Anatomic versus non-anatomic resection for early-stage intrahepatic cholangiocarcinoma: a propensity score matching and stabilized inverse probability of treatment weighting analysis.

BACKGROUND: Radical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients. METHODS: Data of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared. RESULTS: Two hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child-Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05. CONCLUSION: Surgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

Dynamic evaluation of postoperative survival in intrahepatic cholangiocarcinoma patients who did not undergo lymphadenectomy: a multicenter study.

BACKGROUND: The prognosis of Intrahepatic cholangiocarcinoma (ICC) patients who did not undergo lymphadenectomy is difficult to assess. This study aims to have a dynamic evaluation on the postoperative survival of ICC patients by calculating conditional survival. METHODS: Relevant data were from patients treated in 12 large-scale hospitals from December 2011 to December 2017. The influence of relevant clinical baseline data on the prognosis of ICC patients was analyzed by Cox regression. Conditional survival (CS) is a method that may predict the prognostic probability dynamically. For a patient with x years of survival, the 1-year CS (CS1) may be calculated as CS1= OS(x + 1)/OS(x). RESULT: A total of 361 patients who met the criteria were included in the study. Conditional survival (CS) means that the patients' prognosis varies with survival time, meanwhile, relevant factors affecting the prognosis have a time-varying effect. The probability of survival assessed by CS1 increased year by year and the 1,2,3-year survival improved from 68.4% to 87.8%, while the postoperative actuarial OS decreased from 69.4% at 1 years to 36.9% at 3 years. CONCLUSIONS: In terms of CS, the estimated survival for ICC varies with the increase of survival time after excision. Patients who live longer were likely to live longer. At the same time, with the passage of time, the role of the original adverse factors of the tumor would gradually decrease. Conditional survival allows a more accurate assessment of ICC patients who did not undergo lymphadenectomy.

Impact of surgical margin width on long-term outcomes for intrahepatic cholangiocarcinoma: a multicenter study.

BACKGROUND: The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC). METHODS: Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent narrow margin hepatectomy (NMH) using the 1:1 propensity score matching (PSM). RESULTS: Among 478 included patients, 195 (40.8%) underwent WMH whereas 283 (59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: median OS 27 vs 17 months, P < 0.05; median DFS 15 vs 8 months, P = 0.001, after PSM: median OS 41 vs 22 months, p < 0.05; median DFS 16 vs 10 months, p < 0.05). However, subgroup analysis based on the AJCC staging system, WMH could only improve the survival outcomes in AJCC I ICC patients (Stage I: OS, DFS, P<0.05). CONCLUSIONS: Surgeons should strive to achieve a wide surgical margin for patients with AJCC I ICC to optimize the long-term outcome.

Prognostic value and predication model of microvascular invasion in patients with intrahepatic cholangiocarcinoma: a multicenter study from China.

BACKGROUND: At present, hepatectomy is still the most common and effective treatment method for intrahepatic cholangiocarcinoma (ICC) patients. However, the postoperative prognosis is poor. Therefore, the prognostic factors for these patients require further exploration. Whether microvascular invasion (MVI) plays a crucial role in the prognosis of ICC patients is still unclear. Moreover, few studies have focused on preoperative predictions of MVI in ICC patients. METHODS: Clinicopathological data of 704 ICC patients after curative resection were retrospectively collected from 13 hospitals. Independent risk factors were identified by the Cox or logistic proportional hazards model. In addition, the survival curves of the MVI-positive and MVI-negative groups before and after matching were analyzed. Subsequently, 341 patients from a single center (Eastern Hepatobiliary Hospital) in the above multicenter retrospective cohort were used to construct a nomogram prediction model. Then, the model was evaluated by the index of concordance (C-Index) and the calibration curve. RESULTS: After propensity score matching (PSM), Child-Pugh grade and MVI were independent risk factors for overall survival (OS) in ICC patients after curative resection. Major hepatectomy and MVI were independent risk factors for recurrence-free survival (RFS). The survival curves of OS and RFS before and after PSM in the MVI-positive groups were significantly different compared with those in the MVI-negative groups. Multivariate logistic regression results demonstrated that age, gamma-glutamyl transpeptidase (GGT), and preoperative image tumor number were independent risk factors for the occurrence of MVI. Furthermore, the prediction model in the form of a nomogram was constructed, which showed good prediction ability for both the training (C-index = 0.7622) and validation (C-index = 0.7591) groups, and the calibration curve showed good consistency with reality. CONCLUSION: MVI is an independent risk factor for the prognosis of ICC patients after curative resection. Age, GGT, and preoperative image tumor number were independent risk factors for the occurrence of MVI in ICC patients. The prediction model constructed further showed good predictive ability in both the training and validation groups with good consistency with reality.

