Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

AIM: To investigate M2 isoform of pyruvate kinase (PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target.METHODS: All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment. Clinical and pathological information were obtained from the medical records. Gene expression microarray data from 60 cancer and 19 non-cancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA. Tissue microarrays were constructed from 368 gastric cancer patients. Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity. Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated.RESULTS: PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients (log transformed expression level: 7.6 ± 0.65 vs 6.3 ± 0.51, P < 0.001). Moreover, differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers (log transformed expression level: 7.8 ± 0.70 vs 6.7 ± 0.71, P < 0.001). PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368 (39.1%) human gastric cancer cases. PKM2 expression was not related with stage (P = 0.811), but strongly correlated with gastric cancer differentiation (P < 0.001). Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones. Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells; in contrast, signet-ring cell cancers showed only 17.7% PKM2-positive cells. Importantly, PKM2 expression was correlated with shorter overall survival (P < 0.05) independent of stage only in signet-ring cell cancers.CONCLUSION: PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas. Its function and potential as a prognostic marker should be further verified in gastric cancer.     

Predictive value of ¹⁸F-fluorodeoxyglucose PET/CT for transarterial chemolipiodolization of hepatocellular carcinoma

AIM: To investigate the correlation of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) with clinical features and the prediction of treatment response.METHODS: A total of 83 hepatocellular carcinoma (HCC) patients undergoing ¹⁸F-FDG PET before transarterial chemolipiodolization with systemic chemo-infusion between October, 2006 and May, 2009 were retrospectively enrolled. The patients included 68 men and 15 women (mean age, 60 ± 10.7 years). The effect of ¹⁸F-FDG-monitored PET uptake on clinical features and on the evaluated treatment response was ascertained with modified Response Evaluation Criteria in Solid Tumors. The PET parameters of maximal standardized uptake value of the tumor (Tsuv_max), the ratio of the tumor maximal standardized uptake value (SUV) to the liver maximal SUV (Tsuv_max/Lsuv_max) and the ratio of tumor maximal SUV to the liver mean SUV (Tsuv_max/Lsuv_mean) were tested as predictive factors.RESULTS: Among the 3 SUV parameters, the Tsuv_max/Lsuv_mean ratio (cutoff value of 1.90) was significantly associated with tumor burden including tumor size, tumor number, α-fetoprotein levels and tumor stage (P < 0.001, P = 0.008, P = 0.011, P < 0.001, respectively). The objective response rates in patients with a high SUV ratio (≥ 1.90) were significantly better than those with a low SUV ratio (< 1.90) (P = 0.020). The overall survival rates of patients exhibiting a low Tsuv_max/Lsuv_mean ratio (< 1.90) and those with a high SUV ratio (≥ 1.90) was 38.2 and 10.3 mo, respectively (P < 0.01). However, the time to progression showed no significant difference between the groups (P = 0.15).CONCLUSION: ¹⁸F-FDG PET can be an important predictor of HCC treatment. In particular, the Tsuv_max/Lsuv_mean ratio (cutoff value of 1.90) can provide useful information in treatment prognosis for HCC patients treated with locoregional therapy.     

Reporting of myelotoxicity associated with emerging regimens for the treatment of selected solid tumors

In this article, we reviewed and quantified reporting of the risk of myelotoxicity, specifically febrile neutropenia (FN), and the related use of supportive care with colony-stimulating factor (CSF) or antibiotics in clinical trials published between January 2005 and June 2009, evaluating emerging regimens for the treatment of selected solid tumors. Our analysis showed that clinically significant neutropenia and neutropenia-related events were generally described in the studies evaluated (grade 3/4 neutropenia incidence, 72%; FN incidence, 53%). However, use of CSF and antibiotics was infrequently and inconsistently reported (trials reporting prophylactic CSF and antibiotics use: in the methods section, 38% and 10%, respectively; in the results section, 19% and 1%, respectively). These results highlight the need for a standardized approach to reporting neutropenic outcomes and use of supportive care measures. This can assist clinicians in prospectively managing relevant toxicities associated with these emerging regimens and thereby facilitate their safe and effective use in clinical practice.     

Chronic total occlusion by stent fracture in Kawasaki disease: is recanalisation possible?

Despite various medications for Kawasaki disease, a small number of children have been undergoing interventions for severe coronary artery complications. Transcatheter intervention is a feasible alternative to coronary artery bypass grafting in a patient with chronic totally occluded lesion after Kawasaki disease, even by stent fracture.     

Retinoic Acid-related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Rationale: The discovery that retinoic acid-related orphan receptor (Rora)-α is highly expressed in lungs of patients with COPD led us to hypothesize that Rora may contribute to the pathogenesis of emphysema. Objectives: To determine the role of Rora in smoke-induced emphysema. Methods: Cigarette smoke extract in vitro and elastase or cigarette smoke exposure in vivo were used to model smoke-related cell stress and airspace enlargement. Lung tissue from patients undergoing lung transplantation was examined for markers of DNA damage and Rora expression. Measurements and Main Results: Rora expression was induced by cigarette smoke in mice and in cell culture. Gene expression profiling of Rora-null mice exposed to cigarette smoke demonstrated enrichment for genes involved in DNA repair. Rora expression increased and Rora translocated to the nucleus after DNA damage. Inhibition of ataxia telangiectasia mutated decreased the induction of Rora. Gene silencing of Rora attenuated apoptotic cell death in response to cigarette smoke extract, whereas overexpression of Rora enhanced apoptosis. Rora-deficient mice were protected from elastase and cigarette smoke induced airspace enlargement. Finally, lungs of patients with COPD showed evidence of increased DNA damage even in the absence of active smoking. Conclusions: Taken together, these findings suggest that DNA damage may contribute to the pathogenesis of emphysema, and that Rora has a previously unrecognized role in cellular responses to genotoxicity. These findings provide a potential link between emphysema and features of premature ageing, including enhanced susceptibility to lung cancer.     

Oscillometric and spirometric bronchodilator response in preschool children with and without asthma

BACKGROUND:

Bronchodilator responses (BDR) are routinely used in the diagnosis and management of asthma; however, their acceptability and repeatability have not been evaluated using quality control criteria for preschool children.

OBJECTIVES:

To compare conventional spirometry with an impulse oscillometry system (IOS) in healthy and asthmatic preschool children.

METHODS:

Data from 30 asthmatic children and 29 controls (two to six years of age) who underwent IOS and spirometry before and after salbutamol administration were analyzed.

RESULTS:

Stable asthmatic subjects significantly differed versus controls in their spirometry-assessed BDR (forced expiratory volume in 1 s [FEV₁], forced vital capacity and forced expiratory flow at 25% to 75% of forced vital capacity) as well as their IOS-assessed BDR (respiratory resistance at 5 Hz [Rrs₅], respiratory reactance at 5 Hz and area under the reactance curve). However, comparisons based on the area under the ROC curve for ΔFEV₁ % initial versus ΔRrs₅ % initial were 0.82 (95% CI 0.71 to 0.93) and 0.75 (95% CI 0.62 to 0.87), respectively. Moreover, the sensitivity and specificity for ΔFEV₁ ≥9% were 0.53 and 0.93, respectively. Importantly, sensitivity increased to 0.63 when either ΔFEV₁ ≥9% or ΔRrs₅ ≥29% was considered as an additional criterion for the diagnosis of asthma.

CONCLUSION:

The accuracy of asthma diagnosis in preschool children may be increased by combining spirometry with IOS when measuring BDR.