Loss of Krüppel-like factor-10 facilitates the development of chemical-induced liver cancer in mice.

BACKGROUND: Krüppel-like factor 10 (KLF10) is involved in a positive feedback loop that regulates transforming growth factor ß (TGFß) signaling, and TGFß plays an important role in the pathogenesis of liver disease. Here, we investigated whether KLF10 deletion affects the development of liver fibrosis and hepatocellular carcinoma (HCC). METHODS: We induced KLF10 deletion in C57BL/6 mice. Liver fibrosis was induced by feeding a diet high in fat and sucrose (high-fat diet [HFD]), whereas HCC was produced by intraperitoneal administration of N-diethylnitrosamine (DEN). An in vitro experiment was performed to evaluate the role of KLF10 in the cancer microenvironment using Hep3B and LX2 cells. An immunohistochemical study of KLF10 expression was performed using human HCC samples from 60 patients who had undergone liver resection. RESULTS: KLF10 deletion resulted in an increased DEN-induced HCC burden with significant upregulation of SMAD2, although loss of KLF10 did not alter HFD-induced liver fibrosis. DEN-treated mice with KLF10 deletion exhibited increased levels of mesenchymal markers (N-cadherin and SNAI2) and tumor metastasis markers (matrix metalloproteinases 2 and 9). KLF10 depletion in Hep3B and LX2 cells using siRNA was associated with increased invasiveness. Compared with co-culture of KLF10-preserved Hep3B cells and KLF10-intact LX2 cells, co-culture of KLF10-preserved Hep3B cells and KLF10-depleted LX2 cells resulted in significantly enhanced invasion. Low KLF10 expression in resected human HCC specimens was associated with poor survival. CONCLUSION: The results of this study suggest that loss of KLF10 facilitates liver cancer development with alteration in TGFß signaling.

Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications.

BACKGROUND & AIMS: Despite the clinical and genetic significance of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC), its characteristics on imaging have not been described. This study aimed to characterise MTM-HCC on gadoxetic acid-enhanced MRI and to evaluate the diagnostic accuracy and prognostic value of these imaging characteristics. METHODS: We enrolled 3 independent cohorts from 2 tertiary care centres. The 3 cohorts consisted of a total of 476 patients who underwent gadoxetic acid-enhanced MRI and surgical resection for treatment-naïve single HCCs. Independent review of histopathology and MRI by 2 reviewers was performed for each cohort, and inter-reader agreement was evaluated. Based on the result of MRI review in the training cohort (cohort 1), we developed 2 diagnostic criteria for MTM-HCC and evaluated their prognostic significance. The diagnostic performance and prognostic significance were validated in 2 validation cohorts (cohorts 2 and 3). RESULTS: We developed 2 diagnostic MRI criteria (MRIC) for MTM-HCC: MRIC-1, ≥20% arterial phase hypovascular component; MRIC-2, ≥50% hypovascular component and 2 or more ancillary findings (intratumoural artery, arterial phase peritumoural enhancement, and non-smooth tumour margin). MRIC-1 showed high sensitivity and negative predictive value (88% and 95% in the training cohort, and 88% and 97% in the pooled validation cohorts, respectively), whereas MRIC-2 demonstrated moderate sensitivity and high specificity (47% and 94% in the training cohort, and 46% and 96% in the pooled validation cohorts, respectively). MRIC-2 was an independent poor prognostic factor for overall survival in both training and pooled validation cohorts. CONCLUSIONS: Using gadoxetic acid-enhanced MRI findings, including an arterial phase hypovascular component, we could stratify the probability of MTM-HCC and non-invasively obtain prognostic information. LAY SUMMARY: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a histopathologic subtype of HCC characterised by aggressive biological behaviour and poor prognosis. We developed imaging criteria based on liver MRI that could be used for the non-invasive diagnosis of MTM-HCC. HCCs showing imaging findings of MTM-HCC were associated with poor outcomes after hepatic resection.

Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study.

BACKGROUND AND AIMS: Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens. METHODS: During ERCP, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining. RESULTS: In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55; suspicious of malignancy, 60; atypical, 45; negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (P < .0001). CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled the detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings. (Clinical trial registration number: NCT03708445.).

