Fabrication of 3D printed PCL/PEG artificial bile ducts as supportive scaffolds to promote regeneration of extrahepatic bile ducts in a canine biliary defect model.

In this study, a 3D porous poly(ε-caprolactone)/polyethylene glycol (PCL/PEG) composite artificial tubular bile duct was fabricated for extrahepatic bile duct regeneration. PCL/PEG composite scaffolds were fabricated by 3D printing, and the molecular structure, mechanical properties, thermal properties, morphology, and in vitro biocompatibility were characterized for further application as artificial bile ducts. A bile duct defect model was established in beagle dogs for in vivo implantation. The results demonstrated that the implanted PE1 ABD, serving as a supportive scaffold, effectively stimulated the regeneration of a new bile duct comprising CK19-positive and CK7-positive epithelial cells within 30 days. Remarkably, after 8 months, the newly formed bile duct exhibited an epithelial layer resembling the normal structure. Furthermore, the study revealed collagen deposition, biliary muscular formation, and the involvement of microvessels and fibroblasts in the regenerative process. In contrast, the anastomotic area without ABD implantation displayed only partial restoration of the epithelial layer, accompanied by fibroblast proliferation and subsequent bile duct fibrosis. These findings underscore the limited inherent repair capacity of the bile duct and underscore the beneficial role of the PE1 ABD artificial tubular bile duct in promoting biliary regeneration.

Laparoscopic versus open oncological extended re-resection for incidental gallbladder adenocarcinoma: we can do more than T1/2.

BACKGROUND: The laparoscopic and open approaches have comparable safety and oncological efficacy to treat early (T1b or T2) stage incidental gallbladder cancer (IGBC). However, their effects on T3 stage or above tumors unclear. METHODS: Data of IGBC patients who underwent radical re-resection were retrospectively analyzed. Demographic characteristics, surgical variables, and tumor characteristics were evaluated for association with survival. RESULTS: We analyzed retrospectively 201 patients (72 men, 129 women; median age 63 years; range, 36-85 years). 84 underwent laparoscopic re-resection and 117 underwent open surgery. The 5-year OS post-resection was 74.7%, with a median survival of 74.52 months. The median OS (73.92 months vs. 77.04 months, P = 0.67), and disease-free survival (72.60 months vs. 71.09 months, P = 0.18) were comparable between the laparoscopic re-resection and open surgery groups. The survival of patients with T1/T2 (median: 85.50 months vs. 80.14 months; P = 0.67) and T3 (median: 68.56 months vs. 58.85 months; P = 0.36) disease were comparable between the open re-resection and laparoscopic re-resection groups even after PS matching. Open surgery group lost significantly more blood, while laparoscopic surgery took longer. The postsurgical stay in the laparoscopic re-resection group was significantly shorter. Combined extrahepatic bile duct resection, gallbladder perforation, pT, pStage, histological grade, microscopic liver invasion, status of the resected margin, and adjuvant therapy comprised significant independent prognostic indicators for IGBC. CONCLUSIONS: Laparoscopic and open surgery can achieve similar short and long-term outcomes for T3 IGBC; however, careful surgical manipulation is necessary to avoid secondary injuries.

Comprehensive Landscape of ARID Family Members and Their Association with Prognosis and Tumor Microenvironment in Hepatocellular Carcinoma.

As one of the most lethal forms of cancers, hepatocellular carcinoma (HCC) claims many lives around the world, and it is especially common in China. The ARID family plays key roles in the pathogenesis and development of human cancers. The potential of several functional genes used as novel biomarkers has attracted more and more attention. However, the prognostic values of the ARID family in HCC patients are rarely known by people. In this study, we performed comprehensive analysis using TCGA datasets, finding that the expressions of ARID4B, ARID2, ARID3B, JARID2, ARID1A, ARID1B, and ARID3A were increased in HCC specimens compared to nontumor specimens, while the expressions of ARID4A and ARID3C were decreased in HCC specimens. According to the Pearson correlation data, the methylation levels of the majority of ARID members were negatively correlated. Upregulation of ARID3A, ARID5B, and ARID1A was related to a poor HCC outcome according to the data of multivariate assays. Then, we built a LASSO Cox regression model based on ARID3A, ARID5B, and ARID1A in HCC. Overall survival rates were considerably lower for those with high risk scores compared to those with low risk scores. Finally, we studied the associations between risk scores and several types of infiltrating immune cells. The data revealed that the risk score was positively related to the infiltration of CD8+ T cells, B cell, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cell. This study conducted a thorough analysis of the ARID members, resulting in new insights for further examination of the ARID family members as prospective targets in the treatment of HCC.

Prediction of Early Recurrence After R0 Resection for Gallbladder Carcinoma of Stage T1b-T3.

PURPOSE: The time-to-tumor recurrence can predict the prognosis of hepatobiliary cancers following curative-intent resection. Therefore, for patients with gallbladder carcinoma (GBC) of stage T1b-T3 who had undergone R0 resection, we investigated the risk factors for early recurrence of GBC and their prognosis. PATIENTS AND METHODS: A total of 260 patients with GBC with T1b-T3 disease and an R0 margin were identified. Their clinicopathologic characteristics, perioperative details and prognostic data were reviewed. Survival analyses were carried out using the Kaplan-Meier method. Logistic regression models were used to identify the risk factors for early recurrence. RESULTS: The optimal cutoff for early recurrence was 29 months. Early recurrence tended to result in relapse far from the primary tumor, and such patients tended to have significantly worse overall survival. Multivariate analysis revealed that T3 disease, N1/N2 stage, poor differentiation of tumor, and lymphovascular invasion (LI) were associated with a greater risk of early recurrence. Patients diagnosed as having GBC incidentally and who had the risk factors of early recurrence were more likely to benefit from re-resection 2-4 weeks after a cholecystectomy. CONCLUSION: T3 stage, N1-N2 stage, poor differentiation, and LI were independent risk factors associated with early recurrence for patients with GBC with stage T1b-T3 disease after R0 resection.

The preoperative elevated plasma fibrinogen level is associated with the prognosis of hilar cholangiocarcinoma.

PURPOSE: Elevated fibrinogen (Fbg) levels contribute to tumor progression and metastasis. However, little is known regarding the association of the clinicopathological characteristics and the prognosis of hilar cholangiocarcinoma (HC) with plasma fibrinogen. METHODS: Data on the plasma Fbg levels, clinicopathological characteristics, and overall survival were retrospectively collected. Plasma fibrinogen concentrations over 4.0 g/L were classified as hyperfibrinogen, elevated fibrinogen, or abnormal fibrinogen levels. We then analyzed the relationships among plasma fibrinogen level, clinicopathological features, and patient prognosis. RESULTS: A total of 171 HC patients were included. An elevated plasma fibrinogen level was associated with lymph-node metastasis (P < 0.001), the AJCC stage (P < 0.001), the surgical margin (P = 0.005), and vascular invasion (P = 0.027). Univariate analyses revealed that preoperative plasma fibrinogen (P < 0.001), operative blood loss (P = 0.044), vascular invasion (P < 0.001), CA19-9 (P = 0.003), surgical margin (P < 0.001), T stage (P < 0.001), histologic differentiation (P = 0.007), and lymph-node metastasis (P < 0.001) were associated with OS. The survival time of patients with high Fbg levels was shorter than that of patients with normal fibrinogen levels (P < 0.001). Furthermore, a multivariate analysis showed that fibrinogen was negatively and independently associated with the HC prognosis (P = 0.029). CONCLUSIONS: An elevated plasma Fbg level was associated with lymph-node metastasis, vascular invasion, the surgical margin, and the tumor stage, and the Fbg level might therefore be an independent factor associated with poor outcomes in HC patients.

Postsurgical radiotherapy in stage IIIB gallbladder cancer patients with one to three lymph nodes metastases: A propensity score matching analysis.

