[18F]FDG-PET or PET/CT in the evaluation of pelvic and para-aortic lymph nodes in patients with locally advanced cervical cancer: A systematic review of the literature.

PURPOSE: Imaging is essential in detecting lymph node metastases for radiotherapy treatment planning in locally advanced cervical cancer (LACC). There are not many data on the performance of [18F]FDG-PET(CT) in showing lymph node metastases in LACC. We pooled sensitivity and specificity of [18F]FDG-PET(CT) for detecting pelvic and/or para-aortic lymph node metastases in patients with LACC. Also, the positive and negative posttest probabilities at high and low levels of prevalence were determined. METHODS: MEDLINE and EMBASE searches were performed and quality characteristics assessed. Logit-sensitivity and logit-specificity estimates with corresponding standard errors were calculated. Summary estimates of sensitivity and specificity with corresponding 95% confidence intervals (CIs) were calculated by anti-logit transformation. Positive and negative likelihood ratios (LRs) were calculated from the mean logit-sensitivity and mean logit-specificity and the corresponding standard errors. The posttest probabilities were determined by Bayesian approach. RESULTS: Twelve studies were included with a total of 778 patients aged 10-85 years. For pelvic nodes, summary estimates of sensitivity, specificity, LR+ and LR- were: 0.88 (95%CI: 0.40-0.99), 0.93 (95%CI: 0.85-0.97), 11.90 (95%CI: 5.32-26.62) and 0.13 (95%CI: 0.01-1.08). At the lowest prevalence of 0.15 the positive predictive value (PPV) and negative predictive value (NPV) were 0.68 and 0.98, at the highest prevalence of 0.65, 0.96 and 0.81. For the para-aortic nodes, the summary estimates of sensitivity, specificity LR+ and LR- were: 0.40 (95%CI: 0.18-0.66), 0.93 (95%CI: 0.91-0.95), 6.08 (95%CI: 2.90-12.78) and 0.64 (95%CI: 0.42-0.99), respectively. At the lowest prevalence of 0.17 the PPV and NPV were 0.55 and 0.88, at the highest prevalence of 0.50, 0.86 and 0.61. CONCLUSION: The PPV and NPV of [18F]FDG-PET(CT) showing lymph node metastases in patients with LACC improves with higher prevalence. Prevalence and predictive values should be taken into account when determining therapeutic strategies based on [18F]FDG-PET(CT).

18F-FDG-PET/CT guided external beam radiotherapy volumes in inoperable uterine cervical cancer.

BACKGROUND: In patients with advanced stage cancer of the uterine cervix who undergo irradiation with curative intent, there is the necessity to treat all suspicious nodes on imaging. Our hypothesis was that adding fluorodeoxyglucose positron emission computer tomography/computer tomography (FDG-PET/CT) to the imaging workup would alter the external beam radiotherapy (EBRT) treatment plan, either resulting in an extended external beam radiotherapy (EBRT) field to the para-aortal region or an additional boost to suspicious nodes. Since extended field radiotherapy or additional boost can cause toxicity, our secondary aim was to assess the incidence of severe late bowel toxicity in patients treated with extended para-aortal EBRT-field and boost compared to elective pelvic radiotherapy. METHODS: Eighty-eight patients were enrolled. First, the optimal radiation treatment plan (EBRT and boost) was retrospectively determined based on magnetic resonance imaging (MRI) or FDG-PET/CT. Second, the severe bowel toxicity caused by the extended para-aortal field was assessed, based on the executed radiotherapy. RESULTS: Based on MRI 8/88 patients would receive EBRT with para-aortic extension, this was 21/88 for FDG-PET/CT. Based on MRI 47/704 lymph node regions would receive additional boost, while based on PET/CT 91/704. Late severe bowel toxicity was seen in 12/84 patients, 6/65 in the group who received elective pelvic irradiation and 6/19 with para-aortal EBRT and boost at common iliac and/or para-aortal lymph nodes. Significant worse overall survival was seen of patients who needed para-aortal irradiation. CONCLUSIONS: Addition of FDG-PET/CT leads to an extension of the elective EBRT volume and more suspicious lymph nodes receive a boost. However, when deciding to intensify radiation therapy, late severe bowel toxicity has to be taken into account.