T tube sinus tract duodenal fistula: a rare complication of postoperative choledochoscopy for treating retained intrahepatic stones.

BACKGROUNDS: Postoperative percutaneous choledochoscopy via T tube sinus tract is a common modality for treating retained intrahepatic stones in China. We report a rare complication of postoperative choledochoscopy for treating retained hepatolithiasis: T tube sinus tract duodenal fistula. METHODS: From January 2003 to December 2018, intrahepatic duct stones with or without common bile duct stones were detected in 1031 patients. Fifteen of the 1031 patients with intrahepatic stones developed a T tube sinus tract duodenal fistula that was diagnosed by cholangiography and choledochoscopy. RESULTS: The incidence of T tube sinus tract duodenal fistula in patients with retained intrahepatic stones being treated by postoperative choledochoscopy is 1.45% (15/1031) in this series. The chi-squared test showed that hypoalbuminemia (P = 0.003), long duration of T tube (P = 0.002), and high frequency of procedure (P = 0.008) might be associated with the occurrence of T tube sinus tract duodenal fistula. The logistic regression analysis demonstrated that hypoalbuminemia might be the independent risk factor for this special fistula (P = 0.037). CONCLUSIONS: Hypoalbuminemia, long time placement of T tube in situ and high frequency of procedure are probably the main causes of the T tube sinus tract duodenal fistula. Placement of T tube in correct way and improving nutritional status may be the key points to prevent the formation of T tube sinus tract duodenal fistula.

RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance.

BACKGROUND RNA N6-methyladenosine (m6A) methylation, the most abundant and prominent form of epigenetic modification, is involved in hepatocellular carcinoma (HCC) initiation and progression. However, the role of m6A methylation in HCC tumor microenvironment (TME) formation is unexplored. This study aimed to reveal the TME features of HCC patients with distinct m6A expression patterns and establish a prognostic model based on m6A signatures for HCC cohorts. MATERIAL AND METHODS We classified the m6A methylation patterns in 365 HCC samples based on 21 m6A modulators using a consensus clustering algorithm. Single-sample gene set enrichment analysis algorithm was used to quantify the abundance of immune cell infiltration. Gene set variation analysis revealed the biological characteristics between the m6A modification patterns. The m6A-based prognostic model was constructed using a training set with least absolute shrinkage and selection operator regression and validated in internal and external datasets. RESULTS Two distinct m6A modification patterns exhibiting different TME immune-infiltrating characteristics, heterogeneity, and prognostic variations were identified in the HCC cohort. After depicting the immune landscape of TME in HCC, we found patients with high LRPPRC m6A modulator expression had depletion of T cells, cytotoxic cells, dendritic cells, and cytolytic activity response. A high m6A score, characterized by suppression of immunity, indicated an immune-excluded TME phenotype, with poor survival. A nomogram was developed to facilitate HCC clinical decision making. CONCLUSIONS Our results highlight the nonnegligible role of m6A methylation in TME formation and reveal a potential clinical application of the m6A-associated prognostic model for patients with HCC.

