Emotion recognition in relation to tumor characteristics in patients with low-grade glioma.

BACKGROUND: Patients with low-grade gliomas (LGG) treated with surgery, generally function well and have a favorable prognosis. However, LGG can affect neurocognitive functioning. To date, little is known about social cognition (SC) in these patients, although impaired SC is related to social-behavioral problems and poor societal participation. Frontal brain areas are important for SC and LGG frequently have a frontal location. Therefore, the aim of the present study was to investigate whether emotion recognition, a key component of SC, was impaired, and related to general cognition, tumor location, laterality, tumor volume, and histopathological characteristics in patients with LGG, postsurgery, and before start of adjuvant therapy. METHODS: A total of 121 patients with LGG were matched with 169 healthy controls (HC). Tumor location [including (frontal) subregions; insula, anterior cingulate cortex, lateral prefrontal cortex (LPFC), orbitofrontal-ventromedial PFC] and tumor volume were determined on MRI scans. Emotion recognition was measured with the Ekman 60 faces test of the Facial Expressions of Emotion-Stimuli and Tests (FEEST). RESULTS: Patients with LGG performed significantly lower on the FEEST than HC, with 33.1% showing impairment compared to norm data. Emotion recognition was not significantly correlated to frontal tumor location, laterality, and histopathological characteristics, and significantly but weakly with general cognition and tumor volume. CONCLUSIONS: Emotion recognition is impaired in patients with LGG but not (strongly) related to specific tumor characteristics or general cognition. Hence, measuring SC with individual neuropsychological assessment of these patients is crucial, irrespective of tumor characteristics, to inform clinicians about possible impairments, and consequently offer appropriate care.

Diagnostic accuracy of MRI techniques for treatment response evaluation in patients with brain metastasis: A systematic review and meta-analysis.

BACKGROUND: Treatment response assessment in patients with brain metastasis uses contrast enhanced T1-weighted MRI. Advanced MRI techniques have been studied, but the diagnostic accuracy is not well known. Therefore, we performed a metaanalysis to assess the diagnostic accuracy of the currently available MRI techniques for treatment response. METHODS: A systematic literature search was done. Study selection and data extraction were done by two authors independently. Meta-analysis was performed using a bivariate random effects model. An independent cohort was used for DSC perfusion external validation of diagnostic accuracy. RESULTS: Anatomical MRI (16 studies, 726 lesions) showed a pooled sensitivity of 79% and a specificity of 76%. DCE perfusion (4 studies, 114 lesions) showed a pooled sensitivity of 74% and a specificity of 92%. DSC perfusion (12 studies, 418 lesions) showed a pooled sensitivity was 83% with a specificity of 78%. Diffusion weighted imaging (7 studies, 288 lesions) showed a pooled sensitivity of 67% and a specificity of 79%. MRS (4 studies, 54 lesions) showed a pooled sensitivity of 80% and a specificity of 78%. Combined techniques (6 studies, 375 lesions) showed a pooled sensitivity of 84% and a specificity of 88%. External validation of DSC showed a lower sensitivity and a higher specificity for the reported cut-off values included in this metaanalysis. CONCLUSION: A combination of techniques shows the highest diagnostic accuracy differentiating tumor progression from treatment induced abnormalities. External validation of imaging results is important to better define the reliability of imaging results with the different techniques.

An aggressive lactotroph pituitary tumor in a young male: A pituitary carcinoma without metastasis.

This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.

Anti-tumor treatment and healthcare consumption near death in the era of novel treatment options for patients with melanoma brain metastases.

BACKGROUND: Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases. METHODS: Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts. RESULTS: 100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not. CONCLUSION: The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.

Clinical relevance of the radiation dose bath in lower grade glioma, a cross-sectional pilot study on neurocognitive and radiological outcome.

Aim: To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG). Methods: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup. Results: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB.In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = -0.821, p = 0.023 and r = -0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = -0.857, p = 0.014), without correlation between CTV and NCF. Conclusion: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume.

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation.

PURPOSE: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy. METHODS: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points. RESULTS: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined. CONCLUSION: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org.

