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There is a debate regarding the prediction of lymph node metastasis (LNM) in pedunculated T1 colorectal cancer (CRC). In this study with four cases of pedunculated T1 CRCs, we aimed to investigate gene expression variations based on the distance from the Haggitt line (HL) and identify potential molecular risk factors for LNM. By leveraging the Cancer Transcriptome Atlas and digital spatial profiling technology, we meticulously analyzed discrete regions, including the head, HL, proximal stalk region (300–1000 μm from HL), and distal stalk region (1500–2000 μm from HL) to identify spatially sequential molecular changes. Our findings showed significant overall gene expression variations among the head, proximal stalk, and distal stalk regions of pedunculated T1 CRCs compared to the control adenoma. Compared to LNM-negative T1 CRCs, LNM-positive T1 CRC showed that the expression of genes involved in immune-related pathways such as B2M, HLA-B, and HLA-E were significantly downregulated in the distal stalk region compared to the proximal stalk region. In summary, our results may tentatively suggest considering endoscopic resection of the stalk with a minimum 2000 μm margin from the HL, taking into account the gene expression alterations related to immune-related pathways. However, we acknowledge the limitations of this pilot study, notably the small case series, which may restrict the depth of interpretation. Further validation is imperative to substantiate these findings. [ABSTRACT FROM AUTHOR]

Tonsillar squamous cell carcinomas (TSCCs) exhibit high rates of human papillomavirus (HPV) positivity. The expression profiles of microRNA (miRNA), which are small RNA molecules that play pivotal roles in biological processes, in TSCC in relation to the HPV status and cancer-related genetic mutations are not well investigated. Herein, we expanded our previous research, which was focused on established clinicopathological and genetic mutational data, to profile miRNA expression in TSCC, aiming to identify clinically relevant targets for early diagnosis and therapeutic intervention. The miRNA profiles were analyzed using the nCounter Nanostring miRNA Expression assay in 22 surgically resected TSCC tissues and their contralateral normal tonsil tissues. The TERT promoter (TERTp) gene was the only relevant candidate gene associated with differentially expressed miRNAs in TSCC. Hierarchical clustering analysis revealed high expression levels of hsa-miR-1285-5p, hsa-miR-1203, hsa-miR-663a, hsa-miR-1303, hsa-miR-33a-5p, and hsa-miR-3615 coupled with low expression levels of hsa-miR-3182, hsa-miR-219a-2-3p, and hsa-miR-767-3p, which were associated with HPV-positive TSCC (p = 0.009). Functional enrichment analysis revealed that these dysregulated miRNAs tended to be involved in protein binding (molecular function) and cellular components (biological processes). Therefore, hsa-miR-1285-5p and hsa-miR-663a may be associated with HPV-positive TERTp-mutated tumors and may serve as potential treatment targets and biomarkers for early detection. [ABSTRACT FROM AUTHOR]

Several epidemiological studies have demonstrated that genetic and environmental factors contribute to the development of allergic diseases. However, there is limited information on these factors in the Korean population. This study investigated the importance of genetic and environmental factors in allergic diseases, such as allergic rhinitis, asthma, allergic conjunctivitis, or atopic dermatitis, by comparing the disease incidence in Korean adult monozygotic and dizygotic twins. This cross-sectional study utilized data from 1296 twin pairs, including 1052 monozygotic and 244 dizygotic twins, aged over 20 years, from the Korean Genome and Epidemiology Study (2005–2014). The study utilized binomial and multinomial logistic regression models to compute odds ratios of disease concordance. The concordance rate (92%) of the presence or absence of atopic dermatitis in monozygotic twins was slightly higher than that in dizygotic twins (90.2%), which only had a borderline significance (p = 0.090). The concordance rates of other allergic diseases within monozygotic twins were lower compared to dizygotic twins (asthma, 94.3% vs. 95.1%; allergic rhinitis, 77.5% vs. 78.7%; allergic conjunctivitis, 90.6% vs. 91.8%), of which the differences were not statistically significant. Monozygotic twins had a higher proportion of cases in which both siblings had allergic diseases than dizygotic twins (asthma, 1.1% vs. 0.0%; allergic rhinitis, 6.7% vs. 3.3%; atopic dermatitis, 2.9% vs. 0.0%; allergic conjunctivitis, 1.5% vs. 0.0%), of which the differences were also not statistically significant. In conclusion, our results appear to indicate the relative importance of environmental factors over genetic factor in the development of allergic diseases in Korean adult monozygotic twins. [ABSTRACT FROM AUTHOR]

