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Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis. [ABSTRACT FROM AUTHOR]

Purpose: 18F-FDG PET/MR has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MR in hilar cholangiocarcinoma (HCCA) are rare. We investigated the value of PET/MR for preoperative staging and compared it with PET/CT in HCCA. Methods: Fifty-eight patients with HCCA confirmed by pathology were retrospectively analyzed. 18F-FDG PET/CT imaging was performed first, followed with whole-body PET/MR imaging. SUVmax of tumor and normal liver tissue were measured. Paired T test was used to compare SUVmax of tumor and normal liver tissue of PET/CT and PET/MR. In addition, McNemar test was used to compare the accuracy of TNM staging and Bismuth-Corlette typing between PET/CT and PET/MR. Results: There was no significant difference in SUVmax between PET/CT and PET/MR in primary tumor lesions (6.6 ± 5.5 vs. 6.8 ± 6.2, P = 0.439). SUVmax of PET/CT and PET/MR in normal liver parenchyma was significantly different (3.0 ± 0.5 vs. 2.1 ± 0.5, P < 0.001). The accuracy of PET/MR in diagnosing T staging and N staging was significantly higher than those of PET/CT (72.4% vs. 58.6%, P = 0.022 and 84.5% vs. 67.2%, P = 0.002). There was no significant difference between PET/CT and PET/MR in M staging (94.8% vs. 98.3%, P = 0.5). The classification accuracy of PET/MR in Bismuth-Corlette was significantly higher than that of PET/CT (89.7% vs. 79.3%), P = 0.031. Conclusions: The diagnostic accuracy of 18F-FDG PET/MR was superior to that of PET/CT in preoperative T staging, N staging, and Bismuth–Corlette classification of HCCA. In M staging, the diagnostic accuracy of PET/MR was similar to that of PET/CT. [ABSTRACT FROM AUTHOR]

Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved assembly of the targeted genomic region with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assembly, our targeted approach achieved comparable completeness and accuracy with reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal MHC haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses of the MHC region. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology. Low-cost targeted approach to construct haplotype-resolved assemblies is needed to facilitate population genetic studies. Here, the authors demonstrate assembling high-quality MHC haplotypes with CRISPR-based enrichment and long-read sequencings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the role of dual-time point 18F-FDG PET/CT imaging in the primary diagnosis and staging of hilar cholangiocarcinoma (HCCA). Methods: Dual-time point FDG PET/CT findings, including early phase whole-body scanning and abdominal delayed phased performed 1 and 2 h after radiotracer injection, respectively, were retrospective reviewed in 69 patients conformed HCCA by histology. PET/CT was evaluated based on visual interpretation and the semiquantitative index of SUVmax and tumor-to-normal liver tissue ratio (TNR) for both early and delayed images. Results: For all 69 HCCA patients, the mean SUVmax of the lesion and TNR in delayed phase was significantly higher than that in early phase (6.1 ± 4.7, 2.2 ± 1.7, vs 5.1 ± 3.4, 1.6 ± 1.1; P < 0.001). The sensitivity and accuracy value of detection primary lesions was 69.6% and 70% in early phase vs 76.8% and 76.8% in delay phase, respectively. There was a significant correlation between lesion SUVmax and Ki67 index in both dual-time imaging (r = 0.462, P < 0.001 in early phase vs r = 0.47, P < 0.001 in delay phase). The sensitivity, specificity and accuracy value of metastatic lymph nodes prediction was 50%, 67.3% and 71% in early phase vs 62.5%, 73.3% and 76.8% in delayed phase, respectively. The sensitivity, specificity and accuracy of FDG PET/CT in detecting distant metastasis in our study was 75%, 100% and 97.1%. There was no difference of predicting distant metastasis between early phase and delayed phase. Conclusion: Delayed phase in dual-time point 18F-FDG PET/CT scan provides additional usefulness for detection primary tumor and lymph nodes metastases in HCCA, but there was no added benefit of delayed PET/CT imaging in detection of distant metastases in this study. SUVmax in early and delayed phase could be used to assess tumor aggressiveness in pre-treatment HCCA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

