Does the size of the neuroendocrine-carcinoma component determine the prognosis of gallbladder cancer?

Background: Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Methods: Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). Results: The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Conclusion: Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.

The effectiveness of combined extrahepatic bile duct resection in radically resected cases with intrahepatic cholangiocarcinoma: a SEER-based retrospective cohort study and an external validation.

OBJECTIVE: To evaluate the effectiveness of the combined extrahepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) in terms of clinicopathological features and long-term survival. METHODS: Radically resected cases with IHCC from 2000 to 2020 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Comparative analyses were performed between resected IHCC patients who received EHBDR and those without EHBDR. Moreover, an external validation was further performed based on a single-center cohort. RESULTS: A total of 1521 radically resected cases with IHCC (EHBDR: 189) were identified from the SEER database. Comparable age, sex, race, marital status, liver cirrhosis, differentiation status, and adjuvant chemotherapy were acquired between the two groups. EHBDR was associated with a higher incidence of adequate lymphadenectomy ( P <0.001). The incidence of cases with T3-4 or N+ disease was significantly higher in EHBDR group ( P <0.001). Adjuvant radiotherapy was more frequently performed in cases with EHBDR ( P <0.001). EHBDR failed to bring any survival benefit and was associated with a worse prognosis even after matching. Similar findings have also been revealed in the external validation cohort ( n =522, EHBDR: 117). EHBDR was associated with more extended resections, more aggressive tumor biological features, and worse prognosis. In the matched validation cohort, EHBDR was still associated with a higher incidence of early recurrence. CONCLUSION: EHBDR was an indicator of the advanced stage and failed to bring any survival benefit. It is the tumor stage that really determines the prognosis. More in-depth analyses focusing on different situations of EHBDR with more detailed clinical data are required.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

Prognostic factors for resected cases with gallbladder carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Current meta-analysis was performed to systematically evaluate the potential prognostic factors for overall survival among resected cases with gallbladder carcinoma. METHODS: PubMed, EMBASE, and the Cochrane Library were systematically retrieved and hazard ratio (HR) and its 95% confidence interval were directly extracted from the original study or roughly estimated via Tierney's method. Standard Parmar modifications were used to determine pooled HRs. RESULTS: A total of 36 studies with 11 502 cases were identified. Pooled results of univariate analyses indicated that advanced age (HR=1.02, P =0.00020), concurrent gallstone disease (HR=1.22, P =0.00200), elevated preoperative CA199 level (HR=1.93, P <0.00001), advanced T stage (HR=3.09, P <0.00001), lymph node metastasis (HR=2.78, P <0.00001), peri-neural invasion (HR=2.20, P <0.00001), lymph-vascular invasion (HR=2.37, P <0.00001), vascular invasion (HR=2.28, P <0.00001), poorly differentiated tumor (HR=3.22, P <0.00001), hepatic side tumor (HR=1.85, P <0.00001), proximal tumor (neck/cystic duct) (HR=1.78, P <0.00001), combined bile duct resection (HR=1.45, P <0.00001), and positive surgical margin (HR=2.90, P <0.00001) were well-established prognostic factors. Pathological subtypes ( P =0.53000) and postoperative adjuvant chemotherapy ( P =0.70000) were not prognostic factors. Pooled results of multivariate analyses indicated that age, gallstone disease, preoperative CA199, T stage, lymph node metastasis, peri-neural invasion, lymph-vascular invasion, tumor differentiation status, tumor location (peritoneal side vs hepatic side), surgical margin, combined bile duct resection, and postoperative adjuvant chemotherapy were independent prognostic factors. CONCLUSION: Various prognostic factors have been identified beyond the 8th AJCC staging system. By incorporating these factors into a prognostic model, a more individualized prognostication and treatment regime would be developed. Upcoming multinational studies are required for the further refine and validation.

The prognostic value of combined preoperative PLR and CA19-9 in patients with resectable gallbladder cancer.

