Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Low expression of RACK1 is associated with metastasis and worse prognosis in cholangiocarcinoma.

Background: Cholangiocarcinoma is a poorly prognostic malignant tumor, and the metastatic stage of cancer is not an early stage when diagnosed. Lymph node metastasis is common in the early stage. Ribosomal receptor for activated C-kinase 1 (RACK1) has found involved in the oncogenesis of various tumors and in the epithelial-mesenchymal transition (EMT). Nevertheless, its role in cholangiocarcinoma remains unknown. Material and methods: The possible correlation between RACK1 and tumor prognosis was analyzed in cholangiocarcinoma patients. The GEO and TCGA databases were used to evaluate the level of RACK1 in cholangiocarcinoma. The RBE and HCCC-9810 cell lines were used to examine the effects of RACK1 in the behavior of tumor cells in vitro. Results: The Kaplan-Meier analysis indicated that low expression of RACK1 was associated with poor prognosis and RACK1 was negatively related to lymph node metastasis, which were verified in databases TCGA and GEO; downregulation of RACK1 via RNA interference correlated with changes in the expression of EMT biomarkers and promoted the migration of cholangiocarcinoma cell lines. Conclusion: The protein expression of RACK1 is significantly higher in cholangiocarcinoma tissues than in peritumoral tissues, however, the high RACK1 expression indicates better overall survival and less risk for lymph node metastasis. In vitro, RACK1 may suppress the migratory ability of cholangiocarcinoma cells by inhibiting EMT.

Cetuximab or nimotuzumab in combination with chemotherapy for treating recurrent/metastatic nasopharyngeal carcinoma: A meta­analysis and systemic review.

The present study aimed to evaluate the effectiveness and safety of cetuximab (CTX) or nimotuzumab (NTZ) in combination with chemotherapy for patients with recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC), and for this purpose, a single-group rate meta-analysis was performed. A systematic search of the Cochrane library, Pubmed, EMBASE, Chwina National Knowledge Infrastructure and WanFang databases for studies published until February 15, 2022 was performed. The 1-, 2-, 3- and 5-year overall survival (OS) rates were the primary endpoints. Complete response, partial response, stable disease, objective response rate, disease control rate and grade ≥3 toxicities were considered secondary endpoints. Cochran Q test and I2 statistics were performed to assess the heterogeneity among studies. A total of nine studies comprising 435 patients were included in the analysis. The pooled 1-, 2-, 3- and 5-year OS rates were 81.0% [95% confidence interval (CI): 65.0-90.7%], 49.9% (95% CI: 35.3-64.5%), 46.3% (95% CI: 31.4-61.8%) and 31.0% (95% CI: 20.8-43.4%), respectively. The pooled disease control rate and objective response rate were 88.7% (95% CI: 78.4-94.5%) and 55.6% (95% CI: 39.9-70.1%), respectively. In addition, all grade 3-4 adverse events from the included studies were gathered. In conclusion, the use of CTX or NTZ in combination with chemotherapy may be a feasible and safe option for treating RM-NPC.

Dietary proanthocyanidins on gastrointestinal health and the interactions with gut microbiota.

Many epidemiological and experimental studies have consistently reported the beneficial effects of dietary proanthocyanidins (PAC) on improving gastrointestinal physiological functions. This review aims to present a comprehensive perspective by focusing on structural properties, interactions and gastrointestinal protection of PAC. In brief, the main findings of this review are summarized as follows: (1) Structural features are critical factors in determining the bioavailability and subsequent pharmacology of PAC; (2) PAC and/or their bacterial metabolites can play a direct role in the gastrointestinal tract through their antioxidant, antibacterial, anti-inflammatory, and anti-proliferative properties; (3) PAC can reduce the digestion, absorption, and bioavailability of carbohydrates, proteins, and lipids by interacting with them or their according enzymes and transporters in the gastrointestinal tract; (4). PAC showed a prebiotic-like effect by interacting with the microflora in the intestinal tract, and the enhancement of PAC on a variety of probiotics, such as Bifidobacterium spp. and Lactobacillus spp. could be associated with potential benefits to human health. In conclusion, the potential effects of PAC in prevention and alleviation of gastrointestinal diseases are remarkable but clinical evidence is urgently needed.