CA-125, coded by MUC16 gene, is responsible to many kinds of tumor metastasis. However, the related mechanism remains unclear. We have established a novel manner to reveal gallbladder cancer metastasis related to serum CA-125 levels through the C-terminal polypeptide of MUC16 gene production. MUC16 C-terminal polypeptide significantly promoted gallbladder cancer cell migration and invasion in vitro. Mass spectrum indicated that interaction of MUC16 C-terminal fragment with the C-terminal domain of stathmin1 inhibited the phosphorylation of stathmin1 to promote the combination with tubulin. Stathmin1 knockdown inhibited the migration and invasion of gallbladder cancer cells in vitro and lung metastasis in vivo induced by MUC16 C-terminal polypeptide. The high expression level of MUC16c consistent with stathmin1 was also confirmed in gallbladder cancer tissues. Our study revealed the underlying mechanism of gallbladder cancer metastasis related to CA-125 levels, which was beneficial for CA-125 in gallbladder cancer diagnose and therapy. [ABSTRACT FROM AUTHOR]

With the development of electronic components towards high power, high packaging density, and miniaturization of device size, heat dissipation and the electromagnetic interference problems between the electronic components are emerging. In order to solve the undesirable electromagnetic wave and heat emissions produced by electronic device simultaneously, the electronic packaging materials with high thermal conductivity and anti-electromagnetic interference are highly expected. In this work, NiFe2O4-modified short carbon fibers (SCF) were designed and prepared. NiFe2O4 were in situ grown on the surface of SCF by hydrothermal method. The chemical structure and morphology of SCF-NiFe2O4 were characterized by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The microwave absorbing performance test shows that SCF-NiFe2O4 possess superior microwave absorbing performance, where the minimum reflection loss is − 20.7 dB. Finally, SCF-NiFe2O4/epoxy resin composites were prepared by introducing SCF-NiFe2O4 as thermal conductive filler into epoxy resin. The surface-modified SCF with NiFe2O4 is more easily infiltrated by resin and exhibits strong interfacial interaction with the matrix. With the increase of the content of SCF-NiFe2O4, the thermal conductivity of the composites increases obviously. When the content of SCF-NiFe2O4 reaches 20 vol%, the composites show better thermal conductivity, and the thermal conductivity reaches 1.03 W/m K. [ABSTRACT FROM AUTHOR]

