Prospective clinical trial of disulfiram plus copper in men with metastatic castration-resistant prostate cancer.

BACKGROUND: In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy. OBJECTIVE: To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by 64 CuCl2 PET scan. Intravenous (IV) CuCl2 was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro. RESULTS: We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on 64 CuCl2 PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro. CONCLUSIONS: Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.

Hepatic Arterial Infusion Pumps: What the Radiologist Needs to Know.

Hepatic arterial infusion (HAI) entails the surgical implantation of a subcutaneous pump to deliver chemotherapeutic agents directly to the liver in the setting of primary or secondary liver cancer. The purpose of HAI chemotherapy is to maximize hepatic drug concentrations while minimizing systemic toxicity, facilitating more effective treatment. HAI is used in combination with systemic chemotherapy and can be considered in several clinical scenarios, including adjuvant therapy, conversion of unresectable disease to resectable disease, and unresectable disease. Radiologists are key members of the multidisciplinary team involved in the selection and management of these patients with complex liver disease. As these devices begin to be used at more sites across the country, radiologists should become familiar with the guiding principles behind pump placement, expected imaging appearances of these devices, and potential associated complications. The authors provide an overview of HAI therapy, with a focus on the key imaging findings associated with this treatment that radiologists may encounter. ©RSNA, 2021.

Evaluating Alzheimer Disease With Flortaucipir and Florbetapir PET: A Clinical Case Series.

ABSTRACT: Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are ß-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary ß-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.

18F-florbetapir Positron Emission Tomography-determined Cerebral ß-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery.

BACKGROUND: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

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.

Comparison of Bayesian penalized likelihood reconstruction versus OS-EM for characterization of small pulmonary nodules in oncologic PET/CT.

OBJECTIVE: To determine whether the recently introduced Bayesian penalized likelihood PET reconstruction (Q.Clear) increases the visual conspicuity and SUVmax of small pulmonary nodules near the PET resolution limit, relative to ordered subset expectation maximization (OS-EM). METHODS: In this institutional review board-approved and HIPAA-compliant study, 29 FDG PET/CT scans performed on a five-ring GE Discovery IQ were retrospectively selected for pulmonary nodules described in the radiologist's report as "too small to characterize", or small lung nodules in patients at high risk for lung cancer. Thirty-two pulmonary nodules were assessed, with mean CT diameter of 8 mm (range 2-18). PET images were reconstructed with OS-EM and Q.Clear with noise penalty strength ß values of 150, 250, and 350. Lesion visual conspicuity was scored by three readers on a 3-point scale, and lesion SUVmax and background liver and blood pool SUVmean and SUVstdev were recorded. Comparison was made by linear mixed model with modified Bonferroni post hoc testing; significance cutoff was p < 0.05. RESULTS: Q.Clear improved lesion visual conspicuity compared to OS-EM at ß = 150 (p < 0.01), but not 250 or 350. Lesion SUVmax was increased compared to OS-EM at ß = 150 and 250 (p < 0.01), but not 350. CONCLUSION: In a cohort of small pulmonary nodules with size near an 8 mm PET full-width half maximum, Q.Clear significantly increased lesion visual conspicuity and SUVmax compared to our standard non- time-of-flight OS-EM reconstruction, but only with low noise penalization. Q.Clear with ß = 150 may be advantageous when evaluation of small pulmonary nodules is of primary concern.

Patient and tumor characteristics predictive of an elevated hepatopulmonary shunt fraction before radioembolization of hepatic tumors.