Polymorphism of SLC6A2 gene does not influence outcome of myocardial 123I-mIBG scintigraphy in patients with chronic heart failure.

AIM: The NET, encoded by SLC6A2, is responsible for presynaptic NE-reuptake. 123I-mIBG is clinically used to evaluate cardiac sympathetic function. However, it is unknown if polymorphism of SLC6A2 influences cardiac sympathetic activity as assessed with 123I-mIBG. Therefore we studied the influence of SLC6A2 SNPs on myocardial 123I-mIBG parameters in CHF. MATERIALS AND METHODS: Forty-nine adults with stable CHF (age 66.5 ± 8.1 years, LVEF 22.3 ± 6.4) were enrolled. Fifteen minutes (early) and 4 hours (late) after administration of 123I-mIBG planar images were acquired. The H/M ratio was calculated from the manually drawn ROI over the left ventricle and a fixed mediastinal ROI. Fourteen exons of the SLC6A2 gene were analyzed from whole blood samples. RESULTS: We found 6 different SLC6A2 SNPs, although none were functional. LVEF was the only independent predictor for early (adjusted R 2 = 0.063, p = 0.045) and late H/M ratio (adjusted R 2 = 0.116, p = 0.010). NT-proBNP was the only independent predictor for 123I-mIBG WO (adjusted R 2 = 0.074, p = 0.032). SLC6A2 SNPs were not associated with any myocardial 123I-mIBG-derived parameter. CONCLUSION: In this specific CHF population polymorphism of SLC6A2 gene was not associated with any 123I-mIBG derived parameters.

Myocardial 123I-mIBG scintigraphy in relation to markers of inflammation and long-term clinical outcome in patients with stable chronic heart failure.

AIM: Chronic heart failure (CHF) results in both increased cardiac sympathetic activity and myocardial inflammation. The aim of this study was to identify the relationship between severity of heart failure (i.e., NT-proBNP and LVEF), cardiac sympathetic activity (123I-mIBG scintigraphy), and measures of inflammation in subjects with stable, optimally treated CHF. In addition, the predictive value for cardiac events (i.e., ventricular arrhythmia, progression of CHF and cardiac death) of 123I-mIBG parameters and these inflammatory markers was evaluated. MATERIALS AND METHODS: Fifty-five CHF patients (age 66.3 ± 8.0 years, 78% male, LVEF 22.4 ± 6.3) referred for cardiac 123I-mIBG imaging were included. At 15 minutes (early) and 4 hours (late) after i.v. administration of 123I-mIBG (185 MBq), planar images were acquired. Early Heart/Mediastinum (H/M) ratio, late H/M ratio, and 123I-mIBG washout (WO) were calculated. NT-proBNP and markers of inflammation (i.e., C-reactive protein (CRP), IL-1ß, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor-α (TNF-α), soluble (s)E-selectin, myeloperoxidase (MPO), plasminogen activator inhibitor-1 (PAI-1), tPA, tumor necrosis factor receptor (TNFR) 1 and 2, and interferon (IFN) α and ß) were measured in blood plasma samples, taken just before 123I-mIBG administration. RESULTS: Mean early H/M ratio was 2.12 ± 0.39, late H/M ratio was 1.84 ± 0.40, and 123I-mIBG WO was 13.0 ± 10.9. LVEF was the only independent predictor of late H/M ratio (adjusted R 2 = 0.100, p = 0.011). NT-proBNP was an independent predictor of 123I-mIBG WO (adjusted R 2 = 0.090, p = 0.015). CRP, IL12p40, TNF-α, sE-selectin, MPO, PAI-1, tPA, and TNFR2 were not related to late H/M ratio and 123I-mIBG WO. During a median follow-up of 34 months (2-58 months), 13 patients experienced a cardiac event [ventricular arrhythmia (4), progression of CHF (4), and cardiac death (5)]. Univariate Cox regression analysis showed that the risk of a cardiac event was associated with CRP (HR 1.047 [1.013-1.081]), NT-proBNP (HR 1.141 [1.011-1.288]), MPO (HR 0.998 [0.996-1.000]), and late H/M ratio (HR 0.182 [0.035-0.946]). Multivariate Cox regression analysis showed that only CRP, NT-proBNP, MPO, and IL-12p40 were predictors of a cardiac event. CONCLUSION: Inflammation and cardiac sympathetic activity seem not to be related in stable CHF patients. This is corroborated by the finding that they both provide prognostic information in this specific CHF population. The current findings should be regarded as insightful but preliminary.

