Beyond precision surgery: Molecularly motivated precision care for gastric cancer.

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes. Furthermore, this molecular knowledge helps to identify new actionable targets and develop novel therapeutic strategies. To advance the concept of precision patient care in the clinic, patient-derived xenograft (PDX) models have recently been developed. PDX models not only represent histology and genomic features, but also predict responsiveness to investigational drugs in patient tumors. Molecularly curated PDX cohorts will be instrumental in hypothesis generation, biomarker discovery, and drug screening and testing in proof-of-concept preclinical trials for precision therapy. In the era of precision medicine, molecularly tailored therapeutic strategies should be individualized for cancer patients. To improve the overall clinical outcome, a multimodal approach is indispensable for advanced cancer patients. Careful, oncological principle-based surgery, combined with a molecularly guided multidisciplinary approach, will open new horizons in surgical oncology.

Intrahepatic Artery Pseudoaneurysm-induced Hemobilia Caused by a Plastic Biliary Stent After ABO-incompatible Living-donor Liver Transplantation: A Case Report.

Bile leakage after duct-to-duct anastomosis in living-donor liver transplantation (LDLT) can mostly be managed by therapeutic endoscopic retrograde cholangiopancreatography. Following this, various complications such as biliary infection, pancreatitis, perforation, and bleeding can occur, and endoscopic sphincterotomy is primarily associated with post- endoscopic retrograde cholangiopancreatography bleeding; other causes have been published in case reports. In the present case, a plastic biliary stent used for treating liver abscesses and leakage at the bile duct anastomosis site after ABO-incompatible LDLT resulted in an intrahepatic artery pseudoaneurysm and hemobilia, which were managed by angiography and coil embolization. Although the complex postoperative course after LDLT can obscure the prompt diagnosis of an intrahepatic artery pseudoaneurysm and hemobilia, biliary stenting should be considered as a possible cause.

A systematic review of diagnostic accuracy of vertebral fracture assessment (VFA) in postmenopausal women and elderly men.

UNLABELLED: This systematic review was performed to compare the diagnostic accuracy of vertebral fracture assessment (VFA) with that of spinal radiography for identification of vertebral fractures (VFs). VFA appeared to have moderate sensitivity and high specificity for detecting VFs when compared with spinal radiography. INTRODUCTION: VFs are recognized as the hallmark of osteoporosis, and a previous VF increases the risk of a future fracture. Therefore, the timely detection of VFs is important for prevention of further fractures. This systematic review examined the diagnostic accuracy of VFA using dual X-ray absorptiometry (DXA) to identify VFs. METHODS: We searched for potentially relevant studies using electronic databases, including Ovid-Medline, Ovid-EMBASE, Cochrane library, and four Korean databases, from their inception to May 2013. We compared the diagnostic accuracy of VFA with that of spinal radiography for detection of VFs by analyzing the sensitivity and specificity using a 2 × 2 contingency table. Subgroup analyses were also performed on studies with a low risk of bias and applicability. RESULTS: Twelve studies were analyzed for the diagnostic accuracy of VFA. The sensitivity and specificity were 0.70-0.93 and 0.95-1.00, respectively, analyzed on a per-vertebra basis, and 0.65-1.00 and 0.74-1.00 on a per-patient basis. The sensitivity and specificity of five studies in subgroups with a low risk of bias in the intervention test were 0.70-0.84 and 0.96-0.99, respectively. In studies with a low risk of bias in the patient selection, those based on a per-vertebra basis in three studies were 0.70-0.93 and 0.96-1.00, respectively. CONCLUSIONS: VFA had moderate sensitivity and high specificity for detecting VF when compared with spinal radiography. However, the present findings are insufficient to assess whether spinal radiography should be replaced by VFA.

The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function.

While prolonged sleep deprivation (SD) could lead to profound negative health consequences, such as impairments in vital biological functions of immunity and cognition, melatonin possesses powerful ameliorating effects against those harmful insults. Melatonin has strong antioxidant and anti-inflammatory effects that help to restore body's immune and cognitive functions. In this study, we investigated the possible role of melatonin in reversing cognitive dysfunction induced by SD in rats. Our experimental results revealed that sleep-deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups. Furthermore, there was an increased glial activation most prominent in the hippocampal region of the SD group compared to the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine (8-oxo-dG) were significantly increased, while fragile X-mental retardation protein (FMRP) expression was decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following SD. Our data demonstrate that SD induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Furthermore, our results suggest the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in neurological disorders such as Alzheimer's disease and autism.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Estimating retrospective exposure of household humidifier disinfectants.

