Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes.

We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation-phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA-protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2-4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

PD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141+ CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.

Prediction of malignancy in main duct or mixed-type intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND/PURPOSE: Surgical indications of main duct-involved intraductal papillary mucinous neoplasm (IPMN), especially for main pancreatic duct (MPD) of 5-9 mm, remain controversial. We aimed to predict malignancy risk of main duct-involved IPMN. METHODS: Total 258 patients with main duct-involved IPMN between 2000 and 2017 in our institute were retrospectively analyzed. Main duct IPMN was classified into segmental and diffuse-type by dilated MPD pattern. Clinicopathologic features and predictive factors for malignancy were analyzed. RESULTS: Among 258 patients, 47 and 211 had pure main duct (segmental: 27, diffuse type: 20) and mixed type, respectively. Malignant IPMN presented higher in main duct type (66.0%) compared to mixed type (46.9%). The diffuse type (72.2%) had more invasive carcinoma than the segmental type (40.7%). Invasive IPMN risk increased proportionally to the MPD diameter (5 ≤ MPD <10 mm vs 10 ≤ MPD < 15 mm vs MPD ≥ 15 mm; 23.4% vs 40.0% vs 48.6%). Symptoms, elevated serum carbohydrate antigen, MPD ≥10 mm, mural nodule, thickened wall, and distal atrophy were independent predictive factors for malignancy. Patients with MPD of 5-9 mm with at least one predictive factor had 35.0% of malignancy risk. CONCLUSIONS: The invasive IPMN risk was different according to the dilated main duct pattern. Patients with main duct type, diffuse type, MPD ≥10 mm, and MPD 5-9 mm with at least one predictive factor should be candidates for immediate surgery.

Oncologic outcomes according to the location and status of resection margin in pancreas head cancer: role of radiation therapy in R1 resection.

PURPOSE: The clinical significance of margin status in pancreatic head cancer is still controversial due to the nonstandardized definition of R status and pathologic reporting. This study aims to evaluate the impact of the margin status including location and the role of radiation therapy in pancreatic head cancer. METHODS: A total of 314 patients who underwent curative-intent surgery for pancreatic head cancer between 2010 and 2017 were analyzed. Demographics, survival, and local recurrences were compared according to 2 definitions: 0-mm R1 as direct involvement and 1-mm R1 as close resection margin less than 1 mm. The specific margins were divided into 4 groups according to the location around the pancreas: pancreas transection, anterior surface, posterior surface, and vessel (superior mesenteric artery/superior mesenteric vein) margin. RESULTS: The 0-mm R1-rate was 15.6%, and increased to 36.3% in 1-mm R1. The median overall survival rate of 0-mm R0 vs. R1 was 26 months vs. 16 months (P = 0.052) and that of 1-mm R0 vs. R1 was 27 months vs. 18 months, respectively (P = 0.016). In individual margins, posterior, anterior surface, and pancreas transection margin involvement were associated with poor outcome, and the 1 mm posterior surface involvement was an independent risk factor for disease-free survival (hazard ratio, 1.63). Adjuvant radiation therapy had oncologic benefits, especially in R1 patients (P = 0.011) compared to R0 patients (P = 0.088). CONCLUSION: Margin status, especially 1-mm R1 status is an important predictive factor, and involved posterior surface has a clinical impact. Patients with positive margins should be considered adjuvant radiation therapy.

Magnetic Resonance Elastography Versus Transient Elastography in the Prediction of Complications After Resection for Hepatocellular Carcinoma.