[The application of percutaneous transhepatic cholangioscopy in the treatment of benign bilioenteric anastomotic stricture:a report of 9 cases].

Objective: To investigate the feasibility and effectiveness of percutaneous transhepatic cholangioscopy(PTCS) in the treatment of bilioenteric anastomotic stricture after choledochojejunostomy. Methods: From April 2016 to April 2020, the clinical data of 9 patients (7 males and 2 females, aged 40-76 years) who underwent percutaneous transhepatic cholangioscopy(PTCS) for stricture expansion and lithotomy at Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively analyzed. The operation was divided into two stages. In the first stage, ultrasound-guided percutaneous intrahepatic bile duct puncture was performed, and the sheath tube was inserted and fixed. In the second stage, percutaneous choledochoscopy was used for anastomotic stricture after sinus formation.The clinical outcome was evaluated by related biochemical indexes. Results: The operation time was (53.3±31.0)minutes(range:15-120 minutes).The postoperative hospital stay was (4.4±2.3)days(range:2-9 days).After systematic treatment, the preoperative symptoms, such as abdominal pain, jaundice, fever and shivering, disappeared in 8 patients. The range of alkaline phosphatase was 122-1 334 U/L before operation and 85-702 U/L after operation. The range of gamma glutamyl transpeptidase was 44-1 219 U/L before operation and 46-529 U/L after operation. Conclusion: PTCS is a safe and effective option for minimally invasive treatment of bilioenteric anastomotic stricture.

Systematic Analysis of Alternative Splicing Landscape in Pancreatic Adenocarcinoma Reveals Regulatory Network Associated with Tumorigenesis and Immune Response.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors and has an extremely high mortality rate. Recent studies indicate that alternative splicing (AS), a common post-transcriptional process, has important roles in tumor biological behaviors and may provide novel immunotherapeutic targets. This study systematically analyzes AS profiles in PDAC and reveals their potential regulatory effects on cancer immune response. MATERIAL AND METHODS AS event, RNA sequencing, and splicing factor (SF) data were extracted from SpliceSeq, The Cancer Genome Atlas, and SpliceAid2, respectively. Overall survival (OS)-associated AS events and SFs were identified with univariate analysis. The LASSO method and multivariate Cox regression analysis were used to construct predictive signatures for the prediction of patient prognosis. The proportions of immune cells within PDAC samples were evaluated using the CIBERSORT algorithm. The correlations among AS events, SFs, and immune cell proportions were calculated using Spearman correlation analysis. Consensus clustering and immune classification were performed on the PDAC cohort. RESULTS A total of 4812 OS-related AS events from 3341 parent genes were identified, and 8 AS-based predictive models were constructed for PDAC. An OS-related SF-AS regulatory network was constructed. The AS events regulated by ELAVL4 exhibited strong correlations with CD8 T cells and regulatory T cells. In addition, AS-based clusters demonstrated distinct OS outcomes and immune features. CONCLUSIONS AS-based predictive models with high accuracy were constructed to facilitate prognosis prediction and treatment of PDAC. An SF-AS regulatory network was constructed, revealing the potential relationships among SF, AS, and immune response.

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population.

LESSONS LEARNED: Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery. BACKGROUND: The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S). METHODS: Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months. RESULTS: Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively. CONCLUSION: Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy.

A novel approach with holmium laser ablation for endoscopic management of intrahepatic biliary stricture.

BACKGROUND: Hepatolithiasis, featuring high incidence, severe symptoms, and common recurrence, poses a heavy disease burden. Endoscopic management provides an opportunity to cure hepatolithiasis, but fails to properly resolve biliary stricture without additional interventional techniques. An innovative approach towards endoscopic management of biliary stricture is required. METHODS: Holmium laser ablation was applied to biliary strictures via endoscopic access. Patients' demographic, operative, and follow-up data after receiving holmium laser ablation were retrospectively collected for analysis. RESULTS: A total of 15 patients (4 males and 11 females) underwent stricture ablation by holmium laser via cholangioscopy. All the patients successfully received holmium laser ablation, indicating a technical success rate of 100%. No postoperative mortality or no major perioperative complication was observed. During the follow-up period, the recurrence-free rate was 73% at 2 years and 67% at 5 years. CONCLUSIONS: We successfully developed a novel technique of biliary stricture removal by cholangioscopic holmium laser ablation with satisfying clinical outcomes.