UNLABELLED: We conducted a comprehensive humidifier disinfectant exposure characterization for 374 subjects with lung disease who presumed their disease was related to humidifier disinfectant use (patient group) and for 303 of their family members (family group) for an ongoing epidemiological study. We visited the homes of the registered patients to investigate disinfectant use characteristics. Probability of exposure to disinfectants was determined from the questionnaire and supporting evidence from photographs demonstrating the use of humidifier disinfectant, disinfectant purchase receipts, any residual disinfectant, and the consistency of their statements. Exposure duration was estimated as cumulative disinfectant use hours from the questionnaire. Airborne disinfectant exposure intensity (µg/m(3)) was estimated based on the disinfectant volume (ml) and frequency added to the humidifier per day, disinfectant bulk level (µg/ml), the volume of the room (m(3)) with humidifier disinfectant, and the degree of ventilation. Overall, the distribution patterns of the intensity, duration, and cumulative exposure to humidifier disinfectants for the patient group were higher than those of the family group, especially for pregnant women and patients ≤6 years old. Further study is underway to evaluate the association between the disinfectant exposures estimated here with clinically diagnosed lung disease. PRACTICAL IMPLICATIONS: Retrospective exposure to household humidifier disinfectant as estimated here can be used to evaluate associations with clinically diagnosed lung disease due to the use of humidifier disinfectant in Korea. The framework, with modifications to account for dispersion and use patterns, can also be potentially adapted to assessment of other household chemical exposures.

Risk factors for double primary malignancies and their clinical implications in patients with sporadic gastric cancer.

AIMS: We carried out a large scale study to identify the risk factors for double primary malignancy (DPM) development in gastric cancer patients and to evaluate the clinical implications for these patients. METHODS: A total of 2593 patients who underwent gastrectomy for primary gastric cancer from January 2005 to November 2010 were reviewed with regard to DPM. We compared the clinicopathological characteristics, risk factors for developing DPM, and prognosis between the DPM+ group and the DPM- group. RESULTS: Of the 2593 patients, 152 (5.9%) were diagnosed with DPM. The most common accompanying malignancies were colorectal, lung and thyroid. Multivariate analysis indicated that age (p = 0.016) and MSI status (p = 0.002) were associated with a higher frequency of DPM. 30.3% of patients were diagnosed with DPM within 1 year around perioperative period and 53.3% of patients had DPM detected during 5 years of post-operative follow up periods. Although there was no significant difference in overall survival between the DPM+ and DPM- group, DPM+ patients had a worse prognosis than DPM- patients in stage I gastric cancer. CONCLUSIONS: Gastric cancer patients over the age of 60 or with a MSI-high status had an increased risk for developing DPM. Further, in stage I gastric cancer, the presence of DPM was associated with a worse prognosis. Therefore, careful pre- and postoperative surveillance is especially important in these patients.

Prediction for human intelligence using morphometric characteristics of cortical surface: partial least square analysis.

A number of imaging studies have reported neuroanatomical correlates of human intelligence with various morphological characteristics of the cerebral cortex. However, it is not yet clear whether these morphological properties of the cerebral cortex account for human intelligence. We assumed that the complex structure of the cerebral cortex could be explained effectively considering cortical thickness, surface area, sulcal depth and absolute mean curvature together. In 78 young healthy adults (age range: 17-27, male/female: 39/39), we used the full-scale intelligence quotient (FSIQ) and the cortical measurements calculated in native space from each subject to determine how much combining various cortical measures explained human intelligence. Since each cortical measure is thought to be not independent but highly inter-related, we applied partial least square (PLS) regression, which is one of the most promising multivariate analysis approaches, to overcome multicollinearity among cortical measures. Our results showed that 30% of FSIQ was explained by the first latent variable extracted from PLS regression analysis. Although it is difficult to relate the first derived latent variable with specific anatomy, we found that cortical thickness measures had a substantial impact on the PLS model supporting the most significant factor accounting for FSIQ. Our results presented here strongly suggest that the new predictor combining different morphometric properties of complex cortical structure is well suited for predicting human intelligence.

Analyses of short-term follow-up MRI and PET-CT for evaluation of residual tumour after inadequate primary resection of malignant soft-tissue tumours.

