Unique Metastatic Patterns in Neuroendocrine Neoplasms of Different Primary Origin.

INTRODUCTION: Neuroendocrine neoplasms (NEN) can originate in different organs, for example, the gastroenteral tract (GE), pancreas (Pan), or lungs (L). Our aim was to examine metastatic patterns for patients with NEN of various primary origins with a special focus on brain metastases to indicate utility for screening. METHODS: All NEN patients except for small cell lung cancer registered in the Netherlands Cancer Registry from 2008 to 2018 were selected. Metastatic patterns at initial diagnosis for NEN with different primary origins were compared. In a subcohort of patients from 2 referral hospitals (2014-2019), additional information on, for example, development of metastases after initial presentation was available. RESULTS: In the nationwide cohort, 4,768/11,120 (43%) patients had metastatic disease at diagnosis (GE: 1,504/4,710 [32%]; Pan: 489/1,150 [43%]; and L: 1,230/2,978 [41%]). For GE- and Pan-NEN, the most prevalent metastatic site was the liver (25 and 39%), followed by distant lymph nodes (8 and 8%), whereas only few patients with brain metastases were identified (0% in both). In contrast, for L-NEN, prevalence of metastases in the liver (19%), brain (9%), lung (7%), and bone (14%) was more equal. In the reference network cohort, slightly more NEN patients had metastatic disease (260/539, 48%) and similar metastatic patterns were observed. CONCLUSION: Almost half of NEN patients were diagnosed with synchronous metastatic disease. L-NEN have a unique metastatic pattern compared to GE- and Pan-NEN. Remarkably, an important part of L-NEN metastases was in the brain, whereas brain metastases were almost absent in GE- and Pan-NEN, indicating utility of screening in L-NEN.

Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure.

UNLABELLED: Apoptosis, or programmed cell death (PCD), contributes to the decline in ventricular function in heart failure. Because apoptosis comprises a programmed cascade of events, it is potentially reversible, and timely intervention should delay the development of cardiomyopathy. (99m)Tc-Labeled annexin A5 has successfully been used for the noninvasive detection of PCD in myocardial infarction and heart transplant rejection. The present study evaluated the role of annexin A5 imaging for detection of PCD in heart failure patients. METHODS: Annexin A5 imaging was performed on 9 consecutive heart failure patients with advanced nonischemic cardiomyopathy (dilated, n = 8; hypertrophic, n = 1) and in 2 relatives having the same genetic background as the hypertrophic cardiomyopathy patient but no heart failure. RESULTS: Four of the patients with dilated cardiomyopathy and the 1 with hypertrophic cardiomyopathy and heart failure showed focal, multifocal, or global left ventricular uptake of annexin A5. No uptake was visualized in the remaining 4 patients or in the 2 controls. All cases showing annexin A5 uptake within the left ventricle experienced significant reduction in left ventricular function or functional class. In cases with no annexin A5 uptake, left ventricular function and clinical status remained stable. CONCLUSION: These data indicate the feasibility of noninvasive PCD detection with annexin imaging in heart failure patients. Annexin A5 uptake is associated with deterioration in left ventricular function, and this association may lend itself to the development of novel management strategies.

The diagnostic accuracy of myocardial perfusion scintigraphy in athletes with abnormal exercise test results.

Background Previous studies revealed a relatively high prevalence of electrocardiographic findings indicative for myocardial ischemia in asymptomatic athletes undergoing pre-participation screening. Myocardial perfusion scintigraphy is generally considered a valuable diagnostic and prognostic modality and often used for further diagnostic evaluation in these subjects. However, data on the diagnostic accuracy of myocardial perfusion scintigraphy in athletes are scarce. Objectives The main purpose of this study was to investigate the positive predictive value of myocardial perfusion scintigraphy for detection of coronary artery disease in asymptomatic athletes with abnormal exercise testing results during pre-participation screening. The secondary aim was to evaluate the prognostic value of myocardial perfusion scintigraphy. Methods Electronic charts of asymptomatic athletes who underwent myocardial perfusion scintigraphy following an abnormal exercise testing were retrospectively reviewed. Myocardial perfusion scintigraphy and exercise testing studies were revised. Athlete characteristics and cardiovascular risk factors were evaluated. Results One hundred and forty-three athletes were included. 29 athletes (20%) showed concordant abnormal exercise testing and myocardial perfusion scintigraphy results. Coronary imaging was performed in 20 of these 29 athletes. Four athletes showed significant coronary artery disease (positive predictive value = 20%). The positive predictive value increased to 33% when athletes were selected who should have undergone exercise testing according to the guideline recommendations. During a mean follow-up interval of 4.7 ± 2.2 years, eight cardiac events occurred. Athletes with an abnormal myocardial perfusion scintigraphy result had a fourfold increased risk at a future cardiac event (2.9%/year versus 0.75%/year, p = 0.031). Conclusions The positive predictive value of myocardial perfusion scintigraphy for the detection of significant coronary artery disease in asymptomatic athletes with a positive exercise testing result is low, even in a selection of athletes with a relatively high cardiovascular risk. Although an abnormal myocardial perfusion scintigraphy result was associated with a fourfold higher annual event rate, the absolute annual event rate in this group was still low. Efforts should be made to develop better diagnostic strategies to evaluate asymptomatic athletes with abnormal exercise testing results during pre-participation screening.