New Crosslinked Hyaluronan Gel for the Prevention of Intrauterine Adhesions after Dilation and Curettage in Patients with Delayed Miscarriage: A Prospective, Multicenter, Randomized, Controlled Trial.

STUDY OBJECTIVES: To evaluate the efficacy of a new crosslinked hyaluronan (NCH) gel in reducing the formation of intrauterine adhesions (IUAs) after dilation and curettage (D&C). DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTINGS: Six hospitals for maternal and child healthcare in China. PATIENTS: A total of 300 patients were randomized to undergo D&C for delayed miscarriage without previous history of D&C. Twenty-six patients (9%) were lost to follow-up and were excluded from the analysis. INTERVENTIONS: Women were randomly assigned to D&C alone (control group; n = 150) or D&C plus NCH gel application (NCH gel group; n = 150) with 1:1 allocation. MEASUREMENTS AND MAIN RESULTS: All patients were evaluated using the American Fertility Society classification of IUAs during follow-up diagnostic hysteroscopy, scheduled at 3 months after D&C procedure. The primary endpoint was the number of women with IUAs at 3 months, and the secondary endpoints were adhesion scores and severity of IUAs. Postoperative efficacy data were available for 274 women (137 in each group). Intrauterine adhesion formations were observed in 13 of the 137 women (9.5%) in the NCH gel group and in 33 of the 137 women (24.1%) in the control group (p = .0012; relative risk [RR], 0.3939; 95% confidence interval [CI], 0.2107-0.7153), a difference of 14.6% (95% CI, 5.92%-23.28%) between the 2 groups. The extent of intrauterine cavity involved, type of adhesion and menstrual pattern, and cumulative adhesion scores were significantly lower in the NCH gel group compared with the control group (p = .0007, .008, .0012, and .0006, respectively). The proportion of women with moderate to severe IUAs was significantly lower in the NCH gel group than that in the control group (1 of 137 [0.7%] vs 16 of 137 [11.7%]; p = .0002; RR, 0.0625; 95% CI, 0.0084-0.4648), a difference of 11.95% (95% CI, 5.39%-16.51%) between the 2 groups. CONCLUSIONS: The current study demonstrates that IUAs are frequently formed after D&C for delayed miscarriage in women without a previous history of D&C procedures, and the application of NCH gel significantly reduces IUA formation.

A preoperative nomogram predicts prognosis of up front resectable patients with pancreatic head cancer and suspected venous invasion.

BACKGROUND: Pancreatic head adenocarcinoma is commonly diagnosed at an advanced stage when adjacent vascular invasion is present. This study aimed to establish a preoperative prognostic nomogram for patients who underwent attempted curative resectional surgery for pancreatic head cancer with suspected peripancreatic venous invasion. METHODS: Data on all consecutive patients were retrospectively collected from 2012 to 2016 at four academic institutions. The demographic and radiological parameters were analyzed using univariate and multivariate Cox regression analyses. The final nomogram was established using the concordance Harrell's C-indices and calibration curves from data obtained in three institutions and validated in the cohort of patients coming from the fourth institution. RESULTS: The nomogram was constructed using data from 178 patients while the validation cohort consisted of 61 patients. Age, length of tumor contact, peripancreatic venous abnormalities and lymph node staging were independent factors of overall survival. The nomogram showed good probabilities of survival on calibration curves. The C-index of the model in predicting overall survival (OS) was 0.824 for the validation cohort. CONCLUSIONS: The nomogram accurately predicted OS in patients with pancreatic head cancer with suspected peripancreatic venous invasion after attempted curative pancreatic resectional surgery.

