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.

Uncommon Manifestation of Oligometastatic Prostate Cancer: Sister Mary Joseph Nodule.

ABSTRACT: A 76-year-old man with a history of prostate cancer diagnosed in 2008 developed biochemical recurrence in 2010 and started intermittent androgen deprivation therapy. In 2021, due to rising prostate-specific antigen, an 18 F-piflufolastat PSMA PET/CT was performed. It showed a radiotracer-avid sclerotic lesion in the right iliac bone and an indeterminate radiotracer-avid nodule in the umbilical region, demonstrating progressive enlargement and increased uptake on subsequent imaging. Pathologic analysis of the umbilical nodule revealed metastatic prostate cancer-a finding eponymically referred to as a Sister Mary Joseph nodule.

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.

A roadmap for clinical trial design in marginal zone lymphoma.

Marginal zone lymphoma (MZL) is commonly underrepresented in clinical trials collectively studying mostly nodal indolent lymphomas.In this manuscript we propose new inclusion and response criteria defined by MZL subtype and disease location for those with extranodal MZL. Progression of disease within 24 months is associated with poor outcomes in MZL and future studies should assess the efficacy of novel agents in this population.

A single-center analysis of patients with extranodal marginal zone lymphoma of the breast.

Breast extranodal marginal zone lymphoma (EMZL) is a rare malignancy. We performed the largest published to date single-center retrospective analysis of 13 patients with breast EMZL focusing on clinical characteristics and treatment-related outcomes. The rarity of this disease at our center was concordant with the prevalence reported in the literature, with breast EMZL comprising 2% of 654 MZL cases. Most patients presented with stage I-II disease however four (30.8%) patients had stage IV disease mostly due to occult bone marrow (BM) involvement. Interestingly, EMZL was frequently non-FDG avid (66.7%) on staging PET/CT. With a median follow-up of 3.1 years (range 5 months to 10.2 years), the 3-year progression free survival was 68.7% (95%CI 30.2%-88.9%) and overall survival 80.2% (95%CI 40.3%-94.8%). No patient experienced higher-grade transformation. Herein we show that localized breast EMZL can be effectively treated with radiation therapy providing long term disease control.

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.

Ga-68 DOTATATE PET/CT in the Evaluation of Paragangliomas and Other Indeterminate Lesions in the Head and Neck.

Background and Purpose: Paragangliomas (PGLs) are rare neuroendocrine tumors with imaging features that can overlap with other entities. This study hypothesizes that given overexpression of somatostatin receptor (SSTR) 2, PGLs can be differentiated on Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT) from other benign or malignant lesions. Materials and Methods: Ninety-six patients with known tumors of the head and neck who underwent Ga-68 DOTATATE PET/CT from May 2017 to December 2021 were retrospectively reviewed from a single institution. Of these, 43 patients had histopathological confirmation and 66 positive lesions were discovered on PET/CT. For each lesion, the SUV max, the SUV lesion to liver ratio, and the SUV lesion to spleen ratio were analyzed. Results: PGLs (n = 37) showed the most intense uptake, and the mean of SUVmax was 69.3 (range 3.7-225.9). Metastatic PGL and metastasis from other neuroendocrine tumors (n = 13) demonstrated intermediate uptake, the mean of SUVmax was 15.16 (range 2.3-40.3). Meningiomas (n = 3) had intermediate uptake, and the mean of SUVmax was 12.37 (range 2.5-19.4). One patient with esthesioneuroblastoma had 5 lesions in the head and neck, and the mean of SUVmax was 18.9 (range 6.9-49.4). Schwannomas (n = 4) had very low uptake, and the mean of SUVmax was 1.75 (range 1.1-2.2). Other rare cases with low uptake included 1 each of osteosarcoma, acinic cell carcinoma, ectopic thyroid tissue, and plasmacytoma, and the mean of SUVmax was 4.75 (range 2.3-6.1). Conclusions: Ga-68 DOTATATE PET/CT can be a useful adjunct in differentiating tumors in the head and neck. PGLs demonstrate the highest uptake. Meningioma, esthesioneuroblastoma, and neuroendocrine tumor metastasis have intermediate uptake. Schwannomas and other rare tumors exhibit low uptake.

