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KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis. [ABSTRACT FROM AUTHOR]

Importance: High gluten intake during childhood may confer risk of celiac disease.Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children.Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017.Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years.Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels.Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]).Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children. [ABSTRACT FROM AUTHOR]

Objective: The current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important. Methods: We performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations. Results: K-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC. Conclusion: The existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP. [ABSTRACT FROM AUTHOR]

Background: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM.Methods: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model.Results: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation.Conclusions: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM. [ABSTRACT FROM AUTHOR]

β-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing β-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first β-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3–4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing β-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing β-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged ≥2 years. Gestational infections were not associated with the first appearing β-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45–0.91) among CTLA4 -(AG, GG) children (G-RI* CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing β-cell autoantibody in early life. [ABSTRACT FROM AUTHOR]

Background. Adrenal collision tumors (ACTs), in which distinct tumors coexist without intermingling in the same adrenal gland, are rare and their actual prevalence is unknown. ACTs commonly consist of adrenal cortical adenoma, pheochromocytoma, or metastatic malignant tumor. Case Report. A 32-year-old woman who had been experiencing gastric discomfort for one month was referred to our hospital with abnormal imaging findings. The physical examination and the laboratory data including endocrine studies were unremarkable. Abdomen computed tomography (CT) and magnetic resonance imaging (MRI) showed two adjacent masses in the left suprarenal fossa, and a laparoscopic left adrenalectomy was done. Histological and immunohistochemical (IHC) examinations revealed two distinct tumors: a pigmented adrenal cortical oncocytoma (ACO) and a ganglioneuroma, respectively. Conclusion. Both tumors are rare in the adrenal gland and exist as ACTs only exceptionally rarely. This is the first reported case of coexisting oncocytoma and ganglioneuroma in the same adrenal gland to our knowledge. [ABSTRACT FROM AUTHOR]

The article discusses a research study which investigated the association of increased risk of pediatric celiac disease with the presence of human leukocyte antigen (HLA) haplotype DR3-DQ2 or DR4-DQ8 disease and serum antibodies against tissue transglutaminase (tTG) among children from the U.S., Finland, Germany and Sweden. Study results provided show the hazard ratios for celiac disease autoimmunity among heterozygotes and homozygotes as compared to children with the lowest-risk genotypes.

High-quality, Cd-free InP quantum dots (QDs) have been conventionally synthesized by exclusively selecting tris(trimethylsilyl)phosphine (P(TMS)) as a phosphorus (P) precursor, which is problematic from the standpoint of green and economic chemistry. Thus, other synthetic chemistries adopting alternative P sources to P(TMS) have been introduced, however, they could not guarantee the production of satisfactorily fluorescence-efficient, color-pure InP QDs. In this study, the unprecedented controlled synthesis of a series of band-gap-tuned InP QDs is demonstrated through a hot-injection of a far safer and cheaper tris(dimethylamino)phosphine in the presence of a key coordinating solvent of oleylamine that enables successful QD nucleation/growth. Effects of the co-existence of Zn additive, the core growth temperature, and the amount of P source injected on the growth behaviors of InP QD are investigated. After ZnS overcoating by a successive injection of 1-dodecanethiol only, high-fluorescence-quality, green-to-red color emission-tunable core/shell QDs of InP/ZnS are obtained. The fluorescent characteristics of different color-emitting QDs desirably exhibit little fluctuations in quantum yield and emission bandwidth, specifically ranging 51-53 % and 60-64 nm, respectively. Lastly, the utility of the introduction of a secondary shelling process in rendering the QDs are more bright, photostable is also proved. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the ability of the St. George's Respiratory Questionnaire (SGRQ) to assess health-related quality of life (HRQL) in patients with lymphangioleiomyomatosis (LAM). External measures considered include diffusing capacity of the lung for carbon monoxide and distance walked during the 6-minute walk test. Findings revealed correlation between SGRQ scores and majority of anchor values.

Abstract: Background: Dickkopf-1 (DKK1), a secreted protein known as a negative regulator of the Wnt signaling pathway, has been implicated in tumorigenesis. However, the clinical significance of DKK1 in gastric cancer has not been clarified. Methods: Serum concentrations of DKK1 in 153 patients with gastric cancer and 173 healthy controls were assessed. For tissue DKK1, immunohistochemistry was performed in 144 cancer specimens from 153 patients and in an additional 265 consecutive gastric cancer specimens. Results: The serum DKK1 concentrations were significantly higher in the gastric cancer patients than in the healthy controls (p<0.001). At a cutoff concentration of 31.9150pg/ml, the sensitivity and the specificity for gastric cancer diagnosis were 87.6% and 87.9%, respectively. The gastric cancer patients with a serum DKK1 level of ≥60.0pg/ml had significantly diminished survival compared with the patients whose serum DKK1 levels were lower (p=0.033). The DKK1 overexpression in the cancer specimens significantly correlated with the increased serum DKK1 concentrations. Conclusions: Serum DKK1 levels have the potential as a diagnostic marker at a low cutoff value and as a prognostic marker at a high cutoff value. Serum and tissue DKK1 levels may aid in diagnosing gastric cancer and predicting patient outcomes. [Copyright &y& Elsevier]

