Characteristics of Discharged Elderly Patients with Acute Heart Failure Followed by Board-Certified-Cardiologists in a Rural Area of Japan.

The worldwide incidence rates of heart failure (HF) are approaching pandemic status due to aging societies. Board-certified cardiologists (BCCs) of the Japanese Circulation Society (JCS) are cardiologists who have completed the respective fellowship program and passed the examination. However, in rural areas, patients have limited access to medical care for social or geographical reasons. The clinical features of the specialist's follow-up for HF patients in rural areas are unclear.This study consists of 205 consecutive discharged elderly patients who were admitted to our hospital due to acute HF (AHF). All patients were recommended for follow-up with BCCs-JCS by the multidisciplinary HF team at the discharge-care planning meeting. The aim of this study was to investigate the clinical features and impact of BCC follow-up for discharged elderly patients with AHF in rural areas.A total of 156 patients chose follow-up with BCCs-JCS (BCC group), and 49 patients chose follow-up with non-BCCs-JCS (non-BCC group). Patients in the BCC group were younger (83 [76-86] versus 89 [75-93] years old, P < 0.001) and had more frequent use of ß-blockers (67% versus 39%, P < 0.001). The degree of frailty assessed by the clinical frailty scale was more severe in the non-BCC group than in the BCC group (4 [3-5] versus 6 [4-7], P < 0.001). The non-BCC group lived in nursing homes more frequently than the BCC group (16% versus 5%, P = 0.011).The HF patients followed by BCCS-JCS in rural areas were younger and had less frailty.

Target Lesion Lipid Content Detected by Near-Infrared Spectroscopy After Stenting and the Risk of Subsequent Target Lesion Failure.

[Figure: see text].

Vascular Response After Everolimus-Eluting Stent in Acute Myocardial Infarction Caused by Calcified Nodule.

BACKGROUND: Patients with acute myocardial infarction (AMI) caused by calcified nodules (CN) have worse clinical outcomes following primary percutaneous coronary intervention (PCI). This study investigated the late vascular response after everolimus-eluting stent (EES) implantation assessed by optical coherence tomography (OCT) in patients with AMI caused by CN, by comparing with plaque rupture (PR) and plaque erosion (PE).Methods and Results: Based on the OCT findings in AMI culprit lesions before PCI, a total of 141 patients were categorized into 3 groups (PR, PE, or CN), and the OCT findings immediately and 10 months after PCI were compared. The frequency of PR, PE, and CN was 85 (60%), 45 (32%), and 11 patients (8%), respectively. In the 10-month follow-up OCT, the frequency of lesions with uncovered struts and lesions with malapposed struts were highest in the CN group, followed by the PR and PE groups (82% vs. 52% vs. 40%, P=0.042 and 73% vs. 26% vs. 16%, P<0.001, respectively). The incidence of intra-stent thrombus, re-appearance of CN within the stent, and target lesion revascularization were higher in the CN group compared with the PR and PE groups (36% vs. 9% vs. 7%, P=0.028; 27% vs. 0% vs. 0%, P<0.001; and 18% vs. 2% vs. 2%, P=0.024, respectively). CONCLUSIONS: Late arterial healing response at 10 months after EES implantation in the CN was worse compared with PR and PE in patients with AMI.

Usefulness of optical coherence tomography with angiographic coregistration in the guidance of coronary stent implantation.