AIM: To differentiate remnant tumour from postoperative changes on short-term follow-up magnetic resonance imaging (MRI) or combined positron-emission tomography (PET) and computed tomography (CT) after inadequate primary resection of malignant soft-tissue tumours. MATERIALS AND METHODS: From January 2007 through September 2010, 35 patients (18 women and 17 men; mean age 48 years; age range 18-78 years) who underwent MRI and PET-CT within 64 days after surgery for malignant soft-tissue tumours were included. MRI images were assessed for the following findings: the presence of delineated enhancing portions; fascial thickening; and fluid or haematomas with measurable wall thickening. The PET-CT data were analysed using the standardized uptake value (SUV) and the uptake pattern. RESULTS: The correlation of tumour grade and the presence of remnant tumour was significant (p = 0.026). After re-excision, remnant tumour was demonstrated in 15 patients and no tumour cells were discovered in 20 patients. The finding of focally delineated enhancing portions on MRI images and the SUVmax on PET-CT analysis were significantly correlated with the remnant tumour (each p = 0.001 and p = 0.036). CONCLUSIONS: To evaluate the presence of remnant tumour after inadequate excision of malignant soft-tissue tumours, an MRI finding of a focally enhancing area and an SUVmax of >2 on PET-CT might be helpful factors. The coexistence of these two findings would be even more helpful for the detection of residual tumours.

A dose-response study of remifentanil for attenuation of the hypertensive response to laryngoscopy and tracheal intubation in severely preeclamptic women undergoing caesarean delivery under general anaesthesia.

BACKGROUND: Remifentanil is known to attenuate the cardiovascular responses to tracheal intubation. We determined effective doses (ED(50)/ED(95)) of remifentanil to prevent the pressor response to tracheal intubation in patients with severe preeclampsia. METHODS: Seventy-five women with severe preeclampsia were randomly allocated to one of five remifentanil dose groups (0.25, 0.50, 0.75, 1.0, or 1.25 µg/kg) given before induction of anaesthesia using thiopental 5 mg/kg and suxamethonium 1.5 mg/kg. Systolic arterial pressure, heart rate and plasma catecholamine concentrations were measured. Neonatal effects were assessed by Apgar scores and umbilical cord blood gas analysis. A dose was considered effective when systolic arterial pressure did not exceed 160 mmHg for more than 1 min following tracheal intubation. RESULTS: Baseline systolic blood pressure and heart rate did not differ among the groups. The intubation-induced increases of heart rate and blood pressure were attenuated in a dose-dependent manner by remifentanil. ED(50) and ED(95) were 0.59 (95% CI 0.47-0.70) µg/kg and 1.34 (1.04-2.19)µg/kg, respectively. Norepinephrine concentrations remained unaltered following intubation but increased significantly at delivery, with no differences between the groups. Apgar scores and umbilical arterial and venous pH and blood gas values were comparable among the groups. Two women each in the 1.0 and 1.25 µg/kg groups received ephedrine for hypotension defined as systolic arterial pressure <90 mmHg. CONCLUSIONS: The ED(95) of remifentanil for attenuating the hypertensive response to tracheal intubation during induction of anaesthesia in severely preeclamptic patients undergoing caesarean delivery under general anaesthesia was 1.34 µg/kg.

Precuneus hypoperfusion plays an important role in memory impairment of patients with systemic lupus erythematosus.

The present study was designed to identify regional cerebral blood flow (rCBF) abnormalities in systemic lupus erythematosus (SLE) patients with memory impairments. Nineteen SLE patients (mean age 36.1 ± 8.6 years, range 17-47) with subjective memory complaints underwent brain single-photon emission computed tomography (SPECT). The Korean Wechsler Adult Intelligence Scale (K-WAIS) and the Rey-Kim Memory Test (RKMT) were used objectively to evaluate cognitive functions in these patients. On the basis of the Intelligence Quotient-Memory Quotient (IQ-MQ) difference score, patients were classified into two groups: those with below one standard deviation (SD) from the mean for normal subjects of comparable age and education (memory impairment, n = 6) and those with without memory impairment (non-memory impairment, n = 13). Their brain SPECT images were analyzed by statistical parametric mapping (SPM) for group comparisons. The group of SLE patients with memory impairment showed significant hypoperfusion in the right precuneus compared with those with non-memory impairment (p < 0.001). Hypoperfusion of the precuneus may play a significant role in the memory function of SLE patients. SPM analysis of brain SPECT images could be a useful and objective tool for identifying abnormal rCBF in SLE patients with memory impairment.

Seasonal and spatial variation of solvent extractable organic compounds in fine suspended particulate matter in Hong Kong.