OBJECTIVE: To compare the performances of MRE and TE for predicting severe complications after HR in patients with HCC. SUMMARY OF BACKGROUND DATA: LSM may have the potential to predict outcomes after HR in HCC patients. METHODS: Consecutive patients who underwent HR for HCC between 2017 and 2019 were retrospectively enrolled. Before HR, LSM was performed in all patients using both MRE and TE. All postoperative complications were assessed using the comprehensive complication index (CCI). Severe postoperative complications were defined as a CCI ≥26.2. The performances of MRE and TE for predicting high CCI and diagnosing liver fibrosis were compared using the area under the receiver-operating-characteristic curve (AUROC). Uni-/multivariable logistic regression analyses were used to identify factors associated with high CCI. RESULTS: Among the 208 enrolled patients, 28 patients (13.5%) had high CCI. For detecting high CCI, MRE had an AUROC of 0.874 [95% confidence interval (CI), 0.821-0.916], which was significantly higher than the AUROC of TE (0.756; 95% CI, 0.692-0.813) ( P = 0.020). MRE outperformed TE in detecting fibrosis of ≥F2 (AUROC: 0.935 vs 0.767; P = 0.008), ≥F3 (AUROC: 0.902 vs 0.774; P = 0.001) and F4 (AUROC: 0.916 vs 0.767; P < 0.001). LSM by MRE was independently associated with high CCI (odds ratio, 4.207 per kPa; 95% CI, 1.862-9.504; P < 0.001), whereas LSM by TE was not. CONCLUSIONS: MRE better predicted severe postoperative complications than TE in HCC patients who underwent HR. LSM by MRE was independently associated with high CCI after HR.

Fate of Patients With Intraductal Papillary Mucinous Neoplasms of Pancreas After Resection According to the Pathology and Margin Status: Continuously Increasing Risk of Recurrence Even After Curative Resection Suggesting Necessity of Lifetime Surveillance.

OBJECTIVE: This study evaluated the associated factors and prognosis according to pathology and margin after surgical resection of intraductal papillary mucinous neoplasms (IPMN). BACKGROUND: There is limited information on recurrence patterns according to pathology and margin in IPMN. METHODS: Total 577 patients who underwent operation for IPMN at a tertiary center were included. Factors associated with recurrence, survival, and recurrence outcomes according to pathology and margin were analyzed. RESULTS: Among 548 patients analyzed, 353 had low-grade dysplasia (LGD), 78 had high-grade dysplasia (HGD), and 117 had invasive IPMN. Total 50 patients developed recurrences, with 4 resection margins, 10 remnant pancreas, 11 locoregional, and 35 distant recurrences. Invasive IPMN showed worse 5-year cumulative recurrence risk (LGD vs HGD vs invasive: 0.7% vs 4.3% vs 37.6%, P < 0.001) and 5-year survival rate (89.0% vs 84.0% vs 48.4%, P < 0.001). Recurrence risk increased after 5 years, even in LGD and HGD. Malignant margin (HGD and invasive) had worse 5-year cumulative recurrence rate (R0 vs LGD vs malignant: 8.3% vs 5.9% vs 50.6%, P < 0.001) and 5-year survival rate (80.7% vs 83.0% vs 30.8%, P < 0.001). Carbohydrate antigen 19-9 >37 ( P = 0.003), invasive IPMN ( P < 0.001), and malignant margin ( P = 0.036) were associated with recurrence. CONCLUSIONS: Invasive IPMN developed more recurrences and had worse survival than LGD or HGD, indicating the need for more efficient postoperative treatment strategies. Patients with LGD and HGD also need regular follow-up for recurrence after 5 years. Malignant margins need additional resection to achieve negative or at least LGD margin.

Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor.

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

Noninvasive assessment of hepatic steatosis using a pathologic reference standard: comparison of CT, MRI, and US-based techniques.

PURPOSE: The present study compared the performance of computed tomography (CT), magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF), controlled attenuation parameter (CAP), grayscale ultrasonography (US), and attenuation imaging (ATI) for the diagnosis of hepatic steatosis (HS). METHODS: In total, 120 prospectively recruited patients who underwent hepatic resection between June 2018 and June 2020 were retrospectively analyzed. CT, MRI-PDFF, CAP, grayscale US, and ATI were performed within 3 months before surgery. Diagnostic performance for HS ≥5% and HS >33% was compared using the area under the curve (AUC) of receiver operating characteristic curves. Histopathologic examinations served as the reference standard for the degree of HS. RESULTS: For detecting HS ≥5%, MRI-PDFF (AUC, 0.946) significantly outperformed CT, CAP and grayscale US (AUC, 0.807, 0.829, and 0.761, respectively) (P<0.01 for all). ATI (AUC, 0.892) was the second-best modality and significantly outperformed grayscale US (P=0.001). In pairwise comparisons, there were no significant differences between the AUC of ATI and the values of MRI-PDFF, CT, or CAP (P=0.133, P=0.063, and P=0.150, respectively). For detecting HS >33%, all the modalities provided good diagnostic performance without significant differences (AUC, 0.887-0.947; P>0.05 for all). CONCLUSION: For detecting HS ≥5%, MRI-PDFF was the best imaging modality, while ATI outperformed grayscale US. For detecting HS >33%, all five imaging tools demonstrated good diagnostic performance.