Value of screening and follow-up brain MRI scans in patients with metastatic melanoma.

BACKGROUND: Novel treatments make long-term survival possible for subsets of patients with melanoma brain metastases. Brain magnetic resonance imaging (MRI) may aid in early detection of brain metastases and inform treatment decisions. This study aimed to determine the impact of screening MRI scans in patients with metastatic melanoma and follow-up MRI scans in patients with melanoma brain metastases. METHODS: This retrospective cohort study included patients diagnosed with metastatic melanoma or melanoma brain metastases between June 2015 and January 2018. The impact of screening MRI scans was evaluated in the first 2 years after metastatic melanoma diagnosis. The impact of follow-up MRI scans was examined in the first year after brain metastases diagnosis. The number of MRI scans, scan indications, scan outcomes, and changes in treatment strategy were analyzed. RESULTS: In total, 116 patients had no brain metastases at the time of the metastatic melanoma diagnosis. Twenty-eight of these patients (24%) were subsequently diagnosed with brain metastases. Screening MRI scans detected the brain metastases in 11/28 patients (39%), of which 8 were asymptomatic at diagnosis. In the 96 patients with melanoma brain metastases, treatment strategy changed after 75/168 follow-up MRI scans (45%). In patients treated with immune checkpoint inhibitors, the number of treatment changes after follow-up MRI scans was lower when patients had been treated longer. CONCLUSION(S): Screening MRI scans aid in early detection of melanoma brain metastases, and follow-up MRI scans inform treatment strategy. In patients with brain metastases responding to immune checkpoint inhibitors, treatment changes were less frequently observed after follow-up MRI scans. These results can inform the development of brain imaging protocols for patients with immune checkpoint inhibitor sensitive tumors.

Proton therapy for selected low grade glioma patients in the Netherlands.

Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed.

Does an immobilization mask have added value during planning magnetic resonance imaging for stereotactic radiotherapy of brain tumours?

BACKGROUND AND PURPOSE: When using an immobilization mask, a magnetic resonance imaging (MRI) head receive coil cannot be used and patients may experience discomfort during the examination. We therefore wish to assess the added value of an immobilization mask during all MRI scans intended for cranial stereotactic radiotherapy (SRT) planning. MATERIALS AND METHODS: An MRI was acquired with and without a thermoplastic immobilization mask in ten patients eligible for SRT. A planning computed tomography (CT) scan was also made, to which the two MRIs were independently registered. Additionally, the MRI without immobilization was registered to the MRI in mask. On each sequence, gross tumour volume (GTV), the right eye, brain stem and chiasm were delineated. The absolute differences in centre-of-gravity coordinates and Dice coefficients of the volumes of the delineated structures between the two MRIs were compared. RESULTS: Differences in GTV volume between the two MRIs were low, with median Dice coefficients between 0.88 and 0.91. Similarly, the median absolute differences in centre-of-gravity coordinates between the GTVs, organs at risk and landmarks delineated on the two MRIs were within 0.5 mm. The 95% confidence intervals of the median absolute differences in the three GTV coordinates was within 1 mm, which corresponds to the target volume safety margin used to account for possible errors during the SRT treatment chain. CONCLUSIONS: The effect of scanning a patient without the immobilization mask falls within acceptable bounds of error for the geometrical accuracy of the SRT treatment chain. Consequently, placing the head in treatment position during all MRI scans for patients undergoing radiotherapy of brain metastasis is deemed unnecessary.

Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques.

Microvascular changes are increasingly recognised not only as primary drivers of radiotherapy treatment response in brain tumours, but also as an important contributor to short- and long-term (cognitive) side effects arising from irradiation of otherwise healthy brain tissue. As overall survival of patients with brain tumours is increasing, monitoring long-term sequels of radiotherapy-induced microvascular changes in the context of their potential predictive power for outcome, such as cognitive disability, has become increasingly relevant. Ideally, radiotherapy-induced significant microvascular changes in otherwise healthy brain tissue should be identified as early as possible to facilitate adaptive radiotherapy and to proactively start treatment to minimise the influence on these side-effects on the final outcome. Although MRI is already known to be able to detect significant long-term radiotherapy induced microvascular effects, more recently advanced MR imaging biomarkers reflecting microvascular integrity and function have been reported and might provide a more accurate and earlier detection of microvascular changes. However, the use and validation of both established and new techniques in the context of monitoring early and late radiotherapy-induced microvascular changes in both target-tissue and healthy tissue currently are minimal at best. This review aims to summarise the performance and limitations of existing methods and future opportunities for detection and quantification of radiotherapy-induced microvascular changes, as well as the relation of these findings with key clinical parameters.