The results of a 12-month study of more than 100 solvent extractable organic compounds (SEOC) in particulate matter (PM) less than or equal to 2.5 microm (PM2.5) collected at three air monitoring stations located at roadside, urban, and rural sites in Hong Kong are reported. The total yield of SEOC that accounts for approximately 8-18% of organic carbon (OC) determined by a thermal optical transmittance method was 125-2060 ng/m3, which included 14.6-128 ng/m3 resolved aliphatic hydrocarbons, 39.4-1380 ng/m3 unresolved complex mixtures, 0.6-17.2 ng/m3 polycyclic aromatic hydrocarbons, 41.6-520 ng/m3 fatty acids, and < 0.1-12.1 ng/m3 alkanols. Distinct seasonal variations (summer/winter differences) were observed with higher concentrations of the total and each class of SEOC in the winter and lower concentrations in the summer. Spatial variations are also obvious, with the roadside samples having the highest concentrations of SEOC and the rural samples having the lowest concentrations in all seasons. Characteristic ratios of petroleum hydrocarbons, such as carbon preference index, unresolved to resolved components, and carbon number with maximum concentration, suggest that PM2.5 carbon in Hong Kong originates from both biogenic and anthropogenic sources. The proportion of SEOC in PM2.5 from anthropogenic sources is estimated.

Distribution of polycyclic aromatic hydrocarbons in the atmosphere of Hong Kong.

This paper reports the monitoring results of eleven polycyclic aromatic hydrocarbons (PAHs), four to six-ring, at two urban sites-Central & Western (CW) and Tsuen Wan (TW) in Hong Kong from January to December 2000; and the findings of a study conducted in 2001 of the partitioning of the gaseous and particulate phases of PAHs. The sum of the eleven PAHs under study (sigmaPAHs) was found to range from 6.46 to 38.8 ng m(-3). The annual mean levels at 12.2 ng m(-3) and 15.8 ng m(-3) for CW and TW respectively are comparable to those recorded for the previous two years and are also within the reported ranges for other metropolitan cities in the Asia Pacific region. Amongst the selected eleven PAHs, fluoranthene and pyrene were the two most abundant found in the urban atmosphere of Hong Kong during the study period accounting for approximately 80%, of the total PAHs. The ratios of benzo(a)pyrene to benzo(g,h,i)perylene (BaP/BghiP) and indeno(1,2,3-cd)pyrene to benzo(g,h,i)perylene (IDP/BghiP) indicate that diesel and gasoline vehicular exhausts were the predominant local emission sources of PAHs. Seasonal variations with high winter to summer ratios for each of the individual PAHs (CW: 1.6-16.7 and TW: 0.82-8.2) and for sigmaPAHs (CW: 1.9 and TW: 1.8) and a spatial variation of BaP amongst the air monitoring stations are noted. Results of correlation studies illustrate that local meteorological conditions such as ambient temperature, solar radiation, wind speed and wind direction have significant impact on the concentrations of atmospheric PAHs accounting for the observed seasonal variations. A snapshot comparison of the concentrations of PAHs at four sites including a roadside site, a rural site and the two regular urban sites CW and TW was also performed using the profiles of PAHs recorded on two particulate episode days in March 2000.

Characterization of an inducible oxidative stress response in Vitreoscilla C1.

Vitreoscilla becomes resistant to killing by hydrogen peroxide and heat shock when pretreated with nonlethal levels of hydrogen peroxide. The pretreated Vitreoscilla cells (60 microM hydrogen peroxide for 120 min) significantly increased survival of the lethal dose of 20 mM hydrogen peroxide or heat shock (22 degrees C --> 37 degrees C). This indicates the existence of an adaptive response to oxidative stress. However, cells pretreated with 60 microM hydrogen peroxide became nonresistant to a lethal dose of a menadione. This result shows that hydrogen peroxide does not induce cross-resistance to menadione in Vitreoscilla. Furthermore, Vitreoscilla treated with hydrogen peroxide, heat shock, and menadione showed a change in the protein composition, as monitored by a two-dimensional gel analysis. During adaptation to hydrogen peroxide, 12 proteins were induced. Also, 18 new proteins synthesized in response to heat shock were detected by a 2-D gel analysis. The redox-cycling agents also elicited the synthesis of 6 other proteins that were unseen with hydrogen peroxide.

Use of Tc-99m HMPAO leukocyte scans to evaluate bone infection: incremental value of additional SPECT images.