The platelet to lymphocyte ratio (PLR) is the marker of host inflammation and it is a potential significant prognostic indicator in various different tumors. The serum carbohydrate antigen 19-9 (CA19-9) is a tumor-associated antigen and it is associated with poor prognosis of gallbladder cancer (GBC). We aimed to analyze the prognostic value of the combination of preoperative PLR and CA19-9 in patients with GBC. A total of 287 GBC patients who underwent curative surgery in our institution was included. To analyze the relationship between PLR and CA19-9 and clinicopathological features. A receiver operating characteristic (ROC) curve was used to identify the optimal cutoff value for PLR and CA19-9. The Kaplan-Meier method was used to estimate the overall survival (OS). Meanwhile, the univariate and multivariate Cox regression models were used to assess the risk factors for OS. The cutoff values of 146.82 and 36.32U/ml defined as high PLR and high CA19-9, respectively. Furthermore, survival analysis showed that patients with PLR > 146.82 and CA19-9 > 36.32 U/ml had a worse prognosis than patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml, respectively. The multivariate analysis demonstrated that PLR (hazard ratio (HR) = 1.863, 95% CI: 1.366-2.542, P < 0.001) and CA19-9 (HR = 1.412, 95% CI: 1.021-1.952, P = 0.037) were independent prognostic factors in the GBC patients. When we combined these two parameters, the area under the ROC curve increased from 0.624 (PLR) and 0.661 (CA19-9) to 0.711. In addition, the 1-, 3-, and 5-year OS of group A (patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml), group B (patients with either of PLR > 146.82 or CA19-9 > 36.32 U/ml) and group C (patients with PLR > 146.82 and CA19-9 > 36.32 U/ml) were 83.6%, 58.6%, 22.5%, 52.4%, 19.5%, 11.5%, and 42.3%, 11.9%, 0%, respectively. The preoperative PLR and serum CA19-9 are associated with prognosis of patients with GBC. The combination of PLR and CA19-9 may serve as a significant prognostic biomarker for GBC patients superior to either PLR or CA19-9 alone.

Prognostic value of combined preoperative inflammatory marker neutrophil-lymphocyte ratio and platelet distribution width in patients with gallbladder carcinoma.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) and platelet distribution width (PDW) are associated with poor prognosis in various cancers. We aimed to analyze the prognostic value of the combination of preoperative NLR and PDW in patients with gallbladder carcinoma (GBC). METHODS: A total of 287 GBC patients who underwent curative-intent surgery in our institution was included. The relationship between NLR and PDW and clinicopathological features were analyzed. The receiver operating characteristic (ROC) curves were used to determine the optimal cutoff value for NLR and PDW. Overall survival (OS) was estimated using the Kaplan-Meier method. Meanwhile, the univariate and multivariate Cox regression models were used to assess the risk factors for OS. RESULTS: The optimal cutoff value of NLR and PDW was 3.00 and 14.76, respectively. In addition, survival analysis demonstrated that patients with NLR > 3.00 and PDW > 14.76 had a worse prognosis than patients with NLR ≤ 3.00 and PDW ≤ 14.76, respectively. The multivariate analysis showed that NLR and PDW were independent prognostic factors in the patients with GBC. When we combined NLR and PDW, the area under the ROC curve increased from 0.665 (NLR) and 0.632 (PDW) to 0.676. Moreover, the 1-, 3-, and 5-year OS of group A (patients with NLR ≤ 3.00 and PDW ≤ 14.76), group B (patients with either of NLR > 3.00 or PDW > 14.76) and group C (patients with NLR > 3.00 and PDW > 14.76) were 88.7%, 62.6%, 28.1%, 65.1%, 26.9%, 13.1%, and 34.8%, 8.3%, 0%, respectively. CONCLUSION: The combination of NLR and PDW may serve as a significant prognostic biomarker for GBC patients superior to either NLR or PDW alone.

Prognostic Significance of Tumor Necrosis in Patients with Gallbladder Carcinoma Undergoing Curative-Intent Resection.