Background and Aim: Western reports have suggested that the prevalence of gastric cardia cancer (GCC) has been increasing, and indicated some differences between GCC and gastric noncardia cancer (GNCC). However, few studies have been conducted in Asia. The aims of this study were to estimate the prevalence of GCC and to evaluate differences of clinicopathologic characteristics between GCC and GNCC in South Korea. Methods: This study was single-center case-control study. A total of 829 patients with gastric cancer and 270 controls were enrolled between 2003 and 2011. Baseline characteristics, Helicobacter pylori ( H. pylori) infection status, and histologic characteristics were compared among three groups (GCC, GNCC, and control). Results: Sixty cases (7.2%) of gastric cancer were located in cardia. Multivariate analysis showed that male odds ratio (OR, 5.72; 95% CI, 1.72-19.07; p = .005) and cigarette smoking (OR, 5.38; 95% CI, 1.39-20.90; p = .015) were risk factors of GCC in comparison with control group, but H. pylori infection rate was not significant. In the case of GNCC, cigarette smoking (OR, 3.87; 95% CI, 1.81-8.29; p < .001), past alcohol intake (OR, 2.82; 95% CI, 1.28-6.20; p = .010), intestinal metaplasia (OR, 3.22; 95% CI, 2.00-5.17; p < .001), and H. pylori infection (OR, 3.06; 95% CI, 1.90-4.93; p < .001) were risk factors of GNCC. Gastroesophageal reflux disease symptoms were higher in the GNCC (21.2%) than control group (13.5%) ( p = .008). However, in the case of GCC, they were similar between the GCC (12.7%) and control group ( p = .872). According to multivariate analysis, history of H. pylori eradication (OR, 0.34; 95% CI, 0.19-0.61; p < .001) was associated with a protective effect on GNCC. GCC showed higher depth of invasion ( p = .038) and frequent distant metastasis ( p = .012) than GNCC. Conclusion: In this referral center based study, the prevalence of GCC was 7.2% in South Korea. Risk factors and clinicopathologic characteristics for GCC and GNCC were different, supporting that the pathophysiology is different in the development of GCC and GNCC. [ABSTRACT FROM AUTHOR]

Background: We evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed. Methods: The KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled. Results: The KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005). Conclusions: Organs initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%). [ABSTRACT FROM AUTHOR]

Johnson SB, Lee H-S, Baxter J, Lernmark B, Roth R, Simell T for the TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) Study: predictors of early study withdrawal among participants with no family history of type 1 diabetes. Objective: The Environmental Determinants of Diabetes in the Young (TEDDY) study seeks to identify environmental triggers of autoimmunity and type 1 diabetes mellitus (T1DM) in children at increased human-leukocyte-antigen conferred genetic risk for this disease. The objective of this study was to identify predictors of early withdrawal from TEDDY among families with no immediate family history of T1DM. Method: Logistic multiple regression was used to discriminate 2994 (83%) families currently active in the TEDDY study for ≥1 yr from 763 (17%) families who withdrew in the first year. Data collected on the screening form at the time of the child's birth and from interview and questionnaire data obtained at the baby's first study visit (at ≤4.5 months of age) were used. Results: Significant and independent predictors of early withdrawal included country of residence, young maternal age, no father participation, and female gender of the study participant. Mothers of children who withdrew were more likely to report smoking during pregnancy, abstaining from alcohol, and reducing their work hours or not working at all during pregnancy. Mothers who withdrew were also more likely to underestimate their child's risk for T1DM and fail to respond to multiple items on the enrollment questionnaires or interview. Among mothers with accurate risk perceptions, those experiencing high anxiety about their child's risk were more likely to be early withdrawals. Conclusions: Identifying families at high risk for study withdrawal at the time of enrollment allows for targeting these families with individually tailored plans to help maintain their participation in the study. [ABSTRACT FROM AUTHOR]

Aims: Epithelial–mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metastasis of various cancers. The aim was to evaluate the expression of EMT-related proteins in gastric carcinoma (GC). Methods and results: The expression of nine EMT-related proteins in the GC tissues of 598 patients was evaluated by immunohistochemistry using a tissue array method. In addition, clinicopathological characteristics and survival were compared with the expression of EMT-related proteins. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed in GC. These protein alterations were associated with diffuse type histology, advanced stage and poor patient outcome, respectively. Subjects were divided into three groups according to degree of EMT-related protein alteration. Increases in alteration of EMT-related protein were found to be significantly associated with poorly differentiated histology, higher pTNM stage and unfavourable outcome. Multivariate analysis showed that alterations in the expression of EMT-related proteins were independently associated with poor prognosis. Conclusions: Loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with poorly differentiated histology, advanced stage and poor outcome in GC. The awareness and inhibition of EMT offer a promising target for prevention of metastatic progression and invasion. [ABSTRACT FROM AUTHOR]

We analyze familial correlation of a memory score from Caribbean Hispanic families that have multiple family members affected with Alzheimer's disease, adjusting for having at least one APOE-ε4 allele, as well as other confounders. To enhance the efficiency of correlation model, this paper proposes an alternative approach for three generalized estimating equations proposed by Yan and Fine ( Statist. Med. 2004; 23:859-874). The efficiency of correlation model is evaluated through the asymptotic relative efficiency computation and simulations. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Canonical correlation assesses the relationship between two groups of variables. Although it has been a useful tool in a wide variety of research areas, it is not well known that weaker canonical correlations require larger sample sizes to be correctly inferred. In this article, we investigate small sample bias in canonical correlation analysis and apply the jackknife bias correction to the estimation of canonical correlations. We use bootstrap samples to obtain a better confidence interval for the jackknife canonical correlation estimator. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5–16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. Methods: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV–ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. Results: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan–Meier survival curve. However, this effect was evident only in males. Conclusions: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females. [ABSTRACT FROM AUTHOR]

