Adaptive and pathological connectivity responses in Parkinson's disease brain networks.

Functional imaging has been used extensively to identify and validate disease-specific networks as biomarkers in neurodegenerative disorders. It is not known, however, whether the connectivity patterns in these networks differ with disease progression compared to the beneficial adaptations that may also occur over time. To distinguish the 2 responses, we focused on assortativity, the tendency for network connections to link nodes with similar properties. High assortativity is associated with unstable, inefficient flow through the network. Low assortativity, by contrast, involves more diverse connections that are also more robust and efficient. We found that in Parkinson's disease (PD), network assortativity increased over time. Assoratitivty was high in clinically aggressive genetic variants but was low for genes associated with slow progression. Dopaminergic treatment increased assortativity despite improving motor symptoms, but subthalamic gene therapy, which remodels PD networks, reduced this measure compared to sham surgery. Stereotyped changes in connectivity patterns underlie disease progression and treatment responses in PD networks.

The short-term effect of ambient particulate matter on suicide death.

BACKGROUND: Air pollution can cause various respiratory and neurological diseases and continuous exposure can lead to death. Previous studies have reported that particulate matter (PM) exposure increases the risk of depression, suicidal thoughts, and suicidal death; however, the results are inconsistent and limited. This study aimed to examine the relationship between short-term PM exposure and suicide deaths, as well as investigate the short-term effects of PM on suicide death within vulnerable groups based on factors such as sex, age group, suicide-related information (note, method, and cause), psychiatric disorders, and physical diseases. METHODS: Data on a total of 28,670 suicide deaths from 2013 to 2017, provided by the Korea Foundation for Suicide Prevention, were analyzed. The study design employed a time-series analysis with a two-stage approach. In the first step, a generalized additive model combined with a distributed lag nonlinear model was used to estimate the short-term effect of PM exposure on suicide risk specific to each city. In the second step, the estimated results from each city were pooled through a meta-analysis to derive the overall effect. We determined the effects of single lag, cumulative lag, and moving average PM concentrations from days 0-7 before suicide. RESULTS: We confirmed an association between exposure to PM10 (≤ 10 µm in diameter) and deaths due to suicide. In particular, among individuals with psychiatric disorders and those who employed non-violent suicide methods, increased exposure to PM10 was associated with a higher risk of death by suicide, with percentage changes of 5.92 (95% confidence interval [CI]: 3.95-7.92) and 11.47 (95% CI: 7.95-15.11), respectively. Furthermore, in the group with psychiatric disorders, there was an observed tendency of increasing suicide risk as PM10 levels increased up to 120 µg/m3, whereas in the group with non-violent suicide deaths, there was a pronounced trend of rapid increase in suicide risk with an increase in PM10 up to 100 µg/m3. CONCLUSIONS: These results show an association between short-term exposure to PM and suicide. Our study adds evidence for the benefits of reducing PM in preventing diseases and improving mental health.

Defect Engineering of WO3 by Rapid Flame Reduction for Efficient Photoelectrochemical Conversion of Methane into Liquid Oxygenates.

Photoelectrochemical (PEC) conversion is a promising way to use methane (CH4) as a chemical building block without harsh conditions. However, the PEC conversion of CH4 to value-added chemicals remains challenging due to the thermodynamically favorable overoxidation of CH4. Here, we report WO3 nanotube (NT) photoelectrocatalysts for PEC CH4 conversion with high liquid product selectivity through defect engineering. By tuning the flame reduction treatment, we carefully controlled the oxygen vacancies of WO3 NTs. The optimally reduced WO3 NTs suppressed overoxidation of CH4 showing a high total C1 liquid selectivity of 69.4% and a production rate of 0.174 µmol cm-2 h-1. Scanning electrochemical microscopy revealed that oxygen vacancies can restrain the production of hydroxyl radicals, which, in excess, could further oxidize C1 intermediates to CO2. Additionally, band diagram analysis and computational studies elucidated that oxygen vacancies thermodynamically suppress overoxidation. This work introduces a strategy for understanding and controlling the selectivity of photoelectrocatalysts for direct conversion of CH4 to liquids.