BACKGROUND: Tumor necrosis has been indicated to correlate with dismal survival outcomes of a variety of solid tumors. However, the significance and prognostic value of tumor necrosis remain unclear in gallbladder carcinoma. The aim of this research is to explore the relationships between necrosis with long-term survival and tumor-related biological characteristics of patients with gallbladder carcinoma. PATIENTS AND METHODS: Patients with gallbladder carcinoma who accepted curative-intent resection in West China Hospital of Sichuan University (China) between January 2010 and December 2021 were retrospectively analyzed. Tumor necrosis was determined by staining the patient's original tissue sections with hematoxylin and eosin. Based on the presence of tumor necrosis, the pathologic features and survival outcomes were compared. RESULTS: This study enrolled 213 patients with gallbladder carcinoma who underwent curative-intent surgery, of whom 89 had tumor necrosis. Comparative analyses indicated that patients with tumor necrosis had more aggressive clinicopathological features, such as larger tumor size (p = 0.002), poorer tumor differentiation (p = 0.029), more frequent vascular invasion (p < 0.001), presence of lymph node metastasis (p = 0.014), and higher tumor status (p = 0.01), and experienced poorer survival. Univariate and multivariate analyses revealed that tumor necrosis was an independent prognostic factor for overall survival (multivariate: HR 1.651, p = 0.026) and disease-free survival (multivariate: HR 1.589, p = 0.040). CONCLUSIONS: Tumor necrosis can be considered as an independent predictive factor for overall survival and disease-free survival among individuals with gallbladder carcinoma, which was a valuable pathologic parameter.

PI3K-CCL2-CCR2-MDSCs axis: A potential pathway for tumor Clostridia-promoted CD 8+ T lymphocyte infiltration in bile tract cancers.

BACKGROUND: Most patients with resected bile tract cancers (BTCs) survive for less than 5 years; however, some achieve better prognosis. The tumor microbiome can improve survival by regulating the tumor immune microenvironment. However, whether the tumor microbiome promotes immune cell infiltration in BTCs is unknown. This study aimed to determine the association between CD8+ T lymphocyte infiltration and the tumor microbiome in patients with resected BTCs. METHODS: Archived formalin-fixed paraffin-embedded tumor specimens were collected from patients with resected BTCs and analyzed using 16S rRNA gene sequencing to identify that prognosis-related and significantly differentially enriched taxa. Gene ontology (GO) analysis of the differentially enriched taxa was used to assess how CD8+ T lymphocyte infiltration is affected by the tumor microbiome of BTCs. RESULTS: We enrolled 32 patients with resected BTCs. The high CD8+ lymphocyte-infiltration (CD8hi) group had four significantly enriched taxa, and in the low CD8+ lymphocyte-infiltration (CD8low) group comprised one significantly enriched taxon. Patients with higher Clostridia abundance (enriched in the CD8hi group) experienced longer overall survival than those with lower abundance. The enrichment of Clostridia in the CD8hi group corresponded with lower CCL2 expression and downregulation of phosphatidylinositol 3-kinase activity, which might decrease myeloid-derived suppressor cell recruitment to the tumor milieu, thus increasing CD8+ lymphocyte infiltration in BTCs. CONCLUSIONS: The tumor microbiome is related to CD8+ T lymphocyte infiltration in patients with resected BTCs. The relationship between tumor Clostridia and high infiltration of CD8+ T lymphocytes might reflect decreased recruitment of myeloid-derived suppressor cells via the PI3K-CCL2-CCR2 axis.

[Acteoside promotes autophagy and apoptosis of hepatoma cells by regulating JNK signaling pathway].

