Clinical Imaging and Dosimetry of a Pan-Cancer Targeting Alkylphosphocholine Analog, [¹²⁴I]I-NM404

The purpose of this study was to assess organ dosimetry and clinical use of [124I]I-NM404, a radiotheranostic alkylphosphocholine (APC) analog, for accurate detection and characterization of a wide variety of solid primary and metastatic malignancies anywhere in the body. Methods: Patterns of [124I]I-NM404 uptake were quantitatively analyzed and qualitatively compared with [18F]FDG PET/CT in 14 patients (median age, 61.5 years; 7 males, 7 females) with refractory metastatic cancer who were enrolled in one of two Phase I imaging studies. Primary cancer types included bronchogenic (n = 7), colorectal (n = 1), prostate (n = 1), triple-negative breast (n = 1), head and neck (n = 2), pancreatic (n = 1) carcinoma, and melanoma (n = 1). Patients were administered [124I]I-NM404 and imaged via PET/CT at 1–2, 4–6, 24, and 48 h and at 5–10 days post injection, from top of the skull to mid-thigh. Volumes of interest were drawn over lungs, heart, liver, kidneys, and whole body for dosimetry estimation using OLINDA 1.1 Representative metastatic index lesions were chosen when applicable for each case with active sites of disease to calculate maximum and mean tumor-to-background ratios (TBRmax, TBRmean), using the adjacent normal organ parenchyma as background when possible. Results: Administrations of [124I]-NM404 were safe and well-tolerated. The organs with the highest estimated absorbed dose (mean ± SD) were the lungs (1.74 ± 0.39 mSv/MBq), heart wall (1.52 ± 0.29 mSv/MBq), liver (1.28 ± 0.21 mSv/MBq) and kidneys (1.09 ± 0.20 mSv/MBq). The effective dose was 0.77 ± 0.05 mSv/MBq. Preferential uptake within metastatic foci was observed with all cancer subtypes, TBRmax ranged from 1.95 to 15.36 and TBRmean ranged from 1.63 to 6.63. Robust sensitive imaging of lesions was enhanced by delayed timing (2–6 days after single injection of [124I]I-NM404, respectively) due to persistent tumor retention coupled with progressive washout of background activity. NM404 uptake was evident in pulmonary, nodal, skeletal, CNS, and other metastatic sites of disease. Radiation related injury or necrosis were NM404 negative, whereas certain small number of metastatic brain lesions were false negative for NM404. Conclusions: In addition to being well tolerated, selective tumor uptake of NM404 with prolonged retention was demonstrated within a broad spectrum of highly treated metastatic cancers

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline