Management of anastomotic biliary stricture through utilizing percutaneous transhepatic cholangioscopy.

AIM: Occurrence of anastomotic biliary stricture (AS) remains an essential issue following hepatobiliary surgeries, and percutaneous transhepatic cholangioscopy (PTCS) has great therapeutic significance in handling refractory AS for patients with altered gastrointestinal anatomy after cholangio-jejunostomy. This present study aimed to investigate feasibility of PTCS procedures in AS patients for therapeutic indications. MATERIALS AND METHODS: This study was a single-center, retrospective cohort study with a total number of 124 consecutive patients who received therapeutic PTCS due to AS. Clinical success rate, required number, and adverse events of therapeutic PTCS procedures as well as patients survival state were reviewed. RESULTS: These 124 patients previously underwent choledochojejunostomy or hepatico-jejunostomy, and there was post-surgical altered gastrointestinal anatomy. Overall, 366 therapeutic PTCS procedures were performed for these patients through applying rigid choledochoscope, and the median time of PTCS procedures was 3 (1-11). Among these patients, there were 34 cases (27.32%) accompanied by biliary strictures and 100 cases (80.65%) were also combined with biliary calculi. After therapeutic PTCS, most patients presented with relieved clinical manifestations and improved liver functions. The median time of follow-up was 26 months (2-86 months), and AS was successfully managed through PTCS procedures in 104 patients (83.87%). During the follow-up period, adverse events occurred in 81 cases (65.32%), most of which were tackled through supportive treatment. CONCLUSION: PTCS was a feasible, safe and effective therapeutic modality for refractory AS, which may be a promising alternative approach in clinical cases where the gastrointestinal anatomy was changed after cholangio-jejunostomy.

Exosomes derived from TGF-ß1-pretreated mesenchymal stem cells alleviate biliary ischemia-reperfusion injury through Jagged1/Notch1/SOX9 pathway.

BACKGROUND: This study aimed to evaluate the efficacy of exosomes (EXO) derived from TGF-ß1-pretreated mesenchymal stem cells (MSCs) on biliary ischemia reperfusion injury (IRI) and further reveal the possible mechanisms. METHODS: Bone marrow-derived MSCs were treated with exogenous TGF-ß1, Jagged1/Notch1/SOX9 pathway inhibitor LY450139, or their combination. Then, EXO were isolated from the culture supernatants and further characterized. After establishing IRI model of biliary epithelial cells (EpiCs), EXO derived from differently-treated MSCs were applied to detect their protective effects on EpiCs, and LY450139 was applied in EpiCs to detect the possible mechanisms after treatment with MSCs-EXO. EXO derived from differently-treated MSCs were further injected into the hepatic artery immediately after establishment of intrahepatic biliary IRI for animal studies. RESULTS: Pretreatment with TGF-ß1 significantly enhanced MSCs-EXO production and elevated the levels of massive miRNAs associated with anti-apoptosis and tissue repair, which were evidently decreased after TGF-ß1 plus LY450139 cotreatment. Notable improvement was observed in EpiCs after MSCs-EXO treatment, evidenced by reduced cellular apoptosis, increased cellular proliferation and declined oxidative stress, which were more evident in EpiCs that were treated with EXO derived from TGF-ß1-pretreated MSCs. However, application of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs reversely enhanced cellular apoptosis, decreased cellular proliferation and anti-oxidants production. Interestingly, LY450139 application in EpiCs after treatment with MSCs-EXO also reversed the declined cellular apoptosis and enhanced oxidative stress induced by TGF-ß1 pretreatment. In animal studies, administration of EXO derived from TGF-ß1-pretreated MSCs more effectively attenuated biliary IRI through reducing oxidative stress, apoptosis, inflammation and enhancing the expression levels of TGF-ß1 and Jagged1/Notch1/SOX9 pathway-related markers, which were reversed after administration of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs. CONCLUSION: Our results provided a vital insight that TGF-ß1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway.

Identification and Experimental Validation of the Prognostic Significance and Immunological Correlation of Glycosylation-Related Signature and ST6GALNAC4 in Hepatocellular Carcinoma.