This study explored the molecular mechanism of acteoside against hepatoma 22(H22) tumor in mice through c-Jun N-terminal kinase(JNK) signaling pathway. H22 cells were subcutaneously inoculated in 50 male BALB/c mice, and then the model mice were classified into model group, low-dose, medium-dose, and high-dose acteoside groups, and cisplatin group. The administration lasted 2 weeks for each group(5 consecutive days/week). The general conditions of mice in each group, such as mental status, diet intake, water intake, activity, and fur were observed. The body weight, tumor volume, tumor weight, and tumor-inhibiting rate were compared before and after administration. Morphological changes of liver cancer tissues were observed based on hematoxylin and eosin(HE) staining, and the expression of phosphorylated(p)-JNK, JNK, B-cell lymphoma-2(Bcl-2), Beclin-1, and light chain 3(LC3) in each tissue was detected by immunohistochemistry and Western blot. qRT-PCR was performed to detect the mRNA expression of JNK, Bcl-2, Beclin-1, and LC3. The general conditions of mice in model and low-dose acteoside groups were poor, while the general conditions of mice in the remaining three groups were improved. The body weight of mice in medium-dose acteoside group, high-dose acteoside group, and cisplatin group was smaller than that in model group(P<0.01). The tumor volume in model group was insignificantly different from that in low-dose acteoside group, and the volume in cisplatin group showed no significant difference from that in high-dose acteoside group. Tumor volume and weight in medium-dose and high-dose acteoside groups and cisplatin group were lower than those in the model group(P<0.001). The tumor-inhibiting rates were 10.72%, 40.32%, 53.79%, and 56.44% in the low-dose, medium-dose, and high-dose acteoside groups and cisplatin group, respectively. HE staining showed gradual decrease in the count of hepatoma cells and increasing sign of cell necrosis in the acteoside and cisplatin groups, and the necrosis was particularly obvious in the high-dose acteoside group and cisplatin group. Immunohistochemical results suggested that the expression of Beclin-1, LC3, p-JNK, and JNK was up-regulated in acteoside and cisplatin groups(P<0.05). The results of immunohistochemistry, Western blot, and qRT-PCR indicated that the expression of Bcl-2 was down-regulated in the medium-dose and high-dose acteoside groups and cisplatin group(P<0.01). Western blot showed that the expression of Beclin-1, LC3, and p-JNK was up-regulated in acteoside and cisplatin groups(P<0.01), and there was no difference in the expression of JNK among groups. qRT-PCR results showed that the levels of Beclin-1 and LC3 mRNA were up-regulated in the acteoside and cisplatin groups(P<0.05), and the level of JNK mRNA was up-regulated in medium-dose and high-dose acteoside groups and cisplatin group(P<0.001). Acteoside promotes apoptosis and autophagy of H22 cells in mice hepatoma cells by up-regulating the JNK signaling pathway, thus inhibiting tumor growth.

Expression and Correlation of MIF and ERK1/2 in Liver Cirrhosis and Hepatocellular Carcinoma Induced by Hepatitis B.

Objective: To detect expression and phosphorylation level of macrophage migration inhibitor (MIF) and extracellular-regulated kinases 1 and 2 (ERK1/2) in hepatitis B-induced liver cirrhosis (HBILC) and hepatocellular carcinoma (HCC) with a background of HBILC and analyze the correlation of MIF and ERK1/2 with HBILC and HCC. Methods: Twenty cases of normal liver tissues were collected as a control group, and 48 specimens of HBILC tissues and 48 specimens of HCC tissues were collected as the experimental group, which were assigned as the HBILC group and HCC group, respectively. All tissue specimens were processed into tissue chips. The expressions of MIF, ERK1/2, and their phosphorylated proteins were detected via immunohistochemistry, and MIF and ERK1/2 nucleic acid expressions were detected by in situ hybridization. The results were statistically analyzed using the chi-square test. Results: Proteins and nucleic acids of MIF and ERK1/2 presented low expression in the control group and high expression in the HBILC group and HCC group. MIF expression in the three groups was 25.0%, 75.0%, and 79.17%, respectively, while that of the nucleic acids was 25.0%, 70.83%, and 68.75%, respectively. Expression of ERK1/2 in the three groups was 40.0%, 60.42%, and 81.25%, respectively, and that of nucleic acids was 40.0%, 79.17%, and 77.08%. Expression of pERK1/2 was low in the control and HBILC group and high in the HCC group. Expression of pERK1/2 in the three groups was 20%, 45.83%, and 75%, respectively. Expression of pERK1/2 in the HCC group was significantly different from that in the HBILC and control group (P<0.05), but the difference between the HBILC group and control group was not statistically significant (P>0.05). Conclusion: Occurrence and development of HBILC and HCC are not only related to the high expression of MIF but also closely related to the activation of the ERK1/2 signaling pathway.

