The Role of Curcumin in Cancer: A Focus on the PI3K/Akt Pathway.

Cancer is a life-threatening disease and one of the leading causes of death worldwide. Despite significant advancements in therapeutic options, most available anti-cancer agents have limited efficacy. In this context, natural compounds with diverse chemical structures have been investigated for their multimodal anti-cancer properties. Curcumin is a polyphenol isolated from the rhizomes of Curcuma longa and has been widely studied for its anti-inflammatory, anti-oxidant, and anti-cancer effects. Curcumin acts on the regulation of different aspects of cancer development, including initiation, metastasis, angiogenesis, and progression. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway is a key target in cancer therapy, since it is implicated in initiation, proliferation, and cancer cell survival. Curcumin has been found to inhibit the PI3K/Akt pathway in tumor cells, primarily via the regulation of different key mediators, including growth factors, protein kinases, and cytokines. This review presents the therapeutic potential of curcumin in different malignancies, such as glioblastoma, prostate and breast cancer, and head and neck cancers, through the targeting of the PI3K/Akt signaling pathway.

Antineoplastic Activity of 9″-Lithospermic Acid Methyl Ester in Glioblastoma Cells.

To date, many potent compounds have been found which are derived from plants and herbs and possess anticancer properties due to their antioxidant effects. 9″-Lithospermic acid methyl ester is an effective natural compound derived from the Thymus thracicus Velen. It has been proven that this compound has substantial properties in different diseases, but its effects in cancer have not been thoroughly evaluated. The aim of this work was to study the effects of 9″-Lithospermic acid methyl ester (9″-methyl lithospermate) in U87 and T98 glioblastoma cell lines. Its effects on cellular viability were assessed via Trypan Blue and Crystal Violet stains, the cell cycle analysis through flow cytometry, and cell migration by employing the scratch wound healing assay. The results demonstrated that 9″-methyl lithospermate was able to inhibit cellular proliferation, induce cellular death, and inhibit cell migration. Furthermore, these results were intensified by the addition of temozolomide, the most prominent chemotherapeutic drug in glioblastoma tumors. Further studies are needed to reproduce these findings in animal models and investigate if 9″-lithospermic acid methyl ester represents a potential new therapeutic addition for gliomas.

Antitumor activity of 5-hydroxy-3',4',6,7-tetramethoxyflavone in glioblastoma cell lines and its antagonism with radiotherapy.

5-Hydroxy-3',4',6,7-tetramethoxyflavone (TMF) is a plant-origin flavone known for its anti-cancer properties. In the present study, the cytotoxic effect of TMF was evaluated in the U87MG and T98G glioblastoma (GBM) cell lines. The effect of TMF on cell viability was assessed with trypan blue exclusion assay and crystal violet staining. In addition, flow cytometry was performed to examine its effect on the different phases of the cell cycle, and in vitro scratch wound assay assessed the migratory capacity of the treated cells. Furthermore, the effect of in vitro radiotherapy was also evaluated with a combination of TMF and radiation. In both cell lines, TMF treatment resulted in G0/G1 cell cycle arrest, reduced cell viability, and reduced cell migratory capacity. In contrast, there was an antagonistic property of TMF treatment with radiotherapy. These results demonstrated the antineoplastic effect of TMF in GBM cells in vitro, but the antagonistic effect with radiotherapy indicated that TMF should be further evaluated for its possible antitumor role post-radiotherapy.

Nuclear Medicine and Cancer Theragnostics: Basic Concepts.

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177.

Siderol Inhibits Proliferation of Glioblastoma Cells and Acts Synergistically with Temozolomide.