Background: A history of abdominal biliary tract surgery has been identified as a relative contraindication for laparoscopic common bile duct exploration (LCBDE), and there are very few reports about laparoscopic procedures in patients with a history of abdominal biliary tract surgery.Methods: We retrospectively reviewed the clinical outcomes of 227 consecutive patients with previous abdominal biliary tract operations at our institution between December 2013 and June 2019. A total of 110 consecutive patients underwent LCBDE, and 117 consecutive patients underwent open common bile duct exploration (OCBDE). Patient demographics and perioperative variables were compared between the two groups.Results: The LCBDE group performed significantly better than the OCBDE group with respect to estimated blood loss [30 (5-700) vs. 50 (10-1800) ml; p = 0.041], remnant common bile duct (CBD) stones (17 vs. 28%; p = 0.050), postoperative hospital stay [7 (3-78) vs. 8.5 (4.5-74) days; p = 0.041], and time to oral intake [2.5 (1-7) vs. 3 (2-24) days; p = 0.015]. There were no significant differences in the operation time [170 (60-480) vs. 180 (41-330) minutes; p = 0.067]. A total of 19 patients (17%) in the LCBDE group were converted to open surgery. According to Clavien's classification of complications, the LCBDE group had significantly fewer postoperative complications than the OCBDE group (40 vs. 57; p = 0.045). There was no mortality in either group. Multiple previous operations (≥ 2 times), a history of open surgery, and previous biliary tract surgery (including bile duct or gallbladder + bile duct other than cholecystectomy alone) were risk factors for postoperative adhesion (p = 0.000, p = 0.000, and p = 0.000, respectively).Conclusion: LCBDE is ultimately the least invasive, safest, and the most effective treatment option for patients with previous abdominal biliary tract operations and is especially suitable for those with a history of cholecystectomy, few previous operations (< 2 times), or a history of laparoscopic surgery. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic common bile duct exploration (LCBDE) has been widely promoted in recent years as a safe and effective treatment for choledocholithiasis. However, there are no standard guidelines for the treatment of patients who have concomitant hepatolithiasis of the left liver and abdominal adhesions. The aim of the current research was to compare the outcomes of open versus laparoscopic common bile duct exploration with left hepatectomy (OCBDH vs. LCBDH) in patients with choledocholithiasis concomitant with left-sided hepatolithiasis, and to evaluate the safety and feasibility of laparoscopic surgery for choledocholithiasis in patients with abdominal adhesions.Methods: Between October 2012 and October 2015, a total of 321 consecutive patients with choledocholithiasis underwent surgical treatment. LCBDE was performed in 107 patients, and open common bile duct exploration (OCBDE) was performed in 111 patients. Further, 31 patients and 72 patients underwent LCBDH and OCBDH, respectively. A total of 133 patients who underwent LCBDE or OCBDE had abdominal adhesions, which were classified as mild, moderate, or severe according to an abdominal adhesion scoring system, which was validated in the LCBDE group and OCBDE group. The perioperative results were reviewed and analyzed retrospectively.Results: In the mild adhesion group, blood loss, postoperative recovery in the LCBDE group was lesser than those in the OCBDE group. In the moderate adhesion group, the postoperative recovery was significantly shorter in the LCBDE group than in the OCBDE group. In the severe adhesion group, the operation time and blood loss in the LCBDE group were higher than those in the OCBDE group. The postoperative recovery was significantly better in the LCBDH group than in the OCBDH group.Conclusion: LCBDH can obviously improve recovery and shorten the hospitalization period. Further, LCBDE is safe and feasible for patients of choledocholithiasis with mild and moderate abdominal adhesions. [ABSTRACT FROM AUTHOR]

Background: This population-based study examined surgical outcomes and hospital and post-acute care resource use after operations of cholangiocarcinoma during 2005-2012. Study design: Using New York State hospital claims, we identified subjects with intrahepatic tumor who underwent hepatectomy only ( n = 2089), subjects with perihilar tumor who underwent hepatectomy and biliary-enteric anastomosis (BEA; n = 389) or BEA only ( n = 3721), and subjects with distal cholangiocarcinoma undergoing pancreatectomy or pancreaticoduodenectomy ( n = 228). We performed trend analyses for each group and calculated overall risk-adjusted mortality, complication, and 30-day readmission rates for hospitals using multivariable logistic regressions. Results: Mortality rate was roughly 12 % over years for perihilar cases undergoing hepatectomy and BEA, significantly higher than the rates of other 3 groups ( p = 0.000). The overall complication rate was 40 % for subjects undergoing both hepatectomy and BEA, more than doubling the rate for subjects undergoing hepatectomy or BEA alone ( p = 0.000). Average LOS declined markedly for perihilar cases undergoing hepatectomy and BEA (from 21 days in 2005 to 16 days in 2012) and subjects with distal cholangiocarcinoma (from 22 days in 2005 to 16 days in 2012), but other outcomes did not change dramatically. Risk-adjusted hospital outcome rates varied substantially. Conclusions: Surgical patients with cholangiocarcinoma incur considerable mortality, postoperative complications, and resource uses, especially among those undergoing hepatectomy and BEA for perihilar tumors. [ABSTRACT FROM AUTHOR]