The Significance of Tumor Locations in Patients with Gallbladder Carcinoma After Curative-Intent Resection.

OBJECTIVE: To evaluate the significance of tumor locations in patients with resected gallbladder carcinoma (GBC) and to supply the indication of extra-hepatic bile duct resection (EHBDR) according to tumor locations. METHODS: Patients with resected GBC from 2010 to 2020 in our hospital were retrospectively analyzed. Comparative analyses and a meta-analysis were performed according to different tumor locations (body/fundus/neck/cystic duct). RESULTS: Article: A total of 259 patients were identified (neck: 71; cystic: 29; body: 51; fundus: 108). Patients with proximal tumors (neck/cystic duct) were often in a more advanced stage and had more aggressive tumor biological features as well as a worse prognosis compared with those with distal tumors (fundus/body). Moreover, the observation was even more obvious between cystic duct and non-cystic duct tumors. Cystic duct tumor was an independent prognostic factor for overall survival (P = 0.01). EHBDR provided no survival advantage even in those with cystic duct tumor. META-ANALYSIS: With our own cohort incorporated, five studies with 204 patients with proximal tumors and 5167 patients with distal tumors were identified. Pooled results revealed that proximal tumors indicated worse tumor biological features and prognosis versus distal tumors. CONCLUSION: Proximal GBC had more aggressive tumor biological features, and a worse prognosis versus distal GBC and cystic duct tumor can be regarded as an independent prognostic factor. EHBDR had no obvious survival advantage even in those with cystic duct tumor and was even harmful in those with distal tumors. Upcoming more powerful well-designed studies are required for further validation.

Comparison of clinicopathological characteristics of mucinous adenocarcinoma and conventional adenocarcinoma of gallbladder.

BACKGROUND: Gallbladder mucinous adenocarcinoma (GBMAC) is a rare type of gallbladder malignant tumor, whereas little is known regarding the clinicopathological features and surgical outcomes of GBMAC. METHODS: From January 2000 till December 2015, 54 GBMAC patients who underwent curative-intent surgical resection at our institution were retrospectively reviewed. We compared the clinicopathological features and surgical outcomes of these GBMAC patients with a relatively large cohort of surgically resected conventional gallbladder adenocarcinoma (GBAC) patients without existence of mucinous components. RESULTS: The clinicopathological features of GBMAC were significantly different from conventional GBAC, including poorer tumor differentiation (P < 0.001), higher CA19-9 levels (P < 0.001), larger tumor sizes (P = 0.020), advanced AJCC tumor stage (P = 0.002), higher frequency of liver parenchyma invasion (P = 0.020), portal vein invasion (P = 0.003), lymph node metastasis (P = 0.016), lympho-vascular invasion (P < 0.001) and perineural invasion (P = 0.025). Relative to conventional GBAC patients, GBMAC patients showed significantly worse overall survival (OS) (29.0 vs 15.0 months; P < 0.001). Multivariate analysis confirmed the surgical margin (P = 0.046), tumor differentiation grade (P = 0.018), lymph node metastasis (P = 0.024), and presence of signet-ring cell component (P = 0.005) as independent prognostic factors influencing OS of patients with GBMAC. CONCLUSION: GBMAC always had more aggressive biological behaviors and poor survival outcomes even after curative surgery. GBMAC patients with the presence of signet-ring cell component showed even worse survival outcome.

Clinicopathological characteristics and outcome of primary sarcomatoid carcinoma of the gallbladder.