Optical coherence tomography (OCT)-angiography coregistration during stent implantation may be useful to avoid geographical mismatch and incomplete lesion coverage. Untreated lipid-rich plaque at stent edge is associated with subsequent stent edge restenosis. The present study sought to compare the frequency of untreated lipid-rich plaque at the stent edge between OCT-guided percutaneous coronary intervention (PCI) with and without OCT-angiography coregistration. We investigated 398 patients who underwent OCT-guided stent implantation (n = 198 in the coregistration group, and n = 200 in the no coregistration group). In OCT after PCI, untreated lipid-lich plaque was identified by the maximum lipid arc > 180˚ in the 5-mm stent edge segment. The PCI-targeted lesion characteristics and stent length were not different between the coregistration group and the no coregistration group. The frequency of untreated lipid-rich plaque in either proximal or distal stent edge segment was significantly lower in the coregistration group than in the no coregistration group (16% vs. 26%, P = 0.015). The frequency of stent-edge dissection (5% vs. 6%, P = 0.516) and untreated stenosis (2% vs. 3%, P = 0.724) was low and without significant differences between the two groups. In OCT-guided PCI, the use of OCT-angiography coregistration was associated with a reduced frequency of untreated lipid-rich plaque at stent edges. OCT-angiography coregistration has a positive impact on PCI results.

Impact of Optical Coherence Tomography Imaging on Decision-Making During Percutaneous Coronary Intervention in Patients Presented With Acute Coronary Syndromes.

BACKGROUND: Optical coherence tomography (OCT) provides valuable information to guide percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) regarding lesion preparation, stent sizing, and optimization. The aim of the present study was to compare lumen expansion of stent-treated lesions immediately after the procedure for ACS between OCT-guided PCI and angiography-guided PCI.Methods and Results:This study investigated stent-treated lesions immediately after PCI for ACS by using quantitative coronary angiography in 390 patients; 260 patients with OCT-guided PCI and 130 patients with angiography-guided PCI. Before stenting, the frequency of pre-dilatation and thrombus aspiration were not different between the OCT-guided and angiography-guided PCI groups. Stent diameter was significantly larger as a result of OCT-guided PCI (3.11±0.44 mm vs. 2.99±0.45 mm, P=0.011). In post-dilatation, balloon pressure-up (48% vs. 31%, P=0.001) and balloon diameter-up (33% vs. 6%, P<0.001) were more frequently performed in the OCT-guided PCI group. Minimum lumen diameter (2.55±0.35 mm vs. 2.13±0.50 mm, P<0.001) and acute lumen gain (2.18±0.54 mm vs. 1.72±0.63 mm, P<0.001) were significantly larger in the OCT-guided PCI group. Percent diameter stenosis (14±4% vs. 24±10%, P<0.001) and percent area stenosis (15±5% vs. 35±17%, P<0.001) were significantly smaller in the OCT-guided PCI group. CONCLUSIONS: OCT-guided PCI potentially results in larger lumen expansion of stent-treated lesions immediately after PCI in the treatment of ACS compared with angiography-guided PCI.

Intimal thickening and disruption of the media occur in the arterial walls of coronary arteries not associated with coronary arterial aneurysms in patients with Kawasaki disease.

BACKGROUND: Coronary artery aneurysm (CAA) is an important complication of Kawasaki disease (KD) that is associated with arterial structure damage. However, few studies have examined structural changes in coronary arteries that are not associated with CAA. METHODS: We examined coronary arteries in KD patients with CAAs who underwent follow-up coronary angiography (CAG) and optical coherence tomography (OCT). Coronary arterial branches with no abnormal findings during the most recent CAG were classified into two groups. Arteries with an acute-phase CAA that later regressed were classified as group R; arteries with no abnormal findings on either acute or convalescent phase CAG were classified as group N. Coronary arterial wall structural changes were compared between groups using OCT. RESULTS: Fifty-seven coronary arterial branches in 23 patients were evaluated by OCT. Thirty-six branches showed no abnormality during the most recent CAG. Both groups R and N comprised 18 branches. Maximum intimal thicknesses in groups R and N were 475 and 355 µm, respectively (p = 0.007). The incidences of media disruption were 100% and 67%, respectively (p = 0.02). Calcification, macrophage accumulation, and thrombus were not found in either group. CONCLUSIONS: Intimal thickening and disruption of the media occur in coronary arteries with acute phase CAAs that later regress in the convalescent phase, as well as in arteries with normal CAG findings in the acute and convalescent phases.

