Leveraging Programmatic Collaboration for a Radiopharmaceutical Clinic.

Radiation oncologists, radiopharmacists, nuclear medicine physicians, and medical oncologists have seen a renewed clinical interest in radiopharmaceuticals for the curative or the palliative treatment of cancer. To allow for the discovery and the clinical advancement of targeted radiopharmaceuticals, these stakeholders have reformed their trial efforts and remodeled their facilities to accommodate the obligations of a program centered upon radioactive investigational drug products. Now considered informally as drugs and not beam radiotherapy, radiopharmaceuticals can be more easily studied in the traditional clinical trial enterprise ranging from phase 0-I to phase III studies. Resources and physical facilities allocated to radiopharmaceuticals have brought forth new logistics and patient experience for safe and satisfactory drug delivery. The clinical use of theranostic agents-that is, diagnostic and therapeutic radionuclide pairs-has accelerated radiopharmaceutical development.

PET/CT Biomarkers Enable Risk Stratification of Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma Enrolled in the LOTIS-2 Clinical Trial.

PURPOSE: Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell therapy without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT biomarkers in patients treated with loncastuximab tesirine. EXPERIMENTAL DESIGN: We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutoff points. RESULTS: Across 138 patients included in this study, MTV with a cutoff point of 96 mL was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (OR, 5.42; P = 0.002), progression-free survival (HR, 2.68; P = 0.002), and overall survival (HR, 3.09; P < 0.0001). IMPI demonstrated an appropriate performance, however, not better than MTV alone. CONCLUSIONS: Pretreatment MTV demonstrated robust risk stratification, with those patients demonstrating high MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.

The Utility of PET/CT for the Diagnosis of Periosteal Chondrosarcoma in a Patient With Maffucci's Syndrome.

Maffucci's syndrome is a rare congenital nonhereditary syndrome with less than 300 cases having been reported in the United States. It is characterized by multiple enchondromas, hemangiomas, and rarely lymphangiomas. Enchondromas may undergo malignant transformation to chondrosarcomas. Surveillance plays a vital role in detecting early malignant transformation. Fluorodeoxyglucose (FDG) PET/CT, although falling out of favor, may be utilized as an imaging modality by physicians to determine such transformation, allowing for timely management and intervention. In this report, we share our experience with such a case.

Quantitative PET-based biomarkers in lymphoma: getting ready for primetime.

The use of functional quantitative biomarkers extracted from routine PET-CT scans to characterize clinical responses in patients with lymphoma is gaining increased attention, and these biomarkers can outperform established clinical risk factors. Total metabolic tumour volume enables individualized estimation of survival outcomes in patients with lymphoma and has shown the potential to predict response to therapy suitable for  risk-adapted treatment approaches in clinical trials. The deployment of machine learning tools in molecular imaging research can assist in recognizing complex patterns and, with image classification, in tumour identification and segmentation of data from PET-CT scans. Initial studies using fully automated approaches to calculate metabolic tumour volume and other PET-based biomarkers have demonstrated appropriate correlation with calculations from experts, warranting further testing in large-scale studies. The extraction of computer-based quantitative tumour characterization through radiomics can provide a comprehensive view of phenotypic heterogeneity that better captures the molecular and functional features of the disease. Additionally, radiomics can be integrated with genomic data to provide more accurate prognostic information. Further improvements in PET-based biomarkers are imminent, although their incorporation into clinical decision-making currently has methodological shortcomings that need to be addressed with confirmatory prospective validation in selected patient populations. In this Review, we discuss the current knowledge, challenges and opportunities in the integration of quantitative PET-based biomarkers in clinical trials and the routine management of patients with lymphoma.

An Artificial Intelligence System for Optimizing Radioactive Iodine Therapy Dosimetry.

