Melatonin attenuates osteosarcoma cell invasion by suppression of C‐C motif chemokine ligand 24 through inhibition of the c‐Jun N‐terminal kinase pathway

Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor‐suppressing properties for a myriad of tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C‐C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal‐regulated kinase (ERK) 1/2 and c‐Jun N‐terminal kinase (JNK) 1/2, respectively, in a dose‐dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN‐JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin‐mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis.     

Primary Cardiac Lymphoma: Echocardiography and F‐18‐Fluorodeoxyglucose Positron Emission Tomography in Selection of a Biopsy Site

A 63‐year‐old man was referred to our hospital because of a cardiac tumor. Transthoracic echocardiography revealed a rough, mobile tumor in the dilated right atrium, and transesophageal echocardiography showed that the tumor consisted of small, botryoidal masses. Catheter‐based biopsy carried a high risk of embolism. Therefore, we used F‐18‐fluorodeoxyglucose positron emission tomography (FDG‐PET), which revealed an abnormal accumulation in the right cervical lymph nodes, as well as in the heart. We safely performed biopsy of the lymph nodes and diagnosed the patient with primary cardiac lymphoma. We concluded that echocardiography and FDG‐PET are useful for selecting an appropriate biopsy site in primary cardiac lymphoma.     

Cardiac Myxolipoma in a Child: Diagnosis and Surgical Management

We present a case of a rare tumor, a myxolipoma, appearing in a 5‐year‐old child, along with the imaging evaluation and surgical management. The natural history is expected to be that of a benign lesion, but the rarity precludes large studies.     

Regression of Cardiac Valvulopathy Related to Ergot‐Derived Dopamine Agonists

Aims: In a previous echocardiographic prevalence study we reported a significant increase in the frequency of heart valve regurgitation in patients with Parkinson's disease taking the ergot‐derived dopamine agonists pergolide and cabergoline versus controls. We followed‐up our original cohort of patients to ascertain whether valvulopathy regressed after discontinuation of treatment and/or its incidence increased over time. Methods: Prospective follow‐up of 101 patients treated with ergot‐derived dopamine agonists included in the prevalence study: 53 given pergolide and 48 cabergoline (64% male; 66.4 ± 8.7 years of age, 11.5 ± 5.9 years of disease, 21.8 ± 5.9 months of follow‐up); 55 stopped treatment while 46 continued. The main outcomes measures, were: echocardiographic quantification of regurgitant valve disease, abnormal leaflet, or cusp thickening and measurement of mitral valve tenting area. Results: Valve abnormalities regressed in about one third of patients with significant multivalvular and in about half of the patients with monovalvular regurgitation who withdrew; no progression was observed in remaining patients. Patients continuing ergot‐derived dopamine agonists showed progression of cardiac valvulopathy: seven new cases with three to four regurgitation grade of any valve occurred during follow‐up; this regarded also patients who had been on pergolide for many years. Conclusion: Owing to the persistence of risk of heart valve damage over time and the lack of its mid‐term reversibility in many patients, we believe that pergolide and cabergoline should be prescribed only when therapeutic alternatives with a better risk/benefit ratio are unavailable and the patient has access to echocardiography.     

Cost‐Effectiveness of Cardiac Resynchronization Therapy in the MADIT‐CRT Trial

Cost Effectiveness of MADIT‐CRT. Background: The Multicenter Automatic Defibrillator Implantation Trial‐Cardiac Resynchronization Therapy (MADIT‐CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex. Objectives: To evaluate 4‐year cost‐effectiveness of CRT‐ICD compared to ICD alone using MADIT‐CRT data. Research Design: Patients enrolled in the trial were randomized to implantation of either ICD or CRT‐ICD in a 2:3 ratio, with up to 4‐year follow‐up period. Cost‐effectiveness analyses were conducted, and sensitivity analyses by age, gender, and left bundle branch block (LBBB) conduction pattern were performed. Subjects: A total of 1,271 patients with ICD or CRT‐ICD (US centers only) who reported healthcare utilization and health‐related quality of life data. Measures: We used the EQ‐5D (US weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates. Results: Average 4‐year healthcare expenditures in CRT‐ICD patients were higher than costs of ICD patients ($62,600 vs 57,050, P = 0.015), mainly due to the device and implant‐related costs. The incremental cost‐effectiveness ratio of CRT‐ICD compared to ICD was $58,330/quality‐adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost‐effectiveness benefit being evident in the non‐LBBB group. Conclusions: In minimally symptomatic patients with low ejection fraction and LBBB, CRT‐ICD is cost effective within 4‐year horizon when compared to ICD‐only. (J Cardiovasc Electrophysiol, Vol. 24, pp. 66‐74, January 2013)     

