Purpose: Universal screening for Lynch syndrome (LS) refers to routine tumor testing for microsatellite instability (MSI) among all patients with colorectal cancer (CRC). Despite its widespread adoption, real-world data on the yield is lacking in Korean population. We studied the yield of adopting universal screening for LS in comparison with pedigree-based screening in a tertiary center. Materials and Methods: CRC patients from 2007-2018 were reviewed. Family histories were obtained and were evaluated for hereditary nonpolyposis colorectal cancer (HNPCC) using Amsterdam II criteria. Tumor testing for MSI began in 2007 and genetic testing was offered using all available clinicopathologic data. Yield of genetic testing for LS was compared for each approach and step. Results: Of the 5,520 patients, tumor testing was performed in 4,701 patients (85.2%) and family histories were obtained from 4,241 patients (76.8%). Hereditary CRC (LS or HNPCC) was present in 69 patients (1.3%). MSI-high was present in 6.9%, and 25 patients had confirmed LS. Genetic testing was performed in 41.2% (47/114) of MSI-high patients, out of which 40.4% (19/47) were diagnosed with LS. There were six additional LS patients found outside of tumor testing. For pedigree-based screening, Amsterdam II criteria diagnosed 55 patients with HNPCC. Fifteen of these patients underwent genetic testing, and 11 (73.3%) were diagnosed with LS. Two patients without prior family history were diagnosed with LS and relied solely on tumor testing results. Conclusion Despite widespread adoption of routine tumor testing for MSI, this is not a fail-safe approach to screen all LS patients. Obtaining a thorough family history in combination with universal screening provides a more comprehensive ‘universal’ screening method for LS.

Objective: To examine the efficacy of MSH6 and PMS2 immunohistochemistry (IHC) as a screening method for Lynch syndrome in endometrial cancer patients. Methods: Through multidisciplinary discussions, an institutional MSH6 and PMS2 IHC-initiated cascade test (MSH6, PMS2 IHC→microsatellite instability [MSI] assay→germline mismatch repair [MMR] gene sequencing) was developed to screen for Lynch syndrome in endometrial cancer patients. Testing was performed on a consecutive cohort of 218 newly diagnosed endometrial cancer patients who underwent surgery at a tertiary hospital in the Republic of Korea between August 2018 and December 2020. The number of MMR deficiencies (MSH6 or PMS2 loss in IHC) and results of subsequent tests (MSI assay and germline MMR gene sequencing) were examined. Results: MMR deficiency was detected in 52 of the 218 patients (24.0%). Among these 52 patients, 34 (65.0%) underwent MSI testing, of which 31 (91.0%) exhibited high MSI. Of the 31 patients with MSI-high status, 15 (48.0%) underwent germline MMR gene sequencing. Subsequently, Lynch syndrome was diagnosed in five patients (33.0%). Conclusion Lynch syndrome screening using MSH6 and PMS2 IHC-initiated cascade testing is a viable strategy in the management of endometrial cancer. A simplified strategy (MSH6 and PMS2 IHC→germline MMR gene sequencing) was proposed because most women with MMR deficiencies exhibited high MSI.

Purpose: The relationship between microsatellite instability (MSI) and tumor response after neoadjuvant chemoradiotherapy (nCRT) in rectal cancer remains unclear. The present study aimed to evaluate the association between MSI and tumor response to nCRT in rectal cancer treatment. Methods: Patients with rectal cancer from 2 tertiary hospitals who underwent nCRT, followed by radical surgery, were included. The microsatellite status was determined using a PCR-based Bethesda panel. Tumors with a Dworak’s tumor regression grade of 3 or 4 were considered to have a good response. Predictive factors for a good response to nCRT were analyzed. Results: Of the 1,401 patients included, 910 (65.0%) had MSI results and 1.5% (14 of 910) showed MSI-H. Among all the patients, 519 (37.0%) showed a good response to nCRT. A univariate analysis showed that MSI-H tended to be negatively associated with a good response to nCRT, but no statistical significance was observed (7.1% vs. 24.1%, P = 0.208).Multivariate analysis showed that well-differentiated tumors were the only predictive factor for good response to nCRT (odds ratio [OR], 2.241; 95% confidence interval [CI], 1.492–3.364; P < 0.001). MSI status tended to be associated with the response to nCRT (OR, 0.215; 95% CI, 0.027–1.681; P = 0.143). Conclusion MSI-H was not associated with response to nCRT in patients with rectal cancer.