Patterns of re-irradiation for recurrent gliomas and validation of a prognostic score.

PURPOSE OR OBJECTIVE: Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. MATERIAL AND METHODS: We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Centers in Utrecht and Groningen. RESULTS: Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade II-III in 52 patients and grade IV in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2-137] and 39.7 [24.6-64.9] months respectively (p < 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5-14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, the Karnofsky performance scale ≥70% (p < 0.01), re-irradiation for first recurrence (p = 0.02), longer time interval between RT start dates (p < 0.01) and smaller planning target volume (p < 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. CONCLUSION: In our series, mOS after reirradiation was sufficient to justify use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient.

Older coronary thrombus is an independent predictor of 1-year mortality in acute myocardial infarction.

BACKGROUND: We have previously shown that older thrombus is associated with a twofold higher long-term mortality in ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (pPCI). We evaluated whether the addition of the presence of older thrombus to a multimarker model would result in increased predictive power for 1-year mortality in STEMI patients. METHODS: The study population (n = 1442) consists of STEMI patients treated with thrombus aspiration during pPCI. Patients were included if aspirated thrombus material could histopathologically be classified according to thrombus age (n = 870) and laboratory measurements of biomarkers (cardiac troponin T, glucose, N-terminal pro-brain natriuretic peptide, estimated glomerular filtration rate and C-reactive protein) were available. The additional prognostic value of the presence of older thrombus beyond multiple biomarkers and established clinical risk factors was evaluated using multivariate Cox regression models. RESULTS: Serum biomarker concentrations were similar between patients with fresh and older thrombus. Sixty patients (7%) died within 1 year. The presence of older thrombus remained strongly associated with mortality at 1 year after multivariable adjustment for multiple biomarkers and established clinical risk factors. Addition of older thrombus to either a model including clinical risk factors and biomarkers or a model including solely biomarkers resulted in significant increases in the discriminative value, evidenced by net reclassification improvement and integrated discriminative improvement. CONCLUSIONS: The presence of older thrombus provides independent complementary information to a multimarker model including established clinical risk factors and multiple biomarkers for predicting 1-year mortality in STEMI patients treated with pPCI and thrombus aspiration.

Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: A pathology study.

OBJECTIVE: Smooth muscle cells, macrophage infiltration and accumulation of lipids, proteoglycans, collagen matrix and calcification play a central role in atherosclerosis. The early histologic changes of plaque progression from pathologic intimal thickenings (PIT) to late fibroatheroma lesions have not been fully characterized. METHODS: A total of 151 atherosclerotic coronary lesions were collected from 67 sudden death victims. Atherosclerotic plaques were classified as PIT without macrophage infiltration, PIT with macrophages, and early and late fibroatheromas. Presence of macrophages and proteoglycans (versican, decorin and biglycan) were recognized by specific antibodies while hyaluronan was detected by affinity histochemistry. Lipid deposition was identified by oil-red-O, and calcification was assessed following von Kossa and alizarin red staining. RESULTS: Lesion progression from PIT to late fibroatheroma was associated with increase in macrophage accumulation (p < 0.001) and decreasing apoptotic body clearance by macrophages (ratio of engulfed-to-total apoptotic bodies) (p < 0.001). Lipid deposition in lipid pool of PIT had a microvesicular appearance whereas those in the necrotic core were globular in nature. Overall, the accumulation of hyaluronan (p < 0.001), and proteoglycan versican (p < 0.001) and biglycan (p = 0.013) declined along with lesion progression from PIT to fibroatheromas. Microcalcification was first observed only within areas of lipid pools and its presence and size increased in lesions with necrotic core. CONCLUSIONS: PIT to fibroatheroma lesions are accompanied by early lipid accumulation, followed by macrophage infiltration with defective clearance of apoptotic bodies along with decrease in proteoglycan and hyaluronan in lipid pools that convert to necrotic cores. Calcification starts in PIT and increases with plaque progression.