Background: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls.Methods: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale.Results: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes.Conclusions: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials. [ABSTRACT FROM AUTHOR]

HER2-positive luminal B breast cancer (BC), a subset of the luminal B subtype, is ER-positive and HER2-positive BC which is approximately 10% of all BC. However, HER2-positive luminal B BC has received less attention and is less represented in previous molecular analyses than other subtypes. Hence, it is important to elucidate the molecular biology of HER2-positive luminal B BC to stratify patients in a way that allows them to receive their respective optimal treatment. We performed molecular profiling using targeted next-generation sequencing on 94 HER2-positive luminal B BC to identify its molecular characteristics. A total of 134 somatic nonsynonymous mutations, including 131 nonsynonymous single nucleotide variants and three coding insertions/deletions were identified in 30 genes of 75 samples. PIK3CA was most frequently mutated (38/94, 40.4%), followed by TP53 (31/94, 33.0%), and others were detected at lower frequencies. Recurrent germline mutations of MLH1 V384D were found in 13.8% (13/94), with a significantly high TP53 mutations rate. The frequency of MLH1 V384D germline mutation in individuals with HER2-positive luminal B BC was significantly higher than that observed in the controls. All 13 cases were classified as microsatellite stable tumors. Tumor mutation burdens (TMB) were not significantly different between MLH1 V384D carrier and wild type. The concordant results of microsatellite instability (MSI) and TMB suggest that the haploinsufficiency of MLH1 plays a role as a tumor predisposition factor rather than a direct oncogenic driver. Our study identified, for the first time, that MLH1 V384D germline variant is frequently detected in HER2-positive luminal B BC. MLH1 V384D germline variant may not only contribute to gastrointestinal cancer predisposition but may also contribute to BC in East Asians. [ABSTRACT FROM AUTHOR]

Background: Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers. Methods: We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II–III AGC (two academic hospitals). Results: VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012–3.519, P < 0.001) and event-free survival (HR = 2.8, 95% CI = 2.18–3.72, P < 0.001). These findings were successfully validated in independent cohorts. VSIG4 expression was also significantly correlated with low intratumoral CD8 + T-cell infiltration (CD8i) (P = 0.029) and high Foxp3 + /CD8i ratio (P = 0.026), which is consistent with the previously reported immunological function of VSIG4. However, VSIG4 expression was not associated with survival in other cancers (colon, P = 0.459; lung, P = 0.275; kidney, P = 0.121; breast, P = 0.147). Conclusion: Our results suggest that VSIG4 is an independent prognostic factor in AGC and also implies that VSIG4 is a second-tier IC molecule in AGC, thus, providing an important basis for the development of gastric cancer-specific immunotherapeutics. [ABSTRACT FROM AUTHOR]

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case–control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n − 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n − 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Accurate determination of microsatellite instability (MSI) status is critical for optimal treatment in cancer patients. Conventional MSI markers can sometimes display subtle shifts that are difficult to interpret, especially in non-colorectal cases. We evaluated an experimental eight marker-panel including long mononucleotide repeat (LMR) markers for detection of MSI. Methods: The eight marker-panel was comprised of five conventional markers (BAT-25, BAT-26, NR-21, NR-24, and NR-27) and three LMR markers (BAT-52, BAT-59 and BAT-62). MSI testing was performed against 300 specimens of colorectal, gastric, and endometrial cancers through PCR followed by capillary electrophoresis length analysis. Results: The MSI testing with eight marker-panel showed 99.3% (295/297) concordance with IHC analysis excluding 3 MMR-focal deficient cases. The sensitivity of BAT-59 and BAT-62 was higher than or comparable to that of conventional markers in gastric and endometrial cancer. The mean shift size was larger in LMR markers compared to conventional markers for gastric and endometrial cancers. Conclusions: The MSI testing with eight maker-panel showed comparable performance with IHC analysis. The LMR markers, especially BAT-59 and BAT-62, showed high sensitivity and large shifts which can contribute to increased confidence in MSI classification, especially in gastric and endometrial cancers. Further study is needed with large number of samples for the validation of these LMR markers. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the molecular and immune microenvironment characteristics of HER2‐positive gastric cancer (GC) related to the patient's response to first‐line trastuzumab‐based treatment. Methods: Eighty‐three cases of HER2‐positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post‐treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor‐infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression‐free survival (PFS) analysis was performed. Results: Group 1 showed frequent amplification of G1/S cell cycle checkpoint‐related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune‐related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle‐related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune‐related including high density of CD3−CD57+ NK cells and PD‐L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). Conclusion: HER2‐positive GC with favorable response to trastuzumab were characterized by cell cycle‐related gene alterations and increased CD3−CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2‐positive GC. [ABSTRACT FROM AUTHOR]

3Comparisons of gastric cancer-specific survival depending on Helicobacter pylori eradication. The benefits of gastric cancer-specific survival were observed in the successfully eradicated group before (a) and after (b) propensity score matching compared to non-eradicated group, with statistical significance (P < 0.001). Correction: Effect of Helicobacter pylori eradication after subtotal gastrectomy on the survival rate of patients with gastric cancer: follow-up for up to 15 years. [Extracted from the article]

Background: Scoliosis is prominent in Rett syndrome (RTT). Following the prior report from the US Natural History Study, the onset and progression of severe scoliosis (≥40° Cobb angle) and surgery were examined regarding functional capabilities and specific genotypes, addressing the hypothesis that abnormal muscle tone, poor oral feeding, puberty, and delays or absence of sitting balance and ambulation may be responsible for greater risk in RTT.Methods: The multicenter RTT Natural History Study gathered longitudinal data for classic RTT, including mutation type, scoliosis, muscle tone, sitting, ambulation, hand function, and feeding. Cox regression models were used to examine the association between scoliosis and functional characteristics. All analyses utilized SAS 9.4; two-sided P values of <0.05 were considered significant.Results: A total of 913 females with classic RTT were included. Scoliosis frequency and severity increased with age. Severe scoliosis was found in 251 participants (27%), 113 of whom developed severe scoliosis during the follow-up assessments; 168 (18%) had surgical correction. Severe MECP2 mutations (R106W, R168X, R255X, R270X, and large deletions) showed a higher proportion of scoliosis. Individuals developing severe scoliosis or requiring surgery were less likely to sit, ambulate, or use their hands and were more likely to have begun puberty. Significant differences were absent for epilepsy rates, sleep problems, or constipation.Discussion: Scoliosis requires vigilance regarding the risk factors noted, particularly specific mutations and the role of puberty and motor abilities. Bracing is recommended for moderate curves and surgery for severe curves in accordance with published guidelines for scoliosis management. [ABSTRACT FROM AUTHOR]

Data on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited. We sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately. We conducted a propensity score–matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor–SV and ARB-SV users; recent ACE inhibitor–SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately. Compared with ACE inhibitor, SV new (HR: 0.18; 95% CI: 0.11-0.29) and ACE inhibitor–SV users (HR: 0.31; 95% CI: 0.23-0.43) showed lower risk of angioedema. On the other hand, there was no difference in angioedema risk when SV new users (HR: 0.59; 95% CI: 0.35-1.01) or ARB-SV users (HR: 0.85; 95% CI: 0.58-1.26) were compared with ARB new users. Compared with SV new users, ACE inhibitor–SV users (HR: 1.62; 95% CI: 0.91-2.89) trended toward higher angioedema risk, which intensified when the ACE inhibitor to SV switch occurred within 14 days (recent ACE inhibitor–SV) (HR: 1.98; 95% CI: 1.11-3.53). Similarly, ARB-SV users (HR: 2.03; 95% CI: 1.16-3.54) experienced an increased risk compared with SV new users, which intensified for the more recent switchers (recent ARB-SV) (HR: 2.45; 95% CI: 1.36-4.43). We did not observe an increased risk of angioedema among SV new users compared with ACE inhibitor or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACE inhibitor or ARB compared with SV new users. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Tight junction proteins (TJPs) play a role in epithelial defense mechanisms. However, the effect of Helicobacter pylori (Hp) on TJPs remains unclear. This study aimed to evaluate the expression of TJPs in relation to Hp infection and eradication in gastric carcinogenesis. Methods: In total, 510 subjects (284 controls and 226 gastric cancer [GC] patients) were prospectively enrolled in the study. The expression of claudin‐1 and ‐2 (CLDN‐1, ‐2), occludin (OCLN), and tight junction protein 1 (TJP1) was measured based on their Hp infection status in normal corpus mucosa and evaluated following Hp eradication using quantitative real‐time polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Results: The expression of TJP1 in Hp+ controls was significantly lower than that in Hp− controls (p = 0.006), whereas it was higher in Hp+ than in Hp− GC patients (p = 0.001). Moreover, the increased expression of TJP1 in Hp+ GC patients was reduced to levels in Hp−within a year after Hp eradication and was maintained for more than 5 years. Furthermore, IHC results for TJP1 were similar to qPCR results. In particular, the higher IHC staining intensity of TJP1 in the cytosol of GC patients (p = 0.019) decreased after Hp eradication (p = 0.040). Conclusion: Hp infection affects TJP expression. The high expression of TJP1 in Hp+ GC patients was restored to control levels after Hp eradication, suggesting that TJP1 plays a role in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: The PD-L1 IHC 22C3 pharmDx used on the Dako Autostainer Link 48 (ASL48) staining platform is an established method for assessing programmed death-ligand 1 (PD-L1) expression in tumor tissue and determining patient eligibility for pembrolizumab treatment; however, the availability of this platform is limited in Europe and Asia. Objectives: The aims of this study were to develop and optimize protocols for the PD-L1 22C3 antibody concentrate with multiple immunohistochemistry staining platforms and to validate these protocols using PD-L1 combined positive score (CPS) with a cut-off of ≥ 1 in gastric or gastroesophageal junction adenocarcinoma. Design: The 22C3 antibody concentrate was tested and optimized protocols were developed for use with three staining platforms: Dako ASL48, Ventana BenchMark ULTRA, and Leica BOND-MAX. Tumor specimens (N = 120) from patients with gastric or gastroesophageal junction adenocarcinoma were used for the validation study; these specimens were evaluated independently by three pathologists for PD-L1 CPS as a continuous variable and using a cut-off of ≥ 1. PD-L1 IHC 22C3 pharmDx used on the Dako ASL48 platform served as the reference or gold standard. Results: The intraclass correlation coefficient of CPS as a continuous variable between the gold standard and each staining platform assessed was 0.910–0.989. When CPS was dichotomized based on a cut-off of ≥ 1, depending on the pathologist and the platform used, positive percentage agreement was 81–99% and negative percentage agreement was 90–100%. Interobserver agreement using the gold standard showed substantial agreement (κ = 0.779). Conclusion: The PD-L1 22C3 antibody concentrate can potentially be used with the laboratory-developed test on three commercially available immunohistochemistry staining platforms to determine PD-L1 expression in tumor samples from patients with gastric or gastroesophageal junction adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: Rett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact both patients' and caretakers' quality of life in Rett syndrome. We hypothesized that more severe clinical features would negatively impact caretaker physical quality of life but would positively impact caretaker mental quality of life.Methods: Participants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic Rett syndrome. Demographic data, clinical disease features, caretaker quality of life, and measures of family function were assessed during clinic visits. The Optum SF-36v2 Health Survey was used to assess caretaker physical and mental quality of life (higher scores indicate better quality of life). Descriptive, univariate, and multivariate analyses were used to characterize relationships between child and caretaker characteristics and caretaker quality of life.Results: Caretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) vs 44.5 (12.1). No differences were demonstrated between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (P = 0.006) and improved MCS (P = 0.003). Feeding problems were associated with poorer PCS (P = 0.007) and poorer MCS (P = 0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS.Conclusions: Caretaker quality of life in Rett syndrome is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact quality of life, and feeding difficulties may represent an important clinical target for improving both child and caretaker quality of life. The stability of quality-of-life scores between baseline and five years adds important value. [ABSTRACT FROM AUTHOR]