Pathological predictive factors for late recurrence of hepatocellular carcinoma in chronic liver disease.

BACKGROUND & AIMS: Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2 years after curative resection). METHODS: The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured. RESULTS: Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2-3.3), 21.1 (4.3-102.7) and 6.0 (2.1-17.7) respectively (P < .05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell's C index: 0.701 and 0.716; 95% confidence intervals: 0.64-0.76 and 0.64-0.79 respectively). CONCLUSIONS: The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.

New staining method using methionyl-tRNA synthetase 1 antibody for brushing cytology of bile duct cancer.

BACKGROUND AND AIMS: Identifying malignant biliary strictures using endobiliary brushing cytology specimens is important for treatment decision-making and prognosis prediction. The sensitivity of brushing cytology specimens based on Papanicolaou (Pap) staining is low, which hampers accurate diagnosis of indeterminate strictures. Here, we assessed the diagnostic value of immunohistochemical (IHC) and immunofluorescence (IF) staining for methionyl-tRNA synthetase 1 (MARS1). METHODS: Endobiliary brushing cytology specimens were obtained during ERCP from 80 patients with an extrahepatic biliary stricture. Pap and MARS1 IF staining were performed on liquid-based cytology slides derived from these specimens. Sections of bile duct adenocarcinoma and normal bile duct tissue were obtained from 45 patients who underwent surgery for malignant biliary stricture, and MARS1 levels were evaluated by IHC staining. RESULTS: MARS1 IF staining was applied to brushing cytology specimens, and the results showed strong signals in malignant biliary structures but not in the negative for malignancy specimens. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 70.4%, 96.2%, 97.4%, 56.8%, and 78.8%, respectively, for conventional Pap staining and 98.1%, 96.1%, 98.1%, 96.2%, and 97.5%, respectively, for MARS1 IF (P < .0001). When IHC staining was used, MARS1 was detected in 45 bile duct adenocarcinoma sections but not in 15 normal bile duct sections. Moreover, MARS1 mRNA and protein levels were significantly higher in bile duct adenocarcinoma sections according to polymerase chain reaction and Western blot, respectively. CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with indeterminate biliary stricture. Further prospective studies are needed to validate our findings. (Clinical trial registration number: KCT 0003285.).

Clinicopathological characteristics of intrahepatic cholangiocarcinoma according to gross morphologic type: cholangiolocellular differentiation traits and inflammation- and proliferation-phenotypes.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into mass-forming (MF), periductal-infiltrative (PI), and mixed types grossly; however, their clinicopathological significance remains controversial. METHODS: Clinicopathological characteristics of iCCA gross types were analysed according to histopathological type (small-duct, large-duct, indeterminate) or cholangiolocellular differentiation trait (CDT) in 108 iCCAs. The expression levels of inflammation-marker (CRP, FGB) and proliferation-marker (phospho-ERK1/2, Ki-67) were evaluated by immunohistochemistry. RESULTS: There were 87 MF, 8 PI, and 13 mixed-gross type. Small-duct-type (39, 44.8%) and CDT (19, 21.8%) were found only in MF-gross type. The inflammation-marker expression was higher in MF-type than in PI- and mixed-gross types (P = 0.023). It was high in small-duct-type, middle in indeterminate-type, and low in large-duct-type (P = 0.015), and iCCAs with CDT showed higher inflammation-marker expression compared to those without (P < 0.001). Proliferation-marker expression did not differ according to gross type; however it was lower in iCCA with CDT compared to those without (P = 0.004). Subgrouping of the gross type according to histopathological type or CDT revealed that MF-type with small-duct-type or CDT had better overall survival compared to the others (P < 0.05). CONCLUSION: MF-type iCCA is more heterogeneous than other gross types. High inflammation-marker/low proliferation-marker expression in MF-type with CDT or small-duct-type may be related to a good outcome.

Detection of Helicobacter pylori with clarithromycin resistance-associated mutations using peptide nucleic acid probe-based melting point analysis.