Impact of left ventricular ejection fraction and preoperative hemoglobin level on perioperative adverse cardiovascular events in noncardiac surgery.

The prediction of a perioperative adverse cardiovascular event (PACE) is an important clinical issue in the medical management of patients undergoing noncardiac surgery. Although several predictors have been reported, simpler and more practical predictors of PACE have been needed. The aim of this study was to investigate the predictors of PACE in noncardiac surgery. We retrospectively analyzed 723 patients who were scheduled for elective noncardiac surgery and underwent preoperative examinations including 12-lead electrocardiography, transthoracic echocardiography, and blood test. PACE was defined as cardiac death, non-fatal myocardial infarction, unstable angina, congestive heart failure, arrhythmia attack that needs emergency treatment (rapid atrial fibrillation, ventricular tachycardia, and bradycardia), acute pulmonary embolism, asystole, pulseless electrical activity, or stroke during 30 days after surgery. PACE occurred in 54 (7.5%) of 723 patients. High-risk operation (11% vs. 3%, p = 0.003) was more often seen, left ventricular ejection fraction (LVEF) (55 ± 8% vs. 60 ± 7%, p = 0.001) and preoperative hemoglobin level (11.8 ± 2.2 g/dl vs. 12.7 ± 2.0 g/dl, p = 0.001) were lower in patients with PACE compared to those without PACE. By multivariate logistic regression analysis, high-risk operation (odds ratio (OR): 7.05, 95% confidence interval (CI) 2.16-23.00, p = 0.001), LVEF (OR 1.06, every 1% decrement, 95% CI 1.03-1.09, p = 0.001), and preoperative hemoglobin level (OR 1.22, every 1 g/dl decrement, 95% CI 1.07-1.39, p = 0.003) were identified as independent predictors of PACE. Receiver operating characteristic analysis demonstrated that LVEF of 58% (sensitivity = 80%, specificity = 61%, area under the curve (AUC) = 0.723) and preoperative hemoglobin level of 12.2 g/dl (sensitivity = 63%, specificity = 64%, AUC = 0.644) were optimal cut-off values for predicting PACE. High-risk operation, reduced LVEF, and reduced preoperative hemoglobin level were independently associated with PACE in patients undergoing noncardiac surgery.

Global longitudinal strain evaluated by speckle-tracking echocardiography as a surrogate marker for predicting replacement fibrosis detected by magnetic resonance-late gadolinium enhancement in patients with nonischemic cardiomyopathy.

PURPOSE: This study aimed to investigate whether left ventricular (LV) global longitudinal strain (GLS) evaluated by speckle-tracking echocardiography (STE) can be used as a surrogate marker for the detection of replacement fibrosis by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) in patients with nonischemic cardiomyopathy (NICM). METHODS: This study analyzed 41 NICM patients who successfully underwent both STE and CMR, and were divided into those with (Group A, n = 18) and those without CMR-LGE (Group B, n = 23). Echocardiographic indexes, including GLS, were compared between the two groups. RESULTS: No significant differences were observed in LV end-diastolic and end-systolic volume indexes, LV ejection fraction, mitral E/A, deceleration time, E/e', left atrial volume index, and the systolic trans-tricuspid pressure gradient between Groups A and B. STE-GLS was significantly worse in Group A than in Group B (-7.6% ± 3.0% vs -9.9% ± 3.2%, P = .01). Receiver operating characteristic curve analysis showed that STE-GLS of -7.9% was the best cut-off value for detection of CMR-LGE (sensitivity, 78%; specificity, 74%; and area under the curve, 0.74). CONCLUSIONS: STE-GLS may be a potential surrogate marker for the detection of CMR-LGE-derived replacement fibrosis in patients with NICM.

SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity.

Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C-terminal lysine residues. Our results suggest that SIRT2-mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma.