The implementation of an enhanced recovery after surgery (ERAS) program following pancreatic surgery in an academic medical center of China.

INTRODUCTION: The experience of implementing enhanced recovery after surgery (ERAS) programs in pancreatic surgery is limited. The aim of this study was to evaluate the feasibility of ERAS program in pancreatic surgery in an academic medical center of China. METHODS: Between May 2014 and August 2015, 124 patients managed with an ERAS program following pancreatic surgery (ERAS group), were compared to a historical cohort of 63 patients, treated with traditional perioperative care between August 2013 and April 2014 (no-ERAS group). Postoperative hospital stay (POPH), unplanned reoperation, unplanned readmissions, mortality and complications were compared between the two groups. RESULTS: Mean POPH of all patients was significantly reduced (p = 0.007) from 17.1 days (no-ERAS group) to 11.7 days (ERAS group). Especially, mean POPH was reduced significantly in ERAS group of patient with no (7.0 vs. 8.7, p = 0.020) or grade I-II (10.6 vs. 14.4, p = 0.001) complications. There was no difference of complication grades and types between two groups, as well as the rate of mortality, unplanned reoperation and readmission. CONCLUSION: The ERAS program is safe and feasible for patients undergoing pancreatic surgery, and it can decrease the postoperative hospital stay.

[Modified FOLFIRINOX for advanced pancreatic cancer: a tertiary center experience from China].

OBJECTIVE: To explore efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) regimen by dose attenuation in locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer(MPC). METHODS: Between April 2014 and October 2015, 35 patients with LAPC (n=18) or MPC (n=17) were treated with mFOLFIRINOX regimen (irinotecan 135 mg/m(2), oxaliplatin 68 mg/m(2), 5-FU 2 400 mg/m(2), no bolus of 5-FU, leucovorin 400 mg/m(2)) in the Second Affiliated Hospital of Zhejiang University School of Medicine. The primary end point was progression free survival. The second end points were overall survival, objective response rate, adverse effects, surgical resection rate for LAPC. RESULTS: Among 35 patients, 6 patients (17.1%) who dropped out and received less than 2 cycles were excluded for response analysis. Among the other 29 patients, 9 patients had grade 3 or 4 adverse effects. No patients ceased treatment due to adverse effects. The 29 patients received 5 (2-13) cycles were evaluated by efficacy and found partial remission in 16 cases, stable disease in 10 cases, progression disease in 3 cases. Response rate was 55.2%. Nine patients with LAPC accomplished surgery after neoadjuvant treatment without perioperative complication and death, and 6 patients accepted R0 resection. CONCLUSIONS: The mFOLFIRINOX regimen used in the study is well-tolerated in Chinese population with high treatment efficacy on patients with LAPC and MPC. Further investigation of efficacy and adverse effects on more advanced pancreatic cancer patients is necessary.

Hypoxia promotes pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition via modulating the FOXO3a/DUSP6/ERK axis.