Recent studies suggest that miRNA may be involved in the development of rectal neuroendocrine tumors (NETs). We explored the frequency of clinicopathologically relevant mutations and miRNA expression in rectal NETs to examine molecular profiles related to prognosis and behavior. Twenty-four eligible specimens with endoscopically excised rectal NETs were selected. Next-generation sequencing and an miRNA expression assay were used to evaluate the expression profile relevant to common genetic mutations in rectal NETs. Kyoto Encyclopedia of Genes and Genomes analysis predicted that the possible target signaling pathways were correlated with dysregulated miRNAs. Nineteen rectal NETs harbored more than one mutation in the 24 cancer-related genes. Seven miRNAs (hsa-miR-769-5p, hsa-miR-221-3p, hsa-miR-34a-5p, hsa-miR-181c-5p, hsa-miR-1246, hsa-miR-324-5p, and hsa-miR-361-3p) were significantly down-regulated in tumors harboring the FBWX7 mutation. Unsupervised hierarchical clustering analysis showed that up-regulation of these seven miRNAs may result in high mitotic indices, indicating the role of miRNAs in tumor progression. Among the down-regulated miRNAs, hsa-miR-769-5p was strongly correlated with extracellular matrix–receptor interaction and lysine degradation. Among the clinicopathological factors, up-regulated hsa-miR-3934-5p was linked to an increased mitotic count. No change in miRNA expression was associated with a tumor size >1 cm, lymphovascular invasion, or Ki-67 index. In summary, we identified different miRNA signatures involved in FBXW7 mutations or high mitotic indices in rectal NETs, which may play a critical role in tumor behavior. [ABSTRACT FROM AUTHOR]

Data regarding driver mutation profiles in tonsillar squamous cell carcinomas (TSCCs) remain scarce, limiting the understanding of its pathogenesis and unexpected behavior in the updated staging system. We investigated the incidence of clinically relevant mutations and their contribution in the prognosis of the condition, and their association with human papillomavirus (HPV) infection and adjuvant therapy. We subjected 43 surgically resected TSCC samples to targeted next-generation sequencing, determined their HPV status using polymerase chain reaction, and performed The Cancer Genomic Atlas and Gene Set Enrichment analyses. Thirty-five TSCC samples (81.4%) showed at least one oncogenic/likely oncogenic mutation among twenty-nine cancer-related genes. The top five mutated genes were TP53 (46.5%), PIK3CA (25.6%), PTEN (18.6%), EGFR (16.3%), and SMAD4 (14.0%). The EGFR pathway was the most frequently affected (51.2%), followed by the p53 (48.8%), PI3K (39.5%), and RTK (34.9%) pathways. The gene set enrichment analysis confirmed that the genes involved in signal transduction, such as growth factor receptors and second messengers, EGFR tyrosine kinase inhibitors, and PI3K signaling pathways, were mostly related with TSCCs. TP53 mutation was an independent prognostic factor predicting worse overall survival in the adjuvant therapy group. RTK mutations were related to survival in all patients and in the HPV-positive group, but multivariate analyses showed no significance. In conclusion, oncogenic/likely oncogenic mutations were relatively high in TSCCs, and TP53 and RTK mutations may be candidate predictors for poor prognosis in the adjuvant therapy and HPV-positive groups, respectively, under the updated staging system. [ABSTRACT FROM AUTHOR]

Health issues associated with gout and increased occurrence of osteoporosis or fractures have been raised; however, the results are elusive. Herein, we explored the possible link between gout and incident osteoporosis/osteoporotic fractures based on long-term follow-up nationwide data. This study enrolled 16,305 patients with gout and 65,220 controls who were matched by propensity score at a 1:4 ratio on the basis of sex, age, income, and residence from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2015). A Cox proportional hazard model was employed to identify the relevance between gout and incident osteoporosis/fractures, following adjustment for various covariates. In the follow-up period, osteoporosis developed in 761 individuals with gout and 2805 controls (incidence rates: 8.0 and 7.3/1000 person-years, respectively), and each osteoporotic fracture in the distal radius (2.8 vs. 2.7/1000 person-years), hip (1.3 vs. 1.3/1000 person-years), and spine (4.5 vs. 4.5/1000 person-years) occurred in gout and control groups, respectively. After adjustment, the gout group presented an 11% higher development of osteoporosis (95% confidence interval = 1.02–1.20) than the controls (p = 0.011). Subgroup analyses maintained the augment of incident osteoporosis in sufferers with gout, particularly in either men or <60 years. However, no such relevance was identified between gout and incident osteoporotic fractures at any site. In conclusion, gout may result in a slightly elevated likelihood of developing osteoporosis, and not osteoporotic fractures, in the Korean population. [ABSTRACT FROM AUTHOR]

