Search

BackgroundWe aimed to investigate the performance of clinician prediction of survival (CPS) and the association between CPS and the prognostic confidence of clinicians in ambulatory medical oncology outpatients.MethodsEight medical oncologists estimated the expected survival of their patients in a prospective cohort study. They were asked to provide a temporal type of CPS in weeks, together with their level of confidence for each prediction (0-100%). We analyzed the accuracy of CPS, the association between CPS and the prognostic confidence, and the characteristics of patients showing inaccurate CPS.ResultsA total of 200 advanced cancer patients were enrolled and the median overall survival was 7.6 months. CPS was accurate in 67 (33.5%) patients, underestimated in 87 (43.5%), and overestimated in 46 (23.0%). The overall accuracy of CPS for 12-week, 24-week, 36-week, and 48-week survival was 83.0%, 72.0%, 75.5%, and 74.0%, respectively. The specificity was highest for 12-week survival (90.2%) and the sensitivity was highest for 48-week survival (96.1%). The sensitivity of 12-week CPS was 51.4% and the area under the receiver operating characteristic (AUROC) curve was 0.79 (95% confidence interval [CI] 0.71-0.87). The prognostic confidence of clinicians was not significantly associated with the accuracy of prediction (P = 0.359). Patients with overestimated survival had significantly poorer global health status and physical/role/emotional functioning in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Additionally, they showed significantly higher levels of fatigue, nausea/vomiting, pain, dyspnea, and loss of appetite.ConclusionThe overall accuracy of CPS in predicting 12-week to 48-week survival was high in medical oncology outpatients. However the sensitivity of 12-week CPS was low and prognostic confidence was not associated with the accuracy of CPS. Patients with overestimated CPS showed poorer quality of life and higher symptom burden.

PurposeSplanchnic vein thrombosis (SpVT) in solid tumors has not been well investigated. Therefore, the treatment guidelines for SpVT are not well established. We aimed to conduct this prospective study to investigate the clinical characteristics and risk factors influencing survival in patients with gastrointestinal cancer with SpVT.Materials and methodsFifty-one patients with gastrointestinal cancer diagnosed with SpVT were prospectively enrolled. The clinical characteristics and courses of SpVT were analyzed.ResultsSpVT occurred in various clinical situations (at the time of initial cancer diagnosis or tumor recurrence after curative therapy, in the postoperative period, during chemotherapy, or in the period of end-of-life care). Among the total patients, 90.2% had no SpVT-related symptoms at initial SpVT diagnosis, and 82.4% did not receive any anticoagulation therapy. The clinical course of SpVT during the follow-up varied: (1) spontaneous resorption without any anticoagulation (47.1%), (2) resorption with anticoagulation (3.9%), (3) persistent thrombosis without progression (17.6%), and (4) SpVT extension (31.4%). Although the SpVT showed extension in some cases, most of them did not cause symptoms or had little impact on the patient's cancer treatment course. During the follow-up period, 23 patients died, all of which were caused by tumor progression. In the multivariable analysis, performance status and clinical situation at the time of SpVT diagnosis were significant prognostic factors.ConclusionsClinicians could adopt a strategy of close observation for incidentally detected SpVT in patients with gastrointestinal cancer. Anticoagulation should be considered only for SpVT cases selected strictly, weighing the risks and benefits.

PurposeIntensive care unit (ICU)-related mortality for lung cancer is ranked highest among the solid tumors and little information exists on the role of intensivists on clinical outcomes. This study aimed to elucidate the intensivist's contribution toward clinical outcomes.Materials and methodsData of advanced lung cancer patients, including stage IIIB or IV non-small cell lung cancer and extensive-stage small cell lung cancer, admitted to the ICU from 2005 to 2016 were analyzed. Multivariate logistic regression was performed to determine variables associated with ICU and in-hospital mortality. Autoregressive integrated moving average (ARIMA) for time-series was used to assess the intensivist's impact.ResultsOf 264 patients, 85 (32.2%) were admitted to the ICU before and 179 (67.8%) after organized intensive care introduction in 2011. Before and after 2011, the changes observed were as follows: ICU mortality rate, 43.5% to 40.2%, respectively (p = 0.610); hospital mortality rate, 82.4% to 65. 9% (p = 0.006). The duration of ICU and hospital stay decreased after 2011 (14.5±16.5 vs. 8.3 ± 8.6, p < 0.001; 36.6 ± 37.2 vs. 22.0 ± 19.6, p < 0.001). On multivariate analysis, admission after 2011 was independently associated with decreased hospital mortality (Odds ratio 0.42, 95% confidence interval 0.21-0.77, p = 0.006). In ARIMA models, intensivist involvement was associated with significantly reduced hospital mortality. (Estimate -17.95, standard error 5.31, p = 0.001).ConclusionIn patients with advanced lung cancer, organized intensive care could contribute to improved clinical outcomes.

