TGFBR1*6A as a modifier of breast cancer risk and progression: advances and future prospects.

There is growing evidence that germline mutations in certain genes influence cancer susceptibility, tumor evolution, as well as clinical outcomes. Identification of a disease-causing genetic variant enables testing and diagnosis of at-risk individuals. For breast cancer, several genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 act as high- to moderate-penetrance cancer susceptibility genes. Genotyping of these genes informs genetic risk assessment and counseling, as well as treatment and management decisions in the case of high-penetrance genes. TGFBR1*6A (rs11466445) is a common variant of the TGF-ß receptor type I (TGFBR1) that has a global minor allelic frequency (MAF) of 0.051 according to the 1000 Genomes Project Consortium. It is emerging as a high frequency, low penetrance tumor susceptibility allele associated with increased cancer risk among several cancer types. The TGFBR1*6A allele has been associated with increased breast cancer risk in women, OR 1.15 (95% CI 1.01-1.31). Functionally, TGFBR1*6A promotes breast cancer cell proliferation, migration, and invasion through the regulation of the ERK pathway and Rho-GTP activation. This review discusses current findings on the genetic, functional, and mechanistic associations between TGFBR1*6A and breast cancer risk and proposes future directions as it relates to genetic association studies and mechanisms of action for tumor growth, metastasis, and immune suppression.

Hybrid PET/MRI in non-small cell lung cancer (NSCLC) and lung nodules-a literature review.

BACKGROUND: The use of hybrid PET/MRI for clinical staging is growing in several cancer forms and, consequently, PET/MRI has also gained interest in the assessment of non-small cell lung cancer (NSCLC) and lung lesions. However, lung evaluation with PET/MRI is associated with challenges related to technical issues and diagnostic image quality. We, therefore, investigated the published literature on PET/MRI for clinical staging in NSCLC or lung nodule detection specifically addressing diagnostic accuracy and technical issues. METHODS: The data originates from a systematic search performed in PubMed/MEDLINE, Embase, and Cochrane Library on hybrid PET/MRI in patients with cancer for a scoping review published earlier ( https://doi.org/10.1007/s00259-019-04402-8 ). Studies in English and German evaluating the diagnostic performance of hybrid PET/MRI for NSCLC or lung nodule detection in cancer patients were selected. Data reported in peer-reviewed journals without restrictions to year of publication were included. RESULTS: A total of 3138 publications were identified from which 116 published 2012-2018 were included. Of these, nine studies addressed PET/MRI in NSCLC (4) or lung nodule detection (5). Overall, PET/MRI did not provide advantages in preoperative T- and N-staging in NSCLC compared to PET/CT. The data on M-staging were too few for conclusions to be drawn. The lung nodule detection rate of PET/MRI was comparable to that of PET/CT for FDG-avid nodules larger than 10 mm, but the sensitivity of PET/MRI for detection of non-FDG-avid nodules smaller than 5 mm was low. CONCLUSION: PET/MRI did not provide advantages in T- and N-staging of NSCLC compared to PET/CT. PET/MRI had a comparable sensitivity for detection of FDG-avid lung nodules and nodules over 10 mm, but PET/CT yielded a higher detection rate in non FDG-avid lung nodules under 5 mm. With PET/MRI, the overall detection rate for lung nodules in various cancer types remains inferior to that of PET/CT due to the lower diagnostic performance of MRI than CT in the lungs.

Hybrid PET/MRI in major cancers: a scoping review.