Purpose: Glycosylation has been demonstrated to be involved in tumorigenesis, progression, and immunoregulation, and to present specific profiles in different tumors. In this study, we aimed to explore the specific glycosylation-related gene (GRG) signature and its potential immunological roles and prognostic implications in hepatocellular carcinoma (HCC). Patients and Methods: The GRG expression profile was defined using the transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate and the least absolute shrinkage and selection operator Cox analyses were performed to develop a GRG-based risk score model. A nomogram was subsequently established and validated. Its correlation with cancer immune microenvironment and drug susceptibility was further analyzed. The role and immunological correlation of ST6GALNAC4 were further experimentally validated at the tissue and cellular levels in HCC. Results: A total of 87 GRGs were identified to be significantly dysregulated in HCC, and a novel risk score model was constructed using eight critical GRGs, which demonstrated superior prognostic discrimination and predictive power in both training and validation groups. High risk scores in HCC patients were associated with lower OS. The model was also identified as an independent risk factor for HCC, and a novel nomogram was subsequently constructed and validated. Notably, significant correlations were found in risk scores with immune cells infiltration, tumor immunophenotyping, immune checkpoint genes' expression, and sensitivities to multiple drugs. Furthermore, we validated in local HCC samples that ST6GALNAC4 was significantly upregulated and its knockdown significantly inhibited the tumor proliferation, migration and invasion ability and affected the expression of immune checkpoints on hepatoma cells. Conclusion: We identified a novel GRG-based model which showed significant prognostic and immunological correlations in HCC, and the oncogenic role of ST6GALNAC4 has been validated and may serve as a potential drug target.

Efficiency of percutaneous transhepatic cholangioscopy in the treatment of biliary complications after liver transplantation.

BACKGROUND: Percutaneous transhepatic cholangioscopy (PTCS) has provided an alternative therapeutic option for handling refractory biliary complications in liver transplanted recipients. This study aimed to evaluate short-term PTCS efficiency in the management of biliary complications following liver transplantation. METHODS: Clinical data of 25 patients who received therapeutic PTCS due to biliary complications after liver transplantation were retrospectively analyzed. RESULTS: Therapeutic PTCS was successfully performed in 25 patients. Biliary complications were anastomotic strictures in seven cases, intrahepatic cholangiolithiasis in four cases, extra-and intrahepatic cholangiolithiasis in three cases, choledocholithiasis complicated with anastomotic strictures in four cases, intrahepatic cholangiolithiasis complicated with non-anastomotic strictures in one case, intrahepatic cholangiolithiasis complicated with anastomotic strictures in five cases, intrahepatic cholangiolithiasis complicated with anastomotic strictures and ischemic cholangitis in one case. The median time between liver transplantation and first PTCS was 24 months, and median times of PTCS was 2.6. Clinical manifestations were significantly improved in most patients after PTCS, and biliary complications were successfully managed through PTCS in 15 cases, which were partially effective in eight cases and ineffective in two cases. PTCS was more effective in tackling anastomotic strictures and cholangiolithiasis. CONCLUSION: PTCS was an effective therapeutic modality for treating refractory biliary complications following liver transplantation.

Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin With or Without Sorafenib as Initial Treatment for Advanced Hepatocellular Carcinoma.

PURPOSE: Our previous study showed that hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus sorafenib provided a significant survival benefit over sorafenib for advanced hepatocellular carcinoma. However, it is unclear whether the survival benefit should be attributed to the synergism between HAIC and sorafenib or just HAIC alone. We aim to compare HAIC using FOLFOX plus sorafenib with HAIC alone in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: This was a retrospective study including 225 eligible patients treated with HAIC using FOLFOX (HAIC alone group, n=126, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² and 2400 mg/m² for 46 hours, every 3 weeks) alone or HAIC plus sorafenib (soraHAIC group, n=99, sorafenib 400 mg twice daily). Survival curves were calculated by the Kaplan-Meier method, and propensity-score matching was used to reduce bias. RESULTS: The soraHAIC group showed a longer overall survival (12.9 [95% CI, 10.4-15.4] vs. 10.5 [95% CI, 9.5-11.5] months, HR=0.71 [95% CI, 0.53-0.96]; P=0.025), a better progression free survival (7.0 [95% CI, 5.3-8.8] vs. 5.3 [95% CI, 3.5-7.1] months, HR=0.76 [95% CI, 0.58-0.99]; P=0.046), and a higher disease control rate (RECIST 1.1: 74.8% vs. 61.1%, P=0.030) than the HAIC alone group. In multivariate analysis, soraHAIC was an independent favor factor for survival. In terms of the grade 3/4 adverse event, hand-foot skin reaction was more frequent in the soraHAIC group than the HAIC alone group. In the propensity-score matched cohorts (93 pairs), the overall survival, the progression free survival and disease control rates in the soraHAIC group were also better than those in the HAIC group (P<0.05). CONCLUSION: HAIC plus sorafenib may improve overall survival and progression free survival compared with HAIC alone as initial treatment for advanced hepatocellular carcinoma.

Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma.

BACKGROUND: Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma, but prognosis is still unsatisfactory. Recently, hepatic arterial infusion chemotherapy (HAIC), and immune checkpoint inhibitors showed promising results for advanced hepatocellular carcinoma. Considering different anti-malignancy mechanisms, combining these three treatments may improve outcomes. This study aimed to compare the efficacy and safety of lenvatinib, toripalimab, plus HAIC versus lenvatinib for advanced hepatocellular carcinoma. METHODS: This was a retrospective study including patients treated with lenvatinib [8 mg (⩽60 kg) or 12 mg (>60 kg) once daily] or lenvatinib, toripalimab plus HAIC [LeToHAIC group, lenvatinib 0-1 week prior to initial HAIC, 240 mg toripalimab 0-1 day prior to every HAIC cycle, and HAIC with FOLFOX regimen (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 h, every 3 weeks)]. Progression-free survival, overall survival, objective response rate, and treatment-related adverse events were compared. RESULTS: From February 2019 to August 2019, 157 patients were included in this study: 71 in the LeToHAIC group and 86 in the lenvatinib group. The LeToHAIC group showed longer progression-free survival (11.1 versus 5.1 months, p < 0.001), longer overall survival (not reached versus 11 months, p < 0.001), and a higher objective response rate (RECIST: 59.2% versus 9.3%, p < 0.001; modified RECIST: 67.6% versus 16.3%, p < 0.001) than the lenvatinib group. In addition, 14.1% and 21.1% of patients in the LeToHAIC group achieved complete response of all lesions and complete response of the intrahepatic target lesions per modified RECIST criteria, respectively. Grade 3/4 treatment-related adverse events that were more frequent in the LeToHAIC group than in the lenvatinib group included neutropenia (8.5% versus 1.2%), thrombocytopenia (5.6% versus 0), and nausea (5.6% versus 0). CONCLUSIONS: Lenvatinib, toripalimab, plus HAIC had acceptable toxic effects and might improve survival compared with lenvatinib alone in advanced hepatocellular carcinoma.

Comparison of HBV reactivation between patients with high HBV-DNA and low HBV-DNA loads undergoing PD-1 inhibitor and concurrent antiviral prophylaxis.

BACKGROUND: Programmed cell death protein-1 (PD-1) inhibitor is recommended to treat advanced hepatocellular carcinoma (HCC). However, the safety of PD-1 inhibitor in patients with high HBV-DNA load is unknown because of the potential risk of hepatitis B virus (HBV) reactivation. This study was to compare the HBV reactivation between patients with low HBV-DNA loads and high HBV-DNA loads undergoing antiviral prophylaxis and PD-1 inhibitor. METHODS: This was a retrospective study including consecutive hepatitis B surface antigen-positive HCC patients who received PD-1 inhibitor and concurrent antiviral prophylaxis for prevention of clinical hepatitis. Patients were divided into low HBV-DNA group (low group, ≤ 500 IU/ml) and high HBV-DNA group (high group, > 500 IU/ml) according to the baseline HBV-DNA level. The incidences of HBV reactivation, HBV-associated hepatitis, and PD-1 inhibitor disruption were compared between the two groups. RESULTS: Two hundred two eligible patients were included: 94 in the low group and 108 in the high group. Seven patients (5 in the low group and 2 in the high group) developed HBV reactivation, and all recovered from HBV reactivation and HBV-associated hepatitis. The incidence of HBV reactivation in the two groups was low (5.3% vs 1.9%, P = 0.34). There was also no difference in the incidence of HBV-associated hepatitis (P = 0.56), or PD-1 inhibitor disruption (P = 0.82). The multivariable analysis showed PD-1 inhibitor with hepatic arterial infusion chemotherapy was the only significant risk factor for HBV reactivation (P = 0.04) and hepatitis (P = 0.002). CONCLUSION: With concurrent antiviral prophylaxis, HBV-DNA load higher than 500 IU/ml should not be a contraindication for PD-1 inhibitor.