Plants are an important and inexhaustible source of bioactive molecules in food, medicine, agriculture, and industry. In this study, we performed systematic liquid chromatography-mass spectrometry (LC-MS)-based metabolic profiling coupled with antioxidant assays for indigenous plant family extracts. Partial least-squares discriminant analysis of LC-MS datasets for the extracts of 34 plant species belonging to the families Aceraceae, Asteraceae, and Rosaceae showed that these species were clustered according to their respective phylogenies. In particular, seven Aceraceae species were clearly demarcated with higher average antioxidant activities, rationalizing their application for bioconversion studies. On the basis of further evaluation of the interspecies variability of metabolic profiles and antioxidant activities among Aceraceae family plants, we found that Acer tataricum (TA) extracts were clearly distinguished from those of other species, with a higher relative abundance of tannin derivatives. Further, we detected a strong positive correlation between most tannin derivatives and the observed higher antioxidant activities. Following Aspergillus oryzae-mediated fermentative bioconversion of Acer plant extracts, we observed a time-correlated (0-8 days) linear increase in antioxidant phenotypes for all species, with TA having the highest activity. Temporal analysis of the MS data revealed tannin bioconversion mechanisms with a relatively higher abundance of gallic acid (m/z 169) accumulated at the end of 8 days, particularly in TA. Similarly, quercetin precursor (glycoside) metabolites were also transformed to quercetin aglycones (m/z 301) in most Acer plant extracts. The present study underscores the efficacy of fermentative bioconversion strategies aimed at enhancing the quality and availability of bioactive metabolites from plant extracts.

PURPOSE:The survival benefit of second-line chemotherapy in patients with metastatic gastric cancer (MGC) has recently been established. We conducted a nationwide population-based outcomes study of patients with MGC receiving second-line chemotherapy to better understand real-world treatment patterns and outcomes. MATERIALS AND METHODS:Data were collected from the Health Insurance Review and Assessment Service database. We identified 509 newly diagnosed patients with MGC in 2010 who received second-line chemotherapy. These patients were divided into three groups for analyses: Group A comprised all patients who received second-line chemotherapy (N = 509); Group B comprised those who received fluoropyrimidine (Fp) plus platinum as first-line treatment, followed by irinotecan-based or taxane-based regimens as second-line chemotherapy (N = 284); and Group C comprised those who received Fp plus cisplatin as first-line treatment, followed by 5-fluorouracil (5-FU)/oxaliplatin, irinotecan-based, or taxane-based regimens as second-line chemotherapy (N = 184). RESULTS:Among patients who received first-line chemotherapy, 47.2% (509/1,078) continued to receive second-line chemotherapy. The most commonly used second-line chemotherapy regimens were 5-FU/irinotecan, 5-FU/oxaliplatin, and docetaxel. The median overall survival (OS) of all 509 patients was 5.2 months. The time from the start date of first-line chemotherapy to the start date of second-line chemotherapy > 6.1 months was an independent prognostic factor for improved OS. The type of chemotherapy regimen was not a significant factor affecting OS. CONCLUSION:The findings provide a better understanding of second-line treatment patterns and outcomes in patients with MGC and will help guide treatment decisions in real-world clinical practice.

PURPOSE:There is limited data on third-line chemotherapy in patients with metastatic gastric cancer (MGC). This study was conducted to assess third-line treatment patterns, outcomes, and clinical parameters related to survival outcomes in patients with MGC. METHODS:Using the Korean Health Insurance Review and Assessment Service (HIRA) database, a nationwide population-based outcomes study was conducted. From the HIRA database, patients newly diagnosed in 2010 with MGC were identified (N = 1,871), and of these, 229 patients who had received third-line chemotherapy were finally selected for this study. RESULTS:Prior to third-line chemotherapy, more than 90% of patients received fluoropyrimidine and platinum, and 43.7% and 40.6% received taxane and irinotecan, respectively. Various third-line chemotherapy regimens containing taxane (docetaxel or paclitaxel), irinotecan, or oxaliplatin were prescribed. The median overall survival (OS) of all patients receiving third-line chemotherapy was 4.4 months. The median time from the start date of first-line chemotherapy to the start date of third-line chemotherapy (TF1T3) was 9.5 months, and a longer TF1T3 was the only factor that was significantly associated with an increased OS. The median OS of patients who had received fluoropyrimidine, platinum, and taxane followed by third-line irinotecan-based therapy was similar to that of patients who had received fluoropyrimidine, platinum, and irinotecan followed by third-line taxane-based therapy (p = 0.894). CONCLUSION:In patients with MGC receiving third-line chemotherapy, TF1T3 was the only significant factor associated with OS. The sequence of using taxane and irinotecan as subsequent therapy after first-line failure was not shown to impact survival outcome.