A European myocardial 123I-mIBG cross-calibration phantom study.

AIM: Planar myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy is a highly reproducible technique. However, differences in collimator use are one of the most important factors that cause variation among institutions and studies in heart-to-mediastinum (H/M) ratio. Therefore, standardization among various gamma camera-collimator combinations is needed. Previously, a phantom has been developed to cross-calibrate different acquisition conditions in Japan. For further cross-calibration of European myocardial 123I-mIBG imaging, the aim of this study was to collect 123I-mIBG data for H/M ratios from common European gamma camera vendors. METHODS: 210 experiments were performed in 27 European institutions. Based on these experiments, conversion coefficients for each gamma camera-collimator combination were calculated. An averaged conversion coefficient of 0.88 was used to calculate a standardized H/M ratio. RESULTS: On average, LE-collimator-derived H/M ratios were significantly lower compared to ME-collimator-derived H/M ratios. The mean conversion coefficients ranged from 0.553 to 0.605 for the LE-collimator group and from 0.824 to 0.895 for the ME-collimator group. CONCLUSION: Clinically established H/M ratios can be converted into standardized H/M ratios using cross-calibrated conversion coefficients. This standardization is important for identifying appropriate thresholds for adequate risk stratification. In addition, this cross-calibration enables comparison between different national and international data.

FDG-PET/CT for differentiating between aseptic and septic delayed union in the lower extremity.

BACKGROUND: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has proven to have a high diagnostic accuracy for the detection of bone infections. In patients with delayed union it may be clinically important to differentiate between aseptic and septic delayed union. The aim of this study was to evaluate the efficacy and to assess the optimal diagnostic accuracy of FDG-PET/CT in differentiating between aseptic and septic delayed union in the lower extremity. METHODS: This is a retrospective study of consecutive patients who underwent FDG-PET/CT scanning for suspicion of septic delayed union of the lower extremity. Diagnosis of aseptic delayed union or septic delayed union was made based on surgical deep cultures following PET/CT scanning and information on clinical follow-up. FDG-uptake values were measured at the fractured site by use of the maximum standardized uptake value (SUVmax). Sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were calculated at various SUVmax cut-off points. RESULTS: A total of 30 patients were included; 13 patients with aseptic delayed unions and 17 patients with septic delayed unions. Mean SUVmax in aseptic delayed union patients was 3.23 (SD ± 1.21). Mean SUVmax in septic delayed union patients was 4.77 (SD ± 1.87). A cut-off SUVmax set at 4.0 showed sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were 65, 77 and 70% to differentiate between aseptic and septic delayed union, respectively. CONCLUSION: Using a semi-quantitative measure (SUVmax) for interpretation of FDG-PET/CT imaging seems to be a promising tool for the discrimination between aseptic and septic delayed union.

Assessment of 123I-mIBG and 99mTc-tetrofosmin single-photon emission computed tomographic images for the prediction of arrhythmic events in patients with ischemic heart failure: Intermediate severity innervation defects are associated with higher arrhythmic risk.

RATIONALE: 123I-mIBG planar image heart-to-mediastinum ratios effectively risk-stratify heart failure (HF) patients. The value of single-photon emission computed tomographic (SPECT) imaging for identifying increased risk of ventricular arrhythmias is less clear. This study sought to determine if findings from simultaneous interpretation of 123I-mIBG and 99mTc-tetrofosmin SPECT are predictive of arrhythmic events (ArEs). METHODS: 123I-mIBG SPECT images from 622 patients with ischemic HF were presented in standard displays alongside 99mTc-tetrofosmin images. Consensus interpretations using a 17-segment model produced summed scores. Cox proportional hazards analyses related findings to adjudicated ArEs over 2 years. RESULTS: 471 patients had images adequate for total 17-segment scoring. There were 48 ArEs (10.2%). Neither 123I-mIBG nor 99mTc-tetrofosmin SPECT summed scores were univariate predictors. On multivariate proportional hazards analysis, the 123I-mIBG SPECT score was independently predictive of ArEs (HR: 0.975, 95% CI 0.951-0.999, P = 0.042), but HR<1 indicated that risk decreased with increasing score. This occurred because patients with intermediately abnormal SPECT studies had a higher likelihood of ArEs compared to patients with extensive abnormalities. CONCLUSIONS: The presumption of a monotonic increase in ArE risk with increasing summed 123I-mIBG SPECT score may not be correct as ischemic HF patients with abnormalities of intermediate extent appear at highest risk.

Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high-risk neuroblastoma.

BACKGROUND: Patients with newly diagnosed high-risk (HR) neuroblastoma (NBL) still have a poor outcome, despite multi-modality intensive therapy. This poor outcome necessitates the search for new therapies, such as treatment with 131I-meta-iodobenzylguanidine (131I-MIBG). OBJECTIVES: To assess the efficacy and adverse effects of 131I-MIBG therapy in patients with newly diagnosed HR NBL. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 3), MEDLINE (PubMed) (1945 to 25 April 2016) and Embase (Ovid) (1980 to 25 April 2016). In addition, we handsearched reference lists of relevant articles and reviews. We also assessed the conference proceedings of the International Society for Paediatric Oncology, Advances in Neuroblastoma Research and the American Society of Clinical Oncology; all from 2010 up to and including 2015. We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institutes of Health Register for ongoing trials (www.clinicaltrials.gov) on 13 April 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled clinical trials (CCTs), non-randomised single-arm trials with historical controls and cohort studies examining the efficacy of 131I-MIBG therapy in 10 or more patients with newly diagnosed HR NBL. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction. MAIN RESULTS: We identified two eligible cohort studies including 60 children with newly diagnosed HR NBL. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. In one study, the objective response rate (ORR) was 73% after surgery; the median overall survival was 15 months (95% confidence interval (CI) 7 to 23); five-year overall survival was 14.6%; median event-free survival was 10 months (95% CI 7 to 13); and five-year event-free survival was 12.2%. In the other study, the ORR was 56% after myeloablative therapy and autologous stem cell transplantation; 10-year overall survival was 6.25%; and event-free survival was not reported. With regard to short-term adverse effects, one study showed a prevalence of 2% (95% CI 0% to 13%; best-case scenario) for death due to myelosuppression. After the first cycle of 131I-MIBG therapy in one study, platelet toxicity occurred in 38% (95% CI 18% to 61%), neutrophil toxicity in 50% (95% CI 28% to 72%) and haemoglobin toxicity in 69% (95% CI 44% to 86%); after the second cycle this was 60% (95% CI 36% to 80%) for platelets and neutrophils and 53% (95% CI 30% to 75%) for haemoglobin. In one study, the prevalence of hepatic toxicity during or within four weeks after last the MIBG treatment was 0% (95% CI 0% to 9%; best-case scenario). Neither study reported cardiovascular toxicity and sialoadenitis. One study assessed long-term adverse events in some of the children: there was elevated plasma thyroid-stimulating hormone in 45% (95% CI 27% to 65%) of children; in all children, free T4 was within the age-related normal range (0%, 95% CI 0% to 15%). There were no secondary malignancies observed (0%, 95% CI 0% to 9%), but only five children survived more than four years. AUTHORS' CONCLUSIONS: We identified no RCTs or CCTs comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in patients with newly diagnosed HR NBL. We found two small observational studies including chilren. They had high risk of bias, and not all relevant outcome results were available. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in patients with newly diagnosed HR NBL in clinical practice. More high-quality research is needed.

Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease.