Distal embolization of hydrophilic-coating material from coronary guidewires after percutaneous coronary interventions.

BACKGROUND: Coronary guidewires are indispensable during percutaneous coronary interventions. Nowadays, most guidewires have hydrophilic coatings to improve their trackability, allowing easy lesion passage and facilitating balloon and stent positioning. Recent reports, however, have raised concerns about detachment and subsequent embolization of these hydrophilic coatings. METHODS AND RESULTS: We have retrospectively reviewed the histological samples of the myocardium, obtained during autopsies in the period 2009 to 2013, from all patients who had a history of percutaneous coronary interventions (n=40). Foreign material was observed in the distal myocardium in 4 patients (10%). Furthermore, we have reviewed 205 thrombus specimens which were obtained during thrombus aspiration in the setting of primary percutaneous coronary interventions in the period 2005 to 2009. In 45% of the cases, foreign material was observed within the thrombus. Finally, we have examined the histopathologic appearance of hydrophilic-guidewire coating material ex vivo by embedding the coating in placenta specimen and cut and stain it in exactly the same manner as the myocardium and thrombus specimen. The histopathologic appearance of the hydrophilic coating ex vivo was identical to the foreign material found in vivo. CONCLUSIONS: Distal embolization of hydrophilic-coating material was observed in 10% of the patients who had a history of percutaneous coronary interventions. Hydrophilic-coating material was found in 45% of coronary thrombus specimen obtained during thrombus aspiration. These findings suggest that detachment and distal embolization of hydrophilic-coating material from coronary guidewires occur more often than the sparse literature on this topic suggests.

Thrombus aspiration alone during primary percutanous coronary intervention as definitive treatment in acute ST-elevation myocardial infarction.

BACKGROUND: In some patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutanous coronary intervention (pPCI) with thrombus aspiration, residual stenosis after thrombus aspiration is non-significant and additional balloon dilatation or stent placement may be unnecessary. We investigated the angiographic, procedural, and clinical outcomes of these patients in our single center pPCI-database. In addition, to gain insight in the pathological mechanisms of coronary thrombosis in these patients, we established the histopathological characteristics and age of the aspirated material. METHODS: This study consists of STEMI patients who underwent pPCI with thrombus aspiration alone in our institution. Thrombus material was collected and processed and the sections were analyzed for the presence of fresh (<1 day) or older thrombus (>1 day) and plaque components. One year clinical follow-up was obtained and vital status was assessed up to March 2010. RESULTS: We identified 16 STEMI patients who underwent thrombus aspiration alone as the definitive treatment during pPCI. Acceptable flow with minimal non-significant residual stenosis immediately after thrombus aspiration was present in 14 patients (88%). In four patients (25%) repeat angiography was performed after several days and disappearance of the residual thrombus could be confirmed in three patients. During follow-up, repeat target lesion revascularization was performed in one patient at 53 days. No recurrent myocardial infarction was observed. Two patients died 1,166 and 1,228 days after the index-event from non-cardiac causes. CONCLUSIONS: In selected STEMI patients undergoing pPCI, thrombus aspiration alone is feasible and safe on the short-term and there appears to be no high risk of recurrent ischemic events during follow-up. Our results suggest that additional balloon inflation or stent implantation may be unnecessary in selected patients, when there is no significant residual stenosis after thrombus aspiration.

Clinical and angiographic predictors and prognostic value of failed thrombus aspiration in primary percutaneous coronary intervention.