Mycobacterium tuberculosis forms drug-tolerant persister cells that are the probable cause of its recalcitrance to antibiotic therapy. While genetically identical to the rest of the population, persisters are dormant, which protects them from killing by bactericidal antibiotics. The mechanism of persister formation in M. tuberculosis is not well understood. In this study, we selected for high persister (hip) mutants and characterized them by whole genome sequencing and transcriptome analysis. In parallel, we identified and characterized clinical isolates that naturally produce high levels of persisters. We compared the hip mutants obtained in vitro with clinical isolates to identify candidate persister genes. Genes involved in lipid biosynthesis, carbon metabolism, toxin-antitoxin systems, and transcriptional regulators were among those identified. We also found that clinical hip isolates exhibited greater ex vivo survival than the low persister isolates. Our data suggest that M. tuberculosis persister formation involves multiple pathways, and hip mutants may contribute to the recalcitrance of the infection.

We analyzed the expression levels of fluoropyrimidine-metabolizing enzymes (thymidylate synthase [TS], dihydropyrimidine dehydrogenase [DPD], thymidine phosphorylase [TP] and orotate phosphoribosyltransferase [OPRT]) to identify potential biomarkers related to treatment outcomes in gastric cancer (GC) patients receiving adjuvant S-1 chemotherapy. In this study, 184 patients who received curative gastrectomy (D2 lymph node dissection) and adjuvant S-1 were included. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed to measure the protein and mRNA levels of TS, DPD, TP, and OPRT in tumor tissue. In univariate analysis, low intratumoral DPD protein expression was related to poorer 5-year disease-free survival (DFS; 78% vs. 88%; P = 0.068). Low intratumoral DPD mRNA expression (1st [lowest] quartile) was also related to poorer DFS (69% vs. 90%; P < 0.001) compared to high intratumoral DPD expression (2nd to 4th quartiles). In multivariate analyses, low intratumoral DPD protein or mRNA expression was related to worse DFS (P < 0.05), irrespective of other clinical variables. TS, TP, and OPRT expression levels were not related to treatment outcomes. Severe non-hematologic toxicities (grade ≥ 3) had a trend towards more frequent development in patients with low intratumoral DPD mRNA expression (29% vs. 16%; P = 0.068). In conclusion, GC patients with high intratumoral DPD expression did not have inferior outcome following adjuvant S-1 therapy compared with those with low DPD expression. Instead, low intratumoral DPD expression was related to poor DFS.

Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

Geriatric assessment (GA) is resource-consuming, necessitating screening tools to select appropriate patients who need full GA. The objective of this study is to design a novel geriatric screening tool with easy-to-answer questions and high performance objectively selected from a large dataset to represent each domain of GA. A development cohort was constructed from 1284 patients who received GA from May 2004 to April 2007. Items representing each domain of functional status, cognitive function, nutritional status, and psychological status in GA were selected according to sensitivity (SE) and specificity (SP). Of the selected items, the final questions were chosen by a panel of oncologists and geriatricians to encompass most domains evenly and also by feasibility and use with cancer patients. The selected screening questions were validated in a separate cohort of 98 cancer patients. The novel screening tool, the Korean Cancer Study Group Geriatric Score (KG)-7, consisted of 7 items representing each domain of GA. KG-7 had a maximal area under the curve (AUC) of 0.93 (95% confidence interval (CI) 0.92-0.95) in the prediction of abnormal GA, which was higher than that of G-8 (0.87, 95% CI 0.85-0.89) within the development cohort. The cut-off value was decided at ≤ 5 points, with a SE of 95.0%, SP of 59.2%, positive predictive value (PPV) of 85.3%, and negative predictive value (NPV) of 82.6%. In the validation cohort, the AUC was 0.82 (95% CI 0.73-0.90), and the SE, SP, PPV, and NPV were 89.5%, 48.6%, 77.3%, and 75.0%, respectively. Furthermore, patients with higher KG-7 scores showed significantly longer overall survival (OS) in the development and validation cohorts. In conclusions, the KG-7 showed high SE and NPV to predict abnormal GA. The KG-7 also predicted OS. Given the results of our studies, the KG-7 could be used effectively in countries with high patient burden and low resources to select patients in need of full GA and intervention.

