Estimation of Degradation Degree in Road Infrastructure Based on Multi-Modal ABN Using Contrastive Learning.

This study presents a method for distress image classification in road infrastructures introducing self-supervised learning. Self-supervised learning is an unsupervised learning method that does not require class labels. This learning method can reduce annotation efforts and allow the application of machine learning to a large number of unlabeled images. We propose a novel distress image classification method using contrastive learning, which is a type of self-supervised learning. Contrastive learning provides image domain-specific representation, constraining such that similar images are embedded nearby in the latent space. We augment the single input distress image into multiple images by image transformations and construct the latent space, in which the augmented images are embedded close to each other. This provides a domain-specific representation of the damage in road infrastructure using a large number of unlabeled distress images. Finally, the representation obtained by contrastive learning is used to improve the distress image classification performance. The obtained contrastive learning model parameters are used for the distress image classification model. We realize the successful distress image representation by utilizing unlabeled distress images, which have been difficult to use in the past. In the experiments, we use the distress images obtained from the real world to verify the effectiveness of the proposed method for various distress types and confirm the performance improvement.

Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.

BACKGROUND: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-ß signal activation in pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-ß (TGF-ß) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-ß signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-ß signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-ß signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-ß activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-ß signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although PNENs generally have a better prognosis than pancreatic cancers, some PNENs display malignant behavior including lymph node (LN) metastasis. Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs. However, the indications for LN dissection are still controversial. Over the last decade, minimally invasive surgery such as laparoscopic pancreatic surgery (LPS) has been increasingly performed for pancreatic tumors including PNENs. AIM: To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS. METHODS: From April 2001 to December 2019, 92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital. Finally, 82 patients were enrolled in this study. Using perioperative factors, we examined the predictive factors for LN metastasis in PNENs. RESULTS: Among the 82 patients, the percentage of LN metastasis according to the pathological findings was 12% (10/82 cases). The median tumor size was 12 mm (range: 5-90 mm). The median tumor size in the LN-positive group (37 mm) was significantly larger than that in the LN-negative group (12 mm) (P = 0.0001). Multivariate analyses revealed that larger tumor size (≥ 20 mm) was an independent risk factor for LN metastasis (odds ratio 16.8, P = 0.0062). In patients with small tumors (≤ 10 mm), LN metastasis was not found. CONCLUSION: Larger tumor size (≥ 20 mm) is an independent risk factor for LN metastasis in PNENs. In smaller PNENs (≤ 10 mm), we may be able to choose limited surgery without LN dissection.

Brain Decoding of Multiple Subjects for Estimating Visual Information Based on a Probabilistic Generative Model.

Brain decoding is a process of decoding human cognitive contents from brain activities. However, improving the accuracy of brain decoding remains difficult due to the unique characteristics of the brain, such as the small sample size and high dimensionality of brain activities. Therefore, this paper proposes a method that effectively uses multi-subject brain activities to improve brain decoding accuracy. Specifically, we distinguish between the shared information common to multi-subject brain activities and the individual information based on each subject's brain activities, and both types of information are used to decode human visual cognition. Both types of information are extracted as features belonging to a latent space using a probabilistic generative model. In the experiment, an publicly available dataset and five subjects were used, and the estimation accuracy was validated on the basis of a confidence score ranging from 0 to 1, and a large value indicates superiority. The proposed method achieved a confidence score of 0.867 for the best subject and an average of 0.813 for the five subjects, which was the best compared to other methods. The experimental results show that the proposed method can accurately decode visual cognition compared with other existing methods in which the shared information is not distinguished from the individual information.

Clinical impact of atrophic changes in remnant pancreas on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy.