OBJECTIVES: This study sought to investigate which factors are associated with failure of thrombus aspiration (TA) and if this has prognostic implications. BACKGROUND: The pathophysiological mechanism and clinical benefit of TA during primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction is still in debate. METHODS: Between August 2001 and October 2007, TA was attempted in 1,399 patients. Failure of TA was defined as the inability to reach and/or cross the occlusion with the aspiration catheter for effective thrombus removal. In addition, we analyzed patients in which no material could be obtained. We examined baseline clinical and angiographic variables related to failure of TA or to the lack of aspirate. Follow-up on vital status was obtained at 1 year. RESULTS: In 144 (10.3%) patients, the aspiration catheter failed to cross the lesion. After multivariable adjustment, marked proximal tortuosity (odds ratio [OR]: 2.88, 95% confidence interval [CI]: 1.92 to 4.31, p < 0.001), the presence of a calcified lesion (OR: 2.70, 95% CI: 1.77 to 4.13, p < 0.001), and a bifurcation lesion (OR: 1.97, 95% CI: 1.15 to 3.37, p = 0.013) were independent predictors of failed TA. Age over 60 years and the circumflex as infarct-related artery were associated with the lack of aspirate. Mortality rates at 1 year were 6.2% in patients with failed TA and 6.4% with successful TA (hazard ratio: 0.98, 95% CI: 0.49 to 1.95, p = 0.95). CONCLUSIONS: The presence of marked proximal tortuosity of the infarct-related artery, a calcified lesion, and a bifurcation lesion are independent predictors of failure of thrombus aspiration. We found that unsuccessful TA did not affect 1-year mortality.

A pattern of disperse plaque microcalcifications identifies a subset of plaques with high inflammatory burden in patients with acute myocardial infarction.

AIMS: Inflammation plays a crucial role in plaque vulnerability. Calcifications can be detected by means of in vivo imaging techniques. The study purpose is to assess a potential association between tissue localization of calcifications and the inflammatory biomarkers, C-reactive protein (CRP), osteopontin and lipoprotein-associated phospholipase A2 (Lp-PLA2), in plaque tissue of patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Thrombectomy materials obtained from patients with electrocardiographically documented ST-segment elevation type of AMI (STEMI) were histologically screened for presence of thrombus, plaque tissues and calcifications. Size of calcifications was measured morphometrically, and their colocalization with the inflammatory biomarkers macrophages, CRP, osteopontin and Lp-PLA2 was assessed with immunostaining. A total of 171 samples containing plaque tissues were obtained from 562 thrombectomy procedures. Calcifications were observed in 67 (39%) plaque fragments, with diameters ranging from 4 to 170 µm. Plaque tissues with calcifications contained more frequently extracellular CRP and intracellular CRP in macrophages than those without calcifications (85%, 59% vs. 64%, 32%, P=0.012 and 0.005 respectively). Similar results were obtained with osteopontin immunostaining (98%, 76% vs. 56%, 40%; P<0.001 both). Furthermore, samples with calcifications were immunostained for CRP more intensely than those without calcifications (P=0.001). Finally, 96% of the plaque tissues stained positively for Lp-PLA2, but there was no association with presence of microcalcifications. CONCLUSIONS: A pattern of disperse microcalcifications is positively associated with presence of the inflammatory biomarkers macrophages, CRP and osteopontin in thrombectomy materials of STEMI patients. Based on these findings, we speculate that such microcalcifications could have the potential to serve as a surrogate marker for plaques with high inflammatory burden.

