for pulmonary embolus, appendicitis, and renal colic) are below the level thought to induce neurologic detriment to the fetus. Imaging the mother for appendicitis theoretically may double the fetal risk for developing a childhood cancer. Radiation doses to the fetus from pulmonary embolus chest CT angiography are of the same magnitude as ventilation-perfusion (V/Q) scanning.

Pharmacokinetics and radiation dosimetry of 18F-fluorocholine.

UNLABELLED: 18F-Fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) has been developed as an oncologic probe for PET. This study evaluates the kinetics and radiation dosimetry of 18F-FCH using murine and human biodistribution data. METHODS: The biodistribution of 18F-FCH was obtained at time points up to 10 h after administration in control and tumor-bearing anesthetized nude mice. Human biodistribution data within the first hour after injection were obtained from attenuation-corrected whole-body PET scans of male (n = 7) and female (n = 5) cancer patients. Radiation dosimetry estimates were calculated using the murine and human biodistribution data assuming no redistribution of tracer after 1 h. RESULTS: Rapid pharmacokinetics were observed for 18F-FCH in mice and humans. The biodistribution is nearly static after 10 min. The dose-critical organ is the kidney, which receives 0.17 +/- 0.05 and 0.16 +/- 0.07 mSv/MBq (0.64 +/- 0.18 and 0.55 +/- 0.32 rad/mCi) for females and males, respectively. The effective dose equivalent (whole body) from administration of 4.07 MBq/kg (0.110 mCi/kg) is approximately 0.01 Sv for females and males. CONCLUSION: 18F-FCH is rapidly cleared from the circulation and its biodistribution changes very slowly at >10 min after administration. The kidney is the dose-critical organ and limits administration levels of 18F-FCH to 4.07 MBq/kg (0.110 mCi/kg) in human research studies.