Optical Coherence Tomography Comparison of Percutaneous Coronary Intervention Among Plaque Rupture, Erosion, and Calcified Nodule in Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is caused by coronary plaque rupture (PR), plaque erosion (PE), or calcified nodule (CN). We used optical coherence tomography (OCT) to compare stent expansion immediately after primary percutaneous coronary intervention (PCI) in patients with AMI caused by PR, PE, or CN.Methods and Results:In all, 288 AMI patients were assessed by OCT before and immediately after PCI, performed with OCT guidance according to OPINION criteria for stent sizing and optimization. The frequency of OCT-identified PR (OCT-PR), OCT-PE, and OCT-CN was 172 (60%), 82 (28%), and 34 (12%), respectively. Minimum stent area was smallest in the OCT-CN group, followed by the OCT-PE and OCT-PR groups (mean [±SD] 5.20±1.77, 5.44±1.78, and 6.44±2.2 mm2, respectively; P<0.001), as was the stent expansion index (76±13%, 86±14%, and 87±16%, respectively; P=0.001). The frequency of stent malapposition was highest in the OCT-CN group, followed by the OCT-PR and OCT-PE groups (71%, 38%, and 27%, respectively; P<0.001), as was the frequency of stent edge dissection in the proximal reference (44%, 23%, and 10%, respectively; P<0.001). The frequency of tissue protrusion was highest in the OCT-PR group, followed by the OCT-PE and OCT-CN groups (95%, 88%, and 85%, respectively; P=0.036). CONCLUSIONS: Stent expansion was smallest in the OCT-CN group, followed by the OCT-PR and OCT-PE groups. Plaque morphology in AMI culprit lesions may affect stent expansion immediately after primary PCI.

Comparison of Optical Flow Ratio and Fractional Flow Ratio in Stent-Treated Arteries Immediately After Percutaneous Coronary Intervention.

BACKGROUND: Optical flow ratio (OFR) is a recently developed method for functional assessment of coronary artery disease based on computational fluid dynamics of vascular anatomical data from intravascular optical coherence tomography (OCT). The purpose of this study was to investigate the relationship between OFR and fractional flow reserve (FFR) in stent-treated arteries immediately after percutaneous coronary intervention (PCI).Methods and Results:The OFR and FFR were measured in 103 coronary arteries immediately after successful PCI with a stent. An increase in the OFR and FFR values within the stent was defined as in-stent ∆OFR and ∆FFR, respectively. The values of FFR and OFR were 0.89±0.06 and 0.90±0.06, respectively. OFR was highly correlated with FFR (r=0.84, P<0.001). OFR showed a good agreement with FFR, presenting small values of mean difference and root-mean-squared deviation (FFR-OFR: -0.01±0.04). In-stent ∆OFR showed a moderate correlation (r=0.69, P<0.001) and good agreement (in-stent ∆FFR - in-stent ∆OFR: 0.00±0.02) with in-stent ∆FFR. CONCLUSIONS: OFR showed a high correlation and good agreement with FFR in stent-treated arteries immediately after PCI.

Different vascular healing process between bioabsorbable polymer-coated everolimus-eluting stents versus bioresorbable vascular scaffolds via optical coherence tomography and coronary angioscopy (the ENHANCE study: ENdothelial Healing Assessment with Novel Coronary tEchnology).

