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Hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is highly malignant; therefore, continual, multidisciplinary treatments are essential.In this study, two 78- and 81-year-old men were treated with the Vater papilla-preserving strategy. Case 1 had advanced HCC with BDTT expanding to the common bile duct (B4) and portal vein tumor thrombus (PVTT) of the umbilical portion. He showed triple-positive tumor markers. He underwent an extended left hepatectomy without bile duct resection following percutaneous transhepatic biliary drainage and transarterial chemoembolization (TACE). Later, TACE in combination with percutaneous microwave ablation was performed to treat four intrahepatic recurrent HCCs. Case 2 had diffuse-type HCCs accompanied by BDTT (B4) and PVTT to the right portal vein. He underwent liver partition associated with portal vein ligation for staged hepatectomy without bile duct resection. Six months later, he developed a solitary recurrent BDTT with obstructive jaundice. After percutaneous transhepatic biliary drainage, he was treated with two TACE from the various feeding arteries. Both patients achieved complete responses and are doing well without viable tumors approximately 2 years after the initial treatment.The Vater papilla-preserving strategy is essential for obtaining long-term survival and recurrent-free status for patients with HCC with highly extended BDTT.

ESCC prediction accuracy using various number of DMRs identified from ESCC vs. healthy plasma sample analysis

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Differentially expressed chemokine genes (fold change >2) in esophageal cancer tissues

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Hierarchical clustering of HCC and healthy plasma samples

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Hierarchical clustering of GC and healthy plasma samples

Purpose:Emerging evidence indicates that gut microbiome plays a crucial role in the cancer pathogenesis. Although Fusobacterium nucleatum (F. nucleatum) is associated with poor prognosis in multiple cancers, its clinical significance in predicting response to chemotherapy in patients with esophageal squamous cell carcinoma (ESCC) remains unclear.Experimental Design:The F. nucleatum levels were quantified by qPCR assays in tumor tissues from 551 patients with ESCC from two independent cohorts, including 101 patients who received neoadjuvant chemotherapy prior to curative resection. Associations between F. nucleatum burden and recurrence-free survival (RFS), as well with chemotherapeutic response were evaluated using response evaluation criteria in solid tumors (RECISTs), primary tumor metabolic response defined by maximum standardized uptake value (SUVmax) changes in positron emission tomography-CT (PET/CT), and pathologic tumor regression grade (TRG).Results:High burden of F. nucleatum in patients with ESCC associated with poor RFS in both training [log-rank P = 0.02; HR = 1.61; P = 0.03] and validation cohorts (log-rank P = 0.003; HR = 1.96; P = 0.004). Importantly, patients with ESCC with high levels of F. nucleatum displayed poor chemotherapeutic response for all three evaluation methods: RECIST (P = 0.04), SUVmax change in PET/CT (P = 0.0004), and TRG (P = 0.003).Conclusions:We conclude that high levels of intratumoral F. nucleatum have a prognostic significance for predicting poor RFS in patients with ESCC. More importantly, our data indicates that higher F. nucleatum burden correlates with poor response to neoadjuvant chemotherapy, suggesting the possibility that an antibiotic intervention against this bacterium may significantly improve therapeutic response in patients with ESCC.

Previously reported Fusobacterium in cancer tissues and patient prognosis

Purpose:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC.Experimental Design:The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n = 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n = 95), E-MTAB-6134 (n = 288), and GSE71729 (n = 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis.Results:Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36–6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR, 2.63 (1.56–4.41); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14–2.04); P = 0.004], and GSE71729 [HR, 2.33 (1.49–3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC = 0.94), ICGC (AUC = 0.91), E-MTAB-6134 (AUC = 0.80), and GSE71729 (AUC = 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [n = 119; HR, 2.62 (1.50–4.56); P = 0.0004]. A nomogram was established which included the ISP, CA19-9, and T- and N-stage for eventual clinical translation.Conclusions:We report a novel gene signature for risk-stratification and robust identification of patients with PDAC with poor molecular subtypes.