OBJECTIVE: To determine whether any patient or hepatic tumor characteristics are predictive of hepatopulmonary shunt fraction when performed before radioembolization. MATERIALS AND METHODS: A retrospective review was performed on 190 patients who underwent preradioembolization hepatic arteriography with calculation of hepatopulmonary shunt fraction using technetium-99m-labeled macroaggregated albumin perfusion scintigraphy. Patient and tumor characteristics including imaging features were reviewed for correlation with absolute shunt fraction, shunt fraction greater than 10%, and shunt fraction greater than 20%. RESULTS: Most tumor types showed some cases of elevated shunt fraction greater than 10%. Six patients had a shunt fraction greater than 20%: four were hepatocellular carcinoma and two were neuroendocrine tumor metastases. Univariate analysis showed that dominant tumor diameter, hepatic tumor burden, vascular invasion, hepatic venous invasion, and hypervascularity on angiography were associated with a shunt fraction greater than 10%. Only dominant tumor diameter and vascular invasion were associated with a shunt fraction greater than 20%. On multivariate analysis, only tumor diameter (odds ratio 1.2) and hepatic venous invasion (odds ratio 23.0) were associated independently with an increased shunt fraction greater than 10%. CONCLUSION: Multiple patient and tumor-related characteristics were significantly correlated with the hepatopulmonary shunt fraction on univariate analysis. However, on multivariate analysis, only the dominant tumor diameter and presence of hepatic venous invasion were associated independently with a greater than 10% shunt fraction.

Two-day lymphoscintigraphic imaging for melanoma.

OBJECTIVES: Sentinel lymph node mapping has a long history of successful use in the staging and management of cutaneous melanoma. Most practitioners inject the primary site with radiocolloid the evening before or on the day of lymphoscintigraphy. We have found that imaging the day after lymphoscintigraphic injection is quite feasible; it decreases background radioactivity and makes scheduling easier. We aimed to determine whether 2-day lymphoscintigraphy is as effective at defining nodes as 1-day lymphoscintigraphy. MATERIALS AND METHODS: We reviewed the records of 172 patients who underwent lymphoscintigraphy over a 6-year period, all of whom had a diagnosis of melanoma and had undergone 2-day lymphoscintigraphy with imaging on both the day of injection and the day immediately after. The number of basins and the basin pattern were then examined when a discrepancy was seen in the reports in order to decide whether an actual discrepancy between images was present. The number of nodes on same-day and next-day imaging was then evaluated as well. RESULTS: On same-day imaging, the number of basins identified was three node basins (NBs) in five patients, two NBs in 42 patients, one NB in 123 patients and no NB in two patients. On next-day imaging, the number of basins identified was three NBs in five patients, two NBs in 36 patients, one NB in 129 patients and no NB in two patients. The difference in the number of basins between same-day and next-day imaging was not significant once cases such as iliac, para-aortic and pelvic nodes, which do not affect surgical planning, were excluded (P=0.08). The pattern of nodes within the basin was also examined, and the presence or disappearance of disappearing nodes correlated with timing of the next-day images. All cases of disappearing nodes occurred at least 19 h after injection, and cases of disappearance of significant nodes occurred at at least 22 h. The absolute number of nodes declined in 45 cases, remained the same in 124 and increased in three. CONCLUSION: Overall, the same number of basins and, usually, nodes can be detected on the day after injection, as long as the time after injection does not significantly exceed 19 h.

Phase-1 clinical trial results of high-specific-activity carrier-free 123I-iobenguane.

UNLABELLED: A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of (123)I-iobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. METHODS: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. RESULTS: A reference clinical imaging database acquired over time for healthy men and women injected with high-specific-activity (123)I-iobenguane showed organ distribution and whole-body retention similar to those of conventional (123)I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. CONCLUSION: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity (123)I-iobenguane.

Cortical ß-amyloid levels and neurocognitive performance after cardiac surgery.