Purpose: Our study aims to examine the clinicopathological features, disease progression, management, and outcomes of gallbladder sarcomatoid carcinoma (GBSC) patients. Methods: Between January 2000 and December 2020, 50 gallbladder cancer (GBC) patients who received surgical treatment and were pathologically verified as GBSC at our institution were enrolled. The clinical and pathological features and survival of these patients were retrospectively reviewed. Results: The median overall survival (OS) of GBSC patients was 14.5 months, and the 1-, 2- and 3-year OS rates were 68.0%, 32.0%, and 10.0%, respectively. The median progression-free survival (PFS) was 10.0 months, and the 1-, 2-, and 3-year PFS rates were 42.0%, 16.0%, and 2.0%, respectively. Patients who received radical resection had obviously better OS (18.0 vs. 7.0 months, P<0.001) and PFS (12.0 vs. 5.0 months, P<0.001) than those who underwent palliative resection. Multivariate analysis revealed that vascular invasion (P=0.033), curative operation (P<0.001) and postoperative chemotherapy (P=0.033) were independent risk factors for PFS. We further identified postoperative chemotherapy (P=0.010) and curative operation (P<0.001) as independent prognostic factors affecting the OS of GBSC patients. After curative surgery, patients who underwent S-1-based chemotherapy showed significantly longer recurrence-free survival (RFS) than those who underwent other chemotherapy regimens (20.0 vs 11.0 months, P=0.028). Conclusion: GBSC patients always have aggressive biological behaviors and remarkably poor prognoses. Most GBSC patients are diagnosed in advanced stages, and timely radical operation together with postoperative chemotherapy is important. S-1-based chemotherapy may be a selectively efficient regimen to prolong the survival of GBSC patients.

Intestinal mucosal barrier in functional constipation: Dose it change?

BACKGROUND: The intestinal mucosal barrier is the first line of defense against numerous harmful substances, and it contributes to the maintenance of intestinal homeostasis. Recent studies reported that structural and functional changes in the intestinal mucosal barrier were involved in the pathogenesis of several intestinal diseases. However, no study thoroughly evaluated this barrier in patients with functional constipation (FC). AIM: To investigate the intestinal mucosal barrier in FC, including the mucus barrier, intercellular junctions, mucosal immunity and gut permeability. METHODS: Forty FC patients who fulfilled the Rome IV criteria and 24 healthy controls were recruited in the Department of Gastroenterology of China-Japan Friendship Hospital. The colonic mucus barrier, intercellular junctions in the colonic epithelium, mucosal immune state and gut permeability in FC patients were comprehensively examined. Goblet cells were stained with Alcian Blue/Periodic acid Schiff (AB/PAS) and counted. The ultrastructure of intercellular junctional complexes was observed under an electron microscope. Occludin and zonula occludens-1 (ZO-1) in the colonic mucosa were located and quantified using immunohistochemistry and quantitative real-time polymerase chain reaction. Colonic CD3+ intraepithelial lymphocytes (IELs) and CD3+ lymphocytes in the lamina propria were identified and counted using immunofluorescence. The serum levels of D-lactic acid and zonulin were detected using enzyme-linked immunosorbent assay. RESULTS: Compared to healthy controls, the staining of mucus secreted by goblet cells was darker in FC patients, and the number of goblet cells per upper crypt in the colonic mucosa was significantly increased in FC patients (control, 18.67 ± 2.99; FC, 22.42 ± 4.09; P = 0.001). The intercellular junctional complexes in the colonic epithelium were integral in FC patients. The distribution of mucosal occludin and ZO-1 was not altered in FC patients. No significant differences were found in occludin (control, 5.76E-2 ± 1.62E-2; FC, 5.17E-2 ± 1.80E-2; P = 0.240) and ZO-1 (control, 2.29E-2 ± 0.93E-2; FC, 2.68E-2 ± 1.60E-2; P = 0.333) protein expression between the two groups. The mRNA levels in occludin and ZO-1 were not modified in FC patients compared to healthy controls (P = 0.145, P = 0.451, respectively). No significant differences were observed in the number of CD3+ IELs per 100 epithelial cells (control, 5.62 ± 2.06; FC, 4.50 ± 2.16; P = 0.070) and CD3+ lamina propria lymphocytes (control, 19.69 ± 6.04/mm2; FC, 22.70 ± 11.38/mm2; P = 0.273). There were no significant differences in serum D-lactic acid [control, 5.21 (4.46, 5.49) mmol/L; FC, 4.63 (4.31, 5.42) mmol/L; P = 0.112] or zonulin [control, 1.36 (0.53, 2.15) ng/mL; FC, 0.94 (0.47, 1.56) ng/mL; P = 0.185] levels between FC patients and healthy controls. CONCLUSION: The intestinal mucosal barrier in FC patients exhibits a compensatory increase in goblet cells and integral intercellular junctions without activation of mucosal immunity or increased gut permeability.