PURPOSE: PET/MRI was introduced for clinical use in 2011 and is now an established modality for the imaging of brain and certain pelvic cancers, whereas clinical use for the imaging of other forms of cancer is not yet widespread. We therefore systematically investigated what has been published on the use of PET/MRI compared to PET/CT in the imaging of cancers outside the brain, focusing on clinical areas of application related to diagnosis, staging and restaging. METHODS: A systematic search of PubMed/MEDLINE, Embase and the Cochrane Library was performed. Studies evaluating the diagnostic performance of simultaneous PET/MRI in cancer patients were chosen. RESULTS: A total of 3,138 publications were identified and 116 published during the period 2012-2018 were included and were grouped according to the major cancer forms: 13 head and neck (HNC), 9 breast (BC), 21 prostate (PC), 14 gynaecological, 13 gastrointestinal (GIC), and 46 various cancers. Data from studies comparing PET/MRI and PET/CT for staging/restaging suggested the superiority of 18F-FDG PET/MRI for the detection of tumour extension and retropharyngeal lymph node metastases in nasopharyngeal cancer, and for the detection of liver metastases and possibly bone marrow metastases in high-risk BC. FDG PET/MRI tended to be inferior for the detection of lung metastases in HNC and BC. 68Ga-PSMA-11 PET/MRI was superior to PET/CT for the detection of local PC recurrence. FDG PET/MRI was superior to FDG PET/CT for the detection of local tumour invasion in cervical cancer and had higher accuracy for the detection of liver metastases in colorectal cancer. CONCLUSION: The scoping review methodology resulted in the identification of a huge number of records, of which less than 5% were suitable for inclusion and only a limited number allowed conclusions on the advantages/disadvantages of PET/MRI compared to PET/CT in the oncological setting. There was evidence to support the use of FDG PET/MRI in staging of nasopharyngeal cancer and high-risk BC. Preliminary data indicate the superiority of PET/MRI for the detection of local recurrence in PC, local tumour invasion in cervical cancer, and liver metastases in colorectal cancer. These conclusions are based on small datasets and need to be further explored.

15-O-water myocardial flow reserve PET and CT angiography by full hybrid PET/CT as a potential alternative to invasive angiography.

Combined myocardial flow reserve (MFR) by PET and CT coronary angiography (CTA) is a promising tool for assessment of coronary artery disease. Prior analyses of MFR/CTA has been performed as side-by-side interpretation, not as volume rendered, full hybrid analysis, with fused MFR/CTA. We aimed to: (i) establish a method for full hybrid analysis of MFR/CTA, (ii) validate the inter- and intra-observer reproducibility of MFR values, and (iii) determine the diagnostic value of side-by-side versus full hybrid MFR/CTA with 15-O-water PET. Forty-four outpatients scheduled for invasive coronary angiography (ICA) were enrolled prospectively. All underwent rest/stress 15-O-water PET/CTA with ICA as reference. Within two observers of different experience, the Pearson r at global and territorial level exceeded 0.953 for rest, stress, and MFR values, as determined by Carimas software. Within and between observers, the mean differences between rest, stress, and MFR values were close to zero and the confidence intervals for 95% limits of agreement were narrow. The diagnostic performance of full hybrid PET/CTA did not outperform the side-by-side approach, but performed better than MFR without CTA at vessel level: specificity 93% (95% confidence limits: 89-97%) versus 76% (64-88%), p = 0.0004; positive predictive value 71% (55-86%) versus 51% (37-65%), p = 0.0001; accuracy 90% (84-95%) versus 77% (69-84%), p = 0.0009. MFR showed high reproducibility within and between observers of different experience. The full hybrid model was not superior to side-by-side interpretation of MFR/CTA, but proved better than MFR alone at vessel level with regard to specificity, positive predictive value, and accuracy.

Prospective Comparison of FFR Derived From Coronary CT Angiography With SPECT Perfusion Imaging in Stable Coronary Artery Disease: The ReASSESS Study.