PET-CT in the Evaluation of Neoadjuvant/Adjuvant Treatment Response of Soft-tissue Sarcomas: A Comprehensive Review of the Literature.

➢: In soft-tissue sarcomas (STSs), the use of positron emission tomography-computed tomography (PET-CT) through a standardized uptake value reduction rate correlates well with histopathological response to neoadjuvant treatment and survival. ➢: PET-CT has shown a better sensitivity to diagnose systemic involvement compared with magnetic resonance imaging and CT; therefore, it has an important role in detecting recurrent systemic disease. However, delaying the use of PET-CT scan, to differentiate tumor recurrence from benign fluorodeoxyglucose uptake changes after surgical treatment and radiotherapy, is essential. ➢: PET-CT limitations such as difficult differentiation between benign inflammatory and malignant processes, inefficient discrimination between benign soft-tissue tumors and STSs, and low sensitivity when evaluating small pulmonary metastases must be of special consideration.

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.

A Solitary Skull Base Plasmacytoma Mimicking Paraganglioma on 68Ga-DOTATATE PET/CT.

The patient was a 61-year-old man with a history of neck pain starting around October 2019. CT of the neck showed a lytic lesion at the right skull base. Subsequent MRI demonstrated an enhancing destructive mass in the right skull base centered in the occipital bone and condyle involving the jugular foramen and hypoglossal canal. An F-FDG PET/CT was performed showing increased FDG uptake in the right jugular foramen tumor. In addition, a PET/CT with Ga-[DOTA-Tyr3]-octreotate (Ga-DOTATATE) demonstrated a Ga-DOTATATE-avid lesion in the right jugular foramen eroding the adjacent osseous structures. Biopsy revealed a plasmacytoma and not paraganglioma.

223Ra-Dichloride Response Evaluation Using 18F-Fluciclovine PET/CT and Bone Scintigraphy in a Patient With Castration-Resistant Metastatic Prostate Cancer.

A 66-year-old man was diagnosed with metastatic prostate cancer to the bones. The patient started Ra-dichloride (Xofigo) therapy in April 2019. Tc-MDP bone scan and F-fluciclovine (Axumin) PET/CT showed discordant but overall complementary findings that indicated disease progression after 5 doses of Xofigo therapy. The patient's prostate-specific antigen increased from 33.81 ng/mL at baseline before Xofigo therapy and up to 394.3 ng/mL after the fifth dose of Xofigo treatment. Because of disease progression, Xofigo therapy was discontinued.

Clinical and radiological characteristics of patients with pulmonary marginal zone lymphoma: A single center analysis.

Pulmonary marginal zone lymphoma (PMZL) is the most common non-Hodgkin lymphoma affecting the lung. PMZL is usually an indolent disease. Clinical and radiological variables associated with shorter survival are largely unknown and no consensus exists on preferred treatment strategy in PMZL. Herein we aimed to identify clinical and radiological features associated with shorter survival and inferior treatment outcomes. Forty patients with PMZL were analyzed. FDG-avid disease was evident in most patients (93%) with staging PET/CT (n = 15). With a median follow-up in treated patients (n = 38) of 8.4 years (range 0.07-18.44), the median progression-free survival (PFS) and overall survival (OS) were 7.5 years (95% CI 1.8-9.5) and 15.7 years (95% CI 9.3-NE) respectively. Shorter PFS was observed in patients who presented at diagnosis with elevated LDH, B symptoms, advanced stage and failed to achieve complete response (CR) after initial treatment. Patients with multifocal lung disease, extrapulmonary MZL and cavitary lesions on CT scans exhibited shorter PFS. Nevertheless, no clinical or radiologic findings were associated with shorter OS. All patients treated with surgery (n = 4) and radiation therapy (n = 3) achieved and remained in CR. No higher grade transformations occurred during the follow-up period. PMZL exhibited excellent outcomes with a 15-year PMZL-related OS of 94.9% (95% CI: 81.25%-98.7%). Radiation therapy and surgery are potentially curative strategies in localized PMZL.

American Thyroid Association Sonographic Risk and Afirma Gene Expression Classifier Alone and in Combination for the Diagnosis of Thyroid Nodules with Bethesda Category III Cytology.