Smartphone-based combined oral and whole-body exercise programme aimed at improving oral functions: A randomized clinical trial.

OBJECTIVES: To investigate the effects of a smartphone-based oral and whole-body exercise programme on oral function in older adults. METHODS: Individuals aged 65 years or above were randomized into three groups (non-app use, app use and control group), and a combined oral and whole-body exercise programme was conducted for 5 weeks. Oral muscle strength, saliva flow rate, Oral Health Impact Profile-14 (OHIP-14), and Geriatric Oral Health Assessment Index (GOHAI) were measured before and after the intervention. The changes in each group were analysed at the end of the programme using paired sample t-tests, and the differences among the groups were analysed using the chi-square test, Fisher's exact test and ANOVA. RESULTS: The anterior tongue strength increased by 2.80 kPa after the intervention in the non-app use group; however, the change was not statistically significant. In the app use group, the anterior tongue strength significantly increased by 4.48 kPa. The saliva flow rate increased by 0.54 and 0.71 g/min in the non-app and app use groups, respectively, after the intervention (p < 0.05), and the change was greater in the app use group than in the other groups (p < 0.01). There were no significant changes in the posterior tongue strength, cheek strength, OHIP-14 or GOHAI scores over the course of the study. CONCLUSIONS: A smartphone-based combined oral and whole-body exercise programme can improve anterior tongue strength and saliva flow rate in older participants. The programme, however, did not result in significant changes in posterior tongue strength, cheek strength and perceived oral health.

Genomic and evolutionary characteristics of metastatic gastric cancer by routes.

BACKGROUND: In gastric cancer (GC) patients, metastatic progression through the lymphatic, hematogenous, peritoneal, and ovarian routes, is the ultimate cause of death. However, the genomic and evolutionary characteristics of metastatic GC have not been widely evaluated. METHODS: Whole-exome sequencing data were analyzed for 99 primary and paired metastatic gastric cancers from 15 patients who underwent gastrectomy and metastasectomy. RESULTS: Hematogenous metastatic tumors were associated with increased chromosomal instability and de novo gain/amplification in cancer driver genes, whereas peritoneal/ovarian metastasis was linked to sustained chromosomal stability and de novo somatic mutations in driver genes. The genomic distance of the hematogenous and peritoneal metastatic tumors was found to be closer to the primary tumors than lymph node (LN) metastasis, while ovarian metastasis was closer to LN and peritoneal metastasis than the primary tumor. Two migration patterns for metastatic GCs were identified; branched and diaspora. Both molecular subtypes of the metastatic tumors, rather than the primary tumor, and their migration patterns were related to patient survival. CONCLUSIONS: Genomic characteristics of metastatic gastric cancer is distinctive by routes and associated with patients' prognosis along with genomic evolution pattenrs, indicating that both primary and metastatic gastric cancers require genomic evaluation.

Effectiveness of an oral health education programme using a mobile application for older adults: A randomised clinical trial.

OBJECTIVE: To investigate the effectiveness of an oral health education programme using a mobile app for adults aged 65 years or older. METHODS: Participants aged 65 or older were randomly allocated into non-app use (n = 25), app use (n = 22) and control (n = 26) groups. The non-app use group received lecture-based oral health education using PowerPoint presentations and participated in workbook activities twice a week for five weeks, whereas the app use group underwent oral health education using a smartphone app and workbook activities for five weeks. Before and after the intervention, a questionnaire survey and oral health examination were performed to examine changes in oral health-related indices. RESULTS: The non-app use group showed significant changes, with a 2.1 increase in oral health knowledge score, 0.2 decrease in the O'Leary index and 0.6 decrease in tongue coating. The app use group showed significant changes, with a 3.1 increase in oral health knowledge score, a 2.5 increase in oral health perception, a 0.3 decrease in the O'Leary index and a 1.4 decrease in tongue coating. Repeated-measures ANOVA showed that interaction between time and group was significant only in tongue coating variable. CONCLUSION: The smartphone app developed in this study carries the possibility to convey informative content for oral health education among older adults.