BACKGROUND: The effect of postsurgical radiotherapy (PSRT) among T1-3 gallbladder cancer (GBC) patients with one to three lymph node metastases remains controversial. The aim of this study was to assess the impact of PSRT on gallbladder cancer-specific survival (GBCSS) in patients with stage IIIB. METHODS: The data of GBC patients were obtained from the American Surveillance, Epidemiology, and End Results (SEER) Data resources between 2004 and 2015. Then, a 1:1 propensity score matching (PSM) method was performed. GBCSS was compared among all patients. Subgroup analysis was conducted to identify patients who would benefit from PSRT. RESULTS: 726 AJCC (8th edition) stage IIIB GBC patients were included. PSRT failed to improve GBCSS (p = 0.168). Male sex, tumor size ≥ 4 cm and absence of chemotherapy were independent negative prognostic factors. No significant survival benefit from PSRT was found in any subgroup. CONCLUSIONS: PSRT provides no survival benefit for IIIB GBC.

Laparoscopic surgery for oncologic extended resection of T1b and T2 incidental gallbladder carcinoma at a high-volume center: a single-center experience in China.

BACKGROUND: Surgical treatment is still the most effective treatment for gallbladder cancer. For the patients with stage T1b and above, the current guidelines recommend the extended radical operation, and oncologic extended resection can benefit the survival of the patients. The laparoscopic approach is still in the early phase, and its safety and oncological outcomes are not well known. OBJECTIVE: To evaluate the technical feasibility and oncological outcomes of laparoscopic surgery for oncologic extended resection of early-stage incidental gallbladder carcinoma. RESULTS: This study included 18 male and 32 female patients. Twenty patients underwent laparoscopic oncologic extended resection and 30 patients underwent open oncologic extended resection. All of the patients had R0 resection. A laparoscopic approach was associated with less intraoperative blood loss (242 ± 108.5 vs 401 ± 130.3; p < 0.01) and shorter duration of postoperative hospital stay (6.2 ± 2.4 vs 8.6 ± 2.3; p < 0.01). There was no statistically significant difference between two groups for lymph nodes yield (5.4 ± 3.5 vs 5.8 ± 2.1; p > 0.05), incidence of lymphatic metastasis (15% vs 16.67%; p > 0.05), residual disease (20% vs 23.3%; p > 0.05), and postoperative morbidity (15% vs 20%; p > 0.05). During follow-up time of median 20.95 (12-29.5) months, no significant difference was found between the two groups for early tumor recurrence (10% vs 13.33%; p > 0.05) and disease-free survival (p > 0.05). CONCLUSION: Laparoscopic surgery may offer similar intraoperative, perioperative, and short-term oncological outcomes as an open oncologic extended resection for incidental gallbladder carcinoma.

Laparoscopic appendectomy is safe and feasible in pregnant women during second trimester: A retrospective study in a top-level Chinese center.

Acute appendicitis (AA) is the most common nonobstetric surgical emergency during pregnancy. According to the current guidelines and meta-analyses, traditional open appendectomy (OA) is still recommended for pregnant patients over laparoscopic appendectomy (LA), which might be associated with higher rates of fetal loss. Previous studies and experiences indicated that LA might be safe in the second trimester of pregnancy. The current study aimed to evaluate the safety and feasibility of LA in pregnant women during the second trimester.At our institution, a retrospective study was conducted with pregnant patients who underwent LA or OA during the second trimester between January 2016 and August 2018.A total of 48 patients were enrolled. Of them, 12 were managed with laparoscopy and 36 with the open approach. We found that the LA group had higher BMIs than the OA group (4.0 ±â€Š4.3 vs 21.5 ±â€Š2.9, P = .031). The financial results showed that the average daily medical costs for patients who underwent LA was higher than those who underwent OA (444 ±â€Š107 US$ vs 340 ±â€Š115 US$, P = .009), while the total cost of hospitalization was comparable between the 2 approaches. The perioperative and obstetric outcomes were comparable between LA and OA. In each group, only 1 patient had fetal loss. No "Yinao" was found in any of the patients in the LA group.In this study, with the proven advantages of the laparoscopic techniques, LA was found to be safe and feasible for pregnant women during the second trimester.