This study investigated the contribution of genetic and environmental factors to cardiometabolic diseases (CMDs) by comparing disease concordance in monozygotic and dizygotic twins. This cross-sectional study analyzed 1294 (1040 monozygotic and 254 dizygotic) twin pairs (>20 years) based on the Korean Genome and Epidemiology Study data (2005–2014). The odds ratios of disease concordance were calculated using binomial and multinomial logistic regression models. The occurrence of CMDs (hypertension, hyperlipidemia, type 2 diabetes, cerebral stroke, transient ischemic attack, and ischemic heart disease) and related physical and laboratory levels did not differ between the monozygotic and dizygotic twin groups. The odds for concordance of the presence/absence of CMDs and the likelihood of incident CMD within monozygotic twins were comparable to that of dizygotic twins. The absolute differences in hemoglobin A1c, insulin, low- and high-density lipoprotein cholesterol, total cholesterol, triglycerides, and systolic blood pressure were lower in monozygotic twins than in dizygotic twins. Absolute differences in fasting glucose and diastolic blood pressure did not differ between groups. Although baseline levels of several laboratory parameters related to CMD showed a strong likelihood of heritability in monozygotic twins, CMD phenotype appears to be largely affected by environmental factors. [ABSTRACT FROM AUTHOR]

We explored the genetic and environmental inter-relationships among osteoporosis, fracture, arthritis, and bone mineral density concordance in monozygotic twins compared to those in dizygotic twins. This cross-sectional research assessed data of 1032 monozygotic and 242 dizygotic twin pairs aged >20 years included in the Healthy Twin Study data of the Korean Genome and Epidemiology Study between 2005 and 2014. Outcomes of interest included illness concordance and absolute differences in dual-energy X-ray absorptiometry (DEXA) T-scores. We found comparable concordances of osteoporosis, fractures, osteoarthritis, and rheumatoid arthritis between monozygotic and dizygotic twins. Medical histories of osteoporosis, fractures caused by accident or falling, osteoarthritis, and rheumatoid arthritis were not distinct between monozygotic and dizygotic twins. Accidental fracture occurrence in both monozygotic twins showed significantly lower odds than that in dizygotic twins. Genetic influence on liability to fracture risk might thus be maintained. DEXA T-scores for bone mineral density indicated more comparable tendencies within monozygotic twin pairs than within dizygotic ones, suggesting the relative importance of genetic contribution to bone mineral density. The relative importance of genetic factors in bone mineral density is sustained between monozygotic twins; overt disease expression of osteoporosis, fractures, or arthritis may be affected by environmental factors. [ABSTRACT FROM AUTHOR]

We investigated whether the coronavirus disease 2019 (COVID-19) pandemic, in conjunction with public health measures, influenced the incidence of gastrointestinal diseases according to age and sex during the pandemic. Changes in the monthly incidence rates (January 2018 to June 2021) of common gastrointestinal diseases were assessed using data from the Korean National Health Insurance Service by comparing the data of two periods: before COVID-19 (January 2018–February 2020) and during COVID-19 (March 2020–June 2021). The Mann–Whitney U test and Levene's test were used to compare the differences in the incidences before and during the pandemic. In the pandemic period, compared to in the pre-COVID-19 period, the incidence rates of ulcerative colitis, Crohn's disease, cholelithiasis, and esophageal reflux significantly increased, whereas those of infective enteritis and irritable bowel syndrome decreased, regardless of age or sex. There were no significant changes in the incidence rates of pancreatitis, acute appendicitis, liver cirrhosis, and hemorrhoids. No seasonal variations in gastrointestinal disease occurrence were observed. In conclusion, the COVID-19 pandemic may have had unprecedented and long-term impacts on the epidemiology of gastrointestinal disease. These changes may indicate a substantial future burden on healthcare resources during the recovery phase of the pandemic and thereafter. [ABSTRACT FROM AUTHOR]

The potential link between rheumatoid arthritis (RA) and cancer incidence needs to be validated due to inconsistent results between Asian and Western countries. We explored the long-term association of RA with the overall and organ-specific cancer incidence using nationwide population data. This longitudinal follow-up study (2002–2015) included 3070 patients with RA and 12,280 controls (1:4 propensity score-matched for sex, age, residence, and income) from the Korean National Health Insurance Service-Health Screening Cohort database. A Cox proportional hazard model estimated the hazard ratio for malignancy following adjusting for covariates. Despite the similar overall cancer incidence between RA and control groups, differences in the incidence of organ-specific cancers were noted: the RA group had a 1.63-fold greater likelihood for lung cancer (95% confidence interval 1.11–2.40). In the sex-stratified subgroup analyses, the male RA patients exhibited higher odds of lung and thyroid cancer but a lower probability for colorectal cancer; no such associations were detected in either female patients with RA or age subgroups. In summary, the higher likelihood for lung cancer in Korean RA patients, especially thyroid and lung cancer in male RA patients, seems to be characteristic, which needs to be carefully monitored. [ABSTRACT FROM AUTHOR]