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.

In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.

Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth.

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and sirt1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy.

The clinical and prognostic factors for biliary neuroendocrine neoplasm: a study based on the SEER database.

BACKGROUND: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN). METHODS: Cases of biliary system NEN and adenocarcinoma from 1975 to 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. RESULTS: A total of 233 patients with biliary system NEN were enrolled in this study, of which 119 patients' lesions located in gallbladder, while the others' located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P < 0.001). For gallbladder NENs, surgery method (P = 0.020) and lymph node metastasis (P = 0.018) were identified as independent prognostic factors. In terms of ampulla of vater (AOV) NENs, age (P = 0.017) and lymph node metastasis (P = 0.006) were identified as independent prognostic factors, while grade (P = 0.002) and lymph node metastasis (P = 0.036) were identified as independent prognostic factors for extrahepatic bile duct (EBD) NENs. PSM analysis indicated that patients with biliary duct NENs have a better postoperative prognosis than biliary duct adenocarcinoma. CONCLUSIONS: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has an adverse prognosis than that of biliary tract NEN. The pathological subtype, differentiation, lymph node metastasis, surgery method, and lymph node resection could affect the postoperative prognosis of the gallbladder and biliary tract NEN.

Acetylation stabilizes stathmin1 and promotes its activity contributing to gallbladder cancer metastasis.

Gallbladder cancer is the most common biliary tract malignant tumor with highly metastatic characters and poor prognosis. However, the underlying mechanism remains unclear. Stathmin1 is ubiquitous phosphoprotein, regulating microtubule stabilization. We identified the acetylation of stahtmin1 at lysine 9 (K9) in gallbladder cancer. K9 acetylation of stathmin1 was reversely regulated by the acetyltransferase PCAF and the deacetylases sirt2. K9 acetylation of stathmin1 inhibited the combining of stathmin1 to E3 ubiquitin ligase RLIM, thereby inhibiting its ubiquitination degradation. Moreover, K9 acetylation also promoted the activity of stahtmin1 interacting and destabilizing microtubule through the inhibition of stathmin1 phosphorylation. K9 acetylated stathmin1 significantly promoted gallbladder cancer cell migration and invasion viability in vitro and lung metastasis in vivo, and indicated poor prognosis of nude mice. IHC assay suggested the positive correlation of high levels of K9 acetylation and stathmin1 expression in gallbladder cancer. Our study revealed that K9 acetylation up-regulated stathmin1 protein stability and microtubule-destabilizing activity to promoted gallbladder cancer metastasis, which provides a potential target for gallbladder cancer therapy.

Biliverdin reductase B impairs cholangiocarcinoma cell motility by inhibiting the Notch/Snail signaling pathway.

Cholangiocarcinoma (CCA) is one of the most lethal types of solid tumors worldwide. Lymph node metastasis is common in the early stage, which is associated with recurrence and reduced survival time after CCA resection. The molecular pathogenesis of CCA is complex and requires extensive investigation. It involves multiple genomic alterations and the dysregulation of signaling pathways. Biliverdin reductase B (BLVRB) is a non-redundant NAD(P)H-dependent biliverdin reductase that regulates cellular redox status by reducing biliverdin to bilirubin. This study aimed at describing the biological functions and molecular mechanisms of BLVRB in human CCA. Prognostic clinical data showed that low expression BLVRB was associated with poor prognosis and lymph node metastasis. BLVRB depletion accelerated epithelial-mesenchymal transition (EMT), cell migration and invasion. In contrast, BLVRB overexpression was associated with reduced EMT and cell migration and invasion in CCA. BLVRB suppression activated Notch signaling, and activated c-Notch enhanced EMT by upregulating Snail expression levels, thereby increasing cell migration and invasion in CCA. Our results identified an unexpected function of BLVRB in CCA migration and invasion through the regulation of Notch/Snail signaling.

ERBB2 S310F mutation independently activates PI3K/AKT and MAPK pathways through homodimers to contribute gallbladder carcinoma growth.