OBJECTIVES: This study sought to compare the per-patient diagnostic performance of coronary computed tomography angiography (CTA)-derived fractional flow reserve (FFRCT) with that of single-photon emission computed tomography (SPECT), using a fractional flow reserve (FFR) value of ≤0.80 as the reference for diagnosing at least 1 hemodynamically significant stenosis in a head-to-head comparison of patients with intermediate coronary stenosis as determined by coronary CTA. BACKGROUND: No previous study has prospectively compared the diagnostic performance of FFRCT and myocardial perfusion imaging by SPECT in symptomatic patients with intermediate range coronary artery disease (CAD). METHODS: This study was conducted at a single-center as a prospective study in patients with stable angina pectoris (N = 143). FFRCT and SPECT analyses were performed by core laboratories and were blinded for the personnel responsible for downstream patient management. FFRCT ≤0.80 distally in at least 1 coronary artery with a diameter ≥2 mm classified patients as having ischemia. Ischemia by SPECT was encountered if a reversible perfusion defect (summed difference score ≥2) or transitory ischemic dilation of the left ventricle (ratio >1.19) were found. RESULTS: The per-patient diagnostic performance for identifying ischemia (95% confidence interval [CI]), FFRCT versus SPECT, were sensitivity of 91% (95% CI: 81% to 97%) versus 41% (95% CI: 29% to 55%; p < 0.001); specificity of 55% (95% CI: 44% to 66%) versus 86% (95% CI: 77% to 93%; p < 0.001); negative predictive value of 90% (95% CI: 82% to 98%) versus 68% (95% CI: 59% to 77%; p = 0.001); positive predictive value of 58% (95% CI: 48% to 68%) versus 67% (95% CI: 51% to 82%; p = NS); and accuracy of 70% (95% CI: 62% to 77%) versus 68% (95% CI: 60% to 75%; p = NS) respectively. CONCLUSIONS: In patients with stable chest pain and CAD as determined by coronary CTA, the overall diagnostic accuracy levels of FFRCT and SPECT were identical in assessing hemodynamically significant stenosis. However, FFRCT demonstrated a significantly higher diagnostic sensitivity than SPECT.

Outcome of revascularisation in stable coronary artery disease without ischaemia: a Danish registry-based follow-up study.

OBJECTIVES: In stable coronary artery disease (CAD), coronary revascularisation may reduce mortality of patients with a certain amount of left ventricular myocardial ischaemia. However, revascularisation does not always follow the guidance suggested by ischaemia testing. We compared outcomes in patients without ischaemia who had either revascularisation or medical treatment. DESIGN AND POPULATION: Based on registries, 1327 consecutive patients with normal myocardial perfusion scintigraphy (MPS) and 278 with fixed perfusion defects were followed for a median of 6.1 years. Most patients received medical therapy alone (Med), but 26 (2%) with a normal MPS and 15 (5%) with fixed perfusion defects underwent revascularisation (Revasc). OUTCOME MEASURES: Incidence rates of all-cause death (ACD) and rates of cardiac death/myocardial infarction (CD/MI). RESULTS: With a normal MPS, the ACD rate was 6.2%/year in the Revasc group versus 1.9%/year in the Med group (p=0.01); the CD/MI rates were 6.9%/year and 0.6%/year, respectively (p<0.00001). Results persisted after adjustment for predictors of revascularisation, in particular angina score, and in comparisons of matched Revasc and Med patients. With fixed defects, the ACD rate was 9.1%/year in the Revasc group and 6.7%/year in the Med group (p=0.44); the CD/MI rate was 5.0%/year versus 4.2%/year, respectively (p=0.69). If adjusted for angiographic variables or analysed in matched subsets, differences remained insignificant. CONCLUSIONS: With normal MPS, revascularisation conferred a higher risk, even after adjustment for predictors of revascularisation. With fixed defects, the Revascversus Med difference was close to equipoise. Hence, in patients with stable CAD without ischaemia, we could not find evidence to justify exceptional revascularisation.

18F-FDG PET/CT to differentiate malignant necrotic lymph node from benign cystic lesions in the neck.

OBJECTIVE: Patients presenting with cystic lesions in the neck without obvious signs of malignancy constitute a diagnostic challenge since fine needle aspiration is often insufficient and a diagnosis may not be reached until surgical resection/biopsy is performed. The differential diagnosis of a cystic cervical mass comprises a variety of benign conditions, but malignancy must be ruled out. We examined the diagnostic performance of fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT to identify malignancy. METHODS: We retrospectively included consecutive patients referred from the Department of ENT Head and Neck Surgery for 18F-FDG PET/CT-scans because of a solitary neck cyst. Scan results were compared to histopathology and follow-up. RESULTS: The study comprised 58 patients. Twenty patients (34%) were diagnosed with cancer during follow-up. PET/CT suggested malignancy in 34 patients (19 true positive, 15 false positive) and showed no malignancy in 24 (23 true negative, 1 false negative). The sensitivity, specificity, accuracy, positive and negative predictive values were 95% (76-99%), 61% (45-74%), 72% (60-82%), 56% (39-71%), and 96% (80-99%), respectively (95% confidence intervals in brackets). The primary tumor was identified in 14 out of the 20 patients with confirmed cancer. Increased metabolism, as evaluated by PET, was the only imaging characteristic among several others, which associated independently with malignancy in the cystic neck lesions, odds ratio 1.27 (1.07-1.50), p = 0.006. CONCLUSION: 18F-FDG PET/CT could reliably rule out malignancy (NPV 96%), albeit with a high frequency of false positive scans, requiring further diagnostic work-up. Increased metabolism was the best imaging parameter to differentiate between malignant and benign lesions.