BACKGROUND: Human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) may both contribute to the higher prevalence of osteoporosis and osteopenia in HIV-infected individuals. METHODS: Using dual-energy X-ray absorptiometry, we compared lumbar spine, total hip, and femoral neck bone mineral density (BMD) in 581 HIV-positive (94.7% receiving cART) and 520 HIV-negative participants of the AGEhIV Cohort Study, aged ≥45 years. We used multivariable linear regression to investigate independent associations between HIV, HIV disease characteristics, ART, and BMD. RESULTS: The study population largely consisted of men who have sex with men (MSM). Osteoporosis was significantly more prevalent in those with HIV infection (13.3% vs 6.7%; P<.001). After adjustment for body weight and smoking, being HIV-positive was no longer independently associated with BMD. Low body weight was more strongly negatively associated with BMD in HIV-positive persons with a history of a Centers for Disease Control and Prevention class B or C event. Interestingly, regardless of HIV status, younger MSM had significantly lower BMD than older MSM, heterosexual men, and women. CONCLUSIONS: The observed lower BMD in treated HIV-positive individuals was largely explained by both lower body weight and more smoking. Having experienced symptomatic HIV disease, often associated with weight loss, was another risk factor. The low BMD observed in younger MSM remains unexplained and needs further study.

MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis.

PURPOSE: The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma. METHODS: Diagnostic (123)I-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: "focal" (clear margins distinguishable from adjacent background) or "diffuse" (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse. RESULTS: Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P < 0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P < 0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: "limited-focal" and "extensive-diffuse". The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P < 0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60% and 70%, respectively) than patients with the other types of metastases (23% and 28%, respectively; P < 0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P < 0.01). CONCLUSION: Two metastatic patterns were found: a "limited and focal" pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an "extensive and diffuse" pattern found mainly in patients with MYCNsc neuroblastoma.

EANM procedural guidelines for radionuclide myocardial perfusion imaging with SPECT and SPECT/CT: 2015 revision.

Since the publication of the European Association of Nuclear Medicine (EANM) procedural guidelines for radionuclide myocardial perfusion imaging (MPI) in 2005, many small and some larger steps of progress have been made, improving MPI procedures. In this paper, the major changes from the updated 2015 procedural guidelines are highlighted, focusing on the important changes related to new instrumentation with improved image information and the possibility to reduce radiation exposure, which is further discussed in relation to the recent developments of new International Commission on Radiological Protection (ICRP) models. Introduction of the selective coronary vasodilator regadenoson and the use of coronary CT-contrast agents for hybrid imaging with SPECT/CT angiography are other important areas for nuclear cardiology that were not included in the previous guidelines. A large number of minor changes have been described in more detail in the fully revised version available at the EANM home page: http://eanm.org/publications/guidelines/2015_07_EANM_FINAL_myocardial_perfusion_guideline.pdf .

Upfront treatment of high-risk neuroblastoma with a combination of 131I-MIBG and topotecan.

BACKGROUND: (131)I-metaiodobenzylguanidine ((131) I-MIBG) has a significant anti-tumor effect against neuroblastoma (NBL). Topotecan (TPT) can act as a radio-sensitizer and can up-regulate (131) I-MIBG uptake in vitro in NBL. AIM: Determine the efficacy of the combination of (131) I-MIBG with topotecan in newly diagnosed high-risk (HR) NBL patients. METHODS: In a prospective, window phase II study, patients with newly diagnosed high-risk neuroblastoma were treated at diagnosis with two courses of (131) I-MIBG directly followed by topotecan (0.7 mg/m(2) for 5 days). After these two courses, standard induction treatment (four courses of VECI), surgery and myeloablative therapy (MAT) with autologous stem cell transplantation (ASCT) was given. Response was measured after two courses of (131) I-MIBG-topotecan and post MAT and ASCT. Hematologic toxicity and harvesting of stem cells were analysed. Topoisomerase-1 activity levels were analysed in primary tumor material. RESULTS: Sixteen patients were included in the study; median age was 2.8 years. MIBG administered activity (AA) (median and range) of the first course was 0.5 (0.4-0.6) GBq/kg (giga Becquerel/kilogram) and of the second course 0.4 (0.3-0.5) GBq/kg. The overall objective response rate (ORR) after 2 × MIBG/TPT was 57%, the primary tumor RR was 94%, and bone marrow RR was 43%. The ORR post MAT and ASCT was 57%. Hematologic grade four toxicity: after first and second (131) I-MIBG (platelets 25/33%, neutrophils 13/33%, and hemoglobin 25/7%). Topoisomerase-1 activity levels were increased in 10/10 (100%) measured tumors. CONCLUSIONS: Combination therapy with MIBG-topotecan is an effective window treatment in newly diagnosed high-risk neuroblastoma patients.