Co-Localization of Gastrointestinal Stromal Tumors (GIST) and Peritoneal Mesothelioma: A Case Series.

PURPOSE: Gastrointestinal stromal tumor (GIST) is associated with increased risk of additional cancers. In this study, synchronous GIST, and peritoneal mesothelioma (PM) were characterized to evaluate the relationship between these two cancers. METHODS: A retrospective chart review was conducted for patients diagnosed with both GIST and PM between July 2010 and June 2021. Patient demographics, past tumor history, intraoperative reports, cross-sectional imaging, peritoneal cancer index (PCI) scoring, somatic next-generation sequencing (NGS) analysis, and histology were reviewed. RESULTS: Of 137 patients who underwent primary GIST resection from July 2010 to June 2021, 8 (5.8%) were found to have synchronous PM, and 4 patients (50%) had additional cancers and/or benign tumors. Five (62.5%) were male, and the median age at GIST diagnosis was 57 years (range: 45-76). Seventy-five percent of GISTs originated from the stomach. Of the eight patients, one patient had synchronous malignant mesothelioma (MM), and the remaining had well-differentiated papillary mesothelioma (WDPM), which were primarily located in the region of the primary GIST (89%). The median PCI score was 2 in the WDPM patients. NGS of GIST revealed oncogenic KIT exon 11 (62.5%), PDGFRA D842V (25%), or SDH (12.5%) mutations, while NGS of the MM revealed BAP1 and PBRM1 alterations. CONCLUSIONS: One in 17 GIST patients undergoing resection in this series have PM, which is significantly higher than expected if these two diseases were considered as independent events. Our results indicate that synchronous co-occurrence of GIST and PM is an underrecognized finding, suggesting a possible relationship that deserves further investigation.

Clinicopathologic and genomic characteristics of mucinous gastric adenocarcinoma.

BACKGROUND: Mucinous gastric adenocarcinoma (MGC) is a rare but distinctive histologic subtype of gastric cancer (GC). The clinico-pathologic and genomic characteristics of MGC have not been well evaluated. METHODS: We collected individual data from five cohorts targeting the microsatellite instability (MSI) of GC (n = 5089) to evaluate the clinico-pathologic characteristics of MGC. In addition, public genomic databases were used for genomic analysis. The characteristics of MGC were compared with those of non-mucinous GC (NMGC). RESULTS: MGC (n = 158, 3.1%) showed distinctive characteristics in terms of age, sex, and TNM stage compared to NMGC (n = 4931). MGC was frequently associated with MSI-high (OR: 2.24, 95% confidence interval [CI] 1.44-3.40, p < 0.001), while mutually exclusive to the Epstein-Barr virus type. The prognosis of MGC was better than that of NMGC (adj.HR: 0.731, 95% CI 0.556-0.962, p = 0.025). There was no clear benefit from postoperative chemotherapy in MGC. TP53 was the main driver mutation in the MGC without recurrent variants. MGC was related to high expression of GPR120 and B3GNT6 and moderate regulation of epithelial-mesenchymal transition (EMT)-up signature with a high EMT-down signature, and those characteristics was related to favorable prognosis of GC (log-rank p = 0.044, p < 0.001, p < 0.001, respectively). MSI-H of MGC was associated with low cancer-associate fibroblasts but high CD274 (PD-L1) expression compared to microsatellite stable MGC, suggesting that immune checkpoint inhibitors may be useful for the MSI-H of MGC. CONCLUSION: MGC could be a surrogate for performing MSI but not the EBV test in GC. Further, its genetic characteristics lead to a favorable prognosis for MGC.