Plasma membrane lesion type total intestinal eosinophilic enteritis: a case report.

BACKGROUND: Eosinophilic gastroenteritis is a rare gastrointestinal disease that is characterized by diffuse or localized eosinophil infiltration in the gastrointestinal tract, and is accompanied by increased peripheral blood eosinophils. Herein, a case of plasma membrane lesion-type total intestinal eosinophil enteritis is reported. CASE PRESENTATION: We report on a 20-year-old male patient who was admitted to the hospital with "abdominal distension for 15 days". The infiltration of a large number of eosinophils was found by conducting an intestinal biopsy, routine ascites examination, blood routine, smear test, and a bone marrow puncture. A special feature of this patient was that a large number of eosinophils were found in the duodenum, small intestine, and colon. The final diagnosis was plasma membrane lesion type total intestinal eosinophilic enteritis. After four weeks of prednisone treatment, the symptoms disappeared completely and the entire intestinal mucosa was endoscopically observed as smooth. CONCLUSION: Clinical practitioners must pay attention to gastrointestinal endoscopy and biopsy pathology results for patients presenting with abdominal distention and ascites. Combined with an abnormal increase of eosinophils in ascites, bone marrow, and peripheral blood, clinical practitioners must be highly vigilant against plasma membrane lesion type total intestinal eosinophilic enteritis.

Roles of Gut Microbiota and Metabolites in Pathogenesis of Functional Constipation.

Functional constipation (FC), a condition characterized by heterogeneous symptoms (infrequent bowel movements, hard stools, excessive straining, or a sense of incomplete evacuation), is prevalent over the world. It is a multifactorial disorder and can be categorized into four subgroups according to different pathological mechanisms: normal transit constipation (NTC), slow transit constipation (STC), defecatory disorders (DD), and mixed type. Recently, growing evidence from human and animals has pointed that there was a strong association between gut microbiota and FC based on the brain-gut-microbiome axis. Studies have reported that the main characteristics of gut microbiota in FC patients were the relative decrease of beneficial bacteria such as Lactobacillus and Bifidobacterium, the relative increase of potential pathogens, and the reduced species richness. Gut microbiota can modulate gut functions through the metabolites of bacterial fermentation, among which short-chain fatty acids (SCFAs), secondary bile salts (BAs), and methane occupied more important positions and could trigger the release of gut hormones from enteroendocrine cells (EECs), such as 5-hydroxytryptamine (5-HT), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Subsequently, these gut hormones can influence gut sensation, secretion, and motility, primarily through activating specific receptors distributed on smooth muscle cells, enteric neurons, and epithelial cells. However, research findings were inconsistent and even conflicting, which may be partially due to various confounding factors. Future studies should take the associated confounders into consideration and adopt multiomics research strategies to obtain more complete conclusions and to provide reliable theoretical support for exploring new therapeutic targets.

Elevated Platelet Distribution Width Predicts Poor Prognosis in Gallbladder Carcinoma.