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Methylation ratio distribution of the gitBS performed on normal plasma samples (a) and GI cancer plasma samples (b).

Hierarchical clustering of EAC and healthy plasma samples

Hierarchical clustering of ESCC and healthy plasma samples

Hierarchical clustering of PDAC and healthy plasma samples

Hierarchical clustering of CRC and healthy plasma samples

Workflow of model training and test for GI cancer prediction. (a) Initial markers discovery was conducted with 1653 GI cancer and 287 normal tissues. Targeted bisulfite sequencing that covers the initial selected CpG sites was performed on 300 plasma samples, including 254 GI cancer and 46 normal samples. GI plasma samples set was split into training set (70%) and test set (30%). The training set was used for calling differential methylated regions, feature selection and training random forest prediction models. The test set was used for model performance evaluation. (b) Annotations of panGI markers selected from GI cancer tissues.

Purpose: Fusobacterium nucleatum (F. nucleatum) is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. Although there are several reports of the relationship between F. nucleatum and the clinical outcome in human cancers, its prognostic significance in esophageal cancer remains unclear.Experimental Design: We quantified F. nucleatum DNA in 325 resected esophageal cancer specimens by qPCR. Significant pathways in F. nucleatum–positive esophageal cancer tissues were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using microarray data.Results: Esophageal cancer tissues contained significantly more F. nucleatum DNA than matched normal esophageal mucosa (P = 0.021; n = 60). F. nucleatum DNA was detected in 74 of 325 cases (23%). F. nucleatum DNA positivity was significantly associated with tumor stage, but not with sex, age, performance status, tobacco use, alcohol use, histology, tumor location, or preoperative treatment. F. nucleatum DNA positivity was also significantly associated with cancer-specific survival [log-rank P = 0.0039; univariate HR = 2.01; 95% confidence interval (CI), 1.22–3.23; P = 0.0068; multivariate HR = 1.78; 95% CI, 1.06–2.94; P = 0.031]. The top-ranked KEGG pathway in F. nucleatum–positive tissues was “cytokine–cytokine receptor interaction.” A significant relationship between F. nucleatum and the chemokine CCL20 was validated by IHC.Conclusions: F. nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. F. nucleatum might also contribute to aggressive tumor behavior through activation of chemokines, such as CCL20. Clin Cancer Res; 22(22); 5574–81. ©2016 AACR.

Purpose:DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers.Experimental Design:Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panelsResults:We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85–0.95 for most GI cancers.Conclusions:Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.

Chronic pain in temporomandibular disorder (TMD) is a common health problem. Cumulating evidence indicates that the etiology of TMD pain is complex with multifactorial experience that could hamper the developments of treatments. Preclinical research is a resource to understand the mechanism for TMD pain, whereas limitations are present as a disease-specific model. It is difficult to incorporate multiple risk factors associated with the etiology that could increase pain responses into a single animal. This article introduces several rodent models which are often employed in the preclinical studies and discusses their validities for TMD pain after the elucidations of the neural mechanisms based on the clinical reports. First, rodent models were classified into two groups with or without inflammation in the deep craniofacial tissues. Next, the characteristics of each model and the procedures to identify deep craniofacial pain were discussed. Emphasis was directed on the findings of the effects of chronic psychological stress, a major risk factor for chronic pain, on the deep craniofacial nociception. Preclinical models have provided clinically relevant information, which could contribute to better understand the basis for TMD pain, while efforts are still required to bridge the gap between animal and human studies.

Background Bile duct adenomas (BDA) may be precursor lesions of small duct-type, including mass-forming type intrahepatic cholangiocarcinoma (ICC). Case report A 68-year-old woman was transferred to our facility for the treatment of a liver tumor, possibly metastasized from a pancreatic neuroendocrine tumor. Finally, two liver tumors were resected and histopathologically diagnosed as "BDA" and "ICC with a BDA-like component". In the BDA-like component, the MUC6 positive rate was notably lower and the Ki-67 positive rate was higher than the other BDAs and ICC component, respectively. The doubling time of the tumor volume in BDA was very long but was shortened (1,510 and 719 days). Distinct enlargement of the tumor and appearance of enhancement through diagnostic imaging was useful in diagnosing the transformation from a BDA to an ICC. Conclusion An "adenoma-carcinoma sequence" may exist in the transformation process from a BDA to an ICC.

The Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was developed to predict disease-free survival in patients with colorectal liver metastases (CRLM) undergoing upfront hepatectomy. However, the utility of the nomogram in patients with resected CRLM remains unknown in the current situation in which treatment strategies are changing with advances in drugs.Patients in the initial nomogram cohort (n = 727) and validation cohort (n = 2225) were divided into the upfront hepatectomy and preoperative chemotherapy groups. The nomogram was validated by measuring calibration and discrimination in the two cohorts. Calibration curves were plotted, and survival probabilities were compared. Finally, to quantify the discrimination power, we estimated the concordance index (C-index).In the upfront hepatectomy group, the C-index was 0.63, the suitable cutoff value of the Beppu score was 7, and adjuvant chemotherapy was significantly effective limited to high-risk patients (Beppu score ≥7). The C-index was 0.56 in the preoperative chemotherapy group.The JSHBPS nomogram remains beneficial for patients undergoing upfront hepatectomy in the recent era but is less effective for patients undergoing hepatectomy after chemotherapy. Patients with a Beppu score ≥7 showed high-risk recurrence, and adjuvant chemotherapy should be recommended for these patients.

BACKGROUND AND AIMS Tumor recurrence is frequent even in intrahepatic cholangiocarcinoma (ICC), and improved strategies are needed to identify patients at highest risk for such recurrence. We performed genome-wide expression profile analyses to discover and validate a gene signature associated with recurrence in patients with ICC. APPROACH AND RESULTS For biomarker discovery, we analyzed genome-wide transcriptomic profiling in ICC tumors from two public data sets: The Cancer Genome Atlas (n = 27) and GSE107943 (n = 28). We identified an eight-gene panel (BIRC5 [baculoviral IAP repeat containing 5], CDC20 [cell division cycle 20], CDH2 [cadherin 2], CENPW [centromere protein W], JPH1 [junctophilin 1], MAD2L1 [mitotic arrest deficient 2 like 1], NEIL3 [Nei like DNA glycosylase 3], and POC1A [POC1 centriolar protein A]) that robustly identified patients with recurrence in the discovery (AUC = 0.92) and in silico validation cohorts (AUC = 0.91). We next analyzed 241 specimens from patients with ICC (training cohort, n = 64; validation cohort, n = 177), followed by Cox proportional hazard regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model for recurrence in ICC. We subsequently trained this transcriptomic panel in a clinical cohort (AUC = 0.89; 95% confidence interval [CI] = 0.79-0.95), followed by evaluating its performance in an independent validation cohort (AUC = 0.86; 95% CI = 0.80-0.90). By combining our transcriptomic panel with various clinicopathologic features, we established a risk-stratification model that was significantly superior for the identification of recurrence (AUC = 0.89; univariate HR = 6.08, 95% CI = 3.55-10.41, P