Outcome with invasive versus medical treatment of stable coronary artery disease: influence of perfusion defect size, ischaemia, and ejection fraction.

AIMS: Our aim was to address the combined influence of myocardial perfusion defects and left ventricular ejection fraction (LVEF) on outcome with coronary revascularisation in stable CAD patients. METHODS AND RESULTS: Of 527 patients with ischaemia by myocardial perfusion scintigraphy, 343 had medical therapy (Med) and 184 revascularisation (Revasc). During 5.3 years of follow-up, there was no intergroup difference in rates of death/myocardial infarction. Propensity score adjustment demonstrated a benefit of Revasc over Med with large defects (>14% of the myocardium), marked ischaemia (>10% of the myocardium), or LVEF <50%. However, defect size, ischaemia, and LVEF were correlated. In multivariate models, the Med versus Revasc hazard ratio (HR) was 4.06 times larger for LVEF <50% than for LVEF ≥50% (p=0.04) and 3.01 times larger for marked compared to mild/moderate ischaemia (p=0.11), whereas the effect of large compared to small/moderate defects vanished when adjusted for LVEF and ischaemia (HR=1.01, p=0.99). Considering the outcome difference as a function of both LVEF and ischaemia, we found no advantage or even a disadvantage of revascularisation in patients with mild/moderate ischaemia and preserved LVEF. CONCLUSIONS: A benefit of revascularisation was found only in case of marked ischaemia or LVEF <50%. For treatment triage, both perfusion parameters and LVEF should be considered.

FDG PET/CT in cancer: comparison of actual use with literature-based recommendations.

PURPOSE: The Region of Southern Denmark (RSD), covering 1.2 of Denmark's 5.6 million inhabitants, established a task force to (1) retrieve literature evidence for the clinical use of positron emission tomography (PET)/CT and provide consequent recommendations and further to (2) compare the actual use of PET/CT in the RSD with these recommendations. This article summarizes the results. METHODS: A Work Group appointed a professional Subgroup which made Clinician Groups conduct literature reviews on six selected cancers responsible for 5,768 (62.6 %) of 9,213 PET/CT scans in the RSD in 2012. Rapid Evidence Assessment was applied, using the methodology of systematic reviews with predefined limitations to search PubMed, Embase and the Cochrane Library for articles published in English/Danish/Swedish/Norwegian since 2002. PICO questions were defined, data recorded and quality appraised and rated with regard to strength and evidence level. Consequent recommendations for applications of PET/CT were established. The actual use of PET/CT was compared with these, where grades A and B indicated "established" and "useful" and grades C and D "potentially useful" and "non-recommendable" indications, respectively. RESULTS: Of 11,729 citations, 1,729 were considered for review, and 204 were included. The evidence suggested usefulness of PET/CT in lung, lymphoma, melanoma, head and neck, and colorectal cancers, whereas evidence was sparse in gynaecological cancers. The agreement between actual use of PET/CT and literature-based recommendations was high in the first five mentioned cancers in that 96.2 % of scans were made for grade A or B indications versus only 22.2 % in gynaecological cancers. CONCLUSION: Evidence-based usefulness was reported in five of six selected cancers; evidence was sparse in the sixth, gynaecological cancers. Actual use of PET/CT agreed well with recommendations.

Bone Scan Index predicts outcome in patients with metastatic hormone-sensitive prostate cancer.