INTRODUCTION: Neurological and neurocognitive dysfunction occurs frequently in the large number of increasingly elderly patients undergoing cardiac surgery every year. Perioperative cognitive deficits have been shown to persist after discharge and up to several years after surgery. More importantly, perioperative cognitive decline is predictive of long-term cognitive dysfunction, reduced quality of life and increased mortality. The proposed mechanisms to explain the cognitive decline associated with cardiac surgery include the neurotoxic accumulation of ß-amyloid. This study will be the first to provide molecular imaging to assess the relationship between neocortical ß-amyloid deposition and postoperative cognitive dysfunction. METHODS AND ANALYSIS: 40 patients providing informed consent for participation in this Institutional Review Board-approved study and undergoing cardiac (coronary artery bypass graft (CABG), valve or CABG+valve) surgery with cardiopulmonary bypass will be enrolled based on defined inclusion and exclusion criteria. At 6 weeks after surgery, participants will undergo (18)F-florbetapir positron emission tomography imaging to assess neocortical ß-amyloid burden along with a standard neurocognitive battery and blood testing for apolipoprotein E ε-4 genotype. RESULTS: The results will be compared to those of 40 elderly controls and 40 elderly patients with mild cognitive impairment who have previously completed (18)F-florbetapir imaging. ETHICS AND DISSEMINATION: This study has been approved by the Duke University Institutional Review Board. The results will provide novel mechanistic insights into postoperative cognitive dysfunction that will inform future studies into potential treatments or preventative therapies of long-term cognitive decline after cardiac surgery.

Utility of FDG PET/CT in inflammatory cardiovascular disease.

Inflammatory disorders of the cardiovascular system can affect the myocardium, pericardium, or vessel walls. Patients with myocardial and pericardial disease may present with chest pain, palpitations, and shortness of breath, symptoms resembling myocardial ischemia or infarction. The manifestations of vasculitis may include fever, weight loss, and fatigue, mimicking infectious or malignant processes. Because of the difficulty of differentiating these disease processes, patients frequently undergo multiple diagnostic examinations before obtaining a final diagnosis of myocarditis, pericarditis, or vasculitis. Computed tomography (CT) and magnetic resonance imaging play important roles in the assessment of structural abnormalities of the cardiovascular system, and combined positron emission tomography (PET) and CT may depict inflammatory processes before structural changes occur. Familiarity with the PET/CT appearances of inflammatory processes in the myocardium, pericardium, and vessels is important for accurate and prompt diagnosis.

Detection of left ventricular thrombus by delayed-enhancement cardiovascular magnetic resonance prevalence and markers in patients with systolic dysfunction.

OBJECTIVES: This study sought to assess the prevalence and markers of left ventricular (LV) thrombus among patients with systolic dysfunction. BACKGROUND: Prior studies have yielded discordant findings regarding prevalence and markers of LV thrombus. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) identifies thrombus on the basis of tissue characteristics rather than just anatomical appearance and is potentially highly accurate. METHODS: Prevalence of thrombus by DE-CMR was determined in 784 consecutive patients with systolic dysfunction (left ventricular ejection fraction [LVEF] <50%) imaged between July 2002 and July 2004. Patients were recruited from 2 separate institutions: a tertiary-care referral center and an outpatient clinic. Comparison to cine-cardiovascular magnetic resonance (CMR) was performed. Follow-up was undertaken for thrombus verification via pathology evaluation or documented embolic event within 6 months after CMR. Clinical and imaging parameters were assessed to determine risk factors for thrombus. RESULTS: Among this at-risk population (age 60 +/- 14 years; LVEF 32 +/- 11%), DE-CMR detected thrombus in 7% (55 patients) and cine-CMR in 4.7% (37 patients, p < 0.005). Follow-up was consistent with DE-CMR as a better reference standard than cine-CMR, including 100% detection among 5 patients with thrombus verified by pathology (cine-CMR, 40% detection), and logistic regression analysis testing the contributions of DE-CMR and cine-CMR simultaneously, which showed that only the presence of thrombus by DE-CMR was associated with follow-up end points (p < 0.005). Cine-CMR generally missed small intracavitary and small or large mural thrombus. In addition to traditional indices such as low LVEF and ischemic cardiomyopathy, multivariable analysis showed that increased myocardial scarring, an additional parameter available from DE-CMR, was an independent risk factor for thrombus. CONCLUSIONS: In a broad cross section of patients with systolic dysfunction, thrombus prevalence was 7% by DE-CMR and included small intracavitary and small or large mural thrombus missed by cine-CMR. Prevalence increased with worse LVEF, ischemic etiology, and increased myocardial scarring.