Modification of Pathologic T Classification for Non-small Cell Lung Cancer With Visceral Pleural Invasion: Data From 1,055 Cases of Cancers ≤ 3 cm.

BACKGROUND: Visceral pleural invasion (VPI) with PL1 or PL2 increases the T classification from T1 to T2 in non-small cell lung cancers (NSCLCs) ≤ 3 cm. We proposed a modified T classification based on VPI to guide adjuvant therapy. RESEARCH QUESTION: Is it reasonable to upstage PL1-positive cases from T1 to T2 for NSCLCs ≤ 3 cm? STUDY DESIGN AND METHODS: In total, 1,055 patients with resected NSCLC were retrospectively included. Tumor sections were restained with hematoxylin and eosin stain and Victoria blue elastic stain for the elastic layer. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Subgroup analysis and a Cox proportional hazards model were used to further determine the impact of VPI on survival. RESULTS: The extent of VPI was diagnosed as PL0 in 824 patients, PL1 in 133 patients, and PL2 in 98 patients. The 5-year DFS rates of patients with PL0, PL1, and PL2 were 62.6%, 60.2%, and 28.8% (P < .01), whereas the corresponding 5-year OS rates were 78.6%, 74.4%, and 50.0% (P < .01), respectively. As predicted, the DFS and OS of patients with PL2 were much worse than those of patients with PL0 (P < .01) and PL1 (P < .01). However, both the DFS and OS of patients with PL0 and PL1 were comparable (DFS: P = .198; OS: P = .150). For node-negative cases, the DFS and OS of patients with PL0 and PL1 were also comparable (DFS: P = .468; OS: P = .388), but patients with PL2 had much worse DFS and OS than patients with PL0 (P < .01) and PL1 (P < .01). Multivariable analyses suggested that PL2, together with node positivity and poor cell differentiation, was an independent adverse prognostic factor. INTERPRETATION: In NSCLCs ≤ 3 cm, tumors with PL1 should remain defined as T1, not T2. Overtreatment by adjuvant chemotherapy in node-negative NSCLCs ≤ 3 cm might be avoided in PL1 cases.

The incidence and distribution of mediastinal lymph node metastasis and its impact on survival in patients with non-small-cell lung cancers 3 cm or less: data from 2292 cases.

OBJECTIVES: Our goal was to investigate the incidence and distribution of mediastinal lymph node metastases (MLNM) in non-small-cell lung cancers (NSCLC) 3 cm or less, with the purpose of guiding mediastinal lymph node dissection. METHODS: A total of 2292 cases seen between January 2001 and December 2014 were included. These patients were grouped according to the lobes with the primary tumours. The incidence and distribution of pathological MLNM were compared among the groups. The impact of MLNM on overall survival was also compared. RESULTS: The most common mediastinal metastatic sites for different primary tumour lobes were as follows: right upper lobe, 17.7% (87/492) for level 4R; right middle lobe, 14.9% (28/188) for level 7; right lower lobe, 19.8% (82/414) for level 7; left upper lobe, 18.2% (96/528) for level 5; and left lower lobe, 16.6% (42/253) for level 7. For patients with tumours in the upper lobe, the median survival time was 32 months for those with MLNM in the subcarinal zone or lower zone compared with 83 months for those with MLNM only in the upper zone (P < 0.01). When the tumours were 1 cm or less, the incidence of MLNM to the lower zone for upper lobe tumours and of MLNM to the upper zone for lower lobe tumours was zero. CONCLUSIONS: Different primary NSCLC lobe locations have a different propensity to be sites of MLNM for those tumours that are 3 cm or less. For tumours no larger than 1 cm, a lower zone mediastinal lymph node dissection might be unnecessary for upper lobe tumours and an upper zone mediastinal lymph node dissection might be unnecessary for lower lobe tumours.

Incidence and Distribution of Lobe-Specific Mediastinal Lymph Node Metastasis in Non-small Cell Lung Cancer: Data from 4511 Resected Cases.

