Use of approved Lu-177 radiopharmaceuticals in patients with end-stage renal disease: A review of the literature and proposed treatment algorithm.

Peptide receptor radionuclide therapy (PRRT) can be a very useful treatment for patients with neuroendocrine neoplasms and metastatic castration-resistant prostate cancer but it is routinely avoided in those with advanced kidney disease because it can adversely affect the renal function. Accordingly, no clear guidelines exist on the use of PRRT for patients on hemodialysis (HD). We performed a literature review to identify publications on HD patients who received PRRT with Lutetium-177 (Lu177) Dotatate and Y-90 and obtained information on Lu177 pharmacokinetics and early testing data from the manufacturer. We also perused the most recent North American Neuroendocrine Tumor Society (NANETS)/European Neuroendocrine Tumor Society (ENETS) recommendations. Seven relevant publications with a total of 15 patients were included. Patients received dose-adjusted fractions of PRRT with HD occurring usually within 24 h. There were no immediate or long-term serious adverse events attributed to the radioligand, although data was limited. Using available evidence and input from a multidisciplinary group, we have created an institutional workflow. Dose-adjusted PRRT can be offered to patients undergoing HD under careful, multidisciplinary supervision.

Handling Patient Emergencies During Radiopharmaceutical Therapy.

PURPOSE: Radiopharmaceutical therapy (RPT) is a rapidly growing treatment modality. Though uncommon, patients may experience complications during their RPT treatment, which may trigger a rapid response from the hospital team. However, members of this team are typically not familiar with precautions for radiation safety. During these events, it is important to prioritize the patient's health over all else. There are some practices that can help minimize the risk of radiation contamination spread and exposure to staff while tending to the patient. METHODS AND MATERIALS: We formed a team to develop a standard protocol for handling patient emergencies during RPT treatment. This team consisted of an authorized user, radiation safety officer, medical physicist, nurse, RPT administration staff, and a quality/safety coordinator. The focus for developing this standardized protocol for RPT patient emergencies was 3-fold: (1) stabilize the patient; (2) reduce radiation exposure to staff; and (3) limit the spread of radiation contamination. RESULTS: We modified our hospital's existing rapid response protocol to account for the additional staff and tasks needed to accomplish all 3 of these goals. Each team member was assigned specific responsibilities, which include serving as a gatekeeper to restrict traffic, managing the crash cart, performing chest compressions, timing chest compressions, documenting the situation, and monitoring/managing radiation safety in the area. We developed a small, easy-to-read card for rapid response staff to read while they are en route to the area so they can be aware of and prepare for the unique circumstances that RPT treatments present. CONCLUSIONS: Though rapid response events with RPT patients are uncommon, it is important to have a standardized protocol for how to handle these situations beforehand rather than improvise in the moment. We have provided an example of how our team adapted our hospital's current rapid response protocol to accommodate RPT patients.

Logistical, technical, and radiation safety aspects of establishing a radiopharmaceutical therapy program: A case in Lutetium-177 prostate-specific membrane antigen (PSMA) therapy.

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, we describe logistical, technical, and radiation safety considerations for implementing a radiopharmaceutical therapy program, with particular focus on the development of operating procedures for therapeutic administrations. Major steps for a center in the U.S. to implement a new radiopharmaceutical therapy (RPT) program are listed below, and then demonstrated in greater detail via examples for Lu-177-PSMA-617 therapy.

Failure modes and effects analysis of pediatric I-131 MIBG therapy: Program design and potential pitfalls.