Although safety concerns regarding proton pump inhibitor (PPI)/H2-receptor antagonists (H2RA) in the incident esophageal cancer have been raised, the Asian-based report is unclear. We investigated the estimated likelihood of incident esophageal cancer—its mortality depending on prior history of PPI/H2RA use—and gastroesophageal reflux disease (GERD) in Koreans. Using the Korean National Health Insurance Service-Health Screening Cohort data (2002–2015), a case–control study was retrospectively conducted, including 811 patients with incident esophageal cancer and 3244 controls matched with sex, age, income, and residence. Propensity score overlap weighting was adjusted to balance the baseline covariates. Overlap propensity score-weighted logistic regression analyses were assessed to determine associations of the prior exposure of PPI/H2RA (current vs. past) and the medication duration (<30-, 30–90-, vs. ≥90-days) with incident esophageal cancer and its mortality among the total participants or those with/without the GERD episodes, after adjusting for multiple covariates including PPI/H2RA. The current exposure to either PPI or H2RA showed higher odds for incident esophageal cancer than the nonuser group ([13.23; 95%CI 10.25–17.06] and [4.34; 95%CI 3.67–5.14], respectively), especially in all adults over the age of 40 years without GERD. Both current and past exposures to PPI showed a decreased probability of mortality compared with those of the nonuser group ([0.62; 95%CI 0.45–0.86] and [0.41; 95%CI 0.25–0.67], respectively). However, current or past exposure to H2RA harbored the mutually different likelihoods for mortality depending on the presence of GERD and old age. This study carefully speculates on the possible link between PPI/H2RA and incident esophageal cancer in the Korean population. Mortality appears to be affected by certain risk factors depending on drug types, exposure history, old age, and the presence of GERD. [ABSTRACT FROM AUTHOR]

Background : Public health concerns regarding the potential link between osteoporosis and the increased occurrence of Alzheimer's disease (AD) and Parkinson's disease (PD) have been raised, but the results remain inconsistent and require further validation. Here, we investigated the long-term relationship of osteoporosis with the occurrence of AD/PD using data from a large-scale nationwide cohort. Methods : This longitudinal follow-up study included 78,994 patients with osteoporosis and 78,994 controls from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2015) who were matched using propensity score matching at a 1:1 ratio based on age, sex, income, and residential area. A Cox proportional hazard model was used to assess the association between osteoporosis and the occurrence of AD/PD after adjusting for multiple covariates. Results : During the follow-up period, AD occurred in 5,856 patients with osteoporosis and 3,761 controls (incidence rates: 10.4 and 6.8 per 1,000 person-years, respectively), and PD occurred in 1,397 patients and 790 controls (incidence rates: 2.4 and 1.4 per 1,000 person-years, respectively). The incidences of AD and PD were significantly higher in the osteoporosis group than in the matched control group. After adjustment, the osteoporosis group exhibited 1.27-fold and 1.49-fold higher occurrences of AD (95% confidence interval (CI) = 1.22–1.32) and PD (95% CI = 1.36–1.63) than the controls, respectively. The results of subgroup analyses supported the increased occurrence of AD and PD in patients with osteoporosis, independent of income, residential area, obesity, smoking, alcohol consumption, hyperlipidemia, hypertension, or blood glucose level. Conclusion : Our results indicate that the presence of osteoporosis may increase the likelihood of developing two common neurodegenerative diseases in adults aged ≥40 years. [ABSTRACT FROM AUTHOR]

Mitotic counts in the World Health Organization (WHO) grading system have narrow cutoff values. True mitotic figures, however, are not always distinguishable from apoptotic bodies and darkly stained nuclei, complicating the ability of the WHO grading system to diagnose well-differentiated neuroendocrine tumors (NETs). The mitosis-specific marker phosphohistone H3 (PHH3) can identify true mitoses and grade tumors reliably. The aim of this study was to investigate the correspondence of tumor grades, as determined by PHH3 mitotic index (MI) and mitotic counts according to WHO criteria, and to determine the clinically relevant cutoffs of PHH3 MI in rectal and nonrectal gastrointestinal NETs. Mitotic counts correlated with both the Ki-67 labeling index and PHH3 MI, but the correlation with PHH3 MI was slightly higher. The PHH3 MI cutoff ≥4 correlated most closely with original WHO grades for both rectal NETs. A PHH3 MI cutoff ≥4, which could distinguish between G1 and G2 tumors, was associated with disease-free survival in patients with rectal NETs, whereas that cutoff value showed marginal significance for overall survival in patient with rectal NETs. In conclusion, the use of PHH3 ≥4 correlated most closely with original WHO grades. [ABSTRACT FROM AUTHOR]