Aim: The aim of this study was to evaluate risk factors for nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), with a special focus on remnant pancreatic volume (RPV) as assessed using computed tomography (CT). Methods: From February 2004 to June 2017, 101 patients who underwent PD in our institution were enrolled. We defined a CT attenuation value of less than 40 HU as hepatic steatosis and measured RPV at 7 days, 3 months, and 1 year after PD using the SYNAPSE VINCENT system. The incidence of NAFLD and RPV were compared between the two groups according to reconstruction with pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ). Results: The incidence of NAFLD at 3 months after PD was 39.6% (40/101). The RPV ratio (RPV at 3 months or 1 year divided by RPV at 7 days after PD) at both 3 months and 1 year was significantly smaller in the PG group than in the PJ group (59% vs 73%, P < .001 and 53% vs 67% P < .01, respectively). A positive correlation between the RPV ratio and liver CT value at 3 months was found. The multivariate analysis identified three independent risk factors for NAFLD: female sex (odds ratio [OR] 8.16, 95% confidence interval [95% CI] 2.27-35.9, P < .001), PG reconstruction (OR 3.87, 95% CI 1.04-15.6, P = .04), and RPV ratio ≤60% (OR 3.44, 95% CI 1.06-11.8, P = .001). Conclusion: Atrophic change in the remnant pancreas is significantly associated with the development of NAFLD, and PJ reconstruction may be superior to PG from the viewpoint of NAFLD development.

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Major postoperative complications are associated with early recurrence of hepatocellular carcinoma following hepatectomy.

BACKGROUND AND AIM: Early recurrence (ER) is a strong predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to examine manageable factors associated with ER. METHODS: Overall, 475 consecutive patients with primary HCC who underwent curative hepatectomy were included (R0/R1). We defined ER as recurrence within 2 years after hepatectomy and analyzed predictors for ER. We also defined postoperative complication as Clavien-Dindo classification grade III or IV. RESULTS: ER after hepatectomy was observed in 209 cases (44.0%). Patients with ER had a significantly poor prognosis compared with those with late recurrence (log-rank p < 0.0001) and were more likely to be diagnosed with extrahepatic metastasis (p = 0.009). Significant predictors for ER were des-γ-carboxyprothrombin > 40 mAU/mL (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.36-3.14, p = 0.001), multiple tumors (OR 2.80 95%CI 1.83-4.32, p < 0.0001), cirrhosis (OR 1.53, 95%CI 1.01-2.32, p = 0.043), and postoperative complications (OR 1.72, 95% CI 1.05-2.85, p = 0.032). Blood loss (OR 1.09, 95%CI 1.05-1.13, p < 0.0001) and cirrhosis (OR 1.74, 95%CI 1.05-2.86, p = 0.031) were significant predictors for postoperative complications. CONCLUSIONS: We should pay close attention to surgical associated- and disease-specific factors in hepatectomy for HCC to prevent ER.

Alteration of prognostic efficacy of albumin-bilirubin grade and Child-Pugh score according to liver fibrosis in hepatocellular carcinoma patients with Child-Pugh A following hepatectomy.

BACKGROUND: The albumin-bilirubin (ALBI) grade was developed to predict the prognosis of patients with hepatocellular carcinoma (HCC), which can stratify the prognosis even in HCC patients with Child-Pugh A. We evaluated the prognostic efficacy of the ALBI grade and Child-Pugh classification in HCC patients with Child-Pugh A stratified by the presence or absence of advanced fibrosis or a preoperative biomarker for advanced fibrosis. METHODS: We retrospectively analyzed 490 consecutive HCC patients with Child-Pugh A who underwent initial hepatectomies. The accuracy of prognostic prediction using both models was compared by the presence or absence of advanced fibrosis (F3-4) and its predictor, the preoperative platelet count (PLT). RESULTS: The prognostic accuracy of the ALBI grade was better in patients without advanced fibrosis (F3-4; likelihood ratio: 4.39, corrected Akaike information criterion [AICc]: 453.0, P = .074), but Child-Pugh score was better in the advanced fibrosis group (likelihood ratio: 10.67, AICc: 915.2, P = .0014). In the high PLT group (≥140 × 103/µL), the prognostic accuracy using the ALBI grade was better in overall survival (OS) and relapse-free survival (RFS), but in the low PLT group, the Child-Pugh score was the more accurate model in OS and RFS. CONCLUSIONS: Depending on the degree of fibrosis or preoperative PLT, the ALBI grade and Child-Pugh score may provide more accurate prognoses after initial hepatectomy in HCC patients with Child-Pugh A.

