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There have been no clinical guidelines for the management of pancreaticobiliary maljunction (PBM). The Japanese Study Group on Pancreaticobiliary Maljunction (JSPBM) has proposed to establish clinical practice guidelines on how to deal with PBM, with the support of the Japan Biliary Association (JBA). Because the body of evidence-based literature is relatively small, we decided to create guidelines based on the consensus of experts, using the medical literature for reference. A total of 46 clinical questions (CQs) were considered by the members of the editorial committee responsible for the guidelines. The CQs covered distinct aspects of PBM: (1) Concepts and Pathophysiology (10 CQs); (2) Diagnosis (10 CQs); (3) Pancreatobiliary complications (9 CQs); and (4) Treatments and prognosis (17 CQs). Statements and comments for each CQ were prepared by the guidelines committee members and collaborating partners. The CQs were completed after review by members of the editorial committee, meetings of this committee, public comments on the homepages of the JSPBM and the JBA, public hearings, and assessment and approval by the guidelines evaluation board. PBM includes cases where the bile duct is dilated (PBM with biliary dilatation) and those in which it is not (PBM without biliary dilatation). In these guidelines, PBM with biliary dilatation is defined as being identical to congenital biliary dilatation of Todani type I (except for type Ib) and type IV-A, both of which are accompanied by PBM in almost all cases. These guidelines are created to provide assistance in the clinical practice of PBM management; their contents focus on clinical utility, and they include general information on PBM to make this disease more widely recognized.

Targeting the tumor stroma is an important strategy in cancer treatment. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are two main components in the tumor microenvironment (TME) in hepatocellular carcinoma (HCC), which can promote tumor progression. Plasminogen activator inhibitor-1 (PAI-1) upregulation in HCC is predictive of unfavorable tumor behavior and prognosis. However, the crosstalk between cancer cells, TAMs and CAFs, and the functions of PAI-1 in HCC remain to be fully investigated. In the present study, macrophage polarization and key paracrine factors were assessed during their interactions with CAFs and cancer cells. Cell proliferation, wound healing and Transwell and Matrigel assays were used to investigate the malignant behavior of HCC cells in vitro. It was found that cancer cells and CAFs induced the M2 polarization of TAMs by upregulating the mRNA expression levels of CD163 and CD206, and downregulating IL-6 mRNA expression and secretion in the macrophages. Both TAMs derived from cancer cells and CAFs promoted HCC cell proliferation and invasion. Furthermore, PAI-1 expression was upregulated in TAMs after being stimulated with CAF-conditioned medium and promoted the malignant behavior of the HCC cells by mediating epithelial-mesenchymal transition. CAFs were the main producer of C-X-C motif chemokine ligand 12 (CXCL12) in the TME and CXCL12 contributed to the induction of PAI-1 secretion in TAMs. In conclusion, the results of the present study suggested that CAFs promoted the M2 polarization of macrophages and induced PAI-1 secretion via CXCL12. Furthermore, it was found that PAI-1 produced by the TAMs enhanced the malignant behavior of the HCC cells. Therefore, these factors may be targets for inhibiting the crosstalk between tumor cells, CAFs and TAMs.

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer‐adipocyte interaction. We first investigated the ability of adipocytes to de‐differentiate to cancer‐associated adipocytes (CAAs) by co‐culturing with pancreatic cancer cells. We then examined the effects of CAA‐conditioned medium (CAA‐CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3‐L1 adipocytes were co‐cultured with pancreatic cancer cells (PANC‐1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast‐like cells (CAA). Adipocyte‐specific marker mRNA levels significantly decreased but those of fibroblast‐specific markers appeared, characteristic findings of CAA, as revealed by real‐time PCR. When PANC‐1 cells were cultured with CAA‐CM, significantly higher migration/invasion capability, chemoresistance, and epithelial‐mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC‐1 cells cultured with CAA‐CM and found a 78.5‐fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC‐1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1‐positive group was significantly shorter than in the SAA1‐negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de‐differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer. Cancer‐associated adipocyte (CAA) promotes migration/invasion of pancreatic cancer cells. CAA also induced pancreatic cancer cells drug resistance, epithelial‐mesenchymal transition.

Although right‐sided colorectal cancer (CRC) shows a worse prognosis than left‐sided CRC, the underlying mechanism remains unclear. We established patient‐derived organoids (PDOs) from left‐ and right‐sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right‐sided cancer PDOs were significantly higher than in left‐sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT‐PCR to compare 184 genes in 30 pathways among right‐sided and left‐sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right‐sided PDOs. TIMP1 protein levels were upregulated in right‐sided PDOs compared with normal PDOs but was downregulated in left‐sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right‐sided PDOs but not in left‐sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right‐sided PDOs but not in left‐sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right‐sided CRCs was significantly higher than in left‐sided CRCs. Kaplan–Meier survival analysis showed significantly shorter overall survival in high‐TIMP1 patients versus low‐TIMP1 patients with right‐sided CRCs but not left‐sided CRCs. Our data suggest that TIMP1 is overexpressed in right‐sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right‐sided CRCs. Our study suggests that TIMP1 is overexpressed in the right‐sided colorectal cancer, and promotes cell proliferation and invasion capability through TIMP1/FAK/Akt pathway, leading to poor prognosis.