Long‐term outcome of esophagectomy for primary malignant melanoma of the esophagus: a single‐institute retrospective analysis

Primary malignant melanoma of the esophagus (PMME) is a highly malignant tumor with a poor prognosis. Because PMME is an extremely rare disease, therapeutic strategies against the tumor have yet to be established, and the efficacy of esophagectomy remains unclear. The objective of this study was to evaluate the post‐esophagectomy survival of PMME patients. Ten patients who underwent esophagectomy for PMME between March 2005 and April 2013 at the Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan, were identified from the institutional database. We retrospectively retrieved clinical information and data on the long‐term outcomes from the patients' records. Survival rates after esophagectomy were calculated by the Kaplan–Meier method, and the hazard ratios of mortality were determined using the Cox's model. A follow‐up study of the 10 patients revealed 7 cancer recurrences and 5 deaths. Median survival time was 34.5 months, and 5 of 10 patients survived longer than 2 years. The 1‐year disease‐free survival rate was 40%, and the 1‐ and 3‐year overall survival rates were 70% and 60%, respectively. Importantly, all three of the non‐relapsing patients were histologically confirmed as free of lymph node involvement. The four patients with lymph node metastasis relapsed within 1 year. The disease‐free survival was significantly shorter in patients with lymph node involvement than in those without lymph node involvement (univariate hazard ratio = 13.3, 95% confidence interval 1.85–266.4; P = 0.009). In conclusion, esophagectomy might benefit PMME patients with no lymph node metastasis. Further large‐scale cohort studies are needed to establish the treatment strategy for PMME.     

Incidence of Severe Congenital Heart Disease at the Province of Al‐Qassim,Saudi Arabia

Worldwide, congenital heart defects (CHD) are the leading cause of infant deaths owing to congenital anomalies. Knowing the actual incidence of severe CHD is important for defining the requirement for resources and the burden of disease within the total population. Objectives. The aim of the study is to estimate the incidence of severe CHD at the province of Al‐Qassim as a reflection of that in the Kingdom of Saudi Arabia. Study Design. A retrospective database review of all cases diagnosed to have severe CHD at Prince Sultan Cardiac Center‐Qassim during a 3‐year period from January 2008 to December 2010. Results. During the study period, 316 patients were diagnosed to have severe CHD. During the 3‐year study period, the total live birth at the province of Al‐Qassim was 58 908. The incidence of severe CHD is 5.4/1000 live birth/year. Sixty‐five percent of cases were diagnosed at less than 2 months of age, with a median age at diagnosis of 45 days (range of 1 day to 1 year). Ventricular septal defect was the most common lesion diagnosed (22.5%). Collectively, prostaglandin‐dependent lesions constitute 38% of cases. Fifteen percent of patients were proved to have a syndrome. The most common syndrome was Down syndrome. Conclusion. Severe CHD is a major health problem at the Kingdom of Saudi Arabia and worldwide. The incidence of severe CHD likely to require intervention in infancy, in the province of Al‐Qassim, Saudi Arabia, is 5.4 per 1000 live births.     

Low Rate of Secondary Prevention ICDs in the General Population: Multiple‐Year Multiple‐Source Surveillance of Sudden Cardiac Death in the Oregon Sudden Unexpected Death Study

Sudden Cardiac Death. Introduction: Sudden cardiac death (SCD) is a large public health problem that warrants on‐going evaluation in the general population. While single‐year community‐based studies have been performed there is a lack of studies that have extended evaluation to multiple years in the same community. Methods and Results: From the on‐going Oregon Sudden Unexpected Death Study, we analyzed prospectively identified SCD cases in Multnomah County, Ore, (population ≈700,000) from February 1, 2002 to January 31, 2005. Detailed information ascertained from multiple sources (first responders, clinical records, and medical examiner) was analyzed. A total of 1,175 SCD cases were identified (61% male) with a mean age of 65 ± 18 years for men versus 70 ± 20 for women (P < 0.001). The overall incidence rate for the period was 58/100,000 residents/year. One‐quarter (24.6%) was ≤55 years of age. The most common initial rhythm was ventricular tachycardia or fibrillation (39% of cases, survival 27%) followed by asystole (36%, survival 0.7%) and pulseless electrical activity (23%, survival 6%). Among subjects that underwent resuscitation, the rate of survival to hospital discharge was 12% and overall survival to hospital discharge irrespective of resuscitation was 8%. Of the 68 survivors, 16 (24%) received a secondary prevention ICD. Conclusion: We report annualized SCD incidence from a multiple‐year, multiple‐source community‐based study, with higher than expected rates of women and subjects age ≤55 years. The low implantation rate of secondary prevention ICDs is likely to be multifactorial, but there are potential implications for recalibration of the projected need for ICD implantation; larger and more detailed studies are warranted. (J Cardiovasc Electrophysiol, Vol. 24, pp. 60‐65, January 2013)     