OBJECTIVE: To evaluate the Bone Scan Index (BSI) for prediction of castration resistance and prostate cancer-specific survival (PCSS). In this retrospective study, we used novel computer-assisted software for automated detection/quantification of bone metastases by BSI. Patients with prostate cancer are M-staged by whole-body bone scintigraphy (WBS) and categorised as M0 or M1. Within the M1 group, there is a wide range of clinical outcomes. The BSI was introduced a decade ago providing quantification of bone metastases by estimating the percentage of bone involvement. Being too time consuming, it never gained widespread clinical use. PATIENTS AND METHODS: In all, 88 patients with prostate cancer awaiting initiation of androgen-deprivation therapy due to metastases were included. WBS was performed using a two-headed γ-camera. BSI was obtained using the automated platform EXINI bone (EXINI Diagnostics AB, Lund, Sweden). In Cox proportional hazard models, time to castration-resistant prostate cancer (CRPC) and PCSS were modelled as the dependent variables, whereas prostate-specific antigen (PSA) level, Gleason score and BSI were used as explanatory factors. For Kaplan-Meier estimates, BSI groups were dichotomously split into: BSI <1 and BSI ≥1. Discrimination between prognostic models was explored using the concordance index (C-index). RESULTS: The mean (range) age of the patients was 72 (52-92) years, the median (range) PSA level was 73 (4-5 740) ng/mL, the mean (range) Gleason score was 7.7 (2-10), and the mean (range) BSI was 1.0 (0-9.2). During a mean (range) follow-up of 26 (8-49) months, 48 patients became castration resistant and 15 had died; most (13) from prostate cancer. In multivariate analysis including PSA level, Gleason score and BSI, only prediction by BSI was statistically significant. This was true both for time to CRPC (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.22-1.74; C-index increase from 0.49 to 0.69) and for PCSS (HR 1.34, 95% CI 1.07-1.67; C-index increase from 0.76 to 0.95). CONCLUSION: BSI obtained using a novel automated computer-assisted algorithm appears to be a useful predictor of outcome for time to CRPC and PCSS in patients with hormone-sensitive metastatic prostate cancer.

Quantitative myocardial perfusion by O-15-water PET: individualized vs. standardized vascular territories.

AIMS: Reporting of quantitative myocardial blood flow (MBF) is typically performed in standard coronary territories. However, coronary anatomy and myocardial vascular territories vary among individuals, and a coronary artery may erroneously be deemed stenosed or not if territorial demarcation is incorrect. So far, the diagnostic consequences of calculating individually vs. standardly assessed MBF values have not been reported. We examined whether individual reassignment of vascular territories would improve the diagnostic accuracy of MBF with regard to the detection of significant coronary artery disease (CAD). METHODS AND RESULTS: Forty-four patients with suspected CAD were included prospectively and underwent coronary CT-angiography and quantitative MBF assessment with O-15-water PET followed by invasive, quantitative coronary angiography, which served as reference. MBF was calculated in the vascular territories during adenosine stress according to a standardized 17-segment American Heart Association model and an individualized model, using CT-angiography to adjust the coronary territories to their feeding vessels. Individually defined territories deviated from standard territories in 52% of patients. However, MBF in the three coronary territories defined by standard and individualized models did not differ significantly, except in one patient, in whom the MBF of an individualized coronary territory deviated sufficiently as to change the test from a false positive to a true negative result in this particular territory. CONCLUSION: Disparity between standardized and individualized vascular territories was present in half of the patients, but had little clinical impact. Still, caution should be taken not always to rely on standard territories, as this may at times cause misinterpretation.

FDG-PET/CT can rule out malignancy in patients with vocal cord palsy.