Background/Aims: Helicobacter pylori (H. pylori) is an important risk factor of atrophic gastritis (AG), intestinal metaplasia (IM), and gastric cancer (GC). However, no report to date has described the endoscopic improvement of AG and IM after H. pylori eradication. Thus, the aim of this study was to evaluate the improvement of AG and IM after H. pylori eradication using endoscopic and histologic analyses. Methods: A total of 380 subjects were prospectively enrolled for up to 12 years and grouped by their H. pylori infection status: negative, non-eradicated, and eradicated. Endoscopic and histologic analyses of AG and IM were performed in the antrum and the corpus, by annual follow-up endoscopy. Results: Endoscopic AG and IM in the antrum and corpus in the eradicated group improved compared to that in the non-eradicated group (AG, P = 0.002 and P = 0.005; IM, P = 0.038 and P = 0.048, respectively). Histologic AG and IM in the antrum and corpus in the eradicated group also improved compared to that in the non-eradicated group (all P < 0.001). Time taken to the endoscopic improvement of AG and IM after H. pylori eradication was significantly longer than time taken to the histologic improvement in the antrum and corpus (AG in antrum: 3.47 ± 2.60 vs. 2.34 ± 1.71 years, P = 0.004; AG in corpus: 3.19 ± 2.30 vs. 1.87 ± 1.48 years, P = 0.002; IM in antrum: 4.40 ± 2.38 vs. 3.62 ± 2.35 years, P = 0.043; and IM in corpus: 4.82 ± 1.08 vs. 3.61 ± 2.22 years, P = 0.007, respectively). Conclusions: Both endoscopic and histologic improvements of AG and IM were observed after H. pylori eradication, while endoscopic improvement took significantly longer time than histologic improvement. [ABSTRACT FROM AUTHOR]

Objective: AT-rich interactive domain 1A (ARID1A) has recently been identified as a novel tumor suppressor in various tumor types. This study was designed to explore the clinical relevance and prognostic impact of ARID1A expression loss in colorectal cancer (CRC) and gastric cancer (GC). Methods: Immunohistochemistry for ARID1A was performed using tissue microarray blocks containing 196 CRCs and 275 GCs, along with paired normal mucosa. Data on clinicopathologic variables and oncologic outcomes of patients were collected and analyzed. Results: We identified 6.1% (12/196) CRC and 8.0% (22/275) GC cases showing loss of ARID1A expression. Expression of ARID1A in paired mucosal epithelial cells was normal in all patients. Loss of ARID1A expression was significantly correlated with negative lymphatic invasion (p = 0.003) in CRC, with large tumor size (p = 0.037) in GC, and with expanding tumor border in both tumor types (CRC, p = 0.010; GC, p = 0.031). However, no association was evident between ARID1A expression and 5-year overall survival in both tumor types. Conclusions: Loss of ARID1A expression is uncommon and not associated with oncologic outcome but may be related to less invasive clinicopathologic features in CRC and GC. Further studies with a larger number of subjects are needed to establish the possible prognostic impact of ARID1A expression loss. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Aim: Tumor stroma and tumor‐infiltrating lymphocytes (TILs) are major constituents of the tumor microenvironment, although they have different effects on the prognosis of patients with colorectal cancer (CRC). Combinatory statuses of tumor‐stromal percentage (TSP) and TILs are expected to provide more powerful prognostic information but have never been studied in CRCs. Methods: Stage III CRCs from patients (n = 487) treated with adjuvant chemotherapy were assessed for their TSP and CD3‐TIL or CD8‐TIL densities using computer‐aided methodology. With cut‐off values set at median values for intraepithelial TIL (iTIL) and stromal TIL (sTIL) densities, CRCs were sorted into low and high iTIL or sTIL groups. CRCs were classified into five quintile (Q1–Q5) groups according to their TSP and divided into high TSP (Q5) and low TSP (Q1–4) groups. Results: The combination of CD8 iTIL density and TSP was found to be an independent prognostic parameter in multivariate survival analysis in terms of cancer‐specific survival and recurrence‐free survival. CRCs with low CD8 iTIL density and high TSP showed the worst survival. The combinatory status showed more prognostic power than CD8 iTIL density or TSP alone. Multivariate survival analysis in an independent cohort of stage III CRC validated the prognostic power of the combinatory statuses. Conclusions: The findings suggest that the combinatory status might serve as a prognostic parameter in stage III CRCs. Further research in a large‐scale cohort of patients with stage III CRC is needed to validate the prognostic power of the combinatory status. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transition (EMT)-related cancers generally elicit low immune responses. EMT is regulated by several microRNAs (miRNAs) in cancers. Thus, this study aimed to evaluate the prognostic potential of EMT-related miRNAs as biomarkers in colorectal cancer (CRC). Formalin-fixed paraffin-embedded tumor and normal tissue and plasma samples were obtained from 65 patients with pathologically confirmed CRC. In addition, plasma samples were obtained from 30 healthy volunteers. Immunohistochemical staining for E-cadherin, ZEB1, PD-1, PD-L1, CD3, CD4, CD8, Foxp3, and CD68 was conducted on tissue samples. Droplet digital polymerase chain reaction (ddPCR) analysis was performed to evaluate miR-21-5p, 34a-5p, 138-5p, 200a-3p, 200b-5p, 200c-3p, 630, 1246, and 1290 expression in tissue samples and miR-630, 1246, and 1290 expression in plasma samples. miR-21-5p, 34a-5p, 630, 1246, and 1290 expression was higher in tumor tissues than in normal tissues (P < 0.05). EMT was significantly associated with reduced tumor-infiltrating T cells. Moreover, miR-21-5p, miR-34a-5p, miR-200a-3p, and miR-200c-3p expression was negatively correlated with T cell density (P < 0.05). High tissue levels of miR-200c-3p were associated with poor overall survival (OS) (P < 0.001). CRC patients with the EMT phenotype had poor OS; however, PD-L1 positivity and abundant PD-1 positive immune cells were correlated with better OS (P < 0.05). miR-1246 and miR-1290 levels were significantly higher in the plasma of patients with CRC than in the plasma of healthy controls (P < 0.05). High plasma levels of miR-1290 were correlated with advanced stage and poor OS (P < 0.05). The tissue expression of miR-200c-3p and plasma levels of miR-1290 measured by ddPCR indicate their potential as prognostic biomarkers for CRC. [ABSTRACT FROM AUTHOR]