A Novel Nomogram Predicting Distant Metastasis in T1 and T2 Gallbladder Cancer: A SEER-based Study.

Background: Gallbladder cancer (GBC) is the most common malignancy of the biliary system. Early T stage GBC patients with distant metastasis are proven to have a worse prognosis. In this study, our aim was to construct and validate a novel nomogram for predicting distant metastasis in T1 and T2 GBC. Methods: Between 2004 and 2014, patients with T1 and T2 GBC were identified in the Surveillance, Epidemiology, and End Results (SEER) database. All of the eligible patients were randomly divided into training and validation cohorts. Univariate and multivariate analyses were used to assess significant predictive factors associated with distant metastasis. A nomogram was developed and validated by a calibration curve and receptor operating characteristic curve (ROC) analysis. Results: According to the inclusion and exclusion criteria, 3013 patients with historically confirmed AJCC stage T1 and T2 GBC were enrolled. Younger age, high pathological grade, nonadenocarcinoma, T1, N1 and larger tumor size correlated positively with the risk of distant metastasis. A novel nomogram was established to predict distant metastasis in early T stage GBC patients. Internal validation with a calibration plot in the training cohort showed that this nomogram was well calibrated. Through ROC curve analysis, the areas under the ROC curves in the training and validation cohorts were 0.723 and 0.679, respectively. Conclusions: Although some limitations exist in this predictive model, the nomogram revealed the relationship between the clinicopathological characteristics of T1 and T2 GBC patients and the risk of distant metastasis. The novel nomogram will assist in patient counseling and guide treatment decision making for T1 and T2 GBC patients.

Meta-analysis of randomized clinical trials of adjuvant chemotherapy for resected biliary tract cancers.

BACKGROUND: This meta-analysis was performed by analyzing randomized controlled trials (RCTs) to assess the potential prognostic value of adjuvant chemotherapy (ACT) for patients with resected biliary tract cancers (BTCs). METHODS: PubMed, EMBASE, and the Cochrane Library were searched for relevant articles published. Only RCTs affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS). RESULTS: The study identified 1192 patients who met the inclusion and exclusion criteria. ACT had nearly reached a significant better OS (HR, 0.88; 95% CI, 0.77-1.01; P = 0.07) and achieved a significant better RFS (HR, 0.83; 95% CI, 0.69-0.99; P = 0.04). The effectiveness of ACT for OS was significantly modified by fluorouracil-based ACT (HR, 0.83; 95% CI, 0.70-0.99; P = 0.04), but not by gemcitabine-based ACT (HR, 0.91; 95% CI, 0.74-1.12; P = 0.36). The survival benefit was also not modified by primary disease site, resection margin status, and lymph node status. CONCLUSIONS: ACT is correlated with favorable relapse-free survival compared with non-ACT for resected BTCs patients. Fluorouracil-based ACT could be viewed as a standard practice for resected BTCs patients regardless of the primary cancer site, lymph node or margin status.

Biliary antibiotics irrigation for E. coli-induced chronic proliferative cholangitis and hepatolithiasis: A pathophysiological study in rabbits.