Scattering and clustering the proximal screw construct in unilateral locking plate osteosynthesis of distal femoral fractures.

INTRODUCTION: The importance of fixation construct in locking compression plate (LCP) is not well enlightened until recently. The aim of this study was to investigate radiological and clinical outcomes of scattering and clustering of the proximal screw fixation construct in unilateral LCP treatment of the distal femoral fractures. MATERIALS AND METHODS: Patients who were treated for distal femoral fractures using unilateral LCP between January 2014 and December 2019 in our institute were included in this retrospective study. They were divided into groups 1 (35 cases, scattered proximal screw fixation) and 2 (35 cases, clustered proximal screw fixation). Mean follow-up period was 23.6 months for group 1 and 21.3 months for group 2. Medical history, patient demographics, injury characteristics, and surgical characteristics were reviewed and analyzed. Radiological findings including time to callus formation, bridging callus formation, union, and symmetry of the union were assessed and compared between the groups. Clinical outcomes included total blood loss during the operation, postoperative range of motion, and number of revision surgery. RESULTS: The time for callus formation (5.8 weeks in group 1 vs. 4.1 weeks in group 2, p = 0.009) and bridging callus formation (12.5 weeks in group 1 vs. 10.7 weeks in group 2, p = 0.009) was significantly earlier in group 2. Despite similar union rates between groups, the mean time for radiological union was longer in group 2 (10.7 vs 7.4 months, p = 0.001). Though statistically insignificant, more asymmetric union was observed in group 2 (17 vs 11 cases). CONCLUSIONS: Despite a delay in initial callus and bridging callus formation, scattering the proximal screws was better in achieving earlier and more balanced radiographic union than the clustered fixation. We recommend to avoid bridging more than five holes in the whole plate fixation construct to lessen the asymmetric callus formation and to prevent eventual plate breakage.

Microsatellite Instability and Effectiveness of Adjuvant Treatment in pT1N1 Gastric Cancer: A Multicohort Study.

BACKGROUND: Microsatellite status is a prognostic biomarker in advanced gastric cancer. This retrospective study aimed to investigate the usefulness of microsatellite status in predicting prognosis and response to adjuvant treatment in pT1N1 gastric cancer. PATIENTS AND METHODS: Among 875 patients who underwent radical gastrectomy for pT1N1 gastric cancer at two tertiary hospitals, 838 with available microsatellite instability (MSI) data were included and classified into two groups according to microsatellite status: microsatellite stable (MSS) and MSI-high (MSI-H). Recurrence-free survival rate and risk factors for tumor recurrence were analyzed. RESULTS: Of 838 gastric cancer patients, 100 (11.9%) were MSI-H and 307 (36.6%) received adjuvant treatment. During median follow-up of 70 months, 42 (5.0%) patients experienced gastric cancer recurrence; hematogenous recurrences were the most common (45.2%). Recurrence-free survival was similar in the MSS and MSI-H groups (p = 0.27), and adjuvant treatment did not show an oncological benefit over surgery alone for pT1N1 gastric cancer (p = 0.53). On univariate analysis, age, operation period, and Lauren classification were significantly associated with tumor recurrence, while adjuvant treatment and MSI status were not associated with tumor recurrence. On multivariate analysis, MSI status was not associated with tumor recurrence, and adjuvant treatment worsened the tumor recurrence risk [hazard ratio (HR) 2.373, 95% confidence interval (CI) 1.125-5.006, p = 0.023). CONCLUSION: MSI status may not be a prognostic factor for tumor recurrence or a predictor of response to adjuvant treatment in pT1N1 gastric cancer patients. Considering that the effect of adjuvant treatment to decrease the risk of tumor recurrence is not clear, it may not be indicated in pT1N1 patients.

Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism.