Genomic instability and mutability are a prominent character of tumor. The whole-exosome sequence reveals that ERBB2 mutations are the representative mutations of gallbladder carcinoma, which takes potential targets for gallbladder carcinoma therapy. However, the roles of ERBB2 mutations are unclear in gallbladder carcinoma. We identified S310F mutation is the hottest mutation of ERBB2 mutations from TCGA PanCancer Altas data with 10,967 samples and our previous study with 157 gallbladder carcinoma samples. S310F mutation located in ERBB2 extracellular domain, promoted ERBB2 homodimerization and consequent auto-phosphorylation to activate the downstream PI3K/AKT and MAPK pathways, which was independent on ERBB1, ERBB3, and ERBB4. ERBB2 S310F mutation up-regulated aerobic glycolysis and promoted gallbladder carcinoma growth. Our study reveals the roles of ERBB2 S310F mutation, which is beneficial to ERBB2 S310F mutant gallbladder carcinoma therapy.

The impact of preoperative biliary drainage on postoperative outcomes in patients with malignant obstructive jaundice: a retrospective analysis of 290 consecutive cases at a single medical center.

BACKGROUND: The efficacy of preoperative biliary drainage (PBD) has been debated for several decades, and yet indications for PBD remain controversial. The aim of this study was to compare the postoperative morbidity and mortality in patients with malignant obstructive jaundice undergoing direct surgery versus surgery with PBD. METHODS: All consecutive patients with malignant obstructive jaundice who underwent radical resection between June 2017 and December 2019 at Zhongshan Hospital were analyzed retrospectively. The study population was divided into two groups: PBD group (PG) and direct surgery group (DG). The subgroups were chosen based on the site of obstruction. Perioperative indicators and postoperative complications were compared and analyzed. RESULTS: A total of 290 patients were analyzed. Postoperative complications occurred in 134 patients (46.4%). Patients in the PG group had a lower overall rate of postoperative complications compared with the DG group, with perioperative total bilirubin (TB) identified as an independent risk factor in multivariate analysis (hazard ratio = 1.004; 95% confidence interval 1.001-1.007; P = 0.017). Subgroup analysis showed that PBD reduced the complication rate in patients with proximal obstruction. In the proximal-obstruction subgroup, a preoperative TB level > 162 µmol/L predicted postoperative complications. CONCLUSIONS: PBD may reduce the overall rate of postoperative complications among patients with proximal malignant obstructive jaundice. TRIAL REGISTRATION: ClinicalTrials.gov, 2018ZSLC 24 . Registered May 17, 2018, https://clinicaltrials.gov/ .

Erratum: lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC.

[This corrects the article DOI: 10.1016/j.omto.2021.08.016.].

lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC.

Long non-coding RNAs (lncRNAs) have been identified as critical contributors in tumor progression for many types of cancer. However, their functions in gallbladder cancer (GBC) have not been systematically clarified. In this study, the clinical significance, biological function, and underlying mechanism of lncRNA RP11-147L13.8 in GBC were investigated. The quantitative real-time PCR result indicated that lncRNA RP11-147L13.8 was found to be recurrently downregulated in GBC tumor samples. Kaplan-Meier analysis revealed that decreased lncRNA RP11-147L13.8 expression level was associated with poor survival of GBC patients (p = 0.025). Then, both in vitro and in vivo experiments elucidated that the overexpression of lncRNA RP11-147L13.8 suppressed the migration and invasion abilities of GBC cells and promoted the sensitivity to gemcitabine of GBC cells. Furthermore, we found that lncRNA RP11-147L13.8 physically interacted with c-Jun protein and decreased the phosphorylation on serine-73 (c-Jun-Ser73), which might cause the enhancement of the migration, invasion, and sensitivity to gemcitabine of GBC tumor cells. In conclusion, our study identified lncRNA RP11-147L13.8 as a promising prognostic indicator for patients with GBC, providing insights into the molecular pathogenesis of GBC. lncRNA RP11-147L13.8 is a potential therapeutic combination for gemcitabine in GBC treatment.

Prevalence characteristics of human papillomavirus (HPV) infection among women receiving physical examinations in the Shangcheng District, Hangzhou city, China.