Impact of a predefined mediastinal ROI on inter-observer variability of planar ¹²³I-MIBG heart-to-mediastinum ratio.

AIM: Purpose of this study was to assess the impact of mediastinal region of interest (ROI) definition on intra- and inter-observer variability in relation to collimator type. METHODS: Thirty-five subjects with CHF (80% men, mean age 66 ± 9 years, NYHA 2.4 ± 0.5, LVEF 29 ± 8.4%) were enrolled. 15 minutes and 4 hours post-injection (p.i.) of (123)I-MIBG, planar images were sequentially acquired with low energy high energy (LEHR) and medium energy (ME) collimators. In the first analysis, observer-defined mediastinal ROI was used. In the second analysis, a predefined mediastinal ROI was used. Intra- and inter-observer variability of late H/M was assessed using Lin's concordance coefficient (LCC). RESULTS: There was substantial agreement between all three observers using predefined mediastinum ROI. LCCs for LEHR were 0.98, 0.96, and 0.95, for ME 0.98, 0.97, and 0.97. However, observer-defined mediastinal ROI resulted in poor-moderate agreement. LCCs for LEHR were 0.82, 0.94, and 0.70, for ME 0.77, 0.91, and 0.80. Intra-observer analysis using predefined mediastinal ROI showed substantial agreement. LCC was 0.97 for LEHR and 0.96 for ME. CONCLUSION: Predefined mediastinal ROI results in low intra- and inter-observer variability of late H/M and is, therefore, to be preferred over observer-defined mediastinal ROI. Intra- and inter-observer variability of late H/M is not influenced by collimator choice.

Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging.

Tako-tsubo cardiomyopathy (TCM) is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction, commonly preceded by exposure to severe physical or emotional stress. In this review, we give a short overview on clinical presentation and treatment of TCM and discuss the possible pathophysiological mechanisms of TCM and the role of various non-invasive imaging modalities in TCM with a focus on the potential role of (123)I-meta-iodobenzylguanidine (MIBG) scintigraphy. Currently, the dominating hypothesis on the pathophysiology of TCM postulates that high levels of the neurotransmitter epinephrine may trigger a change in intracellular signaling in ventricular myocytes. More specific, epinephrine stimulates G-protein coupled ß2 adenoreceptors (ß2AR) which are located on ventricular myocytes. Normal levels of this neurotransmitter predominantly stimulate the intracellular G-protein, and induce a positive inotropic effect. However, with significant increasing levels of epinephrine, the predominance of stimulation is shifted from G-stimulating to the G-inhibitor protein coupling, which leads to a negative inotropic effect. Interestingly, this negative inotropic effect is the largest in the apical myocardium where the ß2AR:ß1AR ratio is the highest within the heart. Echocardiography and ventriculography are essential to diagnose TCM, but new imaging tools are promising to diagnose TCM and to evaluate therapeutic efficacy. Cardiovascular magnetic resonance can be used to differentiate TCM from other myocardial diseases, such as myocarditis. (123)I-meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy can be used to assess ventricular adrenergic activity and may guide optimization of individual (pharmacological) therapy. These new insights into the possible pathophysiological mechanisms and novel diagnostic imaging modalities can be used as starting point for the development of international guidelines of TCM which may increase the awareness, and optimize the treatment of TCM.

Bone mineral density increases in HIV-infected children treated with long-term combination antiretroviral therapy.

The long-term treatment of human immunodeficiency virus (HIV)-infected children with combination antiretroviral therapy (cART) requires assessment of potential adverse effects, such as osteoporosis. Longitudinal data on bone mineral density (BMD) in HIV-infected children showed that cumulative treatment with cART had a positive impact on BMD over time.

Lymphatic mapping for image-guided radiotherapy in patients with locally advanced uterine cervical cancer: a feasibility study.