The aim was to investigate the performance of (18)F-fluorodeoxyglucose PET/CT to rule out malignancy in patients with confirmed vocal cord palsy (VCP). Between January 2011 and June 2013, we retrospectively included consecutive patients referred to PET/CT with paresis or paralysis of one or both vocal cords. PET/CT results were compared to clinical workup and histopathology. The study comprised 65 patients (32 females) with a mean age of 66±12 years (range 37-89). Eleven patients (17%) had antecedent cancer. Twenty-seven (42%) were diagnosed with cancer during follow-up. The palsy was right-sided in 24 patients, left-sided in 37, and bilateral in 4. Median follow-up was 7 months (interquartile range 4-11 months). Patients without cancer were followed for at least three months. PET/CT suggested a malignancy in 35 patients (27 true positives, 8 false positives) and showed none in 30 (30 true negatives, 0 false negatives). Thus, the sensitivity, specificity, positive and negative predictive values, and accuracy were (95% confidence intervals in parenthesis): 100% (88%-100%), 79% (64%-89%), 77% (61%-88%), 100% (89%-100%), and 88% (78%-94%), respectively. Sixteen patients had palliative treatment, while 11 were treated with curative intent, emphasising the severity of VCP and the need for a rapid and accurate diagnostic work-up. In this retrospective survey, biopsy proven malignancy (whether newly diagnosed or relapsed) was the cause of VCP in almost half of patients (42%). PET/CT had a high sensitivity (100%) with a relatively high false positive rate, but was excellent in ruling out malignancy (negative predictive value 100%).

Area of ischemia assessed by physicians and software packages from myocardial perfusion scintigrams.

BACKGROUND: The European Society of Cardiology recommends that patients with >10% area of ischemia should receive revascularization. We investigated inter-observer variability for the extent of ischemic defects reported by different physicians and by different software tools, and if inter-observer variability was reduced when the physicians were provided with a computerized suggestion of the defects. METHODS: Twenty-five myocardial perfusion single photon emission computed tomography (SPECT) patients who were regarded as ischemic according to the final report were included. Eleven physicians in nuclear medicine delineated the extent of the ischemic defects. After at least two weeks, they delineated the defects again, and were this time provided a suggestion of the defect delineation by EXINI HeartTM (EXINI). Summed difference scores and ischemic extent values were obtained from four software programs. RESULTS: The median extent values obtained from the 11 physicians varied between 8% and 34%, and between 9% and 16% for the software programs. For all 25 patients, mean extent obtained from EXINI was 17.0% (± standard deviation (SD) 14.6%). Mean extent for physicians was 22.6% (± 15.6%) for the first delineation and 19.1% (± 14.9%) for the evaluation where they were provided computerized suggestion. Intra-class correlation (ICC) increased from 0.56 (95% confidence interval (CI) 0.41-0.72) to 0.81 (95% CI 0.71-0.90) between the first and the second delineation, and SD between physicians were 7.8 (first) and 5.9 (second delineation). CONCLUSIONS: There was large variability in the estimated ischemic defect size obtained both from different physicians and from different software packages. When the physicians were provided with a suggested delineation, the inter-observer variability decreased significantly.

Hybrid CT angiography and quantitative 15O-water PET for assessment of coronary artery disease: comparison with quantitative coronary angiography.

PURPOSE: CT angiography (CTA) can rule out significant stenoses with a very high reliability, whereas its ability to confirm significant stenoses is suboptimal. In contrast, measurements of myocardial blood flow (MBF) provide information on the haemodynamic consequences of stenoses. Therefore, a combination of the two might improve diagnostic accuracy. We conducted a head-to-head comparison of CTA, measurement of MBF by (15)O-water PET, and hybrid PET/CTA for the detection of significant coronary artery stenoses. METHODS: The study group comprised 44 outpatients scheduled for invasive coronary angiography (ICA) with an intermediate pretest likelihood of coronary artery disease. The patients underwent 64-slice CTA and baseline and hyperaemic PET before ICA with quantitative coronary angiography analysis. RESULTS: On a per-patient basis, the negative predictive values (NPV; 95% confidence intervals in parentheses) were 88 % (64 - 97%) for CTA, 90% (71 - 97%) for PET and 92% (74 - 98%) for PET/CTA, and the positive predictive values (PPV) were 71% (53 - 85%) for CTA, 87% (68 - 95%) for PET and 100% (84 - 100%) for PET/CTA. Similarly, on a per-vessel basis the NPVs (which were generally high) were 97% (94 - 100%) for CTA, 95 % (90 - 99%) for PET and 97% (95 - 100%) for PET/CTA, and the PPVs (which were lower, but higher with PET/CTA) were 53% (39 - 66%) for CTA, 53 % (40 - 66%) for PET and 85 % (73 - 97%) for PET/CTA. In six patients, CTA analysis was hampered by the presence of severe calcifications. However, with the addition of the PET data, all six patients were correctly categorized. CONCLUSION: Cardiac quantitative hybrid PET/CTA imaging has better diagnostic accuracy than CTA alone and PET alone. CTA has a suboptimal PPV, suggesting that hybrid PET/CTA imaging should be used to assess the significance of coronary stenoses diagnosed by CTA.