Assessment for the minimal invasiveness of laparoscopic liver resection by interleukin-6 and thrombospondin-1.

BACKGROUND: Laparoscopic surgery has been introduced as a minimally invasive technique for the treatment of various field. However, there are few reports that have scientifically investigated the minimally invasive nature of laparoscopic liver resection (LLR). AIM: To investigate whether LLR is scientifically less invasive than open liver resection. METHODS: During December 2011 to April 2015, blood samples were obtained from 30 patients who treated with laparoscopic (n = 10, 33%) or open (n = 20, 67%) partial liver resection for liver tumor. The levels of serum interleukin-6 (IL-6) and plasma thrombospondin-1 (TSP-1) were measured using ELISA kit at four time points including preoperative, immediate after operation, postoperative day 1 (POD1) and POD3. Then, we investigated the impact of the operative approaches during partial hepatectomy on the clinical time course including IL-6 and TSP-1. RESULTS: Serum level of IL-6 on POD1 in laparoscopic hepatectomy was significantly lower than those in open hepatectomy (8.7 vs 30.3 pg/mL, respectively) (P = 0.003). Plasma level of TSP-1 on POD3 in laparoscopic hepatectomy was significantly higher than those in open hepatectomy (1704.0 vs 548.3 ng/mL, respectively) (P = 0.009), and have already recovered to preoperative level in laparoscopic approach. In patients with higher IL-6 Levels on POD1, plasma level of TSP-1 on POD3 was significantly lower than those in patients with lower IL-6 Levels on POD1. Multivariate analysis showed that open approach was the only independent factor related to higher level of IL-6 on POD1 [odds ratio (OR), 7.48; 95% confidence interval (CI): 1.28-63.3; P = 0.02]. Furthermore, the higher level of serum IL-6 on POD1 was significantly associated with lower level of plasm TSP-1 on POD3 (OR, 5.32; 95%CI: 1.08-32.2; P = 0.04) in multivariate analysis. CONCLUSION: In partial hepatectomy, laparoscopic approach might be minimally invasive surgery with less IL-6 production compared to open approach.

The Impact of Histologic Liver Inflammation on Oncology and the Prognosis of Patients Undergoing Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS: The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS: Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-γ-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS: Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Intra-abdominal bleeding caused by amyloid transthyretin amyloidosis in the gastrointestinal tract: a case report.

Diagnosis of gastrointestinal (GI) amyloidosis is often very difficult because of its nonspecific symptoms. However, a few reports have indicated that serious symptoms such as fatal GI bleeding and obstruction or perforation sometimes lead to a diagnosis of GI amyloidosis. A 79-year-old man was transported to our emergency department with a 1-week history of worsening abdominal pain. Abdominal contrast-enhanced computed tomography showed extravasation from part of the transverse colon wall and moderate ascites. Because intra-abdominal bleeding was suspected, the patient urgently underwent partial resection of the transverse colon, which was the source of the bleeding. Postoperative pathological examination of the tissue specimens led to a diagnosis of amyloid transthyretin amyloidosis. This is the first reported case in which intra-abdominal bleeding led to a diagnosis of GI amyloidosis. We should consider the possibility of GI amyloidosis when intraperitoneal bleeding is observed in elderly patients.

Far-advanced Colorectal Liver Metastases Successfully Managed With Modified ALPPS and Radiofrequency Ablation in Combination With Chemotherapy.