Sebaceous carcinoma (SC) represents a rare, aggressive eyelid malignancy with poor prognosis and is a possible component of Muir-Torre syndrome. However, genetic features as driver mutations or potential therapeutic targets are not fully elucidated. Recent a few studies have shown that SCs have concurrently multiple mutations including RAS/RAF/MAPK and PI3K/Akt pathways via next-generation sequencing in western population. Because we recently demonstrated absence of KRAS mutations in Korean eyelid SCs, we extended our previous study to the analysis of NRAS , BRAF , PIK3CA , and CTNNB1 mutations, and the examination of related protein expressions in 15 eyelid SCs. Repeated molecular analysis by peptide nucleic acid-mediated PCR clamping method, PNA clamping-assisted fluorescence melting curve analysis, and direct sequencing revealed that all eyelid SCs had wild type alleles of NRAS , BRAF , and PIK3CA in hotspot exon locations. Only silent mutations in the CTNNB1 gene (p.Q61Q) were identified. Using immunohistochemistry and microsatellite instability analysis, they harbored all intact mismatch repair gene proteins with microsatellite stability. Membranous and cytoplasmic β-catenin staining was found in all tumors, whereas the one third of those tumors showed cyclin D1 overexpression, of which 40% and 80% showed p53 expression and p16 expression, respectively. The lack of KRAS , NRAS , BRAF , and PIK3CA mutation in our study may suggest that a subset of eyelid SCs is unlike that of eyelid SCs of western countries. The mismatch repair gene proteins and microsatellite instability analysis as a screening test for Muir-Torre syndrome may be limited in the Korean eyelid SCs. [ABSTRACT FROM AUTHOR]

Tonsillar squamous cell carcinomas (TSCCs) are the most common human papillomavirus- (HPV-) associated oropharyngeal cancers with poor prognosis. Homeodomain-interacting protein kinase 2 (HIPK2) is a central regulator of p53, which participates in apoptosis during the DNA damage response. HIPK2 is involved in HPV-associated uterine cervical and cutaneous carcinogenesis through its binding of HPV E6, thereby preventing apoptosis and contributing to tumor progression. However, its clinical and prognostic significance in TSCC remains unclear. HIPK2 mRNA levels were analyzed in 20 normal tonsils and 20 TSCC specimens using real-time reverse transcription polymerase chain reaction. Immunohistochemistry of HIPK2 was performed in 79 resected specimens. HIPK2 was expressed in 57% of the TSCCs, and HIPK2 protein expression and HIPK2 mRNA levels were higher in TSCCs than in normal tonsils. HIPK2 overexpression was associated with poorly differentiated carcinoma and low alcohol consumption and was an independent prognostic factor for overall survival and disease-free survival (DFS) in TSCC and a negative independent prognostic factor for DFS in patients receiving postoperative radiotherapy. HIPK2 overexpression had a significant association with poorer DFS in HPV-positive TSCCs, but not in HPV-negative tumors. HIPK2 overexpression may be a potential prognostic marker for predicting prognoses and a high risk of recurrence, particularly in patients with HPV-positive TSCC. [ABSTRACT FROM AUTHOR]

Concerns about the hazards of statins on the development and mortality of stomach cancers remain controversial. Here, we investigated the likelihood of incident gastric cancers and related mortality depending on statin exposure, statin type, and the duration of use. This nested case–control-designed study was composed of 8798 patients who were diagnosed with gastric cancer and matched with 35,192 controls at a 1:4 ratio based on propensity scores of age, sex, residential area, and income from the Korean National Health Insurance Service—Health Screening Cohort database (2002–2015). Propensity score overlap weighting was adjusted to balance the baseline covariates. Overlap propensity score-weighted logistic regression analyses were assessed to determine associations of the prior use of statins (any statin, hydrophilic statins vs. lipophilic statins) with incident gastric cancer and its mortality depending on the medication duration (<180 days, 180–545 days, and >545 days) after adjusting for multiple covariates. After adjustment, the use of any statin, hydrophilic statins, or lipophilic statins showed significant associations with lower odds for incident stomach cancer when used for a short-term period (180–545 days) (OR = 0.88, 95% CI = 0.81–0.86, p = 0.002; OR = 0.78, 95% CI = 0.66–0.92, p = 0.004; and OR = 0.91, 95% CI = 0.84–0.99, p = 0.039, respectively) compared to the control group. Hydrophilic statin use for 180–545 days was associated with 53% lower overall mortality (OR = 0.47; 95% CI = 0.29–0.77). In subgroup analyses, beneficial effects on both cancer development and mortality persisted in patients ≥65 years old, patients with normal blood pressure, and patients with high fasting glucose levels. There were no such associations with long-term statin use (>545 days). Thus, the current nationwide cohort study suggests that prior short-term statin use may have anti-gastric cancer benefits in elderly patients with hyperglycemia. [ABSTRACT FROM AUTHOR]