Thyroid cancer, specifically differentiated thyroid carcinoma (DTC), is one of the most prevalent endocrine malignancies worldwide. Radioactive iodine therapy (RAIT) using I-131 has been a standard-of-care approach for DTC due to its ability to ablate remnant thyroid disease following surgery, thus reducing the risk of recurrence. It is also used for the treatment of iodine-avid metastases. RAIT dosimetry can be employed to determine the optimal treatment dose of I-131 to effectively treat cancer cells while safeguarding against undesirable radiation effects such as bone marrow toxicity or radiation pneumonitis. Conventional dosimetry protocols for RAIT, however, are complex and time-consuming, involving multiple days of imaging and blood sampling. This study explores the use of Artificial Intelligence (AI) in simplifying and optimizing RAIT. A retrospective analysis was conducted on 83 adult patients with DTC who underwent RAIT dosimetry at our institution between 1996 and 2023. The conventional MIRD-based dosimetry protocol involved imaging and blood sampling at 4, 24, 48, 72, and 96 h post-administration of a tracer activity of I-131. An AI system based on a deep-learning neural network was developed to predict the maximum permissible activity (MPA) for RAIT using only the data obtained from the initial 4, 24, and 48 h time points. The AI system predicted the MPA values with high accuracy, showing no significant difference compared to the results obtained from conventional MIRD-based analysis utilizing a paired t-test (p = 0.351, 95% CI). The developed AI system offers the potential to streamline the dosimetry process, reducing the number of imaging and blood sampling sessions while also optimizing resource allocation. Additionally, the AI approach can uncover underlying relationships in data that were previously unknown. Our findings suggest that AI-based dosimetry may be a promising method for patient-specific treatment planning in differentiated thyroid carcinoma, representing a step towards applying precision medicine for thyroid cancer. Further validation and implementation studies are warranted to assess the clinical applicability of the AI system.

A Deep Learning-Aided Automated Method for Calculating Metabolic Tumor Volume in Diffuse Large B-Cell Lymphoma.

Metabolic tumor volume (MTV) is a robust prognostic biomarker in diffuse large B-cell lymphoma (DLBCL). The available semiautomatic software for calculating MTV requires manual input limiting its routine application in clinical research. Our objective was to develop a fully automated method (AM) for calculating MTV and to validate the method by comparing its results with those from two nuclear medicine (NM) readers. The automated method designed for this study employed a deep convolutional neural network to segment normal physiologic structures from the computed tomography (CT) scans that demonstrate intense avidity on positron emission tomography (PET) scans. The study cohort consisted of 100 patients with newly diagnosed DLBCL who were randomly selected from the Alliance/CALGB 50,303 (NCT00118209) trial. We observed high concordance in MTV calculations between the AM and readers with Pearson's correlation coefficients and interclass correlations comparing reader 1 to AM of 0.9814 (p < 0.0001) and 0.98 (p < 0.001; 95%CI = 0.96 to 0.99), respectively; and comparing reader 2 to AM of 0.9818 (p < 0.0001) and 0.98 (p < 0.0001; 95%CI = 0.96 to 0.99), respectively. The Bland-Altman plots showed only relatively small systematic errors between the proposed method and readers for both MTV and maximum standardized uptake value (SUVmax). This approach may possess the potential to integrate PET-based biomarkers in clinical trials.

Prognostic value of presalvage metabolic tumor volume in patients with relapsed/refractory diffuse large B-cell lymphoma.

Identification of new prognostic factors in relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) is essential for developing risk-adapted approaches. We retrospectively analyzed prognostication based on metabolic tumor volume (MTV) in rel/ref DLBCL (n = 108) before platinum-based salvage chemotherapy. Using 41% SUVmax threshold, patients achieving complete response (CR) exhibited significantly lower baseline values of MTV, compared to those achieving partial response (PR) or with progression of disease (medians MTV 16.26 versus 72.51 versus 98.11 ml, respectively). As a continuous variable, log2(MTV) was predictive of failure to achieve CR (1-unit increase odds ratio [OR] = 1.58, p < 0.001). Log2(MTV) significantly predicted progression-free survival (PFS) and overall survival (OS), and one-unit increase in log2(MTV) was associated with shorter PFS (hazard ratio [HR] = 1.12, p = 0.035) and OS (HR = 1.17, p = 0.007). However, heterogeneity in the selection of post-salvage chemotherapy approaches may have affected survival. These data demonstrate the ability of presalvage MTV to discriminate responders from non-responders to platinum-based chemotherapy and predict survival.