BACKGROUND: The gram-negative bacteria secreted endotoxin, Lipopolysaccharide (LPS), plays important roles in the formation and recurrence of hepatolithiasis and chronic biliary inflammation in patients of Southeast Asia. We aimed to elucidate the anti-inflammatory effect and mechanism of local antibiotics irrigation on chronic proliferative cholangitis (CPC) and hepatolithiasis. METHODS: Escherichia coli was injected into rabbit bile ducts to induce CPC. Rabbits were divided into sham operation (SO), povidone-iodine, Metronidazole plus chlorhexidine, ofloxacin, furacillin, Neosporin® G.U., and CPC groups. Local irrigation was performed for 28 days after CPC was established. Residual E. coli and LPS, and the expression of MCP-1, CD14, COX-2, VEGF, IL-6, NF-κB, TNF-α, Fas, TGF-ß1, α-SMA, Collagen-I, ß-glucuronidase, PKC, C-myc, and Mucin 5AC were assessed in bile duct tissues. RESULTS: The residual E. coli and LPS, and expression of MCP-1, CD14, COX-2, IL-6, NF-κB, TNF-α, Fas, TGF-ß1, α-SMA, ß-glucuronidase, PKC, C-myc, and Mucin 5AC in the SO, povidone-iodine, Metronidazole plus chlorhexidine, ofloxacin, and Neosporin® G.U. groups were significantly lower than those in the furacillin and CPC groups (P<0.05). VEGF and Collagen-I levels in the SO, povidone-iodine, metronidazole plus chlorhexidine, and ofloxacin groups were significantly lower than those in the furacillin, Neosporin® G.U., and CPC groups (P<0.05). CONCLUSIONS: LPS affects the pathophysiology of E. coli caused chronic proliferative cholangitis and hepatolithiasis recurrence. Local antibiotics irrigation could prevent chronic proliferative cholangitis and stones formation by decreasing LPS-induced proinflammatory and profibrotic cytokines release. Povidone iodine, metronidazole plus chlorhexidine, and ofloxacin were more effective than Neosporin® G.U. and furacillin.

Extended Lymphadenectomy Versus Regional Lymphadenectomy in Resectable Hilar Cholangiocarcinoma.

AIM: The aim of this study is to compare the effects of extended lymphadenectomy (E-LD) and regional lymphadenectomy (R-LD) on outcome after radical resection of hilar cholangiocarcinoma (HCCA). METHODS: Data of 290 patients who underwent radical resection of HCCA were retrospectively analyzed. Demographic characteristics, surgical variables, and tumor and LN characteristics were evaluated for association with survival. RESULTS: A total of 63 patients underwent E-LD. Patients who underwent E-LD were more likely to have portal vein embolization (14.3% vs. 5.7%), radical hepatectomy (36.2% vs. 26.0%), higher proportion of M1 patients (22.2% vs. 5.3%), more lymph nodes (LNs) retrieved (17 vs. 7), and positive common hepatic artery lymph nodes (21.4% vs. 12.6%) when compared with R-LD (all P < 0.05). The Kaplan-Meier curve of overall survival for patients who underwent E-LD indicated improvement over patients who underwent R-LD in M0 (33.39 vs. 21.31 months; P = 0.032) and R0 resection (32.97 vs. 21.02 months; P = 0.044) disease, but not observed in M1 disease (P > 0.05). After propensity score matching, E-LD was not associated with a significant improvement in overall survival (OS) even in all subgroup analysis (all P > 0.05). On multivariable analysis, E-LD was associated with improved overall survival, but not after propensity score matching. CONCLUSION: E-LD is more likely to be performed in higher stage tumors. E-LD significantly increases LN retrieval, thereby preventing under-staging and improving survival prediction. E-LD should not be adopted for HCCA patients with intraoperatively confirmed distant LN metastases. Future studies are required to further assess whether E-LD should be performed in negative celiac, superior mesenteric, and para-aortic lymph node in HCCA patients.

A simple scoring system to predict early recurrence of Bismuth-Corlette type IV perihilar cholangiocarcinoma.