BACKGROUND: There is growing interest among pediatric institutions for implementing iodine-131 (I-131) meta-iodobenzylguanidine (MIBG) therapy for treating children with high-risk neuroblastoma. Due to regulations on the medical use of radioactive material (RAM), and the complexity and safety risks associated with the procedure, a multidisciplinary team involving radiation therapy/safety experts is required. Here, we describe methods for implementing pediatric I-131 MIBG therapy and evaluate our program's robustness via failure modes and effects analysis (FMEA). METHODS: We formed a multidisciplinary team, involving pediatric oncology, radiation oncology, and radiation safety staff. To evaluate the robustness of the therapy workflow and quantitatively assess potential safety risks, an FMEA was performed. Failure modes were scored (1-10) for their risk of occurrence (O), severity (S), and being undetected (D). Risk priority number (RPN) was calculated from a product of these scores and used to identify high-risk failure modes. RESULTS: A total of 176 failure modes were identified and scored. The majority (94%) of failure modes scored low (RPN <100). The highest risk failure modes were related to training and to drug-infusion procedures, with the highest S scores being (a) caregivers did not understand radiation safety training (O = 5.5, S = 7, D = 5.5, RPN = 212); (b) infusion training of staff was inadequate (O = 5, S = 8, D = 5, RPN = 200); and (c) air in intravenous lines/not monitoring for air in lines (O = 4.5, S = 8, D = 5, RPN = 180). CONCLUSION: Through use of FMEA methodology, we successfully identified multiple potential points of failure that have allowed us to proactively mitigate risks when implementing a pediatric MIBG program.

Calibration and error analysis of metal-oxide-semiconductor field-effect transistor dosimeters for computed tomography radiation dosimetry.

PURPOSE: Metal-oxide-semiconductor field-effect transistors (MOSFETs) serve as a helpful tool for organ radiation dosimetry and their use has grown in computed tomography (CT). While different approaches have been used for MOSFET calibration, those using the commonly available 100 mm pencil ionization chamber have not incorporated measurements performed throughout its length, and moreover, no previous work has rigorously evaluated the multiple sources of error involved in MOSFET calibration. In this paper, we propose a new MOSFET calibration approach to translate MOSFET voltage measurements into absorbed dose from CT, based on serial measurements performed throughout the length of a 100-mm ionization chamber, and perform an analysis of the errors of MOSFET voltage measurements and four sources of error in calibration. METHODS: MOSFET calibration was performed at two sites, to determine single calibration factors for tube potentials of 80, 100, and 120 kVp, using a 100-mm-long pencil ion chamber and a cylindrical computed tomography dose index (CTDI) phantom of 32 cm diameter. The dose profile along the 100-mm ion chamber axis was sampled in 5 mm intervals by nine MOSFETs in the nine holes of the CTDI phantom. Variance of the absorbed dose was modeled as a sum of the MOSFET voltage measurement variance and the calibration factor variance, the latter being comprised of three main subcomponents: ionization chamber reading variance, MOSFET-to-MOSFET variation and a contribution related to the fact that the average calibration factor of a few MOSFETs was used as an estimate for the average value of all MOSFETs. MOSFET voltage measurement error was estimated based on sets of repeated measurements. The calibration factor overall voltage measurement error was calculated from the above analysis. RESULTS: Calibration factors determined were close to those reported in the literature and by the manufacturer (~3 mV/mGy), ranging from 2.87 to 3.13 mV/mGy. The error σV of a MOSFET voltage measurement was shown to be proportional to the square root of the voltage V: σV=cV where c = 0.11 mV. A main contributor to the error in the calibration factor was the ionization chamber reading error with 5% error. The usage of a single calibration factor for all MOSFETs introduced an additional error of about 5-7%, depending on the number of MOSFETs that were used to determine the single calibration factor. The expected overall error in a high-dose region (~30 mGy) was estimated to be about 8%, compared to 6% when an individual MOSFET calibration was performed. For a low-dose region (~3 mGy), these values were 13% and 12%. CONCLUSIONS: A MOSFET calibration method was developed using a 100-mm pencil ion chamber and a CTDI phantom, accompanied by an absorbed dose error analysis reflecting multiple sources of measurement error. When using a single calibration factor, per tube potential, for different MOSFETs, only a small error was introduced into absorbed dose determinations, thus supporting the use of a single calibration factor for experiments involving many MOSFETs, such as those required to accurately estimate radiation effective dose.

Estimating Effective Dose of Radiation From Pediatric Cardiac CT Angiography Using a 64-MDCT Scanner: New Conversion Factors Relating Dose-Length Product to Effective Dose.