Recent clinical trials have raised concerns about the safety and efficacy of ABSORB™ bioresorbable vascular scaffolds (BVS). The difference in the vascular healing process between SYNERGY™ bioabsorbable polymer-coated everolimus-eluting stents (BP-EES) and BVS remains unclear. The aim of the ENHANCE study was to compare vascular healing on BP-EES versus BVS by optical coherence tomography (OCT) and coronary angioscopy (CAS) at 4- and 12-month follow-ups. This is a prospective, non-randomized, single center clinical trial. Thirteen eligible patients with multivessel disease were enrolled. BP-EES and BVS were simultaneously implanted in the same patients, but in different coronary vessels. Imaging follow-up with both OCT and CAS was completed in 11 patients at 12 months. Neointimal coverage rates were similar between the two groups based on OCT measurements. The neointimal thickness of BP-EES was significantly thicker at the 12th month than at the 4th month, whereas the neointimal thickness of BVS did not change between the measurements taken at the 4th and 12th month. Existence of intra-stent thrombus was significantly higher in the BVS group, compared to the BP-EES group. On the other hand, CAS revealed that red-thrombi and yellow-plaque were more frequently observed in BVS at 4 months and up to 12-month follow-ups than in BP-EES. These findings suggested that the evidence of instability remained up to 12 months in the vascular healing with BVS, compared to that with BP-EES. Vascular healing of the stented wall was recognized at the very early phase after BP-EES implantation. However, vascular healing with BVS was still incomplete after 12 months.

Assessment of myocardial damage after acute myocardial infarction by diastolic deceleration time of coronary flow velocity using echocardiography and contrast-enhanced magnetic resonance imaging.

BACKGROUND: There are limited data available regarding the use of diastolic deceleration time (DDT) of three major arteries measured by transthoracic echocardiography (TTE) for assessing coronary microvascular damage after acute myocardial infarction (AMI). Therefore, we aimed to compare the DDT of three major arteries using TTE with the transmural extent of infarction (TEI) and infarct size, which were classified using contrast-enhanced magnetic resonance imaging (CE-MRI), in patients with AMI. METHODS: The DDT of the culprit coronary artery was measured in 74 patients using TTE and CE-MRI 1 week after the onset of AMI. The TEI was graded based on the transmural extent of the hyper-enhanced tissue (grades 1-4). RESULTS: The assessable rate for the DDT was 95%; individual rates were 100% for the left anterior descending coronary artery, 90% for the left circumflex artery, and 93% for the right coronary artery. The DDT decreased gradually as the TEI grade progressed (P = .021). Infarct size was significantly correlated with the DDT (r = -0.51, P < .0001). Univariate analysis revealed that the left ventricular (LV) end-systolic volume, LV ejection fraction, and DDT were significantly associated with TEI grade 4. After adjustment via multiple logistic regression analysis, the DDT was independently remained. With a cutoff value of 950ms, as determined by the ROC curve, DDT could detect TEI grade 4 with 81.1% sensitivity and 80.1% specificity. CONCLUSION: The DDT of three major coronary arteries measured by TTE 1 week after the onset of AMI can assess the extent of myocardial damage, which is determined by CE-MRI.

Expression of Cyclophilin A in Coronary Artery Plaque with Intraplaque Hemorrhage Is More Frequent in Deceased Patients Who Had Impaired Kidney Function.

Patients with impaired kidney function have a high frequency of intraplaque hemorrhage (IPH) in their coronary arteries. Levels of cyclophilin A (CyPA), an indirect matrix metalloproteinase inducer, are increased in deceased patients who had impaired kidney function. In this study, we have examined the relationship between IPH and CyPA.We examined 47 samples of coronary plaque from 27 cadavers with coronary stenosis. These sections, all with > 50% coronary stenosis, were stained with an antibody against CyPA and the expression of CyPA was semi-quantified. Cadavers and plaques were classified into one of two groups depending on the presence or absence of IPH. IPH was defined as the presence of red blood cells stained with hematoxylin and eosin (HE) indicative of overt acute hemorrhage.In an individual analysis, estimation of glomerular filtration rate (eGFR) in the IPH group was significantly lower than that in the non-IPH group (P = 0.002). In a histological analysis, the percentage of stained area of CyPA in the IPH group was significantly higher than that in the non-IPH group (P < 0.0001).IPH was associated with a significantly higher expression of CyPA in this study. In addition, patients with IPH in their coronary arteries had significantly impaired kidney function.