Background: The possible effects of dairy product intake against obesity have been suggested in animal studies; however, the association is still not well established in epidemiological studies. Few studies in Asian countries with relatively low intake of dairy products exist. Objective: We investigated the association between dairy products and calcium intake and obesity in Korean population with relatively low intake of dairy products. Subjects and Methods: Our study population consisted of adults (n = 7173) aged 19–64 among participants of the 2007, 2008 and 2009 Korean National Health and Nutrition Examination Survey who had not made any attempt of intentional weight loss. Dietary intake data from food frequency questionnaire (FFQ) and 24-hour recall were used. Dairy products included milk and yogurt in the FFQ. Obesity was defined as BMI≥25 kg/m2. Results: Higher frequency of dairy product intake was associated with a reduced prevalence of obesity (OR = 0.63; 95% CI = 0.45–0.89 for ≥2 times/day vs. ≤1 time/month; p for trend = 0.003) using the intake data from FFQ. Similarly, high frequency of milk or yogurt intake had an inverse association with obesity. The association between milk and yogurt intake and obesity was similar when the intake from 24-hour recall was examined. Higher calcium intake from dairy products as well as total dietary calcium intake was associated with a decreased prevalence of obesity (OR = 0.83; 95% CI = 0.71–0.98 for highest vs. lowest quintile of dairy calcium intake; p for trend = 0.02, OR = 0.78; 95% CI = 0.64–0.94 for highest vs. lowest quintile of total calcium intake; p for trend = 0.04). The associations appeared to be stronger in women than in men. Conclusion: These results suggest that high consumption of dairy products is associated with a lower prevalence of obesity and that calcium in dairy products may be one of the components contributing to the association. Further longitudinal studies are warranted to replicate our findings. [ABSTRACT FROM AUTHOR]

Individual cell types of human tissues have their own CpG site methylation profiles, which might be utilized for the development of methylation markers to denote tumor-infiltrating lymphocytes (TILs). We aimed to develop DNA methylation markers that recapitulate the densities of TILs in gastric carcinoma (GC). Through genome-wide methylation profiling, NCOR2, PARK2, and ZSCAN12 were found to be highly methylated in CD3-positive and CD8-positive cells and rarely methylated in tumor cells. Scores of the three methylation markers were analyzed for their relationship with the overall survival and recurrence-free survival of patients with advanced GC (n = 471). The scores of three methylation markers were closely associated with densities of CD3-positive or CD8-positive cells at the tumor center or invasive front of GCs and found to be a significant prognostic factor in univariate analysis of overall survival and recurrence-free survival. In multivariate analysis, the highest score showed hazard ratios of 0.513 (CI 0.306–0.857) and 0.434 (CI 0.261–0.720) for overall survival and recurrence-free survival, respectively. The findings suggest that methylation markers signifying TILs might be utilized for the recapitulation of TIL density in GCs and serve as biomarkers for predicting prognosis in patients with GC. [ABSTRACT FROM AUTHOR]

Background: Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC).Methods: We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells.Results: Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival.Conclusions: Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC. [ABSTRACT FROM AUTHOR]