OBJECTIVE: The purpose of this study is to determine the conversion factors that enable accurate estimation of the effective dose (ED) used for cardiac 64-MDCT angiography performed for children. MATERIALS AND METHODS: Anthropomorphic phantoms representative of 1- and 10-year-old children, with 50 metal oxide semiconductor field-effect transistor dosimeters placed in organs, underwent scanning performed using a 64-MDCT scanner with different routine clinical cardiac scan modes and x-ray tube potentials. Organ doses were used to calculate the ED on the basis of weighting factors published in 1991 in International Commission on Radiological Protection (ICRP) publication 60 and in 2007 in ICRP publication 103. The EDs and the scanner-reported dose-length products were used to determine conversion factors for each scan mode. The effect of infant heart rate on the ED and the conversion factors was also assessed. RESULTS: The mean conversion factors calculated using the current definition of ED that appeared in ICRP publication 103 were as follows: 0.099 mSv · mGy-1 · cm-1, for the 1-year-old phantom, and 0.049 mSv · mGy-1 · cm-1, for the 10-year-old phantom. These conversion factors were a mean of 37% higher than the corresponding conversion factors calculated using the older definition of ED that appeared in ICRP publication 60. Varying the heart rate did not influence the ED or the conversion factors. CONCLUSION: Conversion factors determined using the definition of ED in ICRP publication 103 and cardiac, rather than chest, scan coverage suggest that the radiation doses that children receive from cardiac CT performed using a contemporary 64-MDCT scanner are higher than the radiation doses previously reported when older chest conversion factors were used. Additional up-to-date pediatric cardiac CT conversion factors are required for use with other contemporary CT scanners and patients of different age ranges.

Medical imaging radiation safety for the female patient: rationale and implementation.

For the modern practitioner of women's imaging, achieving a balance between the positive diagnostic benefits available from current medical imaging on the one hand, and the potentially deleterious effects of ionizing radiation exposure on the other, has become a central issue. Increased public and professional awareness of the side effects of radiation now require a comprehensive understanding of the facts involved, the various risks to which patients are exposed, and the measures that can be implemented to minimize these risks. The major challenges posed by pregnancy, radiosensitive breast tissue, lactation, and an inability to easily exclude ovaries from the imaging field make female patients particularly vulnerable to medical imaging radiation exposure. The nature of this vulnerability changes frequently and depends on the imaging being performed, the age of the patient, and the clinical situation. For this reason, attention to gynecologic imaging radiation exposure across the whole life span is vitally important.

Quantitative CT: technique dependence of volume estimation on pulmonary nodules.

Current estimation of lung nodule size typically relies on uni- or bi-dimensional techniques. While new three-dimensional volume estimation techniques using MDCT have improved size estimation of nodules with irregular shapes, the effect of acquisition and reconstruction parameters on accuracy (bias) and precision (variance) of the new techniques has not been fully investigated. To characterize the volume estimation performance dependence on these parameters, an anthropomorphic chest phantom containing synthetic nodules was scanned and reconstructed with protocols across various acquisition and reconstruction parameters. Nodule volumes were estimated by a clinical lung analysis software package, LungVCAR. Precision and accuracy of the volume assessment were calculated across the nodules and compared between protocols via a generalized estimating equation analysis. Results showed that the precision and accuracy of nodule volume quantifications were dependent on slice thickness, with different dependences for different nodule characteristics. Other parameters including kVp, pitch, and reconstruction kernel had lower impact. Determining these technique dependences enables better volume quantification via protocol optimization and highlights the importance of consistent imaging parameters in sequential examinations.

Micro-CT dilatometry measures of molecular collagen hydration using bovine extensor tendon.

PURPOSE: This article introduces a new method to study macromolecular hydration using micro-CT dilatometry. The complexity of hydration dependence on solvent temperature, pH, ionic charge, ionic activity, and ionic radii are barriers to comprehensive understanding of protein function. The crystalline character of collagen-tendon suggests that tendon dilatometry may give direct access to measures of molecular tropocollagen solvation response. METHODS: The molecular basis of the stoichiometric hydration model (SHM) provides tools to validate bovine tendon as a model to study protein-solvent shape response by micro-CT measures of tendon diameter, length, and mass during dehydration. The SHM relates macroscopic properties to molecular properties of water interacting with the surface of collagen molecules. There are marked changes at critical SHM hydration levels h = 0.0653, 0.262, and 0.724 g water/g dry weight. RESULTS: Micro-CT analysis of the length, diameter, and volume combined with gravimetric measures of tendon mass as a function of hydration h (g water/g dry solid) shows asymmetric changes in length, diameter, and density as predicted by SHM. The collagen molecules perturb water properties of polar hydration N=11 waters per tripeptide unit or h approximately 0.724 g/g to confirm MDS prediction of elevated hydration density 20%-50% higher than bulk water. CONCLUSIONS: Results validate the use of tendon dilatometry amplification factors of 10(6)-10(8) as an effective model to investigate protein molecule shape change response to solvent molecules. The tendon model for the first time allows direct study of protein hydration and functional response under physiological conditions.