PURPOSE: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known. METHODS: Patients with an uncertain diagnosis of parkinsonism were referred for 18F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism. RESULTS: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p = 0.02) and 87.5% of the APS cases as MSA or PSP (p = 0.03). The final clinical diagnosis was 93.3% accurate (p < 0.001), but needed several years of expert follow-up. CONCLUSION: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty.

First report of field cases of Y280-like LPAI H9N2 strains in South Korean poultry farms: pathological findings and genetic characterization.

H9N2 low-pathogenic avian influenza (LPAI) viruses have long been circulating in the world poultry industry, resulting in substantial economic losses. In addition to bird health consequences, viruses from specific lineages such as G1 and Y280 are also known to have the potential to cause a pandemic within the human population. In South Korea, after introducing inactivated H9N2 vaccines in 2007, there were no field outbreaks of H9N2 LPAI since 2009. However, in June 2020, an H9N2 virus was isolated from an outbreak in a Korean chicken farm. This strain was distinct from the predominant Korean/Y439 lineage and was believed to be part of the Y280-like lineage. Since the first case of this new H9N2 LPAI, nine more cases of field infections in poultry farms were documented through July and December of 2020. Phylogenetic analysis of the haemagglutinin (HA) and neuraminidase genes of these case isolates revealed that all strains were grouped with exotic Y280-like strains that did not previously exist in South Korea and were emerging into a new cluster. Serological assays also confirmed the existence of antibodies to Y280-like viruses in field sera collected from infected birds, and that they had seroconverted. Further analysis of the receptor-binding region in the HA protein also revealed that these isolates harboured a human-like motif that could potentially affect mammals and humans, demonstrating a possible public health risk. This is the first report of field cases caused by Y280-like H9N2 LPAI in the Korean poultry industry.RESEARCH HIGHLIGHTS Field outbreaks caused by Y280-like H9N2 avian influenza viruses were confirmed.A human-like motif was found at the HA receptor-binding region of all isolates.

Association between ambient air pollution and high-risk pregnancy: A 2015-2018 national population-based cohort study in Korea.

BACKGROUND: Several studies have indicated that prenatal exposure to ambient air pollution is associated with an increased risk of gestational diabetes mellitus, hypertensive disorder during pregnancy, preterm birth, and stillbirth. However, no previous study has focused on the association between the number of pregnancy complications and exposure to ambient air pollution. OBJECTIVES: To investigate the association between prenatal exposure to ambient air pollutants and the number of pregnancy complications in high-risk pregnancies. METHODS: We collected data on gestational diabetes mellitus, hypertensive disorder during pregnancy, preterm birth, and stillbirth from the National Health Information Databases, provided by the Korean National Health Insurance Service.R To assess individual-level exposure to air pollutants, a spatial prediction model and area-averaging approach were used. RESULTS: From 2015 to 2018, data of 789,595 high-risk pregnancies were analyzed. The ratio of gestational diabetes mellitus in the country was the highest, followed by preterm birth, hypertensive disorder during pregnancy, and stillbirth. Approximately 71.7% of pregnant women (566,143) presented with one pregnancy complication in identical pregnancies, 27.5% (216,714) presented with two, and 0.9% (6738) presented with three or more. Multiple logistic regression models with adjustments for age, residence, and income variables indicated that the risk of having two or more pregnancy complications was positively associated with the exposure to higher levels of PM10 (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.09-1.12) and PM2.5 (OR, 1.14; 95% CI, 1.12-1.15). The highest quartile presented higher odds of two or more pregnancy complications compared with the lower three quartiles of PM10, PM2.5, CO, NO2, and SO2 exposures (p < 0.001). CONCLUSION: The results indicate that the risk of pregnancy complications is positively associated with the exposure to the high concentrations of PM10, PM2.5, CO, NO2, and SO2.

Single patient classifier as a prognostic biomarker in pT1N1 gastric cancer: Results from two large Korean cohorts.