Glioblastoma (GBM) is the most aggressive primary central nervous system (CNS) tumor in adults with dismal prognosis. Currently, the therapeutic interventions include gross total resection, when possible, followed by radiotherapy and chemotherapy. However, despite treatment, tumor usually recurs within 7-9 months. The presence of glioma cells with stem-like properties and tumor's heterogeneity have been identified as the most important factors driving recurrence. Recently, research efforts have been focused on the use of natural substances as treatment for GBM. Siderol is an ent-kaurane diterpenoid, isolated from the genus Sideritis. Sideritis extracts have already been investigated for their anti-inflammatory, antioxidant, and anticancer effects. In this study, we investigated the antitumoral effects of siderol in GBM T98 and U87 cell lines, as well as the effects of combined treatment with temozolomide (TMZ). Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Different concentrations of siderol were used in order to calculate the IC50 values at 72 h after treatment. Flow cytometry used for the DNA cell cycle analysis after treatment with siderol in concentrations of IC50 and twice the IC50 values for 72 h. Furthermore, the effect of siderol in cell's migratory ability was tested using wound healing assay. Cell viability and proliferation, after combined treatment with siderol and TMZ, also were evaluated with the trypan blue exclusion assay and the effects of the combination treatment were analyzed with CompuSyn software. Treatment with siderol significantly reduced cell viability in T98 and U87 cell lines in a dose-dependent manner and IC50 values were calculated, 18 µM and 13 µM, respectively. Moreover, siderol induced G0/G1 cell cycle arrest in a dose-dependent manner and inhibited the migration in both cell lines. In addition, siderol and TMZ seem to have synergistic action in the majority of tested concentrations in both T98 and U87 cells. In conclusion, siderol may represent an innovative strategy for the treatment of GBM, and further studies are needed on siderol's efficacy and mode of action.

Myocardial perfusion imaging single photon emission computed tomography may detect silent myocardial ischemia in patient with epilepsy.

BACKGROUND: The aim of the present study was to compare the myocardial perfusion imaging (MPI) with [99mTc]tetrofosmin stress - rest single-photon emission computer tomography (SPECT) of patients with epilepsy with matched control individuals. MATERIAL AND METHODS: All 29 adult epileptic patients were receiving antiepileptic drugs (AEDs) for epilepsy. Thirty-two individuals matched for gender and age consisted of the control group. MPIs SPECT were performed, and myocardial summed scores were obtained during stress (SSS) and rest (SRS) images. Abnormal MPI was considered when SSS was ≥ 4. In addition, the difference (SDS) between SSS and SRS was also assessed, which represents a rate of reversibility after stress. RESULTS: Twenty of 29 (68.97%) patients with epilepsy had abnormal MPI and 14/32 (43.75%) of the controls (p = 0.04). Among males, 18/23 patients and 11/25 controls had abnormal MPI (p = 0.01), with quite a significant difference for mean SSS between male patients and controls (p = 0.002). Furthermore, SDS comparison showed that irreversible abnormalities were more common in patients than in control individuals. A difference of inadequately compensated myocardial ischemia between patients treated with enzyme inducing AEDs and patients treated with valproic acid was also detected. CONCLUSIONS: Single-photon emission computer tomography (SPECT) may detect increased risk for coronary artery disease and further cardiovascular events in patients with epilepsy. Our findings favor the conclusion that SPECT could be used for the early identification of cardiovascular comorbidity in epilepsy.

Reproductive health in patients with epilepsy.

The aim of the present study was to review existing knowledge on the impact of epilepsy in reproductive health of both sexes. Extensive searches of relevant documentation published until February 2020 were retrieved from PubMed and Google Scholar literature in English or in other languages with an English abstract. In females, epilepsy may lead to estrogen and androgen level abnormalities. Women with epilepsy may develop Polycystic Ovaries Syndrome (PCOS), anovulatory cycles, and menstrual disorders. In men, epilepsy may cause sex hormone dysregulation and influence spermatogenesis. Males with epilepsy may also suffer from sexual dysfunction. Antiepileptic drugs (AEDs) have adverse effects on peripheral endocrine glands, influence hormones' biosynthesis and protein binding, diminish the bioactivity of serum sex hormones, and lead to secondary endocrine disorders related to changes concerning body weight and insulin sensitivity. Valproic acid (VPA) was the first recognized AED to cause disturbances potentially due to metabolic changes and increasing weight. Women taking VPA may develop PCOS, while men may have sperm abnormalities and/or sexual dysfunction. Liver enzyme inducing AEDs may also cause menstrual and sexual disorders in women and sexual dysfunction in men. Newer AEDs are much safer but studies still suggest reduced sexuality and erectile dysfunction.

Diagnosis and treatment of limbic encephalitis in the cancer patient.