First-pass contrast-enhanced myocardial perfusion MRI using a maximum up-slope parametric map.

Magnetic resonance first-pass perfusion imaging offers a noninvasive method for the rapid, accurate, and reproducible assessment of cardiac function without ionizing radiation. Quantitative or semiquantitative analysis of changes in signal intensity (SI) over the whole image sequence yields a more efficient analysis than direct visual inspection. In this paper, a method to generate maximum up-slope myocardial perfusion maps is presented. The maximum up-slope is defined by comparison of the SI variations using frame-to-frame analysis. A map of first-pass transit of the contrast agent is constructed pixel by pixel using a linear curve fitting model. The proposed method was evaluated using data from eight subjects. The data from the parametric maps agreed well with those obtained from traditional, manually derived region-of-interest methods as shown through ANOVA. The straightforward implementation and increase in image analysis efficiency resulting from this method suggests that it may be useful for clinical practice.

Evidence that collagen and tendon have monolayer water coverage in the native state.

This paper investigates an alternative explanation for widely reported paradoxical intracellular water properties. The most frequent biological explanation assumes water structure extending multiple layers from surfaces of compactly folded macromolecules to explain large amounts of perturbed water. Long range water structuring, however, contradicts molecular models widely accepted by the scientific majority. This study questions whether the paradoxical cell water could result from larger than expected amounts of first layer interfacial water on internal protein surfaces rather than structured multilayers. Native mammalian tendon is selected for the study because (1) the organ consists of highly compact structures of a single macromolecular protein--collagen, (2) molecular structure and geometry of collagen is well characterized by X-ray diffraction, (3) molecular structure extends to the macroscopic tendon level and (4) perturbed water behavior similar to cellular water is reported on tendon. Native tendon holds 1.6 g water/g dry mass. The 62% native water content simulates the water content of many cell types. MicroCT studies of tendon dilatometry as a function of hydration are measured and correlated to X-ray diffraction measurements of interaxial separation. Correlations show that native tendon has sufficient water for only a single monolayer of interfacial water. Thus the paradoxical properties of water in native tendon are first-layer interfacial water properties. Similar water behavior on globular proteins suggests that paradoxical cell water behavior could be caused by larger than expected amounts of first layer interfacial water on internal and external macromolecular surfaces of cell components.

An NMR method to characterize multiple water compartments on mammalian collagen.

A molecular model is proposed to explain water 1H NMR spin-lattice relaxation at different levels of hydration (NMR titration method) on collagen. A fast proton exchange model is used to identify and characterize protein hydration compartments at three distinct Gibbs free energy levels. The NMR titration method reveals a spectrum of water motions with three well-separated peaks in addition to bulk water that can be uniquely characterized by sequential dehydration. Categorical changes in water motion occur at critical hydration levels h (g water/g collagen) defined by integral multiples N = 1, 4 and 24 times the fundamental hydration value of one water bridge per every three amino acid residues as originally proposed by Ramachandran in 1968. Changes occur at (1) the Ramachandran single water bridge between a positive amide and negative carbonyl group at h1 = 0.0658 g/g, (2) the Berendsen single water chain per cleft at h2 = 0.264 g/g, and (3) full monolayer coverage with six water chains per cleft level at h3 = 1.584 g/g. The NMR titration method is verified by comparison of measured NMR relaxation compartments with molecular hydration compartments predicted from models of collagen structure. NMR titration studies of globular proteins using the hydration model may provide unique insight into the critical contributions of hydration to protein folding.