Abstract Objectives Circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, recurrent contact with CLL cells in a stromal microenvironment ...leads to increased aerobic glycolysis and the cells’ overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator(TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. Methods TIGAR mRNA expression was investigated by quantitative PCR in 102 newly diagnosed CLL patients. Furthermore, the relationship between the expression of TIGAR and its clinical characteristics and prognosis were investigated. Moreover, we also investigated the correlation between TIGAR expression and apoptosis in primary CLL cells. Results Our data revealed that TIGAR overexpression was correlated with the protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region ( IGHV ) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with shorter treatment-free survival (median: three months vs . 51 months, P = 0.0108), worse overall survival (median: 74 months vs . not reached, P = 0.0242), and the diverse responses to fludarabine-based chemotherapy. TIGAR expression in patients resistant to chemotherapy was significantly higher than in patients sensitive to chemotherapy (mean: 0.3859 ± 0.1710 vs. 0.0974 ± 0.0291, P = 0.0290). Conclusion Taken together, our findings revealed that high TIGAR expression is closely correlated with worse clinical outcome in CLL patients, and depicted how bioenergetic characteristics could be therapeutically exploited in CLL.
Summary Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart ...failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.
Background The feasibility and safety of thoracoscopic lobectomy using anesthesia without tracheal intubation for treatment of geriatric non-small cell lung cancer patients is unclear, although it ...has been used with success in younger populations. Methods From 2009 through 2011, 84 consecutive patients aged 65 years or older with stage I or II non-small cell lung cancer underwent thoracoscopic lobectomy. Among them, 36 patients were treated without tracheal intubation using epidural anesthesia, intrathoracic vagal blockade, and sedation (nonintubated group). The other 48 patients were treated with single-lung ventilation under general anesthesia intubated with a double-lumen tube (intubated group). The perioperative profiles and short-term outcomes of the two groups were compared. Results The 84 patients were a mean age of 73.0 years (range, 65–87 years). Both groups had comparable preoperative demographic and cancer staging profiles. The anesthetic duration of the nonintubated group was shorter. Both groups had comparable operation duration and blood loss. One patient in the nonintubated group was converted to tracheal intubation due to persistent hypoxemia. Postoperatively, the two groups had comparable hospital stays, complication rates, and dissected lymph nodes. Stridor was noted in 3 patients and delirium in 4 in the intubated group, but none occurred in the nonintubated group. Conclusions Nonintubated thoracoscopic lobectomy is technically feasible and was as safe as thoracoscopic lobectomy performed with tracheal intubation in the geriatric lung cancer patients. Thoracoscopic lobectomy without tracheal intubation during anesthesia is a valid alternative for managing selected geriatric patients with non-small cell lung cancer.
Avian influenza A H6N1 virus is one of the most common viruses isolated from wild and domestic avian species, but human infection with this virus has not been previously reported. We report the ...clinical presentation, contact, and environmental investigations of a patient infected with this virus, and assess the origin and genetic characteristics of the isolated virus.
A 20-year-old woman with an influenza-like illness presented to a hospital with shortness of breath in May, 2013. An unsubtyped influenza A virus was isolated from her throat-swab specimen and was transferred to the Taiwan Centres for Disease Control (CDC) for identification. The medical records were reviewed to assess the clinical presentation. We did a contact and environmental investigation and collected clinical specimens from the case and symptomatic contacts to test for influenza virus. The genomic sequences of the isolated virus were determined and characterised.
The unsubtyped influenza A virus was identified as the H6N1 subtype, based on sequences of the genes encoding haemagglutinin and neuraminidase. The source of infection was not established. Sequence analyses showed that this human isolate was highly homologous to chicken H6N1 viruses in Taiwan and had been generated through interclade reassortment. Notably, the virus had a G228S substitution in the haemagglutinin protein that might increase its affinity for the human α2-6 linked sialic acid receptor.
This is the first report of human infection with a wild avian influenza A H6N1 virus. A unique clade of H6N1 viruses with a G228S substitution of haemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission. Our report highlights the continuous need for preparedness for a pandemic of unpredictable and complex avian influenza.
Taiwan Centres for Disease Control.
Background Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities ...such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. Methods The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. Results and Conclusions The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.
Background Endotracheal intubation and chest tube drainage are considered mandatory for thoracoscopic pulmonary resection. The management of peripheral lung nodules by tubeless uniportal ...thoracoscopic surgical repair has not been reported previously. Methods From October 2015 through January 2016, 30 consecutive patients with peripheral lung nodules underwent uniportal thoracoscopic wedge resection without endotracheal intubation and chest tube drainage (tubeless group). The clinical outcomes were compared with the outcomes in 30 consecutive patients with peripheral lung nodules who underwent uniportal thoracoscopic wedge resection with chest tube drainage from April through October 2015 (chest tube group). Results The demographic, anesthetic, and operative characteristics of the patients were comparable in both groups. No major adverse events occurred after operation. A small residual pneumothorax was noted in 12 (40.0%) patients at 6 hours and day 1 and in 2 (6.6%) patients on day 14 in the tubeless group. No patient required reintervention or readmission to the hospital. Patients in the tubeless group had lower pain scale scores on postoperative day 1 (mean, 1.0 vs 1.5, p = 0.012) and shorter postoperative hospital stays (mean, 3.1 days vs 4.4 days, p = 0.011) than did those in the chest tube group. Conclusions Tubeless uniportal thoracoscopic wedge resection is feasible and safe and may be a less invasive alternative for treating selected patients with peripheral lung nodules.