Limbic encephalitis is an inflammatory process involving the limbic structures of the brain, manifested with short-term memory deficits, confusion, depression and seizures. It is usually a paraneoplastic condition but it may also appear as a nonparaneoplastic syndrome. Patients with this condition may exhibit a variety of antibodies in their serum or/and cerebrospinal fluid targeting basement membrane components that bind to a variety of neurotransmitter receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and GABA B and proteins associated to the ion channels such as LGI1, Caspr2 or intracellular components. Flurodeoxyglucose PET/computed tomography usually demonstrates increased uptake in the limbic structures, and it may reveal the site of the primary tumor. Treatment consists of tumor removal if possible. Symptomatic treatment includes steroids, gamma immune globulin, plasma exchange, immunosuppressive therapies and anti-epileptic drugs. Prognosis is better when it is associated with antibodies against basement membrane rather than intracellular antibodies.

Factors related to the adverse events of antiepileptic drugs.

OBJECTIVE: The aim of the present study was to explore the factors related to the severity of the adverse effects of antiepileptic drugs (AEDs), experienced by patients with epilepsy. MATERIALS AND METHODS: A case study was conducted in adult patients with epilepsy and followed up at the Epilepsy Outpatients of the University Hospital of Ioannina in Northwest Greece. The Adverse Event Profile (AEP) questionnaire for AEDs adverse effects assessment, the Defense style questionnaire (DSQ-88) and the Patient Health Questionnaire (PHQ-9) for depression' severity evaluation were used to estimate the severity of adverse effects, the defense style, and the depressive symptoms, respectively. RESULTS: Sixty-three patients with epilepsy (M/F:28/35), with a mean age of 37.6 ±â€¯13.41, were recruited in the study. The univariate analysis showed that both the Maladaptive style of defense and the PHQ-9 score were significantly associated with the AEP score. After multivariate regression analysis female gender, the load of AEDs, the PHQ-9 score, and the Adaptive defense style remained significant coefficients. CONCLUSION: There are also nonpharmacological factors that may contribute to the severity of the adverse effects of AEDs, experienced by the patients with epilepsy.

Psychological distress symptoms and illness perception in patients with epilepsy in Northwest Greece.

OBJECTIVE: The purpose of the present study was to compare psychological distress between patients with epilepsy and healthy controls and to evaluate potentially related factors to psychological distress in patients with epilepsy. Furthermore, we assessed how psychological distress and other potential factors mediate illness perception in patients with epilepsy in an urban area of Northwest Greece. MATERIALS AND METHODS: A case-control study was conducted in adult patients with epilepsy followed up at the University Hospital of Ioannina and in healthy controls. The Symptom Checklist-90 Revised (SCL-90R) for symptoms of psychological distress and the overall psychological distress Global Severity Index (GSI) evaluation, the brief illness perception questionnaire (B-IPQ), and the Adverse Event Profile (AEP) questionnaire for the antiepileptic drugs (AEDs) were used. RESULTS: Seventy patients with epilepsy and 70 controls were recruited in the study. Somatic, depression, and anxiety symptoms and the GSI were higher in patients than in controls. In patients with epilepsy, the AEP score was significantly associated with psychological distress. Illness perception was associated with the number and the total number of administered AEDs; the AEP score; somatic, obsessive, depressive, and anxiety symptoms; and the GSI. After regression analysis, epilepsy characteristics, AEDs, and psychological distress accounted for 11.7%, 28.7%, and 5.5% of variance in BIP-Q score, respectively. CONCLUSION: Screening for psychological distress in patients with epilepsy is of high importance in clinical practice as somatic, depression, and anxiety symptoms and overall psychological distress are more severe in patients with epilepsy than in healthy controls. The symptoms of psychological distress are strongly associated with the adverse effects of AEDs. The epilepsy characteristics, the AEDs, and the psychological distress could determine a large part of illness perception in epilepsy, with the adverse effects of AEDs being the strongest predictor.

Depression and quality of life in patients with epilepsy in Northwest Greece.

PURPOSE: The purpose of the present study was to compare depression and QoL between patients with epilepsy and healthy controls, evaluating potentially related factors to depression and QoL in patients with epilepsy in Northwest Greece. METHODS: A case study was conducted in adult patients with epilepsy followed up at the University Hospital of Ioannina and in healthy controls. The Patient Health Questionnaire (PHQ-9) for depression's severity evaluation, the WHOQOL-BREF questionnaire for the QoL estimation and the Adverse Event Profile (AEP) questionnaire for the Antiepileptic Drugs (AEDs) adverse effects assessment were used. RESULTS: Seventy patients with epilepsy and 70 controls were recruited. The PHQ-9 score was higher in patients compared to controls and slightly higher than reported in patients with epilepsy. PHQ-9 was significantly associated with the AEP score. Our patients had a poorer QoL compared to controls. The level of education, the AEP and the PHQ-9 scores were associated to QoL, the last two being the most powerful predictors of QoL. CONCLUSION: Patients with epilepsy in Northwest Greece had higher rates of depression than reported in patients with epilepsy and poorer QoL compared to controls. The adverse effects of AEDs were related to depression in our study, while the adverse effects of AEDs and depression were more powerful predictors of QoL compared to demographics and other characteristics of epilepsy.