OBJECTIVE: Benefits of adjuvant treatment in pT1N1 gastric cancer (GC) remain controversial. Additionally, an effective biomarker for early GC is the need of the hour. The prognostic and predictive roles of single patient classifier (SPC) were validated in stage II/III GC. In this study, we aimed to elucidate the role of SPC as a biomarker for pT1N1 GC. METHODS: The present retrospective biomarker study (NCT03485105) enrolled patients treated for pT1N1 GC between 1996 and 2012 from two large hospitals (the Y cohort and S cohort). For SPC, mRNA expression of four classifier genes (GZMB, WARS, SFRP4 and CDX1) were evaluated by real-time reverse transcription-polymerase chain reaction assay. The SPC was revised targeting pT1 stages and the prognosis was stratified as high- and low-risk group by the expression of SFRP4, a representative epithelial-mesenchymal transition marker. RESULTS: SPC was evaluated in 875 patients (n=391 and 484 in the Y and S cohorts, respectively). Among 864 patients whose SPC result was available, 41 (4.7%) patients experience GC recurrence. According to revised SPC, 254 (29.4%) patients were classified as high risk [123 (31.5%) and 131 (27.1%) in the Y and S cohorts, respectively]. The high risk was related to frequent recurrence in both Y and S cohort (log-rank P=0.023, P<0.001, respectively), while there was no difference byGZMB and WARS expression. Multivariable analyses of the overall-cohort confirmed the high risk of revised SPC as a significant prognostic factor [hazard ratio (HR): 4.402 (2.293-8.449), P<0.001] of GC. A significant difference was not detected by SPC in the prognosis of patients in the presence and absence of adjuvant treatment (log-rank P=0.670). CONCLUSIONS: The present study revealed the revised SPC as a prognostic biomarker of pT1N1 GC and suggested the use of the revised SPC for early-stage GC as like stage II/III.

Effectiveness of an oral health education programme for older adults using a workbook.

OBJECTIVE: This study investigated the effects of an oral health education programme utilising a workbook for people aged 65 years or older. MATERIALS AND METHODS: A pre-post quasi-experimental design was used to verify the effectiveness of an oral health education programme using a workbook. Oral health education was provided once a week for 5 weeks from May to June 2019. Intervention group I only received lectures on oral health education, while intervention group II reviewed the content using the workbook immediately after the lecture. Chi-square test, Fisher's exact test and a one-way analysis of variance (ANOVA) were conducted to compare differences among the three groups; a paired t test was also carried out to identify the changes before and after the programme. RESULTS: Intervention group I showed a significant increase of 3.52 on oral health knowledge and 3.47 on oral health recognition, while exhibiting a significant decrease of 0.21 on the O'Leary index and 0.69 on the tongue coating index. Intervention group II depicted a significant increase of 4.48 on oral health knowledge and 3.97 on oral health recognition and a significant decrease of 0.32 on the O'Leary index and 2.10 on the tongue coating index. CONCLUSIONS: The oral health education programme using the workbook increased knowledge and recognition of oral health and lowered the O'Leary and tongue coating indexes. Hence, the use of a workbook may facilitate the effectiveness of oral health education for older people.

Association of oral health and activities of daily living with cognitive impairment.

OBJECTIVES: This study compared the oral health status between elderly individuals with and without cognitive impairment and explored the association of oral health and activities of daily living (ADL) with cognitive impairment. METHODS: We conducted convenience sampling on patients aged more than 65 years and analysed data from 630 participants. Data were collected and analysed via a survey evaluating general characteristics, oral health behaviour, subjective oral health status, Oral Health Impact Profile (OHIP-14), Geriatric Oral Health Assessment Index (GOHAI) and ADL. RESULTS: The path analysis and regression analysis of the association of oral health and ADL with cognitive impairment showed that the OHIP-14 was not significantly associated with cognitive impairment, whereas the GOHAI and ADL had significant associations with cognitive impairment. A 1-point increase in the GOHAI was associated with a 0.024-point increase in the cognitive impairment score, and a 1-point increase in the ADL was associated with a 0.006-point decrease in the cognitive impairment score (normal = 0, cognitive impairment = 1). CONCLUSIONS: Poor oral health and ADL were associated with cognitive impairment. Therefore, oral hygiene management is important in maintaining oral health in elderly individuals with cognitive impairment.