BACKGROUND: Pancreatic cancer (PC) is among the most aggressive types of cancer. Hypoxia has been identified as a key risk factor for cancer progression. The forkhead box (FOX) proteins are multidirectional transcriptional factors that are strongly implicated in malignancies. However, whether FOXO3a, a member of the FOX protein family, is involved in the pro-oncogenic functions of hypoxia in PC has remained largely unelucidated. In this study, we attempted to clarify the role of FOXO3a in metastasis under hypoxic conditions and its underlying mechanism. METHODS: MTT and flow cytometry assays were performed to detect the cell proliferation and cell cycle distribution respectively. Transwell assays were used to determine the potential of cell migration and invasion. qPCR and western blot assays were used to assess the expression of mRNA and protein. Immunofluorescence assay was performed to evaluate the cellular localization of FOXO3a. FOXO3a overexpression plasmid was constructed to perform the rescue experiment. RESULTS: Our data indicated that PANC-1 and SW1990 cells represented enhanced cell migration and invasion abilities under hypoxia, while no statistical differences in cell proliferation and cell cycle distribution were observed. Hypoxia upregulated the messenger RNA (mRNA) and protein expressions of HIF-1α, FOXO3a, and the key epithelial-mesenchymal transition (EMT)-related (EMT) molecules N-cadherin and vimentin, as well as the phosphorylation of FOXO3a. Interestingly, hypoxia promoted the extranuclear localization of FOXO3a. Overexpression of FOXO3a not only significantly decreased the invasion, migration, and EMT of PC cell lines, but also reversed hypoxia-induced extranuclear localization. Finally, FOXO3a might act as a tumor suppressor in PC by inhibiting the ERK signaling pathway by inducing DUSP6 expression, and the ERK activator fisetin could effectively attenuate the inhibitory role of FOXO3a on ERK. CONCLUSIONS: Taken together, our results identified that hypoxia-induced extranuclear localization of FOXO3a promoted cell migration and invasion of human PC by modulating the DUSP6/ERK pathway.

An independent poor-prognosis subtype of hepatocellular carcinoma based on the tumor microenvironment.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor with a particularly poor prognosis. The tumor microenvironment (TME) is closely associated with tumorigenesis, progression, and treatment. However, the relationship between TME genes and HCC patient prognosis is poorly understood. METHODS: In this study, we identified two prognostic subtypes based on the TME using data from The Cancer Genome Atlas and Gene Expression Omnibus. The Microenvironment Cell Populations-counter method was used to evaluate immune cell infiltration in HCC. Differentially expressed genes between molecular subtypes were calculated with the Limma package, and clusterProfiler was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to identify genes related to the independent subtypes. We also integrated mRNA expression data into our bioinformatics analysis. RESULTS: We identified 4227 TME-associated genes and 640 genes related to the prognosis of HCC. We defined two major subtypes (Clusters 1 and 2) based on the analysis of TME-associated gene expression. Cluster 1 was characterized by increased expression of immune-associated genes and a worse prognosis than Cluster 2. CONCLUSIONS: The identification of these HCC subtypes based on the TME provides further insight into the molecular mechanisms and prediction of HCC prognosis.

Clinical application of laparoscopy combined with choledochoscopy in patients with bilioenteric anastomotic stricture with access via the jejunal loops.

OBJECTIVE: Bilioenteric anastomotic stricture is a serious complication following choledochojejunostomy. Some patients develop intrahepatic lithiasis and biliary tract infection without dilation of the intrahepatic bile duct. The present study was performed to investigate the safety and efficacy of laparoscopy combined with choledochoscopy in patients with bilioenteric anastomotic stricture with access via the jejunal loops. METHODS: The data of 10 patients (7 men and 3 women; mean age, 60.8 ± 9.7 years; age range, 51-76 years) with potential bilioenteric anastomotic stricture without dilation of the intrahepatic bile duct from January 2015 to December 2019 were retrospectively reviewed. RESULTS: All 10 patients underwent surgery, and their clinical parameters were recorded. The mean surgery time was 181.5 ± 35.4 minutes, and the mean estimated blood loss was 32.0 ± 15.5 mL. No patients developed serious complications during the perioperative period. The short-term outcome analysis at 12 months indicated that the stenosis had been effectively dilated and that the liver function had improved. CONCLUSIONS: The results of the present study demonstrated that laparoscopy combined with choledochoscopy with access via the jejunal loops is feasible in the treatment of bilioenteric anastomotic stricture and intrahepatic lithiasis.

Prognostic Value of Lymph Node Dissection for Intrahepatic Cholangiocarcinoma Patients With Clinically Negative Lymph Node Metastasis: A Multi-Center Study From China.