BACKGROUND: Detection of Helicobacter pylori in gastric biopsy is important for appropriate treatment and prevention of gastric carcinoma and lymphoma. A novel peptide nucleic acid probe (PNA)-based real-time polymerase chain reaction (PCR) method was developed for detection of H pylori and A2142G/A2143G mutation of the 23S rRNA gene, which is associated with clarithromycin resistance. METHODS: To evaluate the performance of the PNA probe-based PCR method, a total of 409 gastric biopsy samples were analyzed by PNA probe-based PCR and compared with other H pylori detection methods, including hematoxylin and eosin (HE) and Warthin-Starry (WS) staining, immunohistochemistry (IHC). A2142G/A2143G mutation of the 23S rRNA gene was tested by dual priming oligonucleotide (DPO)-based PCR and Sanger sequencing to evaluate PNA probe-based PCR. RESULTS: Among 271 cases that were positive for H pylori on IHC which was considered as a standard method, 264 cases (97.4%) and 259 cases (95.6%) were positively detected by HE/WS and PNA probe-based qPCR, respectively. Of 100 H pylori-positive patients tested by IHC, H pylori was detected in 93 cases (93.0%) by PNA probe-based PCR, 86 cases (86.0%) by DPO-based PCR, and 93 cases (93.0%) by conventional PCR. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PNA probe-based qPCR were 93.0%, 94.9%, 93.9%, 94.9%, and 93.0%, respectively, which were all higher than those of DPO-based PCR. When Sanger sequencing was determined as a standard method to detect A2142G/A2143G mutations, the sensitivity of the PNA- and DPO-based methods was 100% and 94.4%, respectively, and the specificity was 100% for both methods. CONCLUSION: PNA probe-based qPCR is an appropriate method for detecting H pylori and the clarithromycin resistance-associated mutation type.

Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome-wide molecular features and clinical significance remain unclear. METHODS: Based on CD status, we stratified iCCAs into iCCA with CD (n=20) and iCCA without CD (n=102), and performed an integrative analysis using transcriptomic and clinicopathological profiles. RESULTS: iCCA with CD revealed less aggressive histopathological features compared to iCCA without CD, and iCCA with CD showed favourable clinical outcomes of overall survival and time to recurrence than iCCA without CD (P<.05 for all). Transcriptomic profiling revealed that iCCA with CD resembled an inflammation-related subtype, while iCCA without CD resembled a proliferation subtype. In addition, we identified a CD signature that can predict prognostic outcomes of iCCA (CD_UP, n=486 and CD_DOWN, n=308). iCCAs were subgrouped into G1 (positivity for CRP and CDH2, 7%), G3 (positivity for S100P and TFF1, 32%) and G2 (the others, 61%). Prognostic outcomes for overall survival (P=.001) and time to recurrence (P=.017) were the most favourable in G1-iCCAs, intermediate in G2-iCCAs and the worst in G3-iCCAs. Similar result was confirmed in the iCCA set from GSE26566 (n=68). CONCLUSIONS: CD signature was identified to predict the prognosis of iCCA. The combined evaluation of histology of CD and protein expression status of CRP, CDH2, TFF1 and S100P might help subtyping and predicting clinical outcomes of iCCA.

Glycolysis-related protein expression in thyroid cancer.