BACKGROUND: Lymph node metastasis is an important prognostic factor in locally advanced cervical cancer (LACC). No imaging method can successfully detect all (micro)metastases. This may result in (lymph node) recurrence after chemoradiation. We hypothesized that lymphatic mapping could identify nodes at risk and if radiation treatment volumes are adapted based on the lymphatic map, (micro)metastases not shown on imaging could be treated. We investigated the feasibility of lymphatic mapping to image lymph nodes at risk for (micro)metastases in LACC and assessed the radiotherapy dose on the nodes at risk. METHODS: Patients with LACC were included between July 2020 and July 2022. Inclusion criteria were: ≥ 18 years old, intended curative chemoradiotherapy, investigation under anesthesia. Exclusion criteria were: pregnancy and extreme obesity. All patients underwent abdominal MRI, [18F]FDG-PET/CT and lymphatic mapping after administration of 6-8 depots of 99mTc]Tc-nanocolloid followed by planar and SPECT/CT images 2-4 and 24 h post-injection. RESULTS: Seventeen patients participated. In total, 40 nodes at risk were visualized on the lymphatic map in 13/17 patients with a median of two [range 0-7, IQR 0.5-3] nodes per patient, with unilateral drainage in 4/13 and bilateral drainage in 9/13 patients. No complications occurred. The lymphatic map showed more nodes compared to suspicious nodes on MRI or [18F]FDG-PET/CT in 8/14 patients. Sixteen patients were treated with radiotherapy with 34 visualized nodes on the lymphatic map. Of these nodes, 20/34 (58.8%) received suboptimal radiotherapy: 7/34 nodes did not receive radiotherapy at all, and 13/34 received external beam radiotherapy (EBRT), but no simultaneous integrated boost (SIB). CONCLUSION: Lymphatic mapping is feasible in LACC. Almost 60% of nodes at risk received suboptimal treatment during chemoradiation. As treatment failure could be caused by (micro)metastasis in some of these nodes, including nodes at risk in the radiotherapy treatment volume could improve radiotherapy treatment outcome in LACC. Trail registration The study was first registered at the International Clinical Trial Registry Platform (ICTRP) under number of NL9323 on 4 March 2021. Considering the source platform was not operational anymore, the study was retrospectively registered again on February 27, 2023 at CilicalTrials.gov under number of NCT05746156.

Chronic pulmonary embolism in Klippel-Trenaunay syndrome.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is characterized by vascular malformations and disturbed soft tissue or bony growth, involving one or more extremities. A high incidence of venous thromboembolism (VTE) has been reported in this disorder, along with cases of belated diagnosed chronic thromboembolic (CTE) pulmonary hypertension (CTEPH). We performed a cross-sectional study to investigate the prevalence of CTE in patients with KTS. METHODS: Those from our KTS patient cohort willing to participate were examined with a sequential diagnostic workup including perfusion scintigraphy, computed tomography, and echocardiography. RESULTS: Of 68 patients, 48 patients participated in the study (median age 43 years; 29 [60%] were female). Eleven patients (23%) had an abnormal perfusion scan result, of whom computed tomographic scanning showed signs of CTE in two patients (4.2%; 95% confidence interval [CI] 1.2%-14%); both patients had a history of VTE. Echocardiography showed no signs of CTEPH in these patients. In total, 23 patients (48%; 95% CI 35%-62%) had a history of superficial vein thrombosis and 8 patients (17%; 95% CI 8.7%-30%) had a history of deep vein thrombosis or pulmonary embolism, which was associated with more shortness of breath. LIMITATIONS: Echocardiography was only performed in patients with CTE. CONCLUSION: A large proportion of patients with KTS had a history of VTE. The prevalence of CTE in the total KTS cohort, however, appeared less alarming than previously assumed. Based on these results, we suggest that there is only a limited indication for CTEPH screening among patients with KTS. Nevertheless, awareness for CTEPH remains appropriate, especially among patients presenting with shortness of breath and a history of VTE.