Background and Aim: The recommended interval of endoscopic screening for gastric cancer (GC) in a general population is 2 years in Korea. However, it has not been determined whether endoscopic screening with a shorter interval is beneficial, especially for high-risk groups. Methods: A total of 415 patients with GC were categorized according to whether they had (vigilant screening group) or not (non-vigilant screening group) undergone endoscopic screening within 1 year before being diagnosed with GC. Clinicopathologic GC characteristics of the two groups were compared. Next, the same analyses were conducted in subgroups of patients with high risk for GC including males, current smokers, first-degree relatives of GC; and patients with Helicobacter pylori infection, gastric atrophy, or intestinal metaplasia (IM). Results: The proportion of vigilant screening patients was 36.1%. Early gastric cancer (EGC) was more frequently observed in the vigilant screening group than the non-vigilant screening group (62.7% vs 49.4%, P = 0.009). In the high-risk factor analyses, EGC was more frequently detected among patients with severe IM in the vigilant screening group than the non-vigilant screening group (66.7% vs 35.5%, P = 0.047). In addition, more patients in the vigilant screening group had undergone endoscopic submucosal dissection (ESD; 26.7% vs 0%, P = 0.008) and had stage I (84.6% vs 41.7%, P = 0.012) than in the non-vigilant screening group. Conclusions: Endoscopic screening for GC at 1-year intervals would be beneficial for patients with severe IM in South Korea; this method could detect EGC for which the curative modality would be ESD. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic significance of apical-node metastasis around the inferior mesenteric artery (IMA) remains unclear. We investigated the oncological relevance of apical-node metastasis detected after high ligation of the IMA in stage III sigmoid colon or rectal cancer. Methods: Between May 2003 and December 2007, 229 consecutive patients with stage III sigmoid colon or rectal cancer, who had undergone curative resection with high ligation, were analyzed. Cox proportional regression model was used to identify the prognostic factors for disease-free survival. Results: Thirty-one patients (13.5%) had apical-node metastases: 0% with T0-1, 3.8% with T2, 11.5% with T3, and 29.3% with T4 disease ( p = 0.017). Additionally, the factors related to apical-node metastasis were tumor size, number of metastatic lymph nodes, lymph-node ratio, and N-stage. Multivariate analysis showed that the lymph-node ratio (odds ratio (OR) = 40.53, 95% confidence interval (CI) = 8.41-195.22, p < 0.001) was an independent prognostic factor for disease-free survival but that apical-node metastasis was not a factor that predicted a poor outcome (OR = 1.53, 95% CI = 0.81-2.91, p = 0.192). Apical-node metastasis was not a prognostic factor for disease-free survival on multivariate analysis of the subgroups based on tumor location (sigmoid colon cancer: OR = 1.42, 95% CI = 0.42-1.82, p = 0.577; rectal cancer: OR = 1.82, 95% CI = 0.82-4.06, p = 0.141). Conclusions: This study suggests that apical-node metastasis is not a poor prognostic factor for stage III sigmoid colon or rectal cancer after high ligation. [ABSTRACT FROM AUTHOR]

Abstract: Gastrointestinal adenocarcinoma arising in mature cystic teratomas of the ovary is extremely rare. We report a case of well-differentiated intestinal adenocarcinoma arising in a mature cystic teratoma of the ovary in a 77-year-old woman, presenting as acute abdomen with ovarian torsion. An immunohistochemical study revealed expression of CK20 and CK7, and the tumor was also positive for MUC2. The patient had no evidence of disease after 12 months of follow-up. [Copyright &y& Elsevier]

Although it has been well established that overexpression of cyclooxygenase-2 (Cox-2) favors tumorigenesis and metastasis, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. Aberrant methylation of the CpG island is known to be one of the powerful mechanisms for the suppression of gene expression, and usually, CpG islands are very rich in promoter region and exon-1 region. But, it is controversial whether Cox-2 gene expression is regulated by methylation of promoter region or exon-1 region. In this study, we examined whether the hyper-methylation mediated transcriptional silencing of Cox-2 also occurred in human gastric carcinoma tissues and which portion of CpG island methylation is important in Cox-2 gene expression. Genomic DNAs from human gastric carcinoma tissues were treated with three methylation-sensitive restriction enzymes and then Southern blot analysis was performed. Out of 30 primary gastric tumor samples, 26 cases (86.6%) showed overexpression of Cox-2. Four cases (13.3%) with relatively decreased Cox-2 gene expression were associated with the presence of aberrant methylation of Cox-2 CpG island. We also found that methylation of promoter region and not exon-1 region is related with the transcriptional silencing of Cox-2 in gastric carcinoma cancer by detailed methylation mapping using bisulfite sequencing analysis. Our results suggest that the DNA methylation-mediated transcriptional silencing of Cox-2 is a predominant mechanism for the down-regulation of Cox-2 expression in human gastric carcinoma. Furthermore, the results suggest that methylation of not exon-1 region but promoter region is important to regulation of Cox-2 gene expression. [Copyright &y& Elsevier]

Several studies have reported that the prognostic effect of KRAS mutations on colorectal cancers (CRCs) varies depending on the type of mutation. Considering the effect of KRAS mutations on tumor microenvironment, we analyzed the prognostic significance of KRAS mutation types after adjusting for the tumor-infiltrating lymphocytes (TIL) and tumor-stromal percentage (TSP) statuses. In two independent cohorts, KRAS mutations were analyzed by Sanger sequencing and/or next-generation sequencing. TIL density and the TSP were quantified from whole-slide immunohistochemical images. KRAS-mutant CRCs were divided into three subgroups (G12D/V, other codon 12 mutations and codon 13 mutations) to examine their differential effect on TIL density, the TSP and recurrence-free survival (RFS). Among the KRAS mutations, only the G12D/V subgroups showed significantly less TIL infiltration than the wild-type CRCs. According to survival analysis, G12D/V mutations were associated with short RFS; codon 13 mutations showed discordant trends in the two cohorts, and other codon 12 mutations showed no significant association. Multivariate analysis further supported the prognostic value of G12D/V mutations. This result is not only consistent with a recent study suggesting the immunosuppressive effect of mutant KRAS but also provides insight into the type-specific prognostic effect of KRAS mutations. [ABSTRACT FROM AUTHOR]