Lung shunt fraction calculation using 99mTc-MAA SPECT/CT imaging for 90Y microsphere selective internal radiation therapy of liver tumors.

BACKGROUND: 99mTc-macroaggregated albumin (99mTc-MAA) scintigraphy is utilized in treatment planning for Yttrium-90 (90Y) Selective Internal Radiation Therapy (SIRT) of liver tumors to evaluate hepatopulmonary shunting by calculating the lung shunt fraction (LSF). The purpose of this study was to evaluate if LSF calculation using SPECT/CT instead of planar gamma camera imaging is more accurate and if this can potentially lead to more effective treatment planning of hepatic lesions while avoiding excessive pulmonary irradiation. RESULTS: LSF calculation was obtained using two different methodologies in 85 cases from consecutive patients intended to receive 90Y SIRT. The first method was based on planar gamma camera imaging in the anterior and posterior views with geometric mean calculation of the LSF from regions of interest of the liver and lungs. The second method was based on segmentation of the liver and lungs from SPECT/CT images of the thorax and abdomen. The differences in planar imaging versus SPECT/CT derived LSF values along with the estimated absorbed lung mean dose (LMD) were evaluated. The LSF values were higher in planar imaging versus SPECT/CT in 81/85 cases, with a mean value of 8.5% vs. 4.6% respectively; the difference was statistically significant using a paired t-test (alpha = 0.05). In those patients who received SIRT, the estimated absorbed LMD calculated with planar imaging was significantly higher than with SPECT/CT (t-test, P < 0.005). Repeated phantom experiments using an anthropomorphic torso phantom with variable 99mTc activity concentrations for the liver and lungs were performed with the standard patient protocol, demonstrated improved accuracy of the LSF calculation based on SPECT/CT than planar imaging (mean overestimated value of 6% vs. 26%). CONCLUSIONS: This study demonstrates that LSF calculation using planar imaging can be significantly overestimated while calculation using SPECT/CT imaging and appropriate segmentation tools can be more accurate. Minimizing the errors in obtaining the LSF can lead to more effective 90Y SIRT treatment planning for hepatic tumors while ensuring the lung dose will not exceed the standard acceptable safety thresholds.

False Positive Findings on I-131 WBS and SPECT/CT in Patients with History of Thyroid Cancer: Case Series.

Introduction. Although whole body scan (WBS) with I-131 is a highly sensitive tool for detecting normal thyroid tissue and metastasis of differentiated thyroid cancer (DTC), it is not specific. Additional information, provided by single photon emission computed tomography combined with X-ray computed tomography (SPECT/CT) and by the serum thyroglobulin level, is extremely useful for the interpretation of findings. Case Presentation. We report four cases of false positive WBS in patients with DTC: ovarian uptake corresponding to an endometrioma, scrotal uptake due to a spermatocele, rib-cage uptake due to an old fracture, and hepatic and renal uptake secondary to a granuloma and simple cyst, respectively. Conclusions. Trapping, organification, and storage of iodine are more prominent in thyroid tissue but not specific. Physiologic sodium-iodine symporter expression in other tissues explains some, but not all, of the WBS false positive cases. Other proposed etiologies are accumulation of radioiodine in inflamed organs, metabolism of radiodinated thyroid hormone, presence of radioiodine in body fluids, and contamination. In our cases nonthyroidal pathologies were suspected since the imaging findings were not corroborated by an elevated thyroglobulin level, which is considered a reliable tumor marker for most well-differentiated thyroid cancers. Clinicians should be aware of the potential pitfalls of WBS in DTC to avoid incorrect management.

(124)I PET/CT in Patients with Differentiated Thyroid Cancer: Clinical and Quantitative Image Analysis.