2D shear wave elastography is better than transient elastography in predicting post-hepatectomy complication after resection.

OBJECTIVES: Both transient elastography (TE) and 2D shear wave elastography (SWE) are accurate methods to evaluate liver fibrosis. We aimed to evaluate the diagnostic performance of 2D-SWE in predicting post-hepatectomy complication and to compare it with TE. METHODS: We prospectively enrolled 125 patients with liver tumors. Liver stiffness (LS) (kilopascal [kPa]) was measured using both TE and 2D-SWE before surgery. All post-operative complication was evaluated using the comprehensive complication index (CCI), and CCI ≥ 26.2 was defined as severe complication. Logistic regression analysis was performed to identify predictive factors for severe complication. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of TE/2D-SWE in detecting liver fibrosis and severe complication. RESULTS: Severe complication developed in 18 patients. The median LS in patients with severe complication was significantly higher for both 2D-SWE (11.4 kPa vs. 7.0 kPa, p < 0.001) and TE (8.9 kPa vs. 6.2 kPa, p = 0.009). LS obtained from 2D-SWE was a significant factor correlated with severe complication (odds ratio: 1.27 per kPa [1.10-1.46], p = 0.001). The diagnostic performance of 2D-SWE was significantly higher than that of TE in detecting both ≥F3 (p = 0.024) and F4 (p = 0.048). The area under the curve of 2D-SWE to predict severe complication was 0.854, significantly higher than 0.692 of TE (p = 0.004). The optimal cut-off LS from 2D-SWE to predict severe complication was 8.6 kPa, with sensitivity of 88.9% (16/18) and specificity of 73.8% (79/107). CONCLUSION: LS obtained from 2D-SWE was a significant predictive factor for severe complication, and 2D-SWE showed significantly a better diagnostic performance than TE in detecting liver fibrosis and severe complication. KEY POINTS: • The diagnostic performance of 2D-SWE was significantly higher than that of TE in detecting both ≥ F3 (AUC: 0.853 vs. 0.779, p = 0.024) and F4 (AUC: 0.929 vs. 0.872, p = 0.048). • Liver stiffness value obtained from 2D-SWE was a significant factor correlated with the development of severe complication defined as CCI ≥ 26.2 after hepatic resection for liver tumors (odds ratio: 1.27 per kPa [1.10-1.46], p = 0.001). • 2D-SWE provided significantly a better diagnostic performance in predicting severe complication after hepatic resection than TE (AUC for 2D-SWE: 0.853 vs. AUC for TE: 0.692, p = 0.004).