PURPOSE: In this study, the diagnostic value of Tc-99m hexamethylpropylene amine oxime (HMPAO) leukocyte scans and the role of additional SPECT in the diagnosis of bone infection were evaluated. MATERIALS AND METHODS: The Tc-99m HMPAO leukocyte scans of 37 patients with clinically suspected bone infection were reviewed. The patients were divided into two groups according to the presence of orthopedic implants. Early (4 to 6 hours) and delayed (18 to 20 hours) planar images and early SPECT images were obtained. The final diagnosis of infection was made based on the pathologic, bacteriologic, and surgical data and clinical follow-up. RESULTS: Group 1 (25 patients with orthopedic implants) included 15 true-positive, 1 false-negative, 7 true-negative, and 2 false-positive results. Group 2 (12 patients without orthopedic implants) included 7 true-positive, 1 false-negative, and 4 true-negative results. The overall sensitivity of the Tc-99m HMPAO leukocyte scan with SPECT to detect bone infection was 92%, with a specificity rate of 85%. (Group 1: sensitivity, 94%; specificity, 78%. Group 2: 88% and 100% sensitivity and specificity, respectively.) CONCLUSION: The Tc-99m HMPAO leukocyte scan is useful in the diagnosis of bone infection, regardless of the presence of orthopedic implants. The additional SPECT images may be helpful to localize the site of infection more accurately.

Pneumocystis carinii pneumonia associated with a rapid reduction of cortisol level in a patient with ectopic ACTH syndrome treated by octreotide and ketoconazole.

A case is herein reported of pneumocystis carinii pneumonia in a 60-year-old female patient with ectopic production of ACTH at a position 2 cm superior to her right clavicle, revealed in an octreotide scan. Her extremely high plasma ACTH and cortisol levels (460 pg/ml and 80 microg/dl, respectively) were markedly decreased with the combined treatment of octreotide (300 microg/d) and ketoconazole (600 mg/d). As her serum cortisol concentration decreased, pneumocystis carinii pneumonia occurred on the third day of treatment. A secondary E. coli infection was superimposed and the patient died of disseminated intravascular coagulation and adult respiratory distress syndrome. This case suggests that primary prophylaxis for pneumocystis carinii infection should be initiated before cortisol lowering therapy, especially when the plasma cortisol concentration is excessively high, and that early adjunctive glucocorticoid therapy can reduce the acute mortality in patients with endogenous Cushing's syndrome and Pneumocystis carinii pneumonia. This case study would also like to point out that plasma ACTH and cortisol levels were decreased effectively by the combination of octreotide and ketoconazole in this instance of ectopic ACTH syndrome.

Low neonatal risk of thrombocytopenia in pregnancy associated with immune thrombocytopenic purpura.

OBJECTIVE: To estimate the risk of neonatal thrombocytopenia in infants born to mothers with immune thrombocytopenic purpura (ITP). METHODS: During the years 1993-1997, there were 6,082 deliveries. There were 32 infants born to 31 mothers with ITP. Cordocentesis was performed between 34 and 41 weeks of gestation in 16 mothers with ITP. The cord blood platelet count was checked in all cases at delivery. RESULTS: In mothers with ITP, 5 neonates (15.6%) had mild thrombocytopenia and 7 neonates (21.9%) moderate thrombocytopenia. Severe thrombocytopenia was not observed in any neonate born to mothers with ITP. CONCLUSIONS: The means of delivery in pregnant women with ITP can be determined solely on the basis of obstetric indications because the incidence of severe fetal and neonatal thrombocytopenia is very rare, neonatal intracranial hemorrhage is unlikely to be related to the mode of delivery and percutaneous umbilical blood sampling is technically difficult with a risk of fetal death.

Changes of neonatal mortality rate between 'pre' and 'post' surfactant period.

The objective of this study was to determine how the neonatal mortality rate has changed since surfactant (S) therapy was introduced in our Neonatal Intensive Care Unit (NICU), and to evaluate the efficacy of surfactant therapy in respiratory distress syndrome (RDS) patients. Incidences of risk babies such as outborns, prematurity, low birth weight infants and RDS, and neonatal mortality rates were compared between 'pre' (control, 1988 to 1991, n=4,861) and 'post' S period (study, 1993 to 1996, n=5,430). In RDS patients of 'post' S period, neonatal mortality rate was compared between S-treated and non-treated patients, and chest X-ray and ventilatory parameters were compared between pre- and post-72 hr of surfactant treatment. Surfactant therapy showed short term effects, judging by the decrease of early neonatal deaths and improvement of chest X-ray and ventilatory parameters in RDS patients. The overall neonatal mortality rate had a tendency to decrease in spite of increased incidences of risk babies in 'post' S period but it was less than expected. The reasons were thought to be that we had a high proportion of risk babies, and there was some bias in patient selection for surfactant therapy and its use. In conclusion, with the active prevention of risk baby delivery and appropriate use of surfactant, better results could be expected.