Background Programmed cell death protein 1 (PD-1) and its ligand PD-L1 downregulate T cell activation and are related to immune tolerance. The aim of this study was to clarify the significance of PD-1 and PD-L1 expression and to analyze the relationships among PD-1, PD-L1, and Foxp3 expression in gastric cancer. Methods A total of 105 patients who underwent curative gastrectomy for stage II/III gastric cancer were included in this study. PD-1, PD-L1, and Foxp3 expression were examined by immunohistochemistry and related to prognostic factors by univariate and multivariate analyses. Results PD-1 expression was correlated with both PD-L1 and Foxp3 expression. Disease-free survival (DFS) was significantly poorer in PD-1-positive patients than in PD-1-negative patients (3-year DFS, 36.1 % vs. 64.7 %, respectively; p  < 0.05). Overall survival also tended to be poorer in PD-L1-positive patients than in PD-L1-negative patients. Univariate analysis identified sex, T factor, lymphatic invasion, and PD-1 positivity as significant predictors of poor DFS. Multivariate analysis confirmed male sex, lymphatic invasion, and positive PD-1 expression as independent prognostic indicators. Conclusions PD-1 expression is associated with a poor prognosis and is correlated with PD-L1 and Foxp3 expression in patients with gastric cancer.

BackgroundThe concept of frailty becomes important for patients who undergo surgery in this recent aging society. The aim of this study is to investigate the frailty as a prognostic factor in elderly patients with hepatocellular carcinoma (HCC) who underwent hepatectomy.Patients and MethodsA total of 92 patients over 75 years old who underwent hepatectomy were enrolled in this study. Frailty was defined as clinical frailty scale (CFS) ≥ 4. Patients were divided into two groups, i.e., frailty group (n = 21) and no-frailty group (n = 71), and clinicopathological features were compared between them.ResultsThe frailty group showed significant higher PIVKA-II level and larger tumor diameter (p < 0.05). CRP level and modified Glasgow prognostic score were significantly higher in the frailty group (p < 0.05). The frailty group showed higher rate of postoperative complications of Clavien–Dindo III (p = 0.06) and longer postoperative stay (p = 0.08). Cancer-specific, overall, and disease-free survival rates were significantly worse in the frailty group (p < 0.05). Frailty was detected as an independent prognostic factor on multivariate analysis of cancer-specific survival.ConclusionFrailty can estimate the prognosis of HCC patients who underwent hepatectomy.

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other’s work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.

Introduction: It remains unclear which surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group). Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤7, largest HCC diameter ≤3 cm, and ≤3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing. Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range [IQR], 1.5–2.2 cm) in the surgery group and 1.8 cm (IQR, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 vs. 40 min, p < 0.01) and the median duration of hospital stay (17 days vs. 10 days, p < 0.01) were longer in the surgery group than in the RFA group. RFS did not differ significantly between the groups as the median RFS was 3.5 (95% confidence interval [CI], 2.6–5.1) years in the surgery group and 3.0 (95% CI, 2.4–5.6) years in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; p = 0.58). Discussion/Conclusion: Our study did not show which surgery or RFA is the better treatment option for small HCC.

Cancer‐associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab‐paclitaxel (nab‐PTX) is a 130 nm albumin‐binding paclitaxel and recommended for many types of cancer chemotherapy. The nab‐PTX stromal‐disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab‐PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa‐2 and Panc‐1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial‐mesenchymal transition (EMT)‐related marker expression and C‐X‐C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab‐PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT‐related marker expression, CXCL10 expression and secretion, and interleukin‐6 (IL‐6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E‐cadherin and upregulated N‐cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell‐cultured medium, CAF significantly increased IL‐6 expression and secretion. However, nab‐PTX in the coculture system canceled CAF‐induced migration and invasion promotion and EMT‐related gene changes. Moreover, nab‐PTX increased CXCL10 expression of cancer cells which blocked CAF IL‐6 expression and secretion. Nab‐PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion‐promoting effect by inhibiting IL‐6 expression. Pancreatic cancer cells increased IL‐6 expression of cancer‐associated fibroblasts (CAF) which could promote cancer cell metastasis. Nab‐paclitaxel could stimulate CXCL10 expression of pancreatic cancer cells, which could inhibit IL‐6 expression of CAF and decrease its cancer cell migration and invasion‐promoting ability.