Imaging of programmed cell death in arrhythmogenic right ventricle cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibrofatty replacement of the RV myocardium. Apoptosis in ARVC/D has been proposed as an important process that mediates the slow, ongoing loss of heart muscle cells which is followed by ventricular dysfunction. We aimed to establish whether cardiac apoptosis can be assessed noninvasively in patients with ARVC/D. METHODS: Six patients fulfilling the ARVC/D criteria were studied. Regional myocardial apoptosis was assessed with (99m)Tc-annexin V scintigraphy. RESULTS: Overall, the RV wall showed a higher (99m)Tc-annexin V signal than the left ventricular wall (p = 0.049) and the interventricular septum (p = 0.026). However, significantly increased uptake of (99m)Tc-annexin V in the RV was present in only three of the six ARVC/D patients (p = 0.001, compared to (99m)Tc-annexin V uptake in the RV wall of the other three patients). CONCLUSION: Our results are suggestive of a chamber-specific apoptotic process. Although the role of apoptosis in ARVC/D is unsolved, the ability to assess apoptosis noninvasively may aid in the diagnostic course. In addition, the ability to detect apoptosis in vivo with (99m)Tc-annexin V scintigraphy might allow individual monitoring of disease progression and response to diverse treatments aimed at counteracting ARVC/D progression.

Vascular time-activity variation in patients undergoing ¹²³I-MIBG myocardial scintigraphy: implications for quantification of cardiac and mediastinal uptake.

PURPOSE: For the quantification of cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake, the mediastinum is commonly used as a reference region reflecting nonspecific background activity. However, variations in the quantity of vascular structures in the mediastinum and the rate of renal clearance of (123)I-MIBG from the blood pool may contribute to increased interindividual variation in uptake. This study examined the relationship between changes in heart (H) and mediastinal (M) counts and the change in vascular (123)I-MIBG activity, including the effect of renal function. METHODS: Fifty-one subjects with ischemic heart disease underwent early (15 min) and late (4 h) anterior planar images of the chest following injection of (123)I-MIBG. Vascular (123)I-MIBG activity was determined from venous blood samples obtained at 2 min, 15 min, 35 min, and 4 h post-injection. From the vascular clearance curve of each subject, the mean blood counts/min per ml at the time of each acquisition and the slope of the clearance curve were determined. Renal function was expressed as the estimated creatinine clearance (e-CC) and the estimated glomerular filtration rate (e-GFR). Relations between H and M region of interest (ROI) counts/pixel, vascular activity, and renal function were then examined using linear regression. RESULTS: Changes in ROI activity ratios between early and late planar images could not be explained by blood activity, the slope of the vascular clearance curves, or estimates of renal function. At most 3% of the variation in image counts could be explained by changes in vascular activity (p = 0.104). The e-CC and e-GFR could at best explain approximately 1.5% of the variation in the slopes of the vascular clearance curve (p = 0.194). CONCLUSION: The change in measured H and M counts between early and late planar (123)I-MIBG images is unrelated to intravascular levels of the radiopharmaceutical. This suggests that changes in M counts are primarily due to decrease in soft tissue activity and scatter from the adjacent lungs.

Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

PURPOSE: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibro-fatty replacement of RV myocardium. However, patchy inflammatory infiltrates in the RV are also consistently reported using autopsy and myocardial biopsy. Although the role of inflammation in ARVC/D is unresolved, the ability to assess inflammation non-invasively may aid in the diagnostic process. We aimed to establish whether cardiac inflammation can be assessed non-invasively in ARVC/D patients. METHODS: In eight ARVC/D patients and nine controls (haematology/oncology patients), the level of inflammatory activation was assessed by measuring plasma levels of inflammatory cytokines. Regional myocardial inflammation was assessed with (67)Ga scintigraphy. RESULTS: ARVC/D patients had higher plasma levels than controls of the pro-inflammatory cytokines interleukin (IL)-1ß (1.22 ± 0.07 vs 0.08 ± 0.01 pg/ml, p < 0.0001), IL-6 (3.16 ± 0.44 vs 0.38 ± 0.04 pg/ml, p < 0.0001) and tumour necrosis factor (TNF)-α (9.16 ± 0.90 vs 0.40 ± 0.06 pg/ml, p < 0.0001), while levels of the anti-inflammatory cytokine IL-10 were not significantly different (1.36 ± 0.15 vs 1.20 ± 0.30 pg/ml, p = 0.74). (67)Ga uptake in the RV was higher in ARVC/D patients than in controls. In ARVC/D patients, (67)Ga uptake in the RV wall was higher than in the interventricular septum or left ventricular wall. CONCLUSION: Inflammation in the RV wall of ARVC/D patients can be detected non-invasively with the combined analysis of plasma levels of inflammatory cytokines and cardiac (67)Ga scintigraphy.