Cardiac Functional Reserve is Diminished in Growth Hormone‐Deficient Adults

Various studies have shown that patients with severe growth hormone deficiency (GHD) have diverse changes in left ventricular (LV) size or performance but so far there is no direct indication of cardiac reserve ability to maintain the circulation during peak exercise. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls. Eighteen patients with severe GHD were studied and compared with 18 age‐, sex‐, and body mass index (BMI)‐matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive hemodynamic measurements during maximal cardiopulmonary exercise testing. Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean ± SD: 4.4 ± 1.0 watts (W) vs. 5.2 ± 1.0 W, P= 0.02), despite attaining similar aerobic exercise peaks (VO_{2 max}, GHD: 2390 ± 822 mL/min vs. controls: 2461 ± 872 mL/min, P= 0.80) and similar peak respiratory exchange ratios. The lower peak cardiac power could not be accounted for by peripheral alterations because both groups reached similar peak exercise systemic vascular resistances. Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate: 154 ± 21 bpm vs. 174 ± 11 bpm, P= 0.001) and a lower cardiac pressure‐generating capacity (systolic blood pressure [SBP] 160 ± 25 mmHg vs. 200 ± 15 mmHg, P < 0.0001). Using this robust noninvasive method of assessing functional cardiac pumping capacity we have for the first time shown that patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure‐generating capacity.     

Detection of a Coronary Artery Anomaly after a Sudden Cardiac Arrest in a 17 Year‐old with D‐transposition of the Great Arteries Status Post Arterial Switch Operation: A Case Report

Long‐term follow‐up and testing for patients who have undergone congenital heart surgery is an evolving field. We report the case of a 17‐year‐old patient who had an arterial switch operation as an infant for d‐transposition of the great vessels and suffered sudden cardiac arrest while participating in a cross‐country event. Previous evaluations, including a cardiac catheterization and stress testing, did not indicate any identifiable abnormalities. After the arrest, a computed tomography angiogram of his chest showed an abnormal takeoff of the reimplanted left coronary artery.     

Prognostic Study of Cardiac Events in Japanese High Risk Hemodialysis Patients Using 123I‐BMIPP‐SPECT: B‐SAFE Study Design

Cardiovascular disease is the leading cause of morbidity and mortality in patients undergoing hemodialysis. Such patients frequently develop complications such as asymptomatic coronary artery disease (CAD). Accordingly, CAD must ideally be diagnosed at an early stage to improve prognosis. Although myocardial perfusion single photon emission computed tomography (SPECT) is valuable for diagnosing CAD, the stress test is not always applicable to patients on hemodialysis. Thus, we proposed a multicenter, prospective cohort study called “B‐SAFE” to investigate the applicability of resting ¹²³I‐labeled beta‐methyl‐iodophenylpentadecanoic acid (¹²³I‐BMIPP)‐SPECT will be used to diagnose cardiac disease and evaluate the prognosis of hemodialysis patients by imaging myocardial fatty acid metabolism. B‐SAFE began enrolling patients from June 2006 at 48 facilities. We performed ¹²³I‐BMIPP‐SPECT on 702 hemodialysis patients with risk factors for CAD until 30 November 2007 and plan to follow up for three years. The primary endpoints will be cardiac death and sudden death. This study should end in 2010.     