Microsatellite Instability and Programmed Cell Death-Ligand 1 Expression in Stage II/III Gastric Cancer: Post Hoc Analysis of the CLASSIC Randomized Controlled study.

OBJECTIVE: We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III gastric cancer. BACKGROUND: The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated. METHODS: Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial-a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five quasi-monomorphic mononucleotide markers were used to assess tumor MSI status. PD-L1 expressions of tumor and stromal immune cells were evaluated using immunohistochemistry. RESULTS: Of 592 patients, 40 (6.8%) had MSI-high (MSI-H) tumors. Among 582 patients available for immunohistochemistry evaluation, PD-L1 was positive in tumor cells (tPD-L1) of 16 patients (2.7%) and stromal immune cells (sPD-L1) of 165 patients (28.4%). Multivariable analysis of disease-free survival (DFS) showed that MSI-H and sPD-L1-positivity were independent prognostic factors [hazard ratio 0.301 (0.123-0.736), 0.714 (0.514-0.991); P = 0.008, 0.044), as were receiving chemotherapy, age, tumor grade, and TNM stage. Although adjuvant chemotherapy improved DFS in the microsatellite-stable (MSS) group (5-year DFS: 66.8% vs 54.1%; P = 0.002); no benefit was observed in the MSI-H group (5-year DFS: 83.9% vs 85.7%; P = 0.931). In the MSS group, sPD-L1-negative patients, but not sPD-L1-positive patients, had significant survival benefit from adjuvant chemotherapy compared with surgery only (5-year DFS: 66.1% vs 50.7%; P = 0.001). CONCLUSION: MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.

Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response.

BACKGROUND: Microsatellite instability (MSI)-high (MSI-H) colorectal cancer is known to be associated with increased tumor-infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response. MATERIALS AND METHODS: We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti-CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained. RESULTS: Of the 345 patients, 57 demonstrated MSI-H tumors and 288 demonstrated non-MSI-H tumors. MSI-H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI-H tumors and those with non-MSI-H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence-free survival (RFS) or overall survival (OS) in the MSI-H tumor group. In the non-MSI-H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS. CONCLUSIONS: The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response. IMPLICATIONS FOR PRACTICE: This study demonstrates that the density of each subset of tumor-infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)-high and non-MSI-high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI-high (MSI-H) and non-MSI-H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI-high gastric cancer.

Mesothelin Expression Is a Predictive Factor for Peritoneal Recurrence in Curatively Resected Stage III Gastric Cancer.

BACKGROUND: Mesothelin is overexpressed in many solid tumors, and recent studies have shown that mesothelin expression is associated with poor outcomes in several malignant tumors and may play a role in cancer progression. Clinical trials of mesothelin-targeted immunotherapies are currently under way, but the correlation between mesothelin expression and gastric cancer prognosis is still unclear. SUBJECTS, MATERIALS, AND METHODS: Mesothelin expression in tumor cells was evaluated immunohistochemically in 958 patients with advanced gastric cancer and interpreted according to the intensity and extent of staining. Samples were scored from 0 to 2, with high expression defined as a score of 2. Clinicopathological factors, overall survival (OS), recurrence-free survival (RFS), and sites of initial recurrence, including peritoneal recurrence, were evaluated. Staging was performed according to the American Joint Committee on Cancer 7th edition. RESULTS: High mesothelin expression was observed in 49.7% of patients and significantly associated with high pathologic T (p = .021) and peritoneal recurrence (p = .018). Multivariate survival analysis showed that high mesothelin expression was independently associated with poor RFS (p = .001), OS (p = .001), and peritoneal recurrence (p = .002) in addition to stage, lymphovascular invasion, and Lauren classification. In a subgroup analysis of peritoneal recurrence, high mesothelin expression was also an independent prognostic factor in stage III (p = .013) and diffuse/mixed type gastric cancer (p = .010). CONCLUSION: High mesothelin expression is correlated with poor outcomes. In addition, mesothelin expression, Lauren classification, and stage are meaningful predictive factors for peritoneal recurrence. Moreover, mesothelin was a significant predictor of a high risk of peritoneal recurrence in patients with stage III gastric cancer. IMPLICATIONS FOR PRACTICE: This study demonstrates that high mesothelin expression correlates with poor outcomes and is a significant predictor of peritoneal recurrence in patients with stage III gastric cancer. This study provides instrumental evidence for designing anti-mesothelin antibody-drug conjugate clinical trials in patients with diffuse-type gastric cancer to reduce their high risk of peritoneal carcinomatosis.