We aimed to demonstrate the differences in the expression of glucose metabolism-related proteins according to the thyroid cancer subtypes and investigate the implications of these differences. A total of 566 thyroid cancer patients, including 342 cases of papillary thyroid carcinoma, 112 cases of follicular carcinoma, 70 cases of medullary carcinoma, 23 cases of poorly differentiated carcinoma, 19 cases of anaplastic carcinoma, and 152 cases of follicular adenoma, were enrolled in the study. Immunohistochemical staining for glucose transporter 1, hexokinase II, carbonic anhydrase IX, and monocarbonylate transporter 4 was performed, and the relationship between immunoreactivity and clinicopathologic parameters was analyzed. Glucose transporter 1 and tumoral monocarbonylate transporter 4 expression levels were shown to be the highest in anaplastic carcinoma, and medullary carcinoma showed the highest carbonic anhydrase IX and lowest hexokinase II levels compared with other subtypes. Stromal expression of monocarbonylate transporter 4 was observed in papillary thyroid carcinoma and anaplastic carcinoma samples. Conventional papillary thyroid carcinoma tumors expressed higher levels of glucose transporter 1, and tumoral and stromal monocarbonylate transporter 4, than the follicular variant, which showed a higher expression of carbonic anhydrase IX. Papillary thyroid carcinoma samples with BRAF V600E mutation were shown to have higher glucose transporter 1, hexokinase II, carbonic anhydrase IX, and tumoral monocarbonylate transporter 4 expression levels. Univariate analysis showed that papillary thyroid carcinoma cases with glucose transporter 1 positivity had shorter overall survival, patients with medullary carcinoma and hexokinase II positivity were shown to have a shorter disease-free survival and overall survival, and tumoral monocarbonylate transporter 4 positivity was associated with shorter overall survival compared with papillary thyroid carcinoma patients with negativity for each marker. Disease-free survival and overall survival of patients with poorly differentiated carcinoma were shown to be significantly decreased when glucose transporter 1 and tumoral monocarbonylate transporter 4 are expressed. We demonstrated that the expression levels of glycolysis-related proteins differ between thyroid cancer subtypes and are correlated with poorer prognosis, depending on the subtype.

Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization.

Hypoxia is known to be important in the generation and maintenance of stemness; however, its clinical significance is yet to be determined in human hepatocellular carcinoma. The expression of stemness (K19, EpCAM) and hypoxia (carbonic anhydrase-IX (CAIX))-related markers were investigated by immunohistochemistry in three hepatocellular carcinoma cohorts. The clinicopathologic features, response to transarterial chemoembolization, and outcomes were compared. In cohort 1 (n=14, biopsy-transarterial chemoembolization-resection-matched hepatocellular carcinoma), all K19-, EpCAM-, or CAIX-positive hepatocellular carcinomas on initial biopsy (6/6, 100%) showed residual tumors after transarterial chemoembolization, whereas 75% (6/8) of all-negative hepatocellular carcinomas on biopsy showed complete necrosis in the post-transarterial chemoembolization-resected specimens. In cohort 2 (n=85, explanted hepatocellular carcinomas with/without transarterial chemoembolization; totally necrotic hepatocellular carcinoma after transarterial chemoembolization was not included), the expression of K19, EpCAM, and CAIX, and their coexpression, was more frequently observed with a greater number of transarterial chemoembolization sessions, and the expression of these markers was also correlated to each other. CAIX expression was shown to be an independent factor for recurrence and survival, and combination of CAIX with Milan criteria significantly increased the time-dependent integrative area under the curve values for recurrence and survival. In cohort 3 (n=339, resected hepatocellular carcinomas without transarterial chemoembolization), CAIX(+) hepatocellular carcinomas exhibited higher K19 and EpCAM expression, and more invasive pathological features. CAIX expression and TNM stage were independent predictors of extrahepatic recurrence, and the addition of CAIX to the TNM stage significantly increased time-dependent integrative area under the curve values. In conclusion, the expression of stemness (K19, EpCAM) and hypoxia (CAIX)-related markers were correlated each other, and hepatocellular carcinoma expressing these markers showed resistance to transarterial chemoembolization and poorer outcome. Evaluation for both markers of stemness and hypoxia may have an additional value in predicting hepatocellular carcinoma outcome, especially for transarterial chemoembolization-treated hepatocellular carcinomas.

Transforming acidic coiled-coil-containing protein 3 (TACC3) overexpression in hepatocellular carcinomas is associated with "stemness" and epithelial-mesenchymal transition-related marker expression and a poor prognosis.