BACKGROUND: Early recurrence has been reported to be predictive of a poor prognosis for patients with perihilar cholangiocarcinoma (pCCA) after resection. The objective of our study was to construct a useful scoring system to predict early recurrence for Bismuth-Corlette type IV pCCA patients in clinic and to investigate the value of early recurrence in directing post-operative surveillance and adjuvant therapy. METHODS: In total, 244 patients who underwent radical resection for type IV pCCA were included. Data on clinicopathological characteristics, perioperative details and survival outcomes were analyzed. Survival curves were generated using the Kaplan-Meier method. Univariate and multivariate logistic-regression models were used to identify factors associated with early recurrence. RESULTS: Twenty-one months was defined as the cutoff point to distinguish between early and late recurrence. Univariate and multivariate analysis revealed that CA19-9 level >200 U/mL, R1 resection margin, higher N category and positive lymphovascular invasion were independent predictors of early recurrence. The scoring system was constructed accordingly. The early-recurrence rates of patients with scores of 0, 1, 2, 3, 4, and 5 were 23.9%, 38.7%, 60.0%, 78.6%, 83.4%, and 100%, respectively. Adjuvant therapy was significantly associated with higher overall survival rate for patients with early recurrence, but not for those with late recurrence. Patients in the early-recurrence group with scores ≥2 had better prognoses after adjuvant therapy. CONCLUSIONS: A simple scoring system using CA19-9 level, N category, resection margin and lymphovascular invasion status could predict early recurrence, and thus might direct post-operative surveillance and adjuvant therapy for patients with type IV pCCA.

Prognostic significance of mucinous component in hilar cholangiocarcinoma after curative-intent resection.

BACKGROUND: The presence of mucinous component has been indicated to have a prognostic value in adenocarcinoma. However, little is known regarding the clinicopathological characteristics and prognosis of hilar cholangiocarcinoma (HC) with mucinous component (HCM). METHODS: Between January 1996 and December 2014, a total of 61 HCM patients who underwent curative-intent resection at West China Hospital were retrospectively reviewed. The clinicopathological characteristics and survival of these patients were compared with a large cohort of 217 surgically resected conventional HC patients during the same period. RESULTS: The clinicopathological characteristics of HCM were distinct from conventional HC, including higher CA19-9 levels, larger tumor sizes, less differentiation, and a high frequency of liver parenchyma invasion, portal vein invasion, and lymphovascular invasion. HCM patients showed significantly worse recurrence-free survival (13.4 vs 23.9 months; P = .011) and overall survival (18.2 vs 32.1 months; P = .019) compared with conventional HC patients. Multivariate analysis confirmed liver parenchyma invasion, N stage, surgical margin, and histological grade as independent prognostic factors influencing overall survival in HCM patients. CONCLUSION: HCM showed distinct clinicopathological features, more aggressive biological behaviors, and poor prognosis in comparison with conventional HC. Therefore, the mucinous component is an adverse prognostic factor for HC.

Preoperative serum ferritin is an independent prognostic factor for liver cancer after hepatectomy.

BACKGROUND AND AIMS: Serum ferritin (SF) may have a close relationship with the tumor. But no study has investigated the prognostic value of SF in hepatocellular carcinoma (HCC) patients receiving curative resection yet. Aim of this study is to explore the role of preoperative SF in survival outcomes of such patients. METHODS: We retrospectively analyzed 427 HCC patients who received curative hepatic resection in our medical center. Significant clinical and pathological data along with the association between SF and clinicopathological parameters were compared and analyzed. The prognostic significance of SF was determined by Kaplan-Meier analysis and the Cox proportional hazards regression model. RESULTS: The optimal cut-off value of SF for overall survival (OS) was 267 ng/ml. Preoperative SF level could predict OS (P = 0.001, HR = 1.651, 95%CI: 1.213-2.247) and recurrence-free survival (RFS) (P < 0.001, HR = 1.570, 95%CI: 1.221-2.018) independent of other prognostic factors. Patients with a low SF were more likely to have both favorable OS and RFS (both P < 0.001), and vice versa. The 1-, 3-, and 5-year OS and RFS rates were 91.4%, 80.1%, 71.7%, and 78.0%, 53.0%, 47.3% in low SF group, and 91.6%, 60.2%, 45.2%, and 61.3%, 36.4%, 29.0% in high SF group, respectively. CONCLUSIONS: Preoperative SF was a simple, inexpensive, convenient and reliable prognostic factor that could predict survival outcomes in HCC patients who received radical hepatic resection.