BACKGROUND: Previous studies have demonstrated that platelet distribution width (PDW) is a reliable predictor of prognosis of a variety of tumors. Nevertheless, the prognostic value of PDW in gallbladder carcinoma (GBC) remains unknown. We aimed to explore the correlation between PDW and prognosis in patients with GBC. METHODS: A total of 303 patients with GBC who underwent curative surgery between January 2005 and February 2017 were enrolled. The relationship between PDW and clinicopathological features was analyzed. Receiver operating characteristic (ROC) curve was used to identify the optimal cutoff value of PDW. The overall survival (OS) rate was estimated by Kaplan-Meier method. Meanwhile, univariable and multivariable Cox regression model were used to evaluate the risk factors for OS. RESULTS: There was significant correlation between elevated PDW and AJCC stage. In addition, survival analysis revealed that the patients with PDW>14.95 have a worse prognosis than patients with PDW14.95 (P < 0.001). The multivariable Cox regression model analysis demonstrated that PDW was an independent prognostic factor in GBC patients (hazard ratio=1.976, 95% confidence interval:1.474-2.650, P<0.001). CONCLUSION: Elevated PDW can predict poor prognosis in GBC patients, and further studies are needed to verify the reliability and clarify the exact molecular mechanistic of PDW in GBC.

De Novo and Divergent Synthesis of Highly Functionalized Furans by Cascade Reactions of 2-Hydroxy-1,4-diones with Nucleophiles.

Herein, a divergent synthesis of a variety of 2α- and 5α-substituted furan derivatives from 2-hydroxy-1,4-diones is reported. By using appropriate substrates and an acid catalyst, the reactions occurred selectively through cyclization/1,6-conjugate addition or cyclization/Friedel-Crafts-type cascade reactions. A broad range of nucleophilic reagents (>10 types for the 1,6-conjugate addition for 5α substitution and >20 types for the Friedel-Crafts-type cascade reaction for 2α substitution), including alcohols, amides, furan, thiophene, pyrrole, indole, phenols, and many others, can successfully participate in the reactions, providing a universal strategy for a diversity-oriented synthesis of α-substituted furan derivatives. Deuteriation experiments and DFT calculations were carried out to support the proposed reaction mechanisms. Antifungal activity experiments revealed that products with an indole or 4-hydroxycoumarin core substituted at the 2α position showed moderate activities against Rhizoctorzia solani and Botrytis cinerea, respectively.

Current status and future perspectives of minimally invasive surgery in gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) is the most common biliary tract malignancy, which is characterized by easy local invasion, lymph nodes metastasis, local vascular invasion. Hence, minimally invasive surgery (MIS) can be performed in a limited number of patients. In our study, we reviewed the current studies on laparoscopic surgery (LS) and robotic surgery (RS) for GBC and analysed the limitations and difficulties of MIS for GBC. METHODS: Multiple electronic databases were used for a systematic literature retrieval. All studies involving MIS of GBC were included (up to August 2019). RESULTS: A total of 24 studies were included, of which 18 studies involved LS for GBC and six studies concerned RS of GBC. For LS, 16 studies contained relevant information of T stage, and 323 patients (98.8%) had T3 or lower stage; the average rate of R0 resection, conversion, postoperative complications and mortality was 95.3% (range 80.5-100%), 1.9% (range 0-16.7%), 13.4% (range 0-33.3%) and 1.0% (range 0-10%), respectively. For RS, four studies contained relevant information of T stage, and all patients were T3 or lower stage; the average rate of R0 resection, conversion and postoperative complications was 96.8% (range 81.8-100%), 5.5% (range 0-14.8%) and11.9% (range 0-36.4%), respectively. In addition, no patient had perioperative mortality. CONCLUSIONS: MIS for GBC is limited to highly selected patients and is considered to be technically feasible in experienced surgeons. However, improvements in technical and instrumental are needed to reduce the associated postoperative complications and implantation metastasis, and to promote MIS in the treatment of GBC.