There is accumulating evidence that hepatocellular carcinomas (HCCs) expressing "stemness"-related markers, e.g., keratin 19 (K19) and epithelial cell adhesion molecule (EpCAM), are associated with aggressive biological behavior. In order to further investigate the molecular characteristics of this subgroup of HCCs, we examined copy number alterations of K19-positive and K19-negative HCCs and found frequent amplifications of the 4p16.3 locus containing the TACC3 gene, which has previously not been described in HCCs. We performed an immunohistochemical analysis of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in HCCs in whole tissue sections and tissue microarrays and examined the clinicopathological characteristics of TACC3-overexpressing HCCs in relation to stemness-related marker (K19, EpCAM) expression, epithelial-mesenchymal transition (EMT)-related proteins, and survival. Cytoplasmic TACC3 protein expression was seen in 7/7 whole tissue sections of K19-positive HCCs, while TACC3 expression was negative or patchy in K19-negative cases. In the tissue microarray cohort, TACC3 was overexpressed in 105/188 (55.9 %) HCCs and was associated with poor differentiation (p = 0.028), major vascular invasion (p = 0.039), higher tumor stages (p = 0.015), younger age (p = 0.003), higher proliferative activity (p < 0.001), and more frequent multipolar mitoses (p < 0.001). TACC3 expression was significantly correlated with K19 (p = 0.010) and EpCAM (p < 0.001) positivity. In addition, TACC3 overexpression was associated with frequent expression of S100A4, uPAR, and ezrin (p < 0.001, all) and loss of E-cadherin expression (p = 0.014), and overall survival was significantly decreased in patients with TACC3-positive HCCs (p = 0.014). In conclusion, TACC3 overexpression was associated with clinicopathological features of aggressiveness, increased EMT-related protein expression, and poor survival, suggesting a potential role for TACC3 as a prognostic biomarker and therapeutic target in HCC.

Intrahepatic mass-forming cholangiocarcinoma: prognostic value of preoperative gadoxetic acid-enhanced MRI.

OBJECTIVES: To assess whether gadoxetic acid-enhanced MRI could be used as a prognostic factor for intrahepatic mass-forming cholangiocarcinomas (IMCCs). METHODS: Forty-one patients with pathologically proven IMCCs who underwent preoperative gadoxetic acid-enhanced MRI were included. The signal intensity of the IMCCs on hepatobiliary phase (HBP) MRI was qualitatively analyzed by two radiologists, and categorized into intermediate or hypointense groups. Analysis of clinicopathological prognostic factors and correlations of imaging and histology were also performed. Survival time and time to recurrence (TTR) were analyzed. RESULTS: Of the 41 IMCCs, 23 were in the intermediate group and 18 were in the hypointense group on HBP MRI. IMCCs in the intermediate group were associated with shorter survival time (P = 0.048) and TTR (P = 0.002) than the IMCCs of the hypointense group. Only the intermediate group on HBP MRI had a significantly shorter TTR on multivariate analysis (P = 0.012). The IMCCs of the intermediate group showed a tendency for more abundant tumour fibrous stroma than those of the hypointense group (P = 0.027). CONCLUSIONS: The enhancement of IMCCs on HBP gadoxetic acid-enhanced MRI appears to correlate with tumour aggressiveness and outcomes due to the tumour fibrous stromal component. Thus, HBP images could be a useful prognostic factor for IMCCs after surgery. KEY POINTS: • The enhancement of IMCCs on HBP correlates with the tumour fibrous stroma. • The enhancement of IMCCs on HBP MRI appears to correlate with prognosis. • Gadoxetic acid-enhanced MRI is helpful for predicting prognosis of IMCCs after surgery.

De novo C3 glomerulonephritis in a renal allograft.

C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti-rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident.

Expression of Immunoglobulin G4 in Eosinophilic Esophagitis.

Background: Eosinophilic esophagitis (EoE) is a disease that has been subcategorized into two endoscopic phenotypes: inflammatory and fibrostenotic. Moreover, studies have shown a link between EoE and immunoglobulin G4 (IgG4), a subclass of the immunoglobulin G (IgG) antibody. In this study, we aimed to evaluate the relationship between histologic IgG4 expression and endoscopic phenotypes in patients with EoE. Methods: This case-control study included patients diagnosed with EoE (n = 19) and patients with non-obstructive dysphagia without abnormal findings as controls (NOD; n = 12). The EoE group was further divided into three subgroups based on endoscopic phenotype: inflammatory, fibrostenotic, or combined. Retrospective examination of endoscopic findings and pathological slides was performed to analyze IgG4 staining. Results: Histological analysis revealed a significant difference in IgG4 cell count (15.00 vs. 0.58, p = 0.003) and eosinophil cell count (84.67 vs. 0.08, p < 0.001) between the EoE and NOD groups. Symptom manifestation and blood test results were similar across all three endoscopic EoE phenotypes. However, histological analysis revealed a significant difference in IgG4 cell count between the inflammatory, fibrostenotic, and combined phenotypes (4.13 vs. 17.6 vs. 59.7, p = 0.030). Conclusions: IgG4 expression was higher in EoE patients than in those with NOD, the highest being in the combined phenotype subgroup. These findings emphasize the important role of endoscopic and histological examination in diagnosing EoE and the need for further research in this area.

Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Therapeutic strategies for well-differentiated papillary mesothelioma of the peritoneum.

OBJECTIVE: Well-differentiated papillary mesothelioma is an uncommon subtype of mesothelioma with a frequently indolent course, although it occasionally manifests in a more aggressive form. To establish a treatment strategy for this rare disease, we report the clinical characteristics and outcomes of 15 patients with well-differentiated papillary mesothelioma. METHODS: All pathologically diagnosed well-differentiated papillary mesothelioma cases were reviewed between 1998 and 2012. RESULTS: Of the 15 cases, 8 and 7 presented with single and multiple lesions, respectively. All cases with single lesions were asymptomatic, while 4 out of the 7 cases with multiple lesions were symptomatic. After tumor excision, none of the eight single-lesion cases experienced tumor recurrence. Among the other seven cases with multiple lesions, only one patient with disseminated lesions died due to disease burden. Five patients with multiple lesions received cisplatin-based intravenous or intraperitoneal chemotherapy, with a mix of complete (n= 2) and partial (n= 2) responses observed. Of particular note, one patient receiving cisplatin and pemetrexed combination chemotherapy experienced complete tumor resolution without any serious toxicity. CONCLUSIONS: We recommend different treatment strategies based on the disease status. If the tumor is completely resectable, an excisional biopsy seems to be sufficient. If complete resection is unavailable for the asymptomatic patient with a localized tumor extent, close follow-up is an appropriate option. When the tumor is extensive or accompanied by symptoms, chemotherapy should be strongly considered.

Retrospective analysis of 8th edition American Joint Cancer Classification: Distal cholangiocarcinoma.

Backgrounds/Aims: This is a retrospective analysis of whether the 8th edition American Joint Committee on Cancer (AJCC) was a significant improvement over the 7th AJCC distal extrahepatic cholangiocarcinoma classification. Methods: In total, 111 patients who underwent curative resection of mid-distal bile duct cancer from 2002 to 2019 were included. Cases were re-classified into 7th and 8th AJCC as well as clinicopathological univariate and multivariate, and Kaplan-Meier survival curve and log rank were calculated using R software. Results: In patient characteristics, pancreaticoduodenectomy/pylorus preserving pancreaticoduodenectomy had better survival than segmental resection. Only lymphovascular invasion was found to be significant (hazard ratio 2.01, p = 0.039) among all clinicopathological variables. The 8th edition AJCC Kaplan Meier survival curve showed an inability to properly segregate stage I and IIA, while there was a large difference in survival probability between IIA and IIB. Conclusions: The 8th distal AJCC classification did resolve the anatomical issue with the T stage, as T1 and T3 showed improvement over the 7th AJCC, and the N stage division of the N1 and N2 category was found to be justified, with poorer survival in N2 than N1. Meanwhile, in TMN staging, the 8th AJCC was able differentiate between early stage (I and IIA) and late stage (IIB and III) to better explain the patient prognosis.

Comparison of Programmed Cell Death Ligand 1 Status between Core Needle Biopsy and Surgical Specimens of Triple-Negative Breast Cancer.