Histopathology of aspirated thrombus and its association with ST-segment recovery in patients undergoing primary percutaneous coronary intervention with routine thrombus aspiration.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) with thrombus aspiration, the histopathology of aspirated thrombus was previously related to long-term mortality. In this study, we sought to investigate the association between histopathology of aspirated thrombus and ST-segment recovery, a marker of microvascular dysfunction, immediately at the end of the PCI procedure. METHODS: We included 892 STEMI patients who underwent primary PCI with routine thrombus aspiration and for whom combined data on histopathology of aspirated thrombus and ST-segment recovery were available. Patients were categorized according to histopathology of aspirated thrombus: fresh only (<1 day), older (>1 day), or no material aspirated. ST-segment recovery was defined as incomplete if <50%. RESULTS: Incomplete ST-segment recovery occurred in 134 of 363 patients (37%) with fresh thrombus, in 104 of 238 patients (44%) with older thrombus, and in 142 of 291 patients (49%) with no material. Unadjusted odds ratios for incomplete ST-segment recovery of patients with older thrombus and no material, when compared with patients with fresh thrombus, were 1.33 (95% CI, 0.95-1.85; P = 0.097) and 1.63 (95% CI 1.19-2.23; P = 0.002), respectively. Both associations were unchanged after multivariable adjustment for clinical predictors of ST-segment recovery. ST-segment recovery was a strong predictor of long-term mortality, independent of the histopathology of aspirated thrombus. CONCLUSIONS: This study shows that ST-segment recovery immediately at the end of the PCI procedure was a significant prognosticator, independent of the histopathology of aspirated thrombus. We found that the histopathology of aspirated thrombus (fresh, older, no material) was associated with ST-segment recovery in STEMI patients undergoing primary PCI with thrombus aspiration.

Relationship of thrombus healing to underlying plaque morphology in sudden coronary death.

OBJECTIVES: The aim of this study was to assess differences in thrombus healing between ruptured and eroded plaques, given the natural difference in lesion substrate and that thrombi might exist days to weeks before the presentation of sudden coronary death. BACKGROUND: Although the ability to distinguish ruptures and erosions remains a major clinical challenge, in-hospital patients dying with acute myocardial infarction establish that erosions account for 25% of all deaths, where women experience a higher incidence compared with men. METHODS: Coronary lesions with thrombi (ruptures, n = 65; erosions, n = 50) received in consultation from the Medical Examiner's Office from 111 sudden death victims were studied. Thrombus healing was classified as early (<1 day) or late stage characterized in phases of lytic (1 to 3 days), infiltrating (4 to 7 days), or healing (>7 days). Morphometric analysis included vessel dimensions, necrotic core size, and macrophage density. RESULTS: Late-stage thrombi were identified in 79 of 115 (69%) culprit plaques. Women more frequently had erosion with a greater prevalence of late-stage thrombi (44 of 50, 88%) than ruptures (35 of 65, 54%, p < 0.0001). The internal elastic lamina area and percent stenosis were significantly smaller in erosions compared with ruptures (p < 0.0001 and p = 0.02), where plaque burden was greater (p = 0.008). Although macrophage infiltration in erosions was significantly less than ruptures (p = 0.03), there was no established relationship with thrombus organization. Other parameters of thrombus length and occlusive versus nonocclusive showed no association with healing. CONCLUSIONS: Approximately two-thirds of coronary thrombi in sudden coronary deaths are organizing, particularly in young individuals-especially women, who perhaps might require a different strategy of treatment.

Histopathological features of aspirated thrombi after primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction.

BACKGROUND: Plaque disruption with superimposed thrombus is the predominant mechanism responsible for the onset of acute coronary syndromes. Studies have shown that plaque disruption and thrombotic occlusion are frequently separated in time. We established the histopathological characteristics of material aspirated during primary percutaneous coronary intervention (PCI) in a large consecutive ST-elevation myocardial infarction (STEMI) population. METHODOLOGY/PRINCIPAL FINDINGS: Thrombus aspiration during primary PCI was performed in 1,362 STEMI patients. Thrombus age was classified as fresh (<1 day), lytic (1-5 days), or organized (>5 day). Further, the presence of plaque was documented. The histopathological findings were related to the clinical, angiographic, and procedural characteristics. Material could be aspirated in 1,009 patients (74%). Components of plaque were found in 395 of these patients (39%). Fresh thrombus was found in 577 of 959 patients (60%) compared to 382 patients (40%) with lytic or organized thrombi. Distal embolization was present in 21% of patients with lytic thrombus compared to 12% and 15% of patients with fresh or organized thrombus. CONCLUSIONS/SIGNIFICANCE: Material could be obtained in 74% of STEMI patients treated with thrombus aspiration during primary PCI. In 40% of patients thrombus age is older than 24 h, indicating that plaque disruption and thrombus formation occur significantly earlier than the onset of symptoms in many patients.