BACKGROUND: Although radioactive iodine (RAI) imaging/therapy is one of the earliest applications of theranostics, there remain a number of unresolved clinical questions as to the optimization of diagnostic techniques/protocols and improvements in patient-specific treatment planning strategies. The objectives of this study were to determine the imaging characteristics and clinical feasibility of (124)I positron emission tomography/computed tomography (PET/CT) for the determination of extent of disease and evaluation of RAI kinetics in its physiologic and neoplastic distribution in patients with differentiated thyroid cancer (DTC). METHODS: The study was designed as a prospective phase II diagnostic trial of patients with confirmed DTC. Following adequate preparation, patients received 2 mCi (124)I in liquid form and sequential whole-body PET/CT imaging was performed at five time points (2-4 h, 24 ± 6 h, 48 ± 6 h, 72 ± 6 h, and 96 ± 6 h post-administration). All patients who had (124)I imaging subsequently underwent RAI treatment with (131)I, with administered activities ranging from 100 to 300 mCi. Post-treatment scans were obtained 5-7 days after RAI treatment. A by-patient and by-lesion analysis of the (124)I images was performed and compared with the post-treatment (131)I scans as well as F-18 FDG PET/CT images. Quantitative image analysis was also performed to determine the total functional volume (mL), activity per functional volume (µCi/mL), and cumulated activity (µCi/h) for remnants, salivary glands, and nodal metastases. RESULTS: Fifteen patients (6 women; Mage = 57 years; range 29-91 years) were enrolled into the study. Forty-six distinct lesions were identified in these 15 patients on (124)I PET/CT images, with a sensitivity of 92.5%. In addition, (124)I identified 22.5% more foci of RAI-avid lesions compared with the planar (131)I post-treatment scans. This study demonstrates different kinetic profiles for normal thyroid remnants (peaked at 24 h with mono-exponential clearance), salivary glands (peaked at 4 h with bi-exponential clearance), and metastatic lesions (protracted retention), as well as individual variations in functional volumes and thus cumulated activities. CONCLUSIONS: (124)I PET/CT is a valuable clinical imaging tool/agent, both in determining the extent of disease in the setting of metastatic DTC and in the functional volumetric and kinetic evaluation of target lesions.

Optimization of FDG-PET/CT imaging protocol for evaluation of patients with primary and metastatic liver disease.

BACKGROUND: Accurate determination of the extrahepatic extent and intrahepatic distribution of disease is very important in patients with primary and metastatic liver disease for deciding whether a patient receives potentially curable surgery or palliative treatment. Our objective was to evaluate the efficacy of delayed phase FDG-PET/CT imaging in lesion detection and to define its clinical impact compared to triple-phase contrast enhanced CT (CECT). METHODS: 30 patients underwent delayed phase FDG-PET/CT imaging (90 min whole body scan followed by a delayed abdominal scan at 120 min). Maximum standard uptake values (SUVs) and SUV ratios between tumor and normal liver parenchyma (T/N) were evaluated. In addition, comparison was made to CECT obtained within 10 days of the FDG-PET/CT to evaluate for lesion concordance within individual liver segments (Couinaud designation). RESULTS: Sites of primary malignancies included: colorectal (19), breast (3), pancreas (2), lung (2), carcinoid (2), cholangiocarcinoma (1), and hepatocellular carcinoma (1). There was a significant increase in SUV value of liver lesions between early and delayed acquisition (P < 0.001). Although there was not a significant reduction in liver background activity between the two studies, there was a strong increase in T/N ratio (P < 0.001) allowing better lesion detection by visual inspection. New lesions were identified in 5 of the 30 patients, which were not appreciated on the early scan. Delayed phase FDG-PET/CT identified one lesion which was not present on the corresponding CECT. Delayed phase FDG-PET/CT revealed extrahepatic sites of metastases not appreciated on CECT in 6 patients. CONCLUSION: Delayed phase FDG-PET/CT protocol improved lesion detectability in primary and metastatic liver disease, revealing new lesions in 17% of the patients. Moreover, FDG-PET/CT identified extrahepatic disease not seen on CECT in 20% of the patients.