Subclinical signs of vascular damage relate to enhanced platelet responsiveness among nonpregnant formerly preeclamptic women.

OBJECTIVE: In nonpregnant formerly preeclamptic women, the prevalence of occult cardiovascular abnormalities is increased. These high-risk women mildly benefit from low-dose aspirin in the prevention of recurrent disease. How this effect is mediated, either by affecting platelet or vascular function, is still unsettled. In this study, we tested the hypothesis that in these nonpregnant women, enhanced platelet responsiveness is common and related to microvascular damage. STUDY DESIGN: At least 6 months' postpartum we evaluated in 66 formerly preeclamptic women platelet count, volume, and in vitro response to low-dose ADP (0.5 microg/mL). Peripheral levels of fibronectin (microg/mL), von Willebrand factor antigen (%), C-reactive protein (high-sensitive CRP, mg/L), urinary albumin, and protein (24-hour collection, g/mol creatinine) served as markers of vascular damage. Hemodynamic function was determined by plasma volume (iodine I 125 HSA indicator dilution method, mL/kg lean body mass), cardiac index (Doppler, mL/min/m2), blood pressure and heart rate (Dinamap [Critikon, Tampa, FL], mm Hg and beats/min, respectively). Thereafter, we subdivided these 66 women into 2 subgroups either with (n = 10, 15%) or without increased platelet responsiveness (n = 56, 85%). Both groups were compared nonparametrically. RESULTS: Groups were comparable with respect to age, blood pressure, body mass index, parity, plasma volume, and cardiac index. Women with enhanced platelet responsiveness had higher levels of circulation fibronectin and CRP, and displayed more often albuminuria and proteinuria. In addition, even though platelet count was comparable between groups, the mean platelet volume was higher among women with enhanced platelet responsiveness. CONCLUSION: Fifteen percent of formerly preeclamptic women had enhanced platelet responsiveness, which was associated with elevated levels of various markers for (micro) vascular damage. We speculate that in these women platelets are presensitized on a relatively dysfunctional endothelium. Although this association does not prove causality, these results may indicate a subgroup of women who benefit from low-dose aspirin in the prevention of recurrent disease in a next pregnancy.

In vivo detection of cell death in the area at risk in acute myocardial infarction.

UNLABELLED: Annexin A5 is a phospholipid binding protein with high affinity for phosphatidyl-serine, which is externalized by cells undergoing programmed cell death. An increased programmed cell death rate has been reported in the heart after myocardial infarction (MI). The aim of this study was to correctly localize annexin A5 uptake in vivo and to determine the area at risk in humans with acute MI. METHODS: Nine patients were studied. Before reperfusion was achieved, (99m)Tc-sestamibi was injected intravenously. Myocardial (99m)Tc-sestamibi perfusion scintigraphy was performed after reperfusion. Thereafter, (99m)Tc-labeled annexin A5 was administered intravenously, followed by scintigraphic imaging of the heart. Myocardial (99m)Tc-sestamibi scintigraphy was repeated 1-3 wk after the MI onset. (99m)Tc-Annexin uptake was also studied in the subacute phase of the MI in 2 patients. RESULTS: All patients clearly showed perfusion defects on (99m)Tc-sestamibi scintigraphy in concordance with the infarct location. Furthermore, all patients showed accumulation of (99m)Tc-annexin A5 at the infarct site, indicating that cardiomyocytes with externalized phosphatidyl-serine are present in the infarct area. (99m)Tc-sestamibi defects determined 1-3 wk after the MI onset were significantly smaller than the defects in the acute phase. (99m)Tc-annexin uptake was absent in the 2 patients studied in the subacute phase. CONCLUSION: In acute MI, an increase of programmed cell death can be correctly localized in vivo in the area at risk. Furthermore, the decrease in (99m)Tc-sestamibi defect size in the subacute phase of the MI further suggests that in parts of the area at risk, reversible myocardial damage rather than necrosis is present in cardiomyocytes.

Compensatory uptake of I-123 MIBG in the contralateral adrenal gland after removal of a pheochromocytoma.

The identification of recurrent or residual tumor tissue is sometimes complicated. The authors describe a 53-year-old woman in whom I-123 metaiodobenzylguanidine (MIBG) scintigraphy revealed a pheochromocytoma in the right adrenal gland. After the tumor was removed, the patient's catecholamine levels normalized. At the 3-month follow-up examination, I-123 MIBG scintigraphy did not reveal uptake in the right adrenal region but rather showed uptake in the left adrenal region. The patient's blood pressure remained in the normal range. A third scintigram, obtained 1 year after tumor resection, no longer detected I-123 MIBG accumulation in the left adrenal gland. These findings suggest that compensatory hyperplasia of the left adrenal gland led to enhanced uptake of I-123 MIBG. They also highlight the need for careful follow-up of such patients to distinguish between physiologic and pathologic processes.