Accuracy of Two-Dimensional Shear Wave Elastography and Attenuation Imaging for Evaluation of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: We evaluated the accuracy of a multiparametric approach using attenuation imaging and 2-dimensional shear wave elastography (2D-SWE) for the detection of steatosis and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We studied 102 patients with increased levels of liver enzymes or suspicion of NAFLD, examined by attenuation imaging and 2D-SWE, immediately before biopsy collection and analysis (reference standard), from January 2018 to July 2019. We collected data on the attenuation coefficient (dB/cm/MHz) from attenuation imaging, liver stiffness measurements, and shear wave dispersion slope (SWDS, [m/s]/kHz) from 2D-SWE. Multivariate linear regression analysis was performed to identify factors associated with each parameter. Diagnostic performance was determined from area under the receiver operating curve (AUROC) values. RESULTS: The attenuation coefficient was associated with steatosis grade (P < .01) and identified patients with steatosis grades S1 or higher, S2 or higher, and S3 or higher, with AUROC values of 0.93, 0.88, and 0.83, respectively. Liver stiffness associated with fibrosis stage (P < .01) and lobular inflammatory activity was the only factor associated with SWDS (P < .01). SWDS detected inflammation grades I1 or higher, I2 or higher, and I3 or higher with AUROC values of 0.89, 0.85, and 0.78, respectively. We developed a risk scoring system to detect steatohepatitis based on the attenuation coefficient (score of 1 for 0.64 < attenuation coefficient ≤ 0.70; score of 2 for 0.70 < attenuation coefficient ≤ 0.73; and score of 3 for attenuation coefficient >0.73) and SWDS (score of 2 for 10.5 [m/s]/kHz < SWDS ≤ 11.7 [m/s]/kHz; and score of 3 for SWDS >11.7 [m/s]/kHz), using an unweighted sum of each score. Based on histopathology analysis, 55 patients had steatohepatitis. Risk scores correlated with NAFLD activity score (rho = 0.73; P < .01). Our scoring system identified patients with steatohepatitis with an AUROC of 0.93-this value was significantly higher than that of other parameters (P < .05), except SWDS (AUROC, 0.89; P = .18). CONCLUSIONS: In the evaluation of patients with suspected NAFLD, the attenuation coefficient can identify patients with steatosis and liver stiffness can detect fibrosis accurately. SWDS was associated significantly with lobular inflammation. We developed a risk scoring system based on the attenuation coefficient and SWDS that might be used to detect steatohepatitis.

Association between spleen volume and the post-hepatectomy liver failure and overall survival of patients with hepatocellular carcinoma after resection.

OBJECTIVES: Post-hepatectomy liver failure (PHLF) can occur as a major complication after hepatic resection (HR) in patients with hepatocellular carcinoma (HCC) and negatively affects the prognosis. We aimed to retrospectively assess whether the spleen volume (SV) measured from preoperative CT images would be associated with the development of PHLF and overall survival (OS) after HR in patients with HCC. METHODS: We enrolled 317 consecutive patients with very early/early stage HCC who underwent a preoperative CT and HR between January 2010 and December 2016. The SV was obtained from preoperative CT images using semi-automated volumetric software and was divided by body surface area to yield SVBSA. Receiver operating characteristic (ROC) curves and logistic regression analyses were performed to identify factors affecting the development of PHLF. The Cox proportional hazard model was used to identify prognostic factors for OS. RESULTS: PHLF was observed in 72 patients (22.7% [72/317]). SVBSA was associated with the development of PHLF (odds ratio, 2.321; 95% CI, 1.347-4.001; p = 0.002) with the area under the ROC curve of 0.663 using the cutoff value of 107.5 cm3 (p < 0.001). SVBSA was also an influencing factor for OS (hazard ratio, 3.935; 95% CI 1.520-10.184; p = 0.005), with the optimal cutoff of 146 cm3. The 5-year OS rate was higher in 245 patients with a SVBSA ≤ 146 cm3 than in 72 patients with a SVBSA > 146 cm3 (95.0% vs. 78.7%, p < 0.001). CONCLUSIONS: In patients with HCC, a larger SVBSA was associated with a higher rate of PHLF and worse OS after HR. The SVBSA may be useful in selecting good surgical candidates. KEY POINTS: • A significantly higher spleen volume divided by body surface area was observed in patients who experienced post-hepatectomy liver failure than in patients who did not (148 cm3 vs. 112 cm3, p < 0.001). • The area under the receiver operating characteristic curve of spleen volume divided by body surface area to predict the development of post-hepatectomy liver failure was 0.663 (p < 0.001). • Spleen volume divided by body surface area was a significant influencing factor for overall survival (hazard ratio, 3.935; 95% CI, 1.520-10.184; p < 0.001), with the optimal cutoff of 146 cm3.

Survival benefit of adjuvant chemoradiotherapy for positive or close resection margin after curative resection of pancreatic adenocarcinoma.