Portal vein embolization (PVE) for hepatocellular carcinoma (HCC) was first introduced in 1986 and has been continuously developed throughout the years. Basically, PVE has been applied to expand the indication of liver resection for HCC patients of insufficient future liver remnant. Importantly, PVE can result in tumor progression in both embolized and non‐embolized livers; however, long‐term survival after liver resection following PVE is at least not inferior compared with liver resection alone despite the smaller future liver remnant volume. Five‐year disease‐free survival and 5‐year overall survival were 17% to 49% and 12% to 53% in non‐PVE patients, and 21% to 78% and 44% to 72% in PVE patients, respectively. At present, it has proven that PVE has multiple oncological advantages for both surgical and nonsurgical treatments. PVE can also enhance the anticancer effects of transarterial chemoembolization and can avoid intraportal tumor cell dissemination. Additional interventional transarterial chemoembolization and hepatic vein embolization as well as surgical two‐stage hepatectomy and associated liver partition and portal vein ligation for staged hepatectomy can enhance the oncological benefit of PVE monotherapy. Taken together, PVE is an important treatment which we recommend for listing in the guidelines for HCC treatment strategies., Oncological benefits of portal vein embolization (PVE) for hepatocellular carcinoma were summarized. PVE can result in tumor progression in both embolized and non‐embolized livers; however, long‐term survival after liver resection following PVE is at least not inferior compared with liver resection alone despite the smaller future liver remnant volume. Further, PVE has multiple oncological advantages for both surgical and nonsurgical treatments.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. While the extracellular matrix component plays an integral role in PDAC pathogenesis and mediating chemoresistance, its role in predicting response to chemotherapy in patients with PDAC remains unclear.We performed a systematic biomarker discovery by analysing genome-wide transcriptomic profiling data from 423 patients (GSE71729, GSE21501 and The Cancer Genome Atlas [TCGA]) for predicting overall survival (OS). This was subsequently validated in two independent clinical cohorts of 270 patients with PDAC (training cohort, n = 121, and validation cohort, n = 149). In addition, we investigated endoscopic ultrasound-fine needle aspiration biopsy specimens from 51 patients with PDAC with an unresectable cancer for predicting therapeutic response to gemcitabine-based therapy.After rigorous bioinformatic analysis, we identified laminin γ2 (LAMC2) to be a significant prognostic factor in all three PDAC data sets (GSE71729: hazard ratio [HR] = 2.04, P = 0.002; GSE21501: HR = 2.17, P = 0.031; TCGA: HR = 2.57, P 0.001). High LAMC2 expression in patients with PDAC was associated with a significantly poor OS and relapse-free survival in both the training (P 0.001, P 0.001) and validation cohorts (P = 0.001, P = 0.026). More importantly, LAMC2 expression robustly identified patients with PDAC and unresectable disease and those who responded to gemcitabine-based therapy (area under the curve = 0.79; 95% confidence interval [CI], 0.65-0.89). The univariate logistic regression analysis revealed that high LAMC2 expression was the only factor that predicted poor response to gemcitabine in patients with PDAC (odds ratio = 4.90; 95% CI, 1.45-16.6; P = 0.011).We conclude that LAMC2 is a novel prognostic and predictive biomarker for gemcitabine-based therapy in both the adjuvant and palliative setting; which could have significant impact on precision and individualised treatment of patients with PDAC.

Background/aim The prognosis of cholangiolocarcinoma, a rare malignant liver tumor derived from hepatic progenitor or stem cells, is considered relatively good; however, it frequently recurs. We herein present the diagnosis, histological findings, and treatment of cholangiolocarcinoma. Case report A 65-year-old woman with a large liver tumor (70 mm in diameter) was referred. Hepatocellular carcinoma was suspected based on strong early enhancement and delayed washout by enhanced computed tomography. The patient underwent curative left tri-sectionectomy. Histologically, she was diagnosed with pure cholangiolocarcinoma in a slightly fibrous liver. Three metachronous recurrent lesions (all ≤10 mm in diameter) were found between fifteen and twenty months after the initial hepatectomy. One lesion and the remaining two lesions were treated with hepatectomy and radiofrequency ablation, respectively. Two years after the initial diagnosis, she was doing well without recurrence. Conclusion Repeated hepatectomy and radiofrequency ablation might be useful for small intrahepatic recurrences of cholangiolocarcinoma.

Background Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.

Aim To assess the utility of the perioperative use of direct oral anticoagulants for patients with hepatocellular carcinoma (HCC) with cancer-associated thrombosis. Case report An 83-year-old woman was admitted with a solitary HCC (10-cm diameter), as well as with multiple sites of venous thromboembolism and macroscopic portal vein tumor thrombosis. She had appropriate liver function without viral hepatitis, triple-positive tumor markers, and secondary polycythemia. Edoxaban at 30 mg was initiated 10 days before surgery to remove HCC. Complete remission of the pulmonary embolism and stability of the deep vein thrombosis and massive superior mesenteric vein thrombosis were recognized preoperatively. An extended left hepatectomy was successfully performed. To avoid hemorrhage complications, we used intravenous administration of nafamostat mesylate for 2 days, thereafter we restarted edoxaban. Superior mesenteric vein thrombosis resolved 5 months after surgery. Conclusion Perioperative oral administration of edoxaban was useful in multidisciplinary treatment for a patient with advanced HCC with cancer-associated thrombosis.