Selective Cytotoxicity of the NAMPT Inhibitor FK866 Toward Gastric Cancer Cells With Markers of the Epithelial-Mesenchymal Transition, Due to Loss of NAPRT.

BACKGROUND & AIMS: Markers of the epithelial-to-mesenchymal transition (EMT) in gastric tumor tissues are associated with poor patient outcomes. We performed a screen to identify pharmacologic compounds that kill gastric cancer cells with EMT-associated gene expression patterns and investigate their mechanisms. METHODS: We identified 29 gastric cancer cell lines with a gene expression signature previously associated with an EMT subtype, based on data from RNA sequence analyses, and confirmed the mesenchymal phenotypes of 7 lines (Hs746T, SNU1750, MKN1, SK4, SNU484, SNU668, and YCC11), based on invasive activity and protein markers. We screened 1,345 compounds for their ability to kill cells with the EMT signature compared with cell lines without this pattern. We tested the effects of identified compounds in BALB/c nude mice bearing GA077 tumors; mice were given intraperitoneal injections of the compound or vehicle (control) twice daily for 24 days and tumor growth was monitored. Proteins associated with the toxicity of the compounds were overexpressed in MKN1 and SNU484 cells or knocked down in MKN45 and SNU719 using small interfering RNAs. We performed immunohistochemical analyses of 942 gastric cancer tissues and investigated associations between EMT markers and protein expression patterns. RESULTS: The nicotinamide phosphoribosyltransferase inhibitor FK866 killed 6 of 7 gastric cancer cell lines with EMT-associated gene expression signatures but not gastric cancer cells without this signature. The 6 EMT-subtype gastric cell lines expressed significantly low levels of nicotinic acid phosphoribosyltransferase (NAPRT), which makes the cells hypersensitive to nicotinamide phosphoribosyltransferase inhibition. Gastric cell lines that expressed higher levels of NAPRT, regardless of EMT markers, were sensitized to FK866 after knockdown of NAPRT, whereas overexpression of NAPRT in deficient EMT cell lines protected them from FK866-mediated toxicity. Administration of FK866 to nude mice with tumors grown from GA077 cells (human gastric cancer tumors of the EMT subtype) led to tumor regression in 2 weeks; FK866 did not affect tumors grown from MKN45 cells without the EMT expression signature. Loss of NAPRT might promote the EMT, because it stabilizes ß-catenin. We correlated the EMT gene expression signature with lower levels of NAPRT in 942 gastric tumors from patients; we also found lower levels of NAPRT mRNA in colorectal, pancreatic, and lung adenocarcinoma tissues with the EMT gene expression signature. CONCLUSIONS: FK866 selectively kills gastric cancer cells with an EMT gene expression signature by inhibiting nicotinamide phosphoribosyltransferase in cells with NAPRT deficiency. Loss of NAPRT expression, frequently through promoter hypermethylation, is observed in many gastric tumors of the EMT subtype. FK866 might be used to treat patients with tumors of this subtype.