Background/Aims: We evaluated the usefulness in kidney transplant (KT) candidates of cytomegalovirus (CMV)-specific enzyme-linked immunospot (ELISPOT) assays for predicting the development of post-transplant CMV infections. Methods: All adult recipients admitted for living-donor KT between March 2014 and March 2015 were prospectively enrolled except donor CMV-seropositive and recipient seronegative (D+/R–) recipients. All the enrolled patients underwent CMV-specific ELISPOT assays before transplant, and a researcher blinded to the results of these assays examined the patients for CMV infection at least 6 months post-transplant. Results: Of 133 KT recipients, 44 (33%) developed CMV infections. When we used the cut-off determined by receiver operator characteristic curve, 16 of the 34 patients (47%) with negative pp65-specific ELISPOT results (< 11 spots/200,000 cells) developed CMV infections, whereas 28 of the 99 patients (39%) with positive pp65-specific ELISPOT results at baseline (≥ 11 spots/200,000 cells) developed CMV infections after KT (p = 0.02). Based on the multivariable Cox regression model, negative pp65-specific ELISPOT assay results was an independent risk factor for CMV infection (adjusted hazard ratio [AHR], 1.87; 95% confidence interval [CI], 1.01 to 3.46; p = 0.047) as well as age (AHR, 1.05; 95% CI, 1.01 to 1.08; p = 0.007). Conclusions Pre-transplant CMV-specific ELISPOT assay appears to predict the development of CMV infections after KT in recipients at moderate risk such as CMV-seropositive recipients (Clinical Trial Registration Number NCT 02025335).

Lipoma arborescens or synovial lipomatosis is a rare disorder that is characterized by mature fat infiltration of the hypertrophic synovial villi, most frequently affecting the supra-patellar pouch of the knee. This paper presents a case of lipoma arborescens of the ankle joint bilaterally in an adult patient with involvement of both the intra-articular synovium and the synovial sheath of the tendons around the ankle.
Adult ; Ankle Joint ; Ankle ; Humans ; Knee ; Lipoma ; Lipomatosis ; Magnetic Resonance Imaging ; Synovial Membrane ; Tendons

BACKGROUND: As the number of big-cohort studies increases, validation becomes increasingly more important. We aimed to validate administrative database categorized as colorectal cancer (CRC) by the International Classification of Disease (ICD) 10th code. METHODS: Big-cohort was collected from Clinical Data Warehouse using ICD 10th codes from May 1, 2003 to November 30, 2016 at Seoul National University Bundang Hospital. The patients in the study group had been diagnosed with cancer and were recorded in the ICD 10th code of CRC by the National Health Insurance Service. Subjects with codes of inflammatory bowel disease or tuberculosis colitis were selected for the control group. For the accuracy of registered CRC codes (C18–21), the chart, imaging results, and pathologic findings were examined by two reviewers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for CRC were calculated. RESULTS: A total of 6,780 subjects with CRC and 1,899 control subjects were enrolled. Of these patients, 22 subjects did not have evidence of CRC by colonoscopy, computed tomography, magnetic resonance imaging, or positron emission tomography. The sensitivity and specificity of hospitalization data for identifying CRC were 100.00% and 98.86%, respectively. PPV and NPV were 99.68% and 100.00%, respectively. CONCLUSIONS: The big-cohort database using the ICD 10th code for CRC appears to be accurate.
Classification ; Colitis ; Colonoscopy ; Colorectal Neoplasms ; Hospitalization ; Humans ; Inflammatory Bowel Diseases ; Magnetic Resonance Imaging ; National Health Programs ; Positron-Emission Tomography ; Retrospective Studies ; Sensitivity and Specificity ; Seoul ; Tuberculosis