Background: The Afirma gene expression classifier (GEC) has been used to aid in the diagnosis and management of thyroid nodules having Bethesda category III fine-needle aspiration cytologic diagnosis (B3 nodules). The American Thyroid Association sonographic risk stratification system for thyroid nodules (ATA-US) may stratify B3 nodules and aid in the decision to order a molecular test. The aim of this study was to assess the association between ATA-US and GEC as well as to determine their individual and combined diagnostic performances when applied to B3 nodules. Methods: A retrospective single-center study included B3 nodules that had undergone evaluation by GEC. Each ultrasound was reviewed by three radiologists, and nodules were classified using the 2015 ATA sonographic risk categories. Nodules were determined to be benign or malignant based on surgical pathology or minimum 11 months of follow-up. Positive predictive values (PPV) and negative predictive values (NPV) were calculated for GEC, ATA-US, and GEC across all ATA-US categories. Results: One hundred twenty-six B3 nodules with GEC results were included and deemed benign or malignant based on final pathology or follow-up. Prevalence of malignancy was 32%. The rate of malignancy was similar in the ATA-US high suspicion (HS) and intermediate suspicion (IS) categories at 42% and 38%, respectively; and lower in nodules with low suspicion sonography (LS) and very low suspicion sonography (VLS) at 23% and 11%, respectively. The PPV and NPV of ATA-US was calculated by designating HS or IS sonography as a "positive" test and the lower risk categories as "negative." ATA-US had a PPV of 40% and NPV of 79%. The GEC PPV was 40% and NPV was 83%. The PPV of GEC was 50% in nodules with HS or IS ATA-US and lower at 28% and 20%, respectively, in LS and VLS nodules. The NPV of GEC was 80% in HS, 77% in IS, 84% in LS, and 100% in VLS sonography categories. Conclusions: In B3 nodules, ATA-US and GEC have similar diagnostic performance. The PPV of GEC varies across ATA-US categories, while the NPV remains similar. These data support the need for future prospective studies.

Pituitary Adenoma on 18F-Fluciclovine PET/CT.

A 69-year-old man presented with lower urinary tract symptoms and prostate biopsy showed prostate cancer. F-Fluciclovine PET/CT revealed abnormal increased radiotracer uptake within the prostate gland, and multiple osseous structures, suspicious for tumoral involvement. Incidentally, an expansile soft tissue density mass arising from sella turcica demonstrated increased radiotracer activity. MRI showed a lobulated enhancing mass centered in the sella and eroding into the sphenoid sinus. The differential diagnosis includes pituitary macroadenoma versus prostate cancer metastasis. The tumor was resected and the pathological diagnosis was pituitary adenoma.

Marine-Lenhart Syndrome: Case Report, Diagnosis, and Management.

The coexistence of thyroid functioning nodules and Graves' disease is called Marine-Lenhart syndrome. This condition is estimated to occur in 0.8-2.7% of patients with Graves' disease with few cases reported in the literature. Criteria for the diagnosis are not well defined. Here, we present a case of hyperthyroidism characterized by the presence of stimulating TSH receptor antibodies and severe bilateral exophthalmos. A thyroid uptake and scan revealed an elevated 24-hour iodine-131 uptake and a discrete hot nodule in the upper pole of the right lobe which was also observed with a thyroid ultrasound. The patient was diagnosed with Marine-Lenhart syndrome complicated by thyroid eye disease and was treated with methimazole followed by thyroidectomy and orbital decompression. We review the existing literature and propose criteria for the diagnosis and treatment of this condition.

Hematopoietically Active Adrenal Myelolipoma Mimicking Breast Cancer Metastasis.

A 66-year old woman had a left breast mass. Biopsy showed invasive ductal carcinoma. A PET/CT scan demonstrated hypermetabolism in the left breast and atypical heterogeneously increased uptake throughout the skeleton as well as a minimally FDG-avid right adrenal myelolipoma. PET/CT 4 months later after 6 cycles of neoadjuvant chemotherapy demonstrated increased size and FDG avidity of this adrenal mass concerning for metastasis and uniformly increased skeletal FDG avidity. Biopsy demonstrated adrenal myelolipoma. The growth and increased FDG avidity of the adrenal myelolipoma were due to the action of colony-stimulating factors on the tumor's hematopoietic component.