Eyelid sebaceous carcinoma (SC) represents a highly aggressive malignancy. Despite the poor prognosis, genetic alterations as potential molecular targets are not available. KRAS mutation and HER2 gene amplification may be candidates related to their genetic alterations. We examined the HER2 and KRAS alteration status in eyelid SCs and compared it with that in other eyelid tumors. The controversial topics of the human papillomavirus (HPV) and p16 expression were also investigated. HER2 amplification was determined by silver in situ hybridization, while immunohistochemistry was performed to study protein expressions in 14 SCs and controls, including 23 other eyelid malignancies and 14 benign tumors. Peptide nucleic acid-mediated PCR clamping and direct sequencing were used to detect KRAS mutations. HER2 protein overexpression was observed in 85.7% (12/14) of the SCs, of which two-thirds showed HER2 gene amplification. HER2 protein overexpression and HER2 amplification were found more frequently in eyelid SCs than in other eyelid tumors. All SCs harbored wild type KRAS genes. No HPV infections were identified in the SCs. Nevertheless, p16 overexpression was found in 71.4% (10/14) of SCs, irrespective of the status of HPV infection. Furthermore, p16 overexpression in eyelid SCs was also significantly higher than that in other eyelid tumors. HER2 protein overexpression, HER2 gene amplifications, and wild type KRAS genes are common in eyelid SCs. HER2 gene amplification may represent potential therapeutic targets for the treatment of eyelid SCs. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) and MET are candidates of targeted therapies for cancer patients. Although MET and HGF are commonly expressed in biliary tract cancers, their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas (A-ACs), one of the aggressive periampullary cancers. MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 62 surgically resected, paraffin-embedded tumors, respectively. High MET and HGF protein expressions were detected in 24 (38.7%) and 15 (24.2%) tumors. High MET expression was associated with KRAS mutation. However, there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival. MET SISH positivity was detected in 19 tumors (30.6%), where 84.2% were due to high trisomy or polysomy and only 3 cases (15.8%) were MET gene amplification. The overall MET protein overexpression was well correlated with MET SISH positivity. The concurrent MET SISH positivity and KRAS mutation, not each alone, was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs, but not in intestinal subtype. Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs, indicating those markers could be potent candidates for a new therapeutic target in this cancer type. MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers. [ABSTRACT FROM AUTHOR]

Res. Pract. Erratum to "BRAF and NRAS mutations and antitumor immunity in Korean malignant melanomas and their prognostic relevance: Gene set enrichment analysis and CIBERSORT analysis" [Pathol. [Extracted from the article]

Cutaneous malignant melanomas (CMMs) are rare but are the cause of the highest skin cancer-related mortality in Korea. Very few studies have investigated the associations between KRAS , NRAS , BRAF , and PIK3CA mutations and TICs, as well as their prognostic impact on Korean CMMs. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper and immunohistochemistry were used to detect these mutations in 47 paraffinized CMMs. BRAF and NRAS mutations were detected in 21.3% and 12.8% of CMMs, respectively. No KRAS or PIK3CA mutations were identified. NRAS mutations correlated with low FOXP3 (regulatory T lymphocyte marker) and indoleamine 2,3-dioxygenase (IDO) (activated dendritic cell marker) TICs in CMMs, which is consistent with the negative correlation of regulatory T cells with NRAS mutations in TCGA data, while BRAF mutations were not associated with any TICs. In gene set enrichment analysis, BRAF and NRAS mutations were enriched in decreased CD8 (suppressor/cytotoxic T lymphocyte marker) T cell-linked and increased CD4 (helper/inducer T lymphocyte marker) T cell-linked gene signatures, respectively, confirming the trend in our cohort of associations only with NRAS. BRAF or NRAS mutations alone did not affect any prognosis. In the subgroup analyses, BRAF mutations, as well as high CD4, CD8, FOXP3, and IDO TICs, caused worse overall survival in NRAS -mutated melanoma. No correlation of CD163 (monocyte–macrophage-specific marker) was detected. We found that approximately one-third of our cohort had BRAF and NRAS mutations, none had KRAS or PIK3CA mutations, and most displayed decreased anti-tumor immunity. These findings may warrant further study on combined immunotherapeutic and molecular targeted therapy in Korean CMMs. Subgroup analyses according to TICs and BRAF / NRAS mutations may help to identify high-risk patients with worse prognoses. [ABSTRACT FROM AUTHOR]