BACKGROUND: The clinical value of lymph-node dissection (LND) for intrahepatic carcinoma (ICC) patients with clinically negative lymph node metastasis (LNM) remains unclear; hence we conducted a multi-center study to explore it. METHODS: Patients who were diagnosed ICC with clinically negative LNM and underwent hepatectomy with or without LND from December 2012 to December 2015 were retrospectively collected from 12 hepatobiliary centers in China. Overall survival (OS) was analyzed using the Kaplan-Meier method, and then subgroup analysis was conducted stratified by variables related to the prognosis. RESULTS: A total of 380 patients were eligible including 106 (27.9%) in the LND group and 274 (72.1%) in the non-LND group. Median OS in the LND group was slightly longer than that in the non-LND group (24.0 vs. 18.0 months, P = 0.30), but a significant difference was observed between the two groups (24.0 vs. 14.0 months, P = 0.02) after a well-designed 1:1 propensity score matching without increased severe complications. And, LND was identified to be one of the independent risk factors of OS (HR = 0.66, 95%CI = 0.46-0.95, P = 0.025). Subgroup analysis in the matched cohort showed that patients could benefit more from LND if they were male, age <60 years, had no HBV infection, with ECOG score <2, CEA ≤5 ug/L, blood loss ≤400 ml, transfusion, major hepatectomy, resection margin ≥1 cm, tumor size >5 cm, single tumor, mass-forming, no satellite, no MVI, and no perineural invasion (all P < 0.05). Furthermore, only patients with pathologically confirmed positive LNM were found to benefit from postoperative adjuvant therapy (P < 0.001). CONCLUSION: With the current data, we concluded that LND would benefit the selected ICC patients with clinically negative LNM and might guide the postoperative management.

Efficacy of licartin combined with transcatheter hepatic arterial chemoembolization in the treatment of middle-advanced primary liver cancer.

PURPOSE: To explore the clinical efficacy and safety of Licartin combined with transcatheter hepatic arterial chemoembolization (TACE) in the treatment of middle-advanced primary liver cancer. METHODS: The clinical data of 112 patients with middle-advanced primary liver cancer treated in our hospital from March 2015 to March 2017 were collected. Fifty-six patients underwent TACE combined with Licartin (Licartin+TACE group), while the remaining 56 patients were treated with TACE alone (TACE group). The short-term efficacy, peripheral hemogram, liver function, alpha fetoprotein (AFP) level, count of circulating tumor cells (CTCs) and cluster of differentiation (CD)147 phenotype before and after treatment were assessed in both groups, the incidence of adverse reactions was compared, and the postoperative survival and disease development were recorded during follow-up. RESULTS: At 2 weeks after treatment, the levels of ALT and AST were significantly higher in Licartin + TACE group than those in TACE group (p<0.05). After treatment, the white blood cell count (WBC) and platelet count (PLT) obviously declined in both groups, and they were obviously lower in Licartin + TACE group than those in TACE group (p<0.05). After treatment, the count of CTCs evidently declined in both groups compared with that before treatment (p<0.05), and it was evidently lower in Licartin + TACE group than in TACE group (p<0.001). All patients were followed up for 3-36 months. In Licartin + TACE group and TACE group, the mean overall survival (OS) was 13.1±3.6 months and 11.3±2.8 months, respectively, and the mean progression-free survival (PFS) was 7.9±1.4 months and 6.1±1.2 months, respectively. At the end of follow-up, the Kaplan-Meier survival curves were plotted and log-rank test found that the OS rate was remarkably superior in Licartin + TACE group to that in TACE group (p=0.047), but the PFS rate had no statistically significant difference between the two groups (p=0.372). CONCLUSIONS: Licartin combined with TACE has better efficacy than TACE alone in the treatment of middle-advanced primary liver cancer, with tolerable adverse reactions, which prolongs patients' survival time.

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration.

The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.