Background: Inactivation of TP53, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the correlation between the overexpression of p53 and survival in different Lauren-type GCs. Methods: From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression. Results: Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (P = 0.026) and Early gastric cancer (P = 0.044) in intestinal-type GC, and with advanced TNM stage (P < 0.001) and Advanced gastric cancer (P < 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio [aHR] = 1.423, P = 0.022; OS in diffuse-type: aHR = 1.401 P = 0.035; cancer recurrence in diffuse-type: aHR = 1.502, P = 0.039). Conclusion: p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC. [ABSTRACT FROM AUTHOR]

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance "ImmunoCRIT") using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4–2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors. [ABSTRACT FROM AUTHOR]

The microbial enhanced oil recovery (MEOR) method is an eco-friendly and economical alternative technology. The technology involves a variety of uncertainties, and its success depends on controlling microbial growth and metabolism. Though a few numerical studies have been carried out to reduce the uncertainties, no attempt has been made to consider temperature, pressure, and salinity in an integrated manner. In this study, a new modeling method incorporating these environmental impacts was proposed, and MEOR analysis was performed. As a result, accurate modeling was possible to prevent overestimating the performance of MEOR. In addition, oil recovery was maximized through sensitivity analysis and optimization based on an integrative model. Finally, applying MEOR to an actual reservoir model showed a 7% increase in oil recovery compared to waterflooding. This result proved the practical applicability of the method. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer metastasis is a highly fatal disease with a five-year survival rate of less than 5%. One major obstacle in studying gastric cancer metastasis is the lack of faithful models available. The cancer xenograft mouse models are widely used to elucidate the mechanisms of cancer development and progression. Current procedures for creating cancer xenografts include both heterotopic (i.e., subcutaneous) and orthotopic transplantation methods. Compared to the heterotopic model, the orthotopic model has been shown to be the more clinically relevant design as it enables the development of cancer metastasis. Although there are several methods in use to develop the orthotopic gastric cancer model, there is not a model which uses various types of tumor materials, such as soft tissues, semi-liquid tissues, or culture derivatives, due to the technical challenges. Thus, developing the applicable orthotopic model which can utilize various tumor materials is essential. Results: To overcome the known limitations of the current orthotopic gastric cancer models, such as exposure of tumor fragments to the neighboring organs or only using firm tissues for the orthotopic implantation, we have developed a new method allowing for the complete insertion of soft tissue fragments or homogeneously minced tissues into the stomach submucosa layer of the immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. With this completely-closed transplantation method, tumors with various types of tissue may be used to establish orthotopic gastric cancer models without the risks of exposure to nearby organs or cell leakage. This surgical procedure was highly reproducible in generating forty-eight mouse models with a surgery success rate of 96% and tumor formation of 93%. Among four orthotopic patient-derived xenograft (PDX) models that we generated in this study, we verified that the occurrence of organotropic metastasis in either the liver or peritoneal cavity was the same as that of the donor patients. Conclusion: Here we describe a new protocol, step by step, for the establishment of orthotopic xenograft of gastric cancer. This novel technique will be able to increase the use of orthotopic models in broader applications for not only gastric cancer research but also any research related to the stomach microenvironment. [ABSTRACT FROM AUTHOR]

The prognostic impact of Immunoscore (IS) in gastric cancer (GC) patients treated with adjuvant chemotherapy remains unelucidated. We evaluated the CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in tumor centers and invasive margin regions of 389 patients with surgically resected stage II/III GC who received 5-FU-based adjuvant chemotherapy and investigated the impact of IS on survival. In univariate analysis, high CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in the invasive margin were correlated with better prognosis (all P < 0.05). Patients with high IS had significantly longer disease-free survival (DFS; P < 0.001) and overall survival (OS; P < 0.001). In multivariate analysis, IS demonstrated a powerful prognostic impact on patient outcome [DFS, hazard ratio (HR) = 0.465; 95% confidence interval (CI), 0.306–0.707, P < 0.001; OS, HR = 0.478; 95% CI, 0.308–0.743, P = 0.001]. Additionally, although all EBV-positive cases had high IS, IS was similar in both microsatellite instability (MSI)-high and microsatellite stable (MSS)/MSI-low groups (83.3% and 80.5%, respectively). Subgroup analysis according to MSI status revealed that high IS patients had significant DFS and OS benefits in both MSS/MSI-low (DFS, HR = 0.527, 95% CI, 0.341–0.816, P = 0.004; OS, HR = 0.528, 95% CI, 0.334–0.837, P = 0.007) and MSI-high (DFS, HR = 0.166, 95% CI, 0.033–0.826, P = 0.028; OS, HR = 0.177, 95% CI, 0.036–0.883, P = 0.035) groups. Thus, the assessment of immune cell infiltration based on IS may provide a strong indicator of survival in stage II/III GC patients with curative resection following 5-FU-based adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]