PURPOSE: Pembrolizumab is currently used to treat advanced triple-negative breast cancer (TNBC) and high-risk early TNBC with neoadjuvant chemotherapy (NAC). The tumor-infiltrating lymphocyte (TIL) level and programmed cell death ligand 1 (PD-L1) status are predictors of response to NAC and immune checkpoint inhibitor treatment. We aimed to investigate whether the PD-L1 status in core needle biopsies (CNBs) could represent the whole tumor in TNBC. MATERIALS AND METHODS: A total of 49 patients diagnosed with TNBC who received upfront surgery without NAC between January 2018 and March 2021 were included. The PD-L1 expression (SP142 and 22C3 clones) and TIL were evaluated in paired CNBs and resected specimens. The concordance PD-L1 status and TIL levels between CNBs and resected specimens were analyzed. RESULTS: PD-L1 positivity was more frequently observed in resected specimens. The overall reliability of TIL level in the CNB was good [intraclass correlation coefficient (ICC)=0.847, p<0.001]. The agreements of PD-L1 status were good and fair, respectively (SP142, κ=0.503, p<0.001; 22C3, κ=0.380, p=0.010). As the core number of CNB increased, the reliability and agreement also improved, especially from five tumor cores (TIL, ICC=0.911, p<0.001; PD-L1 [22C3], κ=0.750, p=0.028). Regarding PD-L1 (SP142), no further improvement was observed with ≥5 tumor cores (κ=0.600, p=0.058). CONCLUSION: CNBs with ≥5 tumor cores were sufficient to represent the TIL level and PD-L1 (22C3) status in TNBC.

Prediction of Prognosis in Pancreatic Cancer According to Methionyl-tRNA Synthetase 1 Expression as Determined by Immunohistochemical Staining.

The serum level of CA 19-9 is a prognostic marker for pancreatic ductal adenocarcinoma (PDAC). We evaluated the ability of the expression level of methionyl-tRNA synthetase 1 (MARS1)-which facilitates cancer growth by modulating protein synthesis and the cell cycle-to predict the prognosis of PDAC. Immunohistochemical (IHC) staining was performed on pancreatic specimens obtained from patients with PDAC who were undergoing surgery. High MARS1 expression was defined as equal to, or greater than, that in normal acinar cells. Low MARS1 expression was defined as weaker than in normal acinar cells, and stronger than in the pancreatic duct epithelium. Univariate and multivariate analyses were performed on other factors related to prognosis. Among 137 PDAC patients, no significant differences in baseline characteristics were found between those with high (n = 82) and low (n = 55) MARS1 expression. The median overall survival time of patients with high MARS1 expression was shorter than that of those with low expression (15.2 versus 17.2 months, log-rank test p = 0.044). The median disease-free survival (DFS) was not significantly different between the two groups. However, the DFS was shorter in patients with high than in those with low MARS1 expression (8.9 versus 11.2 months, log-rank test p = 0.067). In a multivariate analysis, lymph node metastasis and high MARS1 expression were associated with a poor prognosis of PDAC. Elevated MARS1 expression detected by IHC staining is associated with a poor prognosis of PDAC, suggesting that MARS1 has potential as a prognostic marker.

Diagnostic Accuracy of Vitreous Cytology in Patients with Vitreoretinal Lymphoma.

(1) Background: To determine the diagnostic value of vitreous cytology in patients with vitreoretinal lymphoma (VRL) and evaluate its diagnostic accuracy relative to that of other diagnostic tests. (2) Methods: In total, 38 eyes from 38 patients with VRL who underwent diagnostic vitrectomy and were followed up for at least 6 months were analyzed. The clinical manifestations and VRL diagnostic rates for all diagnostic tests were determined. (3) Results: The presence of vitreous cells/opacity was the most common ophthalmic finding (97.4%), followed by sub-retinal pigment epithelial infiltration (65.8%) and retinal hemorrhage (21.1%). The VRL diagnostic rates were 89.3% for interleukin (IL)-10 levels > 50 pg/mL; 82.1% for IL-10/IL-6 ratios > 1; 60.0% and 63.3% for immunoglobulin heavy chain and kappa light chain clonality assays, respectively; and 44.4% for vitreous cytology. The VRL diagnostic rate for vitreous cytology was significantly lower in the steroid pretreatment group than in the non-steroid pretreatment group (p = 0.007). (4) Conclusions: The VRL detection rate for vitreous cytology was lower than that for the other tests, especially in patients who received steroid pretreatment. These findings suggest that even if vitreous cytology findings are negative, other tests and characteristic fundus findings should be evaluated to confirm VRL diagnosis.