BACKGROUND: This study was conducted to identify patients who may benefit from adjuvant chemoradiotherapy (CRT) for positive or close resection margin (RM) after curative resection of pancreatic adenocarcinoma. METHODS: From 2004 to 2015, total of 472 patients with pancreatic adenocarcinoma underwent curative resection. After excluding patients with RM > 2 mm or unknown, remaining 217 patients were retrospectively analyzed. Forty-six (21.2%) patients were treated with adjuvant chemotherapy alone (CTx; mainly gemcitabine-based), 142 (65.4%) with adjuvant CRT (mainly upfront), and 29 (13.4%) patients didn't receive any adjuvant therapy (noTx group). RESULTS: Locoregional recurrence rate was significantly lower in the CRT group (43.7%) than in the CTx group (71.7%) or noTx group (65.5%) (p = 0.001). Significant survival benefits of CRT over CTx (HR 0.602, p = 0.020 for overall survival (OS); HR 0.599, p = 0.016 for time to any recurrence (TTR)) were demonstrated in multivariate analysis. CRT group had more 5-year survivors than other groups. In the subgroup analysis, such benefits of adjuvant CRT over CTx was observed only in patients with head tumor & vascular RM > 0.5 mm, but not in patients with body/tail tumor or vascular RM ≤ 0.5 mm. In the CRT group, radiation dose≥54 Gy was significantly associated with better TTR and OS. CONCLUSIONS: Adjuvant CRT could improve TTR and OS compared to adjuvant CTx alone in patients with close RM under 2 mm. Radiation dose escalation may be beneficial when feasible. Modern CRT regimen-based randomized evidence is needed for these high-risk patients.

How to Best Detect Portal Vein Tumor Thrombosis in Patients with Hepatocellular Carcinoma Meeting the Milan Criteria: Gadoxetic Acid-Enhanced MRI versus Contrast-Enhanced CT.

INTRODUCTION: The detection of portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC) meeting the Milan criteria is of critical importance as PVTT is known to be a contraindication to transplantation and an indicator of a dismal prognosis. OBJECTIVE: To determine which modality may best detect PVTT, we compared the diagnostic performance of gadoxetic acid-enhanced MRI (GA-MRI) and contrast-enhanced CT (CECT) in HCC patients meeting the Milan criteria. METHODS: We retrospectively enrolled 310 patients with HCCs meeting the Milan criteria who underwent both GA-MRI and CECT between June 2007 and May 2017. Among them, 44 patients were demonstrated to have PVTT while 266 patients had no PVTT. Two radiologists then assessed GA-MRI and CECT images for the presence of PVTT on a 5-point scale as well as vessel expansion, continuity with tumors, and enhancement on both modalities, as well as T2 hyperintensity and diffusion restriction on GA-MRI. The McNemar test was used to compare sensitivity and specificity of GA-MRI and CECT for the detection of PVTT, and Fisher's exact test was used to compare their imaging features. RESULTS: GA-MRI showed higher sensitivity values than CECT in detecting PVTT (reviewer 1, 93.2% [41/44] vs. 77.3% [34/44]; reviewer 2, 88.6% [39/44] vs. 70.5% [31/44]) (both p = 0.039). Specificity of GA-MRI and CECT demonstrated no difference (reviewer 1, 95.5% [254/266] vs. 95.1% [253/266]; reviewer 2, 97.0% [258/266] vs. 97.4% [259/266]) (both p > 0.999). Continuity with tumors and enhancement were more frequently observed on GA-MRI than on CECT (p < 0.050, both reviewers). CONCLUSION: GA-MRI detected PVTT more often than CECT in HCC patients meeting the Milan criteria and better depicted PVTT in continuity with tumors and those showing enhancement than CECT.

Two-Dimensional-Shear Wave Elastography with a Propagation Map: Prospective Evaluation of Liver Fibrosis Using Histopathology as the Reference Standard.