Long‐term outcome following remote ischemic postconditioning during percutaneous coronary interventions—the RIP‐PCI trial long‐term follow‐up

The clinical value of ischemic conditioning during percutaneous coronary intervention (PCI ) and mode of administration is controversial. Our aim was to assess the long‐term effect of remote ischemic postconditioning among patients undergoing PCI . We randomized 360 patients undergoing PCI who presented with a negative troponin T at baseline into 3 groups: 2 groups received remote ischemic postconditioning (with ischemia applied to the arm in 1 group and to the thigh in the other group), and the third group acted as a control group. Remote ischemic postconditioning was applied during PCI immediately following stent deployment, by 3, 5‐minute cycles of blood pressure cuff inflation to >200 mm Hg on the arm or thigh (20 mm Hg to the arm in the control), with 5‐minute breaks between each cycle. There were no differences in baseline characteristics among the 3 groups. Periprocedural myocardial injury occurred in 33% (P = 0.64). After 1 year, there was no difference between groups in death (P = 0.91), myocardial infarction (P = 0.78), or repeat revascularization (P = 0.86). During 3 years of follow‐up, there was no difference in death, myocardial infarction, and revascularization among the groups (P = 0.45). Remote ischemic postconditioning during PCI did not affect long‐term cardiovascular outcome. A similar effect was obtained when remote ischemia was induced to the upper or lower limb. ClinicalTrials.gov Identifier: NCT00970827     

Acute Intradialytic Cardiac Function and Inflammatory Cytokine Changes During High‐Efficiency Online Hemodiafiltration With Acetate‐Free and Standard Dialysis Solutions

Acetate in standard acetate‐containing bicarbonate (AC) dialysis fluid could induce peripheral vasodilatation, suppression of myocardial function, and inflammatory cytokine production, resulting in intradialytic hypotension in conventional hemodialysis (HD) patients. Online hemodiafiltration (HDF) provides superior hemodynamic stability over HD. The potentially additive hemodynamic benefits of the novel acetate‐free bicarbonate (AF) dialysis fluid in online HDF have never been explored before. The present randomized, double‐blind, crossover study was conducted in 22 online HDF patients to investigate the impact of AF dialysis fluid on hemodynamic and cytokine changes compared with AC dialysis fluid in online HDF. The results demonstrated the comparable changes of arterial pressure between AF and AC online HDF. During the study periods, the incidences of composite intradialytic hypotension and other adverse events were not different. The baseline and hourly changes of cardiac index, cardiac output, and peripheral vascular resistance during dialysis were comparable (P = 0.534, 0.199, and 0.641, respectively). The percent reductions of NT‐proBNP and cTnT were not significantly different (72.6 ± 12.3 vs. 72.6 ± 12.8%, P = 0.99 and 35.2 ± 12.8 vs. 36.7 ± 12.0%, P = 0.51). The changes of all pro‐inflammatory cytokines (IL‐2β, IL‐6, IL‐8, and TNF‐α) and anti‐inflammatory cytokine (IL‐10) during dialysis were comparable between both groups. In conclusion, AF dialysis solution does not offer additional hemodynamic benefit for stable online HDF patients. The hemodynamic stability provided by online HDF might protect the adverse effects of acetate.     

Current Therapies for Cardiac Allograft Vasculopathy in Children

Heart transplantation is an accepted therapy for end‐stage heart disease in children and adults. Over the past 25 years, the perioperative and 1‐year mortality has steadily improved, leading to an increased focus on midterm and late‐term complications. Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss in children. The prevalence of disease increases steadily after transplantation from 5% at 2 years to 35% by 10 years according to multiple database analyses. Allograft vasculopathy is the end point of a complex interaction of stimuli including chronic rejection, endothelial dysfunction, infection, and traditional cardiac risk factors. While an increased understanding of risks associated to CAV has led to more aggressive surveillance approaches, the rates of CAV remain high and outcomes after diagnosis of CAV are very poor with up to 50% of children suffering graft loss or death within 2 years of diagnosis. In an attempt to combat the development and progression of CAV, multiple medical and interventional strategies have been utilized. Pharmacologic approaches have focused on the use of various immunosuppressants and adjuvant medications to combat inflammation and immune mediated graft injury. While randomized controlled trials are rare in pediatric heart transplant cohorts, sufficient adult data have been developed in both controlled and observational trials to provide a framework for the prevention and management of patients with CAV. However, none of these interventions have been shown to be effective in significantly prolonging graft survival and retransplantation remains the only reliable therapy for severe CAV.     