BACKGROUND: Large numbers of synchronous colorectal liver metastases are associated with poor prognosis. CASE REPORT: A 47-year-old male patient with rectal cancer and unresectable colorectal liver metastases (over 15 cm in diameter and over 30 metastases) was treated with a multidisciplinary treatment including systemic chemotherapy with mFOLFOX6/panitumumab and surgical therapies (colostomy, modified associating liver partition and portal vein ligation for staged hepatectomy together with radiofrequency ablation). For solitary recurrent colorectal liver metastases, percutaneous radiofrequency ablation with chemoembolization and open radiofrequency ablation in combination with the same systemic chemotherapy was performed. Since the diagnosis 3 years ago, he has been leading a good quality of life, free of any tumor or treatment. CONCLUSION: For patients with far-advanced but liver-only colorectal liver metastases, surgical therapy, systemic chemotherapy, and interventional treatment can be important for achieving good prognosis.

Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer.

Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Recent advances in precision medicine for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum-based anti-cancer agents and poly-ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.

A case of primary carcinosarcoma of the liver with combined hepatocellular carcinoma and cholangiocarcinoma.

Primary carcinosarcoma of the liver is extremely rare. Here, we report an unusual case of carcinosarcoma of the liver containing combined hepatocellular carcinoma and cholangiocarcinoma. A 66-year-old man with a history of viral hepatitis B was admitted for investigation of multiple liver masses. Dynamic computed tomography revealed a mostly hypoenhancing main tumor with a peripheral ring enhancement and several satellite nodules. After transcatheter arterial chemoembolization and portal vein embolization, an extended right posterior sectionectomy was performed. The resected tumor was macroscopically a simple nodular type, 4.3 × 4.2 cm in diameter, with a dense fibrous capsule. The pathological findings showed that both carcinomatous and sarcomatous elements were present, and diagnosis of carcinosarcoma of the liver was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and cholangiocarcinoma. The sarcomatous element was composed of spindle cells. Immunohistochemical studies demonstrated that cytokeratin AE1/AE3, human serum albumin, cytokeratin 7, and Arginase-1 were partially positive in tumor cells of the carcinomatous element but not in tumor cells of the sarcomatous element. Follow-up for 30 months after surgery has shown no signs of recurrence.

Novel Approach via the Round Ligament in Portal Vein Embolization.

BACKGROUND: The objective of this study was to describe the detailed technique and clinical outcomes of portal vein embolization via the round ligament (RL-PVE) prior to major hepatectomy. METHODS: Between January 2010 and March 2020, a total of 50 portal vein embolization (PVE) procedures were performed in 50 patients. Of them, seven patients who underwent RL-PVE were enrolled in this study. Percutaneous transhepatic portal vein embolization (PTPE) was not indicated due to the following reasons: bile duct dilation (n = 4), difficulty in visualizing the portal vein on ultrasonography because of severe fatty liver (n = 1), large tumor size (n = 1), and combined surgery with staging laparoscopy (n = 1). The following were reasons for avoiding trans-ileocecal PVE: past laparotomy (n = 5), difficulty in accessing the portal vein due to a large tumor (n = 1), and purpose of preventing small intestinal adhesions before hepatopancreatoduodenectomy (n = 1). The percentage of functional hepatic remnant rates was calculated before and after RL-PVE. RESULTS: Technical success was achieved in all cases. Five patients underwent embolization of the right portal vein, while two underwent embolization of the left portal vein. The median operative time and blood loss during RL-PVE were 181 min and 33 g, respectively. Morbidity and mortality related to RL-PVE were not observed. The median functional hepatic remnant rate before and after PVE was 55.6% and 63.2%, respectively. Liver functions including Child-Pugh classification were equivalent before and after RL-PVE. CONCLUSIONS: The RL-PVE technique may be useful in elective cases for which it is difficult to safely perform PTPE or trans-ileocecal approaches.

MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma.

BACKGROUND: MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin-proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated. METHODS: Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro. RESULTS: miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro. CONCLUSION: miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.