Objective: Accumulating evidence from other countries indicates potential associations between gout and cardiovascular diseases; however, the associations of gout with cardiovascular diseases, particularly stroke, ischemic heart disease, and heart failure, remain ambiguous in the Korean population. We hypothesized that individuals with gout are at a higher likelihood of stroke, ischemic heart disease, or heart failure. This study expands upon previous research by ensuring a comparable baseline between patient and control groups and analyzing 16 years of data derived from an extensive healthcare database., Methods: We selected 22,480 patients with gout and 22,480 control individuals from the Korean National Health Insurance Service-Health Screening Cohort database (2002-2019), and matched them at a 1:1 ratio according to sex, age, income, and residence. A Cox proportional hazard model with weighted overlap was employed to examine the relationship between gout and the risk of stroke, ischemic heart disease, or heart failure after adjustment for several covariates., Results: The incidences of stroke, ischemic heart disease, or heart failure in participants with gout were slightly higher than those in controls (stroke: 9.84 vs. 8.41 per 1000 person-years; ischemic heart disease: 9.77 vs. 7.15 per 1000 person-years; heart failure: 2.47 vs. 1.46 per 1000 person-years). After adjustment, the gout group had an 11% (95% confidence interval [CI] = 1.04-1.19), 28% (95% CI = 1.19-1.37), or 64% (95% CI = 1.41-1.91) higher likelihood of experiencing stroke, ischemic heart disease, or heart failure, respectively, than the control group., Conclusion: The present findings suggest that individuals with gout in the Korean population, particularly those aged ≥ 60 years, were more likely to have stroke, ischemic heart disease, or heart failure., Competing Interests: Author HC was employed by the company M.D. Analytics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Lee, Yoo, Han, Hong, Choi, Lim, Kim, Kim, Cho, Nam, Park, Kim, Baek, Lee and Kwon.)

Health issues associated with gout and increased occurrence of osteoporosis or fractures have been raised; however, the results are elusive. Herein, we explored the possible link between gout and incident osteoporosis/osteoporotic fractures based on long-term follow-up nationwide data. This study enrolled 16,305 patients with gout and 65,220 controls who were matched by propensity score at a 1:4 ratio on the basis of sex, age, income, and residence from the Korean National Health Insurance Service-Health Screening Cohort database (2002−2015). A Cox proportional hazard model was employed to identify the relevance between gout and incident osteoporosis/fractures, following adjustment for various covariates. In the follow-up period, osteoporosis developed in 761 individuals with gout and 2805 controls (incidence rates: 8.0 and 7.3/1000 person-years, respectively), and each osteoporotic fracture in the distal radius (2.8 vs. 2.7/1000 person-years), hip (1.3 vs. 1.3/1000 person-years), and spine (4.5 vs. 4.5/1000 person-years) occurred in gout and control groups, respectively. After adjustment, the gout group presented an 11% higher development of osteoporosis (95% confidence interval = 1.02−1.20) than the controls (p = 0.011). Subgroup analyses maintained the augment of incident osteoporosis in sufferers with gout, particularly in either men or <60 years. However, no such relevance was identified between gout and incident osteoporotic fractures at any site. In conclusion, gout may result in a slightly elevated likelihood of developing osteoporosis, and not osteoporotic fractures, in the Korean population.

Programmed death-ligand 1 (PD-L1) plays an essential protein for immune evasion, contributing to tumor development and progression. Recent studies have reported MET as an upregulator for PD-L1 overexpression through an oncogenic pathway. However, an association between PD-L1 expression with MET has not been reported in gastric cancer.The prognostic significance of PD-L1 and its association with Epstein-Barr virus (EBV), microsatellite instability (MSI), and mucin phenotype remain controversial. We performed in situ hybridization for EBV-encoded RNA and immunohistochemistry in tissue microarrays for 394 gastric cancers. A multiplex polymerase chain reaction with five quasimonomorphic markers was performed for MSI. PD-L1 expression was observed in 123 cases (31.2%), and clinicopathological features such as MET overexpression, high pT stage, and a lack of lymphatic invasion represent significant risk factors associated with PD-L1 overexpression in gastric cancers. No associations of EBV, MSI, or mucin phenotype with PD-L1 expression were statistically significant. PD-L1 expression was a strong indicator for worse overall survival (OS) but borderline significant in disease-free survival (DFS). A combined analysis of PD-L1 and MET expression indicated that the PD-L1+/MET+ subgroup showed the worst prognosis when compared to the PD-L1-/MET- subgroup, which had the best clinical outcome. Furthermore, PD-L1 overexpression exhibited poor prognosis in terms of both OS and DFS in EBV-negative, microsatellite stable, and intestinal mucin phenotype tumors. In conclusion, this is the first study to evaluate the overexpression of MET as a risk factor for PD-L1 positivity in gastric cancer tissue as well as the reliability and prognostic relevance of PD-L1/MET co-expression after surgery., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Aim: To identify the frequency, clinicopathological risk factors, and prognostic significance of lymphovascular invasion (LVI) in endoscopically resected small rectal neuroendocrine tumors (NETs)., Methods: Between June 2005 and December 2015, 104 cases of endoscopically resected small (≤ 1 cm) rectal NET specimens at Hallym University Sacred Heart Hospital in Korea were retrospectively evaluated. We compared the detected rate of LVI in small rectal NET specimens by two methods: hematoxylin and eosin (H&E) and ancillary immunohistochemical staining (D2-40 and Elastica van Gieson); in addition, LVI detection rate difference between endoscopic procedures were also evaluated. Patient characteristics, prognosis and endoscopic resection results were reviewed by medical charts., Results: We observed LVI rates of 25.0% and 27.9% through H&E and ancillary immunohistochemical staining. The concordance rate between H&E and ancillary studies was 81.7% for detection of LVI, which showed statistically strong agreement between two methods (κ = 0.531, P < 0.001). Two endoscopic methods were studied, including endoscopic submucosal resection with a ligation device and endoscopic submucosal dissection, and no statistically significant difference in the LVI detection rate was detected between the two (26.3% and 26.8%, P = 0.955). LVI was associated with large tumor size (> 5 mm, P = 0.007), tumor grade 2 ( P = 0.006). Among those factors, tumor grade 2 was the only independent predictive factor for the presence of LVI (HR = 4.195, 95%CI: 1.321-12.692, P = 0.015). No recurrence was observed over 28.8 mo regardless of the presence of LVI., Conclusion: LVI may be present in a high percentage of small rectal NETs, which may not be associated with short-term prognosis., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