Cancer-associated stroke: Pathophysiology, detection and management (Review).

Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment options, such as chemotherapy, radiotherapy and surgery have all been shown to aggravate the risk of stroke as well. The clinical manifestation varies greatly depending upon the underlying cause; however, in general, cancer­associated strokes tend to appear as multifocal in neuroimaging. Furthermore, several serum markers have been identified, such as high D­Dimer levels and fibrin degradation products. Managing cancer patients with stroke is a delicate matter. The cancer should not be considered a contraindication in applying thrombolysis and recombinant tissue plasminogen activator (rTPA) administration, since the risk of hemorrhage in cancer patients has not been reported to be higher than that in the general population. Anticoagulation, on the contrary, should be carefully examined. Clinicians should weigh the benefits and risks of anticoagulation treatment for each patient individually; the new oral anticoagulants appear promising; however, low­molecular­weight heparin remains the first choice. On the whole, stroke is a serious and not a rare complication of malignancy. Clinicians should be adequately trained to handle these patients efficiently.

Skull Base Metastasis Revealed by Bone Scintigraphy in a Patient With Hypoglossal Nerve Palsy.

Even though different imaging modalities are available in sole or in combination for the optimal detection of bone metastases, whole-body bone scintigraphy (BS) in a single session seems to be advantageous. We present an 80-year-old male with unilateral left hypoglossal nerve palsy (HNP) and no other focal deficits on neurological examination. Initial brain computed tomography (CT) scan revealed no pathological findings, while the subsequent cranial CT and magnetic resonance imaging (MRI) scans uncovered only mild nonspecific sclerotic lesions in left occipital condyle. All laboratory examinations were within normal limits, except for an elevated alkaline phosphatase (170 U/L) and a markedly increased prostate-specific antigen (609 ng/mL). The patient underwent whole-body BS with technetium-99m that revealed increased radiotracer deposition compatible with metastases in multiple foci, including the left occipital condyle. Prostate biopsy confirmed the diagnosis of prostate adenocarcinoma. Our case suggests that a complete and thorough workup for hidden malignancies should be performed in all patients with HNP, even in the absence of a finding in brain neuroimaging. Bone scintigraphy is an essential investigation that should be considered in uncertain cases of HNP, and especially in those with negative CT and MRI scans.

Detecting Myocardial Ischemia With 99mTechnetium-Tetrofosmin Myocardial Perfusion Imaging in Ischemic Stroke.

BACKGROUND: To assess the myocardial status in patients with stroke, employing myocardial perfusion imaging (MPI) with 99mTechnetium-tetrofosmin (99mTc-TF)-single-photon emission computed tomography (SPECT). METHODS: Fifty-two patients with ischemic stroke were subjected to 99mTc-TF-SPECT MPI within 1 month after stroke occurrence. None of the patients had any history or symptoms of coronary artery disease or other heart disease. Myocardial perfusion imaging was evaluated visually using a 17-segment polar map. Myocardial ischemia (MIS) was defined as present when the summed stress score (SSS) was >4; MIS was defined as mild when SSS was 4 to 8, and moderate/severe with SSS ≥9. Patients with SSS >4 were compared to patients with SSS <4. Parameters such as age, body mass index, waist perimeter, smoking habits, and medical history (diabetes mellitus, dyslipidemia, etc) were evaluated according to MPI results. RESULTS: Myocardial ischemia was present in 32 (62%) of 52 patients with stroke. Among them, 20 (62%) of 32 patients had mild abnormalities and 12 (38%) of 32 had moderate/severe. The age and waist perimeter showed a tendency to relate to severe MIS when patients with SSS >9 were compared to patients with SSS <4. In MPI-positive patients, an age was to be association with SSS, with the oldest age exhibiting the highest SSS (P = .01). The association of age with SSS remained statistically significant in the multivariate analysis (P = .04). CONCLUSION: The study suggested that more than half of patients with stroke without a history of cardiac disease have MIS. Although most of them have mild MIS, we suggest a thorough cardiological evaluation in this group of patients for future prevention of severe myocardial outcome.