PURPOSE: Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients’ survival with CRC. MATERIALS AND METHODS: The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH. RESULTS: Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands–/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis. CONCLUSION: Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.
Betacellulin ; Colorectal Neoplasms* ; Disease-Free Survival ; Epidermal Growth Factor* ; Heparin ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Incidence ; Ligands ; Multivariate Analysis ; Prognosis* ; Receptor, Epidermal Growth Factor* ; RNA, Messenger ; Silver ; Transforming Growth Factors

BACKGROUND/AIMS: We evaluated the proposed clinical application of the combined interpretation of host factors and viral factors in two different cytomegalovirus (CMV) co-infection models. METHODS: We prospectively enrolled all human immunodeficiency virus non-infected patients with confirmed Pneumocystitis jirovecii pneumonia (PCP) and those with suspected gastrointestinal CMV disease in a tertiary hospital. All patients underwent CMV interferon-γ releasing assay (IGRA) for CMV (T-track CMV, Lophius Biosciences). We created the 2-axis model with the CMV IGRA results as the x-axis and the results for CMV virus replication as the y-axis, and hypothesized that cases falling in the left upper quadrant (high viral load and low CMV-specific immunity) of the model would be true CMV infections. The CMV IGRA results were concealed from the attending physicians. RESULTS: Of 39 patients with PCP, four (10%) were classified as combined CMV pneumonia, 13 (33%) as bystander activation, and the remaining 22 (56%) as no CMV infection. The data for all four patients with PCP and CMV pneumonia fell in the left upper quadrant of the 2-axis model. Of 24 patients with suspected gastrointestinal CMV disease, 12 (50%) were classified as gastrointestinal CMV disease and the remaining 12 (50%) as bystander activation with no gastrointestinal CMV disease. The data for 11 of the 12 patients (92%) with gastrointestinal CMV disease were located in the left upper quadrant of the 2-axis model. CONCLUSIONS: Cases yielding low CMV IGRA results and high CMV viral replication appear to be true CMV infections. Further studies with large number of cases in different types of CMV disease should be proposed.
Accidental Falls ; Coinfection ; Cytomegalovirus* ; Enzyme-Linked Immunospot Assay ; HIV ; Humans ; Pneumonia ; Prospective Studies ; Tertiary Care Centers ; Viral Load ; Virus Replication

BACKGROUND: The aim of this study was to determine the regional heterogeneity and clinicopathological significance of microRNA-21 (miR-21) in advanced colorectal cancer (CRC) patients with distant metastasis. METHODS: miR-21 expression was investigated by using locked nucleic acid- fluorescence in situ hybridization in the center and periphery of the primary cancer and in distant metastasis from 170 patients with advanced CRC. In addition, α-smooth muscle actin and desmin were evaluated to identify cancer-associated fibroblasts (CAFs) by using immunohistochemistry. RESULTS: The miR-21 signal was observed in the cancer stroma. The expression of miR-21 (a score of 1-4) in the center and periphery of the primary cancer and in distant metastasis was observed in specimens from 133 (78.2%), 105 (61.8%), and 91 (53.5%) patients, respectively. miR-21 expression was heterogeneous in advanced CRC. Discordance between miR-21 expression in the center of the primary cancer and either the periphery of the primary cancer or distant metastasis was 31.7% or 44.7%, respectively. miR-21 stromal expression in the periphery of the primary cancer was significantly associated with a better prognosis (p=.004). miR-21 expression was significantly associated with CAFs in the center of the primary cancer (p=.001) and distant metastases (p=.041). CONCLUSIONS: miR-21 expression is observed in cancer stroma related to the CAF quantity and frequently presents regional heterogeneity in CRC. Our findings indicate that the role of miR-21 in predicting prognosis may be controversial but provide a new perspective of miR-21 level measurement in cancer specimens.
Actins ; Colorectal Neoplasms* ; Desmin ; Fibroblasts ; Fluorescence ; Genetic Heterogeneity ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Neoplasm Metastasis* ; Population Characteristics ; Prognosis

PURPOSE: Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. MATERIALS AND METHODS: We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. RESULTS: Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models. CONCLUSION: In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.
Area Under Curve ; Colorectal Neoplasms ; Colorectal Neoplasms, Hereditary Nonpolyposis ; DNA Mismatch Repair* ; Genetic Association Studies ; Genetic Testing ; Germ-Line Mutation ; Humans ; ROC Curve ; Sensitivity and Specificity