[Usefulness of CT in the Lateral Decubitus Position for Preoperative Evaluation of Cranioplasty].

Patients with massive brain swelling undergo external decompressive craniectomy to manage intracranial pressure. Following supratentorial craniectomy, and after the brain swelling is relieved, cranioplasty is performed. Although feasibility of the surgery is usually assessed by CT scanning in a supine position, it is sometimes difficult to determine whether the surgery can be performed safely. Although nine patients underwent a decompressive craniectomy during the study period, only six patients could undergo brain CT-first in a supine position and next in a lateral decubitus position with the surgical side upward-before cranioplasty. On CT images, the distance from the midline to the brain surface was measured on the image where brain bulging was maximal, and the bulging was calculated by comparing the image with the distance measured on the contralateral side. In all cases, brain bulging decreased with this change in position. The decrease ranged from 5.5-9.2mm(mean 7.1mm). Patients with brain bulging of 2.8-3.6mm in the lateral decubitus position needed no additional procedure, or only required drainage of a very small amount of cerebrospinal fluid(CSF)from the brain surface. Those with brain bulging of 5.1-12mm showed ventricular dilatation on CT images, and required ventricular puncture or spinal CSF drainage to decrease brain bulging for cranioplasty. We believe that the lateral decubitus position, with the surgical side upward, ameliorates the local brain shift induced by gravity. A lateral position during CT simulates the surgical head position for cranioplasty and can help to assess whether cranioplasty is feasible.

Value of tissue-tracking tricuspid annular plane by speckle-tracking echocardiography for the assessment of right ventricular systolic dysfunction.

BACKGROUND: Assessment of right ventricular (RV) function remains challenging because of its complex geometry. Application of speckle-tracking echocardiography (STE) to the tricuspid annulus provides rapid and automated assessment of the midpoint of the tricuspid annular plane displacement (TAD). The aim of this study was to investigate the value of tissue-tracking TAD for the assessment of RV systolic dysfunction. METHODS: We retrospectively studied 61 patients in whom RV ejection fraction (EF) measured by 3-dimensional echocardiography was performed. STE-derived displacement of the midpoint between the septal and lateral tricuspid annulus and its percentage of RV length at end-diastole (MTAD) were automatically assessed. We performed comparative analyses between the RVEF ≥45% group and the RVEF <45% group in each parameter for the assessment of RV systolic function. RESULTS: MTAD was successfully assessed in 56 (91.2%). According to receiver operating characteristics analysis, RVEF <45% was best detected by MTAD <14.7% with area under curve (AUC) 0.97, sensitivity 93%, specificity 95%, followed by RV free wall longitudinal strain (AUC 0.86), RV fractional area change (AUC 0.84), tricuspid annular plane systolic excursion (AUC 0.79), and systolic peak velocity of tricuspid annulus (AUC 0.70), although there was no significant difference between MTAD and RV free wall strain (P = 0.14). CONCLUSION: The present study showed that MTAD was simple index and useful for the assessment of RV systolic dysfunction.

Assessment of decreased left ventricular longitudinal deformation in asymptomatic patients with organic mitral regurgitation and preserved ejection fraction using tissue-tracking mitral annular displacement by speckle-tracking echocardiography.