This paper aimed to investigate the characteristics of female HPV infection in the Shangcheng District, Hangzhou city, China. The retrospective study was designed to analyze the HPV prevalence rate of 22,382 women receiving physical examinations from 2016 to 2020 in the Shangcheng District of Hangzhou city in China. A commercial kit was designed to detect the HPV genotypes. Trends were examined for age-specific groups (≤ 30 years, 31-44 years, 45-54 years, 55-64 years, ≥ 65 years). A receiver operating characteristic (ROC) analysis was used to assess the correlation of age classification in high risk HPV (HR-HPV) infection. 22.41% (5015/22,382) of samples were HPV positive, 91.28% (4578/5015) of HPV positive women were infected by HR-HPV. The most prevalent HR-HPV genotypes were 16, 52, 18, 58, 56, and 51. The trend of HPV prevalence showed the significant differences in age-specific groups (χ2 = 164.70, P < 0.001). Moreover, the areas under ROC curve (AUC) was 0.712 in 55-64 years group which showed a strong contribution of age classification for HR-HPV infection. This study provided baseline data on the prevalence characteristics of HPV infection and the critical age group of HR-HPV prevalence rate was 55-64 y among the samples receiving physical examinations.

Knockdown of SLC39A4 Expression Inhibits the Proliferation and Motility of Gallbladder Cancer Cells and Tumor Formation in Nude Mice.

PURPOSE: Gallbladder cancer (GBC) is a common malignancy of the biliary tract and is characterized by rapid progression and early metastasis. Elucidating the molecular mechanisms of GBC could help to develop better treatment strategies. MATERIALS AND METHODS: Human GBC cell lines (GBC-SD and NOZ) were applied to determine the capacity of the proliferation and migration of cells using the MTT assay, colony formation, wound-healing assay as well as the Transwell™ assay. A nude xenograft was used to evaluate tumor growth in vivo. RESULTS: Using two types of GBC cell lines, we found that absence of solute carrier family (SLC) 39A4 (which encodes the zinc transporter ZRT/IRT-like protein [ZIP]4), could suppress the proliferation and migration of cells. Additionally, absence of ZIP4 could impair growth of xenografts in nude mice. While, over-expression of SLC39A4 could promote the GBC cell proliferation and migration, and inhibit apoptosis. We revealed that SLC39A4 might affect GBC progression by modulating the signaling pathways responsible for the survival, energy supply and metastasis of cells, and indicated that SLC39A4 could serve as a novel therapeutic target for GBC. CONCLUSION: SLC39A4 promoted the viability and motility of GBC cells, and tumor formation in nude mice. We demonstrated an oncogenic potential for SLC39A4.

Preoperative ICG Test to Predict Posthepatectomy Liver Failure and Postoperative Outcomes in Hilar Cholangiocarcinoma.

Preoperative evaluation of hepatic functional reserve in patients with hilar cholangiocarcinoma (hCCA) has vital clinical significance for prevention of posthepatectomy liver failure (PHLF) and mortality. The aim of the present study was to evaluate the clinical significance of the indocyanine green retention rate at 15 minutes (ICG R15) and related factors of postoperative outcomes in patients with hCCA. 147 patients who scheduled for hCCA resection underwent a preoperative ICG test between May 2015 and May 2020 and were prospectively analyzed. Single-factor analysis was used to evaluate the risk factors for PHLF and postoperative outcomes in hCCA. After univariate analysis, significant differences in ICG R15 were found between the PHLF group and the liver function recovered well (LFRW) group (P ≤ 0.05). In terms of postoperative complications, ICG R15 was also a risk factor for moderate-to-severe postoperative complications. Preoperative ICG R15 was significantly associated with PHLF and moderate-to-severe postoperative complications. ICG R15 may become an ideal clinical indicator for the evaluation of liver function reserve before hCCA and can better predict the postoperative complications.

Clinical correlation of cadherin-17 marker with advanced tumor stages and poor prognosis of cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.

Phosphorylation at Ser10 triggered p27 degradation and promoted gallbladder carcinoma cell migration and invasion by regulating stathmin1 under glucose deficiency.