Several molecular assays to detect resistance to Rifampin, the Fluoroquinolones, and Aminoglycosides in Mycobacterium tuberculosis (M. tuberculosis) have been recently described. A systematic approach for comparing these assays in the laboratory is needed in order to determine the relative advantage of each assay and to decide which ones should be advanced to evaluation. We performed an analytic comparison of a Sloppy Molecular Beacon (SMB) melting temperature (Tm) assay and a Dual labeled probe (DLP) Tm assay. Both assays targeted the M. tuberculosis rpoB, gyrA, rrs genes and the eis promoter region. The sensitivity and specificity to detect mutations, analytic limit of detection (LOD) and the detection of heteroresistance were tested using a panel of 56 clinical DNA samples from drug resistant M. tuberculosis strains. Both SMB and DLP assays detected 29/29 (100%) samples with rpoB RRDR mutations and 3/3 (100%) samples with eis promoter mutations correctly. The SMB assay detected all 17/17 gyrA mutants and 22/22 rrs mutants, while the DLP assay detected 16/17 (94%) gyrA mutants and 12/22 (55%) rrs mutants. Both assays showed comparable LODs for detecting rpoB and eis mutations; however, the SMB assay LODs were at least two logs better for detecting wild type and mutants in gyrA and rrs targets. The SMB assay was also moderately better at detecting heteroresistance. In summary, both assays appeared to be promising methods to detect drug resistance associated mutations in M. tuberculosis; however, the relative advantage of each assay varied under each test condition.

Several Western guidelines recommend the routine use of pharmacologic thromboprophylaxis for cancer surgery patients to prevent venous thromboembolism (VTE). However, the necessity of routine pharmacologic perioperative thromboprophylaxis in Asian gastric cancer (GC) patients has not been clearly determined. To determine the necessity of routine perioperative pharmacologic thromboprophylaxis in Korean gastric cancer patients, the incidence of postoperative VTE was prospectively evaluated in gastric cancer patients receiving surgery. Among 610 GC patients who had received surgery, 375 patents underwent routine duplex Doppler ultrasonography (DUS) on days 5-12 following surgery to detect VTE and then VTE-related symptoms and signs were checked at 4 weeks after surgery (cohort A). The 235 patients that declined DUS were registered to cohort B and the occurrence of postoperative VTE was retrospectively analyzed. In cohort A, symptomatic or asymptomatic VTE until 4 weeks after surgery was detected in 9 patients [2.4%; 95% confidence interval (CI); 0.9-3.9]. Tumor stage was a significant factor related to VTE development [stage I, 1.4%; stage II/III, 2.4%; stage IV, 9.7% (P = 0.008)]. In multivariate analysis, patients with stage IV had a higher postoperative VTE development [odds ratio, 8.18 (95% CI, 1.54-43.42)] than those with stage I. In cohort B, a low incidence of postoperative VTE was reaffirmed; only one postoperative VTE case (0.4%) was observed. In conclusion, the incidence of postoperative VTE in Korean GC patients was only 2.4%. Risk-stratified applications of perioperative pharmacologic thromboprophylaxis are thought to be more appropriate than the routine pharmacologic thromboprophylaxis in Korean GC patients receiving surgery.

Apoptosis and activation of macrophages play an important role in the host response to mycobacterial infection involving TNF-alpha as a critical autocrine mediator. The underlying mechanisms are still ill-defined. Here, we demonstrate elevated levels of methylglyoxal (MG), a small and reactive molecule that is usually a physiological product of various metabolic pathways, and advanced glycation end products (AGE) during mycobacterial infection of macrophages, leading to apoptosis and activation of macrophages. Moreover, we demonstrate abundant AGE in pulmonary lesions of tuberculosis (TB) patients. Global gene expression profiling of MG-treated macrophages revealed a diverse spectrum of functions induced by MG, including apoptosis and immune response. Our results not only provide first evidence for the involvement of MG and AGE in TB, but also form a basis for novel intervention strategies against infectious diseases in which MG and AGE play critical roles.