Background An ectopic hepatocellular carcinoma (EHCC) arises from the ectopic liver which is defined as a hepatic organ or tissue not connected to surrounding tissues. EHCC is a rare disease and it is difficult to diagnose preoperatively. Furthermore, the clinical features are not fully elucidated. Case summary A retroperitoneal tumor (6 cm) was located at the dorsal side of the pancreas head on abdominal ultrasonography in an 81-year old woman positive for hepatitis C virus antibody. Contrast enhanced-computed tomography and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging showed viable HCC patterns with early enhancement and delayed washout. The tumor markers - serum alpha-fetoprotein and alpha-fetoprotein-L3% - were increased to 30.1 ng/mL and 83.1%, respectively. Protein induced by vitamin K absence or antagonist-II was within normal levels (17 mAU/mL). Positron emission tomography-computed tomography showed strong accumulation into the tumor (Standardized Uptake Value max: 13.8), and the tumor cytology following endoscopic ultrasound-guided fine needle aspiration showed poorly differentiated carcinoma. Tumor extirpation was performed, and operative findings showed that the retroperitoneal tumor was disconnected from the pancreas and the liver. Swollen lymph nodes near the tumor were histologically normal. On histological examination, the tumor was finally diagnosed as EHCC with Arginase-1 positive expression. Conclusion We report our experience of a rare EHCC which was difficult to diagnose, and we present a review of the literature.

Background/Purpose We examined therapeutic strategies for pancreatic neuroendocrine neoplasm (pNEN) associated with MEN1 (M‐pNEN) by investigating clinicopathological features and menin expression. Methods Seventy‐seven patients who underwent resection of pNEN at our department from January 2001 to December 2017 were retrospectively analyzed. Immunohistochemical analysis of menin was performed using resected specimens. Results Seven patients (9%) met the diagnostic criteria for MEN1. M‐pNEN had more tumors (P, This study aimed to describe therapeutic strategies for pancreatic neuroendocrine neoplasm associated with multiple endocrine neoplasia type 1 (M‐pNEN) by investigating the clinicopathological features and menin expression. Sonoda and colleagues concluded that minimal resection with strict follow‐up is recommended rather than extensive pancreatic resections for consideration of recurrence in M‐pNEN.

Human fascioliasis is a rare parasitic disease outside of countries in which it is endemic. The diagnosis of hepatic-phase fascioliasis by diagnostic imaging alone is challenging. A 69-year-old female was referred to our hospital for the treatment of a solitary solid cystic mass lesion, 6 cm in diameter, accompanied with mild symptoms and minimal changes in laboratory parameters. Intrahepatic cholangiocarcinoma was suspected, and she underwent extended posterior sectionectomy. Four months later, she was re-admitted because of fatigue, high fever, and epigastric pain. Her eosinophil fraction and immunoglobulin E levels were extremely elevated (49.1% and 6833 IU/ml, respectively). She was found to have two new reticular cystic hepatic tumors. Serum dot enzyme-linked immunosorbent assay for parasites revealed strong positivity for Fasciola hepatica. Praziquantel was ineffective, and multi-cystic tumors rapidly developed in the left lateral section, requiring emergency left lateral sectionectomy. An F. hepatica helminth, approximately 3 cm in size, was observed on the cut liver surface during hepatic resection. Prophylactic triclabendazole (1,000 mg/day) was administered twice. She has been well for over 10 years without relapse of fascioliasis. In patients with hepatic tumors accompanied by inflammatory changes and eosinophilia, detailed medical history and serological testing by dot enzyme-linked immunosorbent assay for parasites are strongly recommended.