BACKGROUND: Application of speckle-tracking echocardiography (STE) provides rapid assessment of tissue-tracking mitral annular displacement (TMAD). We investigated the value of TMAD for the assessment of decreased LV longitudinal deformation in asymptomatic patients with severe or moderate-to-severe mitral regurgitation (MR) and preserved LV ejection fraction (LVEF). METHODS: We retrospectively studied 50 patients with severe or moderate-to-severe organic MR and preserved LVEF (>60%) in whom global longitudinal strain (GLS) was successfully measured by STE. TMAD was quickly assessed in the apical four-chamber view using STE. We calculated the percentage of TMAD to LV length from the midpoint of mitral annulus to the apex at end-diastolic (%TMAD). The study population was divided into two groups: decreased GLS patients (>-20%; Group A) and preserved GLS patients (≤-20%; Group B). We examined whether %TMAD could be used as a diagnostic factor of decreased GLS. RESULTS: %TMAD was significantly lower in Group A than Group B (12.5 ± 0.5 vs 16.8 ± 2.2, P < 0.0001). By univariate logistic regression analysis, %TMAD was a diagnostic factor of decreased GLS. By multiple regression analysis, %TMAD remained an independent diagnostic factor of decreased GLS (Odds ratio [OR] = 4.21, 95% confidence interval [CI] = 1.34-28.94, P < 0.0001). A cutoff value of %TMAD <14.6 had a sensitivity of 94% and specificity of 94% for the presence of decreased GLS. CONCLUSIONS: Tissue-tracking mitral annular displacement is useful in the assessment of decreased LV longitudinal deformation in asymptomatic patients with severe or moderate-to-severe MR and preserved LVEF.

Identification of a novel fusion gene HMGA2-EGFR in glioblastoma.

Glioblastoma is one of the most malignant forms of cancer, for which no effective targeted therapy has been found. Although The Cancer Genome Atlas has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown. To search for novel fusion genes, we obtained RNA-seq data from TGS-01 human glioma-initiating cells, and identified a novel fusion gene (HMGA2-EGFR), encoding a protein comprising the N-terminal region of the high-mobility group AT-hook protein 2 (HMGA2) fused to the C-terminal region of epidermal growth factor receptor (EGFR), which retained the transmembrane and kinase domains of the EGFR. This fusion gene product showed transforming potential and a high tumor-forming capacity in cell culture and in vivo. Mechanistically, HMGA2-EGFR constitutively induced a higher level of phosphorylated STAT5B than EGFRvIII, an in-frame exon deletion product of the EGFR gene that is commonly found in primary glioblastoma. Forced expression of HMGA2-EGFR enhanced orthotopic tumor formation of the U87MG human glioma cell line. Furthermore, the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS-01 cells in culture and inhibited tumor formation in vivo. These findings suggest that, in addition to gene amplification and in-frame exon deletion, EGFR signaling can also be activated by gene fusion, suggesting a possible avenue for treatment of glioblastoma.

Third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice.

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited, as was the case for contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas.

Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells' responses to chemotherapeutics remains controversial. To investigate the roles of autophagy in malignant gliomas, we used CRISPR/CAS9 to knock out the ATG5 gene, which is essential for autophagosome formation, in tumor cells derived from patients with glioblastoma. While ATG5 disruption inhibited autophagy, it did not change the phenotypes of glioma cells and did not alter their sensitivity to temozolomide, an agent used for glioblastoma patient therapy. Screening of an anticancer drug library identified compounds that showed greater efficacy to ATG5-knockout glioma cells compared to control. While several selected compounds, including nigericin and salinomycin, remarkably induced autophagy, potent autophagy inducers by mTOR inhibition did not exhibit the ATG5-dependent cytoprotective effects. Nigericin in combination with ATG5 deficiency synergistically suppressed spheroid formation by glioma cells in a manner mitigated by Ca2+ chelation or CaMKK inhibition, indicating that, in combination with autophagy inhibition, calcium-mobilizing compounds contribute to efficient anticancer therapeutics. ATG5-knockout cells treated with nigericin showed increased mitochondria-derived reactive oxygen species and apoptosis compared to controls, indicating that autophagy protects glioma cells from mitochondrial reactive oxygen species-mediated damage. Finally, using a patient-derived xenograft model, we demonstrated that chloroquine, a pharmacological autophagy inhibitor, dramatically enhanced the efficacy of compounds selected in this study. Our findings propose a novel therapeutic strategy in which calcium-mobilizing compounds are combined with autophagy inhibitors to treat patients with glioblastoma.