RISKY ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION FOR ASYMPTOMATIC RETROPERITONEAL TUMORS

Paraganglioma, a sporadically occurring rare tumor should be included in the differential diagnosis of retroperitoneal tumors, such as malignant lymphomas, gastrointestinal stromal tumors, sarcoma and carcinoma of unknown primary site. A 58‐year‐old Japanese woman presented with a large retroperitoneal tumor detected by ultrasonography (US). She had no medical history of hypertension. Computed tomography showed a mass, 7 cm in diameter, located between the pancreas and the inferior vena cava. It was unclear whether the mass originated from the duodenum or the mesentery. Endoscopic ultrasonography (EUS) demonstrated a large solid paraduodenal mass. Doppler US revealed sparse vascularity in the tumor. With the differential diagnosis of retroperitoneal tumor, we carried out EUS‐FNA. At the time of the third needle puncture, transient severe hypertension was noted, with a blood pressure measurement of 269/130 mmHg. Data obtained from urine and blood examinations after EUS‐fine‐needle aspiration indicated a diagnosis of paraganglioma.     

Primary esophageal mucosa‐associated lymphoid tissue lymphoma diagnosed by using stacked forceps biopsy

Non‐Hodgkin lymphoma involving the esophagus is very rare. Only a few cases have been reported in the English literature to date, and it accounts for less than 1% of all cases of gastrointestinal lymphoma. As this malignancy manifests as a submucosal tumor, pathological diagnosis by using a simple endoscopic biopsy alone is difficult. Therefore, surgical biopsy, endoscopic mucosal resection, and endoscopic ultrasound‐guided fine‐needle aspiration have been used in most cases. Herein, we report a case of esophageal mucosa‐associated lymphoid tissue lymphoma in a 49‐year‐old man, which involved the use of a stacked forceps biopsy to obtain adequate samples for pathological analysis; the use of the stacked forceps biopsy method is unlike those used in previous cases. The patient received cyclophosphamide, vincristine, and prednisolone chemotherapy; he achieved a complete response. In addition, we review the literature relevant to this case.     

Increased leucocyte apoptosis in transfused β‐thalassaemia patients

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β‐thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase‐3/7, 48% higher caspase‐8 and 88% higher caspase‐9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl‐2 (BCL2), (−27·3%/year), and caspase‐9 activity (−13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.     

Changes and analysis of anti‐HBs titres after primary immunization in 1‐ to 16‐year‐old Chinese children: A hospital‐based study

Immunization with the hepatitis B vaccine is the most effective measure to prevent Hepatitis B Virus (HBV) infection. The aim of this study was to investigate the change in antibody levels induced by administration of the hepatitis B vaccine in children aged 1‐16 year old in a large sample sized investigation. HBV markers were determined in 93 326 1‐ to 16‐year‐old hospitalized children who completed primary immunization as infants from south‐west China, Chongqing. Analyses were performed on anti‐HBs titre changes with increasing age, and the revaccination effect was evaluated in children aged 7‐14. The percentage of protective antibody was between 45.29% and 63.33% in all age groups, but was higher in the 1‐, 2‐ and 3‐year‐old groups (90.31%, 83.95% and 71.82%, respectively), and the rate of high‐responder was 5.03%‐10.56%, except in the 1‐year‐old group (23.33%). Additionally, 3.33%‐25.79% of subjects had not seroconverted. There was no significant difference in antibody levels between girls and boys (P > .05). The Geometric Mean Titers in children with confirmed revaccination history were significantly higher than those with unknown or no revaccination history (P < .0001). In conclusion, the overall rate of protective anti‐HBs was 67.10% with consecutive age groups from 1 to 16, it decreased from 90.31% to 45.29% for 1‐ to 8‐year‐old individuals, and interestingly, the rate increased from 45.46% to 63.33% for subjects aged 9‐15. Anti‐HBs titres were significantly improved after revaccination. Booster doses are recommended for those without seroconversion, especially children who live in school with other students or have family members with positive HBsAg.     

Sudden Cardiac Arrest Due to Subtotal Absence of Left‐sided Pericardium—Case Report and Review of the Literature

Congenital absence of the pericardium is a very rare cardiac malformation, usually diagnosed fortuitously on autopsy or surgery. Symptoms related to these abnormalities are usually benign, and fatalities reported in the literature are almost exclusively secondary to herniation of the heart through a partial defect. We present the unusual case of a 44‐year‐old woman admitted for sudden cardiac arrest. Initial evaluation suggested acute anterior myocardial infarction, but further investigation ruled out coronary heart disease. No arrhythmia could be initiated on electrophysiological study, and absence of most of the left pericardium was confirmed by cardiac magnetic resonance imaging. After the exclusion of common etiologies such as idiopathic ventricular fibrillation, transient great vessel torsion due to hypermobility of the heart with secondary malignant arrhythmia was considered to be the most likely mechanism for the sudden cardiac arrest. A review of the available literature on clinical presentation, diagnostic tools, and therapeutic options is also presented.