When is reacquisition necessary due to high extra-cardiac uptake in myocardial perfusion scintigraphy?

BACKGROUND: Technetium-labeled agents, which are most often used for assessing myocardial perfusion in myocardial perfusion scintigraphy (MPS), are cleared by the liver and excreted by the biliary system. Spillover from extra-cardiac activity into the myocardium, especially the inferior wall, might conceal defects and lower the diagnostic accuracy of the study. The objective was to determine rules of thumb for when reacquisition is useful due to high extra-cardiac uptake, i.e., when interpretation of the studies was affected by poor image quality. METHODS: Patients admitted to MPS at any of the three study sites, who also underwent a reacquisition due to high extra-cardiac uptake were included. Image quality was assessed by ten technologists on a scale ranging from 1 to 5. Interpretations regarding the presence/absence of ischemia/infarction, including the certainty of the diagnosis, were made by three physicians. RESULTS: There was a statistically significant increase in image quality between the first and the repeated acquisition (1,256 cases of increased quality at the repeated study (66%), 134 cases of decreased quality at the repeated study (7%), 510 cases of unchanged quality (27%) P < 0.0001). The number of equivocal studies, interpreted by physicians, decreased when evaluating the repeated studies compared to the first studies for all physicians, both for the interpretations of ischemia and for infarction. Receiver operating characteristic analyses revealed that for both endpoints (ischemia, infarction) and all physicians, the optimal cutoff point for performing a reacquisition was between quality categories 2 and 3. CONCLUSION: This study indicates that repeat acquisition is useful when (1) the intensity of the extra-cardiac uptake is equal to or higher than the cardiac uptake when there is no separation between the extra-cardiac uptake and the inferior cardiac wall and (2) when the intensity of the extra-cardiac uptake is higher than the cardiac uptake when there is a separation between the extra-cardiac uptake and the inferior wall of less than one cardiac wall.

Prognosis in patients with suspected or known ischemic heart disease and normal myocardial perfusion: long-term outcome and temporal risk variations.

BACKGROUND: The prognostic value of a normal myocardial perfusion scintigraphy (MPS) may be well described, but long-term follow-up data are sparse, and temporal variations in risk are insufficiently elucidated. METHODS AND RESULTS: During long-term follow-up (mean 6.2 years) of 1,327 consecutive Danish patients with normal MPS, the rate of all-cause death (ACD) was 1.9%/year (differing by gender) and of cardiac death (CD)/myocardial infarction (MI) 0.8%/year (differing by coronary artery disease, CAD). Female gender (HR: 0.60), age (HR: 1.07 per-year increment), and known CAD without prior revascularization (HR: 2.17) were statistically significant factors for ACD, whereas diabetes and previous MI per se were not. Known CAD with previous revascularization carried a low risk of ACD when adjusted for gender and age (HR: 0.56). For CD/MI, risk increased with age and threefold with known CAD, previous MI, and previous percutaneous coronary intervention. Judged from smoothed hazard functions, mortality risk increased further with time for men, elderly, and diabetics and markedly further with known CAD without prior revascularization. CONCLUSIONS: Following a normal MPS, rates of death and hard cardiac events were low. Risk varied with age, gender, and disease history. Novel aspects of temporal risk variation suggested a general warranty period of 5 years, but less in risk groups.

Non-invasive assessments reveal that more than half of randomly selected middle-aged individuals have evidence of subclinical atherosclerosis: a DanRisk substudy.