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting.

PURPOSE: The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. METHODS: A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4±16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. RESULTS: Patients had epilepsy for a mean period of 14.1±10.6years and the mean daily LEV dose was 2583.3±763.7mg. The mean AUC±SD and Cmax±SD was 288.4±86.3(mg/L)h and 37.8±10.4mg/L respectively for brand LEV and 319.2±104.7(mg/L)h and 41.6±12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. CONCLUSIONS: In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV.

High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis.

Emerging studies highlight high on-treatment of platelet reactivity (HTPR) as a major hindrance to the secondary prevention of cardiovascular ischemic events. The aim of this systematic review and meta-analysis is to assess the prevalence of HTPR in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and reveal a possible relation with a higher risk of cerebrovascular event recurrence. Studies were selected if they reported absolute numbers or percentages of HTPR with ASA or clopidogrel in IS/TIA patients at any time point after the cerebrovascular event onset and assessed with any type of platelet function tests. We included 52 full-text studies with a total of 8364 patients. Overall, the pooled prevalence of HTPR was 24% (95%CI: 20-27%). In subgroup analyses, the prevalence of HTPR on ASA was 23% (95%CI: 20-28%), on clopidogrel 27% (95%CI: 22-32%) and on dual antiplatelet treatment (DAPT) 7% (95%CI: 5-10%). The overall analysis of all studies providing data on the risk of IS/TIA recurrence, indicates that the patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR=1.81, 95%CI: 1.30-2.52; p<0.001). In conclusion the present study shows a significant lower prevalence of HTPR in DAPT and an increased rate of recurrent cerebrovascular ischemic events in patients presenting HTPR.

Difluoromethylornithine in cancer: new advances.

Difluoromethylornithine (DFMO; eflornithine) is an irreversible suicide inhibitor of the enzyme ornithine decarboxylase which is involved in polyamine synthesis. Polyamines are important for cell survival, thus DFMO was studied as an anticancer agent and as a chemoprevention agent. DFMO exhibited mainly cytostatic activity and had single agent efficacy as well as activity in combination with other chemotherapeutic drugs for some cancers and leukemias. Herewith, we summarize the current knowledge of the anticancer and chemopreventive properties of DFMO and assess the status of clinical trials.

Multiple sclerosis and inflammatory bowel diseases: a systematic review and meta-analysis.

The association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) has been suggested, apart from their common epidemiological and immunological patterns, also due to observations of increased incidence of both IBD among MS patients and MS among IBD patients. We estimated the risk of concurrent IBD and MS comorbidity, using data from all available case-control studies. We calculated the corresponding Risk ratios (RRs) in each included case-control study to express the risk of IBD and MS concurrence at a given population. We performed additional subgroup analyses according to the type of registry from which the data of the cases were exported (IBD or MS registry) and the IBD type (Crohn's disease, CD or Ulcerative colitis, UC). We included 10 studies, comprising a total of 1,086,430 patients (0.08% of them with concurrent IBD and MS). Pooled RR for IBD/MS comorbitity was 1.54 (95% CI 1.40-1.67; p < 0.0001) with no differences (p = 0.91) among IBD and MS registries (RR 1.53, 95% CI 1.36-1.72, p < 0.001 for MS comorbidity in IBD patients vs. RR 1.55, 95% CI 1.32-1.81, p < 0.001 for IBD comorbidity in MS patients). No difference was also found on the risk of MS comorbidity among patients with CD or UC (RR 1.52, 95% CI 1.34-1.72, p < 0.001 vs. RR 1.55, 95% CI 1.38-1.74, p < 0.001; p for subgroup differences: 0.84). In all analyses no evidence of heterogeneity or publication bias was detected. Both IBD and MS patients seem to have a fifty-percent increased risk of MS or IBD comorbidity, respectively, with no apparent differences between patients with CD or UC.

The value of transesophageal echocardiography for embolic strokes of undetermined source.

OBJECTIVE: Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS). METHODS: We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups. RESULTS: We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3-8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%-65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%-28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%-10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%-9.6%]), ESUS (8.1% [95% CI: 3.4%-18.1%]), and IS (9.4% [95% CI: 7.5%-11.8%]). CONCLUSIONS: Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.