OBJECTIVE: We aimed to investigate the incidence and distribution of mediastinal lymph node metastases (MLNM) in operable non-small cell lung cancer (NSCLC) with the purpose of guiding mediastinal lymph node dissection (MLND). METHODS: A total of 4511 NSCLC patients who underwent resection between January 2001 and December 2014 were included. These patients were preoperatively untreated and grouped according to the primary tumor lobes. The incidence and distribution of pathologic MLNM were compared among groups, and multivariate analysis was conducted to find the independent factors impacting MLNM. RESULTS: Lymph node involvement was observed in 1784 patients (39.5%). A total of 628 cases (13.9%) were N1-positive only, 752 cases (16.7%) were both N1- and N2-positive, and 404 cases (9.0%) were N2-positive only. The most common sites of mediastinal metastasis for different primary tumor lobes were the right upper lobe, station 4R (21.5%, 192/893); right middle lobe, station 7 (21.1%, 69/327); right lower lobe, station 7 (24.1%, 212/878); left upper lobe, station 5 (22.2%, 224/1008); and left lower lobe, station 7 (21.7%, 136/628). However, when only N2 cases were considered, each mediastinal lymph node zone can be involved with metastasis to a high proportion (> 5%). Multivariable analyses showed that poor cell differentiation, adenocarcinoma, larger tumor size, central type, and younger age were independent factors favoring MLNM. CONCLUSIONS: Different primary tumor locations have a different propensity to be sites of MLNM; however, once MLNM occurs, each zone can be involved and should not be neglected. Systematic MLND is the preferred procedure for operable NSCLC.

Efficacy of Endoscopic Ultrasonography for Determining Clinical T Category for Esophageal Squamous Cell Carcinoma: Data From 1434 Surgical Cases.

BACKGROUND: The efficacy of endoscopic ultrasonography (EUS) for determining T category is variable for esophageal squamous cell carcinoma (ESCC). We aimed to assess the efficacy of EUS in accurately identifying T category for ESCC based on the 8th AJCC Cancer Staging Manual. METHODS: A retrospective analysis was conducted using a prospectively collected ESCC database from January 2003 to December 2015, in which all patients underwent EUS examination followed by esophagectomy. The efficacy of EUS was evaluated by sensitivity, specificity, and accuracy compared with pathological T category as gold standard. Overall survival of different EUS-T (uT) categories was assessed. RESULTS: In total, 1434 patients were included, of whom 58.2% were correctly classified by EUS, with 17.9% being overstaged and 23.9% being understaged. The sensitivity and accuracy of EUS for Tis, T1a, T1b, T2, T3, and T4a categories were 15.8 and 98.8%, 16.3 and 95.7%, 33.1 and 89.3%, 56.8 and 65.0%, 65.8 and 70.0%, and 27.3 and 97.5%, respectively. The survival difference between uT1a and uT1b was not statistically significant (p = 0.90), nor was that between uT4a and uT4b (p = 0.34). However, when uT category was integrated as uTis, uT1, uT2, uT3, and uT4, overall survival was clearly distinguished between the categories (p < 0.01). CONCLUSIONS: EUS is in general feasible for classifying clinical T category for ESCC. However, EUS should be used with caution for discriminating between Tis, T1a, and T1b disease, as well as T4 disease.

Cyclin D1 expression predicts postoperative distant metastasis and survival in resectable esophageal squamous cell carcinoma.

PURPOSE: We aim to identify esophageal squamous cell carcinoma patients with increased risk of postoperative metastases. RESULTS: A high level of cyclin D1 expression, together with poor tumor cell differentiation and advanced tumor stages, increased risk of postoperative metastasis and decreased distant metastasis-free survival in ESCC in both cohorts. A high level of cyclin D1 expression also decreased overall survival in the training cohort (p < 0.01) but not in the validation cohort (p = 0.415). However, when the two cohorts of patients were pooled to obtain a larger case number, a high level of cyclin D1 expression was again demonstrated as an independent predictor that decreased overall survival (p < 0.01). METHODS: We used data from two institutions to establish training (n = 319) and validation (n = 164) cohorts. Tissue microarrays were generated for immunohistochemical evaluation. The correlation among cyclin D1 expression, clinicopathologic variables, postoperative distant metastases, overall survival, and distant metastasis-free survival were analyzed. Multivariate analyses were used to test the independent factors impacting postoperative distant metastases and survival. The outcomes generated from the training cohort were then tested using the validation cohort and pooled dataset. CONCLUSIONS: High level of cyclin D1 expression increased distant metastasis, decreased overall survival and distant metastasis-free survival in resectable ESCC. Using a combination of cyclin D1 expression, tumor cell differentiation grade, and tumor stages, identifying patients with increased risk of postoperative metastases becomes possible.