Screening of the general population for subclinical atherosclerosis is controversial. We assessed the prevalence of subclinical atherosclerosis in healthy middle-aged individuals by 4 non-invasive modalities. In 277 randomly selected males (n = 121) and females (n = 156), aged 50 or 60 years, without known cardiovascular disease or diabetes, intima-media thickness/presence of carotid plaques by ultrasound; coronary artery calcification (CAC) by non-contrast enhanced cardiac CT; occurrence of peripheral artery disease (PAD) by ankle brachial index (ABI), and vascular leakage by urine albumin creatinine ratio (ACR), were evaluated. Traditional risk factors were obtained and HeartScore was calculated. A total of 56 % had morphological signs of atherosclerosis in one of the vascular territories; 41 % had CAC and 31 % a carotid plaque. Among individuals with atherosclerosis, 28 % had lesions in both vascular territories. Subclinical atherosclerosis was significantly more frequent in older males. Signs of PAD and microalbuminuria were very uncommon and detected in only 1 % of the entire population. No association was found between morphological signs of subclinical atherosclerosis and ABI or ACR. More than half of randomly selected apparently healthy middle aged individuals had subclinical atherosclerosis located in the coronary or carotid arteries.

Can preoperative myocardial perfusion scintigraphy predict changes in left ventricular perfusion and function after coronary artery bypass graft surgery?

OBJECTIVES We wanted to evaluate whether preoperative myocardial perfusion scintigraphy (MPS) could predict changes in cardiac symptoms and postoperative myocardial perfusion and left ventricular function after coronary artery bypass grafting (CABG). METHODS Ninety-two patients with stable angina pectoris (and at least one occluded coronary artery) underwent MPS before, and 6 months after, undergoing CABG. The result of the MPS was kept secret from the surgeons. RESULTS Before CABG, 90% of the patients had angina. After CABG, 97% of the patients were without symptoms. Overall graft patency was 84%. Before CABG, one patient had normal perfusion; in the rest of them the defects were classified as follows: reversible (60%), partly reversible (27%) and irreversible (12%). Following CABG, 33% had normal perfusion; in the rest the defects were reversible in 29%, partly reversible in 12% and irreversible in 26%. Left ventricular ejection fraction (LVEF), which was normal before operation in 45%, improved in 40% of all patients. The increase in LVEF was not related to the preoperative pattern of perfusion defects. Of 30 patients with normalized perfusion after CABG, 29 (97%) had reversible defects and one patient had partly reversible defects. Of 83 perfusion defects, which were normalized after CABG, 67 were reversible (81%) or partly reversible (12%). Seventy-five percent of all reversible coronary artery territories before CABG were normalized after operation. CONCLUSIONS Our results indicate that reversible or partly reversible perfusion defects at a preoperative MPS have a high chance of normalized myocardial perfusion assessed by MPS 6 months after operation. Normal perfusion is obtained almost exclusively in territories with reversible ischaemia. Symptoms improved in nearly all patients and LVEF in a significant fraction of the patients, not related to preoperative MPS.

Rate, affinity and calcium dependence of nitric oxide synthase isoform binding to the primary physiological regulator calmodulin.

Using interferometry-based biosensors the binding and release of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) from calmodulin (CaM) was measured. In both isoforms, binding to CaM is diffusion limited and within approximately three orders of magnitude of the Smoluchowski limit imposed by orientation-independent collisions. This suggests that the orientation of CaM is facilitated by the charge arrays on the CaM-binding site and the complementary surface on CaM. Protein kinase C phosphorylation of eNOS T495, adjacent to the CaM-binding site, abolishes or greatly slows CaM binding. Kinases which increase the activity of eNOS did not stimulate the binding of CaM, which is already diffusion limited. The coupling of Ca(2+) binding and CaM/NOS binding equilibria links the affinity of CaM for NOS to the Ca(2+) dependence of CaM binding. Hence, changes in the Ca(2+) sensitivity of CaM binding always imply changes in the NOS-CaM affinity. It is possible, however, that in some regimes binding and activation are not synonymous, so that Ca(2+) sensitivity need not be tightly linked to CaM sensitivity of activation. This study is being extended using mutants to probe the roles of individual structural elements in binding and release.