Gallbladder carcinoma (GBC) is a considerable challenge because of its high metastatic potential. The tumor microenvironment is characterized by nutrient starvation, which promotes tumor metastasis. Stathmin1, an important microtubuleregulating protein, is overexpressed and promotes metastasis in GBC. It remains unclear how the harsh tumor microenvironment regulates stathmin1 expression to affect GBC metastasis. We employed glucose deficiency to mimic nutrient starvation and found that glucose deficiency upregulated stathmin1 transcription. However, glucose deficiency also promoted p27 degradation. There was a significant negative correlation between stathmin1 and p27 protein levels under glucose deficiency. Further study revealed that, under glucose deficiency, human kinase interacting with stathmin (hKIS) induced phosphorylation at Ser10 of p27 and its translocation to the cytoplasm for degradation, which upregulated the transcription factor E2F1 to promote stathmin1 transcription. hKIS knockdown significantly inhibited p27 cytoplasmic translocation and its consequent degradation. Stathmin1 knockdown significantly inhibited GBC cell migration and invasion in vitro. Our study revealed the role of the hKIS/p27/E2F1 axis in upregulating stathmin1 transcription to promote GBC cell migration and invasion under glucose deficiency conditions.

3D laparoscopic common bile duct exploration versus 2D in choledocholithiasis patients: a propensity score analysis.

BACKGROUND: This study was designed to investigate whether 3D laparoscopic common bile duct (LCBDE) could improve surgical outcomes in choledocholithiasis patients compared with 2D LCBDE. METHOD: Propensity score-matched analysis was performed to balance the bias in baseline characteristic between two groups. RESULTS: 213 patients underwent 3D LCBDE and 212 patients receiving 2D LCBDE were enrolled in this study. The operation time and blood loss in 3D group were significantly less than that in 2D group. After propensity score matching, a total of 114 paired cases were selected from the two groups. The operation time and blood loss in 3D group remain significantly lower than in 2D group. In the end, the subgroup analysis based on abdominal adhesion level was performed and it was observed that for patients with adhesion level 1 and level 2, 3D surgery could obviously decrease the operation time and intraoperative blood loss. CONCLUSIONS: 3D LCBDE would significantly reduce operation time, blood loss, and conversion rate to laparotomy in choledocholithiasis patients versus 2D LCBDE. For patients with abdominal adhesions level 1 and level 2, 3D LCBDE could provide better surgical outcomes than 2D LCBDE.

Prediction Efficacy for Clinical Outcome of Prognostic Nutritional Index in Patients with Resectable Biliary Tract Cancer Depends on Sex and Obstructive Jaundice Status.

BACKGROUND: The Prognostic Nutritional Index (PNI), a marker of nutritional status and systemic inflammation, is a proven prognostic biomarker in some cancers. The predictive value of PNI in biliary tract cancer (BTC) has not been established. OBJECTIVE: The aim of this study was to determine the relationship between the PNI and outcomes of resectable BTC. METHODS: In total, 430 patients with stage I-III resectable BTC [gallbladder cancer (GBC), n = 212; cholangiocarcinoma (CHO), n = 218] who had attended Fudan University Zhongshan Hospital were enrolled. The relationship between the PNI and clinical outcomes was evaluated both in the whole cohort and in selected subgroups. RESULTS: Eligible patients were classified into PNI-low (PNI < 45) and PNI-high (PNI ≥ 45) groups. The PNI-low group had significantly worse overall survival (OS) in both the whole cohort (p = 0.002) and in the GBC subgroup (p = 0.001), but had similar OS as the PNI-high group in the CHO subgroup (p = 0.328). Multivariate analysis revealed that low PNI is an independent risk factor for worse survival in GBC (hazard ratio 1.623, 95% confidence interval 1.063-2.480, p = 0.026). PNI was found to predict clinical outcome in women (p < 0.001) and patients without obstructive jaundice (p = 0.017) with GBC, but was not a prognostic factor in any subgroup with CHO. The estimated area under the time-dependent receiver operating characteristic curve was significantly greater when TNM stage was combined with PNI in women with GBC. CONCLUSIONS: PNI is an independent predictor of OS in GBC, but not in CHO. It has no prognostic value in men with GBC or patients with obstructive jaundice.