OBJECTIVE: The aim of this study was to prospectively evaluate whether liver stiffness (LS) assessments, obtained by two-dimensional (2D)-shear wave elastography (SWE) with a propagation map, can evaluate liver fibrosis stage using histopathology as the reference standard. MATERIALS AND METHODS: We prospectively enrolled 123 patients who had undergone percutaneous liver biopsy from two tertiary referral hospitals. All patients underwent 2D-SWE examination prior to biopsy, and LS values (kilopascal [kPa]) were obtained. On histopathologic examination, fibrosis stage (F0-F4) and necroinflammatory activity grade (A0-A4) were assessed. Multivariate linear regression analysis was performed to determine the significant factors affecting the LS value. The diagnostic performance of the LS value for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis, and the optimal cut-off value was determined by the Youden index. RESULTS: Reliable measurements of LS values were obtained in 114 patients (92.7%, 114/123). LS values obtained from 2D-SWE with the propagation map positively correlated with the progression of liver fibrosis reported from histopathology (p < 0.001). According to the multivariate linear regression analysis, fibrosis stage was the only factor significantly associated with LS (p < 0.001). The area under the ROC curve of LS from 2D-SWE with the propagation map was 0.773, 0.865, 0.946, and 0.950 for detecting F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The optimal cut-off LS values were 5.4, 7.8, 9.4, and 12.2 kPa for F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The corresponding sensitivity and specificity of the LS value for detecting cirrhosis were 90.9% and 88.4%, respectively. CONCLUSION: The LS value obtained from 2D-SWE with a propagation map provides excellent diagnostic performance in evaluating liver fibrosis stage, determined by histopathology.

Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a Japan-Korea collaborative study.

BACKGROUND: The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location. METHODS: IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid-tubular components. Medical data were evaluated. RESULTS: Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P < 0.001). There were significant differences in 5-year cumulative survival rates (75.2% vs 50.9%; P < 0.0001) and 5-year cumulative disease-free survival rates (64.1% vs 35.3%; P < 0.0001) between the two groups. CONCLUSION: Type 1 and Type 2 IPNBs differ in their clinicopathological features and prognosis. This classification may help to further understand IPNB.

Detection of Circulating Tumor Cells in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Evaluation as a Prognostic Marker.

Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.

Shear-Wave Dispersion Slope from US Shear-Wave Elastography: Detection of Allograft Damage after Liver Transplantation.

Background Allograft damage (hepatic parenchymal damage) after liver transplant is associated with the degree of necroinflammation in graft liver. According to a recent animal study, shear-wave dispersion slope obtained at US shear-wave elastography (SWE) is associated with necroinflammatory activity in the liver. Purpose To evaluate the role of shear-wave dispersion slope in detecting allograft damage after liver transplant. Materials and Methods In this prospective study, 104 liver transplant recipients underwent percutaneous liver biopsy for allograft evaluation from December 2017 to November 2018. All participants underwent allograft SWE examination just before liver biopsy, and liver stiffness and shear-wave dispersion slope were obtained. Allograft damage was diagnosed by histopathologic analysis. Clinical and imaging factors related to liver stiffness and shear-wave dispersion slope were determined by multivariable linear regression analysis. Diagnostic performance of each variable in detecting allograft damage was evaluated by comparing area under the receiver operating curve (AUC) values. Results There were 104 study participants (35 women); median age was 56 years (interquartile range, 50-62 years). Allograft damage was found in 46 of 104 (44.2%) of participants. The median liver stiffness (8.2 kPa vs 6.3 kPa; P < .01) and shear-wave dispersion slope (14.4 [m/sec]/kHz vs 10.4 [m/sec]/kHz; P < .01) were higher in participants with allograft damage than in those without damage, respectively. Fibrosis stage was the only determinant factor for liver stiffness (coefficient, 1.8 kPa per fibrosis stage; 95% confidence interval: 0.1, 3.5; P = .03), whereas both fibrosis stage (coefficient, 1.4 [m/sec]/kHz per fibrosis stage; 95% confidence interval: 0.3, 2.6; P = .02) and necroinflammatory activity (coefficient, 1.6 [m/sec]/kHz per necroinflammatory activity grade; 95% confidence interval: 0.5, 2.7; P < .01) affected shear-wave dispersion slope. The AUC for shear-wave dispersion slope in detecting allograft damage was 0.86, which was higher than that of liver stiffness (AUC, 0.75; P < .01). Conclusion Shear-wave dispersion slope determined at US shear-wave elastography may help in detecting allograft damage after liver transplant. © RSNA, 2019 Online supplemental material is available for this article.