Summary Background Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with ...metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. Methods We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. Findings Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. Interpretation Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
Background Intubated general anesthesia with one-lung ventilation is considered mandatory for anatomical pulmonary resections. Nonintubated thoracoscopic segmentectomy for management of lung tumors, ...which is technically challenging, has not been reported previously. The goal of this study was to evaluate the feasibility and safety of thoracoscopic anatomical segmentectomy without endotracheal intubation. Methods From August 2009 to December 2012, 21 patients with lung tumors were treated using thoracoscopic anatomical segmentectomy without endotracheal intubation using a combination of thoracic epidural anesthesia, intrathoracic vagal blockade, and target-controlled sedation. Results There were 16 patients with primary or metastatic lung cancers and 5 patients with nonmalignant tumors. Left upper lobe apical trisegmentectomy was most commonly performed (n = 6), followed by superior segmentectomy of the right lower lobe (n = 4) and left lower lobe (n = 4). One patient required conversion to intubated single-lung ventilation because of vigorous mediastinal and diaphragmatic movement. No patient required conversion to a thoracotomy or lobectomy. Operative complications developed in 1 patient who had an air leak for more than 3 days postoperatively. The mean duration of postoperative chest tube drainage and mean hospital stay were 2.5 days and 6.0 days, respectively. Anesthetic induction and the operation required a mean 26.5 minutes and 148.0 minutes, respectively. Conclusions Nonintubated thoracoscopic segmentectomy is technically feasible and safe. It can be an alternative to intubated single-lung ventilation for management of lung tumors in selected patients.
Background The prognostic significance of hilar structures invasion, which remains undefined for non-small cell lung cancer (NSCLC), may have potential application for cancer staging. Tumor extension ...along the bronchus and pulmonary vessels was examined for survival significance. Methods In all, 213 pathologically proved central-type stage I NSCLC cases were enrolled. Four study groups were assigned based on the extent of resections: standard lobectomy (group L, n = 32), bronchoplastic procedures (group B, n = 94), standard lobectomy combined with pulmonary angioplasty (group A, n = 48), and bronchial sleeve resection combined with pulmonary artery angioplasty (group BA, n = 39). Univariate and multivariate analysis were performed by the Kaplan-Meier method and the Cox regression model. Results There were 2 postoperative deaths (pulmonary embolism and serious pulmonary infection). Complications were noted in 39 patients (18.3%). Among these patients, the overall 5-year survival rate was 60.2% ± 0.05%, with a median survival time of 75.0 ± 7.5 months. The 5-year survival rates of subgroups were 79.5%, 59.7%, 59.0%, and 47.9%, respectively for groups L, B, A, and BA. Univariate analysis indicated tumor size, bronchial invasion, arterial involvement, and type of operation as closely associated with long-term survival. Multivariate analysis indicated that type of operation and tumor size were the most prominent prognostic factors of 5-year survival. Conclusions Proximal tumor extension into bronchus, invasions into extrapericardial pulmonary vessels, and tumor size were the most important risk factors for 5-year survival with central-type stage I NSCLC. Tumor extension in the hilum was highly related to prognosis and might provide pertinent information to accurately define a tumor (“T”) subclass.
Abstract Objective To assess the tolerability and efficacy of the investigational use of the angiotensin II receptor blocker losartan added to β-blockade (BB) to prevent progressive aortic root ...dilation in patients with Marfan syndrome (MFS). Patients and Methods Between May 1, 2007, and September 31, 2011, 28 patients with MFS (11 males 39%; mean ± SD age, 13.1±6.3 years) with recognized aortic root dilation ( z score >2.0) and receiving BB (atenolol or propranolol) treatment were enrolled. They were randomized to receive BB (BB: 13 patients) or β-blockade and losartan (BB-L: 15 patients) for 35 months. Results In the BB-L group, aortic root dilation was reduced with treatment, and the annual dilation rate of the aortic root was significantly lower than that of the BB group (0.10 mm/yr vs 0.89 mm/yr; P =.02). The absolute aortic diameters at the sinus of Valsalva, annulus, and sinotubular junction showed similar trends, with a reduced rate of dilation in the BB-L group ( P =.02, P =.03, and P =.03, respectively). Five patients (33%) treated with BB-L were noted to have a reduced aortic root diameter. However, the differences between the groups regarding changes in aortic stiffness and cross-sectional compliance were not statistically significant. Conclusion This randomized, open-label, active controlled trial mostly based on a pediatric population demonstrated for the first time that losartan add-on BB therapy is safe and provides more effective protection to slow the progression of aortic root dilation than does BB treatment alone in patients with MFS. Trial Registration clinicaltrials.gov Identifier: NCT00651235.
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