POEMS syndrome is a rare paraneoplastic syndrome and there are few reports of polyneuropathy and monoclonal gammopathy associated with kidney dysfunction. Here, we report a case of POEMS syndrome with recurrent acute kidney injury (AKI). A 52-year-old man presented with bilateral aggravating paresthesia and latermotor weakness of the lower extremities accompanied by repeated elevation of serum creatinine. The patient was finally diagnosed with POEMS syndrome on the basis of fulfilling the two mandatory major criteria (polyneuropathy and monoclonal gammopathy), one other major criterion (sclerotic bone lesion), and several minor criteria. A renal biopsy was performed to clarify the cause of AKI and showed membranoproliferative glomerulonephritis-like lesions with mesangiolysis and endothelial cell injury. This case illustrates that renal manifestations, not included in the diagnostic criteria for POEMS, can be apparent before various other systemic symptoms.

Acne vulgaris is the most common skin diseases that people experience during their lives. Thirteen rhizosphere isolates were screened against Propionibacterium acnes. The bacterium exhibited the highest activity against P. acnes was identified as Bacillus methylotrophicus YML008 by 16S rRNA gene sequencing. Scanning electron microscopy was used to assess the changes in morphology of P. acnes. Preliminary studies on the antimicrobial substance demonstrated the hydrophilic nature of compound with MIC of 0.17mg/ml and MBC of 0.3mg/ml. The cytotoxic effect of the extract was least (80% survival) as compared to benzyperoxide (40% survival). These results suggest YML008 as a promising bioresource and may be useful as a lead bacterium to develop a new type of anti-acne skin care prep to cure or prevent acne. Further, mechanism of action and proper clinical trials may be promising for this research.

Up-to-date imaging modalities such as three-dimensional dynamic contrast-enhanced CT (3D CT) and MRI may contribute to detection of hypervascular nodules in the liver. Nevertheless, distinguishing a malignancy such as hepatocellular carcinoma from benign hypervascular hyperplastic nodules (HHN) based on the radiological findings is sometimes difficult. Multiple incidental liver masses were detected via abdominal ultrasonography (US) in a 65-year-old male patient. He had no history of alcohol intake and no remarkable past medical history or relevant family history, and his physical examination results and laboratory findings were normal. 3D CT and MRI showed numerous enhanced nodules with hypervascularity during the arterial phase. After US guided liver biopsy, the pathological diagnosis was HHN. To date, several cases of HHN have been reported in patients with chronic alcoholic liver disease or cirrhosis. Herein, we report on a case of HHN in a patient with no history of alcoholic liver disease or cirrhosis.

Objectives: Low prevalence and prognostic relevance of KRAS mutations in Korean pancreatic ductal adenocarcinomas (PDACs) need to be validated with sensitive detection method., Methods: Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping was used to precisely detect KRAS mutation in 72 paraffinized tumor samples and was validated by pancreatic cell lines to compare the efficiency of direct sequencing., Results: The PNA-mediated PCR clamping detected mutant allele proportions of as low as 0.5% against a background of wild-type DNA and was 20-fold more sensitive than direct sequencing through the validation of pancreatic cell lines. Peptide nucleic acid-mediated PCR clamping detected KRAS mutations in 47.2% of 72 PDACs. Low tumor cellularity and low PCR amplification efficiency led to be undetected or failed by direct sequencing in pancreatic paraffinized samples.KRAS mutations were an independent worse prognostic factor predicting a reduced progression-free survival rate in the postoperative chemotherapy group., Conclusions: Peptide nucleic acid clamp real-time PCR was a sensitive method for detecting KRAS status in paraffinized PDAC samples. We identified a low KRAS mutation rate among the Korean PDAC patients using PNA clamp real-time PCR, potentially implicating epidemiological characteristics. The low KRAS mutation rate and its prognostic role may suggest the further survival benefit in Korean PDAC patients.