Members of the Kruppel-like factor (KLF) family have been considered as the tumor suppressors for their inhibitory effects on cell proliferation. Dysregulation of KLF2, a member of KLF family, has been observed in various cancer types. However, its expression pattern and functions in the pancreatic ductal adenocarcinoma (PDAC) are unknown. In this study, we examined the expression of KLF2 in PDAC clinical samples and evaluated the functions of KLF2 in the progression of PDAC. KLF2 is shown to be downregulated in PDAC clinical samples and overexpression of KLF2 inhibits the growth, migration, and metastasis of PDAC cancer cells. KLF2 interacts with beta-catenin and negatively regulates the beta-catenin/TCF signaling. Taken together, this study suggests the suppressive functions of KLF2 in PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies in the world. Numerous studies have linked the activation of AKT to the progression of PDAC. Phosphatidylethanolamine-binding protein 4 (PEBP4) has been reported to be upregulated in various cancer types. However, its expression pattern and biological functions in PDAC are unknown. In this study, it was found that the messenger RNA (mRNA) and protein level of PEBP4 was elevated in PDAC samples. Forced expression of PEBP4 in PDAC cell lines promoted cell growth and migration, while downregulation of PEBP4 in PDAC cells by RNA interference (RNAi) inhibited the growth, migration, and metastasis of the cancer cells. PEBP4 interacted with AKT and promoted the phosphorylation of serine 473 in AKT. Collectively, this study suggested that PEBP4 might promote the progression of PDAC through activating AKT signaling and PEBP4 might be a promising therapeutic target for PDAC treatment. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is one of the most common and aggressive diseases among the gastrointestinal tract malignancies, and the molecular mechanism underlying this disease remains largely unknown. CIZ1 (Cip1 interacting zinc finger protein 1), a binding partner of p21, has been found to be involved in the tumorigenesis recently. However, the expression pattern and biological functions of CIZ1 in the progression of GBC are not fully understood. In this study, it was found that the expression of CIZ1 was significantly elevated in GBC samples compared to their adjacent normal tissues. Moreover, overexpression of CIZ1 promoted the growth and migration of GBC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and tumorigenesis of GBC cells in vitro and in vivo. Mechanistically, CIZ1 was found to interact with TCF4 (T-cell factor) and activate beta-catenin/TCF signaling. Our study demonstrated that CIZ1 played an oncogenic role in the progression of GBC and CIZ1 might be a promising target for the treatment of GBC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor response to chemotherapy. It is very important to identify novel diagnosis biomarkers and therapeutic targets. RIP140, a regulator of estrogen receptor, recently has been found to be involved in the tumorigenesis. However, its function in the progression of HCC remains poorly understood. Here, we found that the expression of RIP140 was downregulated in the HCC tissues. Moreover, overexpression of RIP140 in HCC cells inhibited cell proliferation and migration, while downregulation of RIP140 promoted the tumorigenicity of HCC cells in vitro and in vivo. Mechanistically, RIP140 interacted with beta-catenin and negatively regulated beta-catenin/TCF signaling. Taken together, our study suggests the suppressive roles of RIP140 in the pathogenesis of HCC. [ABSTRACT FROM AUTHOR]

SLIT, a secretory glycoprotein, and its receptor roundabout (ROBO) are expressed in several types of cancer and have been implicated in tumor angiogenesis. The purpose of this study was to determine the prognostic implications of SLIT and ROBO1 expression and their association with clinicopathologic characteristics in gallbladder cancer. A retrospective analysis of 109 consecutive patients who underwent primary gallbladder cancer resection was conducted. Univariate and multivariate models were used to analyze the effect of clinicopathologic factors on survival. Expression of SLIT and ROBO1 was evaluated by immunohistochemistry, and their association with clinicopathologic characteristics was analyzed using mean testing. Multivariate linear regression analysis was also applied to investigate the independent predictors of ROBO1 expression. Seventy-five patients were included in the post-resection survival analysis, with 1-year and 3-year overall survival rates of 60 and 40 %, respectively. Univariate analysis revealed that pN classification, pT classification, pM classification, liver involvement, perineural invasion, TNM staging, Nevin staging, and microscopic resection margins affect prognosis. Multivariate analysis confirmed that pN classification, liver involvement, and perineural invasion are independent prognostic factors. In the mean tests of 109 cases, the mean difference of SLIT immunoreactivity was significant according to the presence of gallstones ( P = 0.003) and liver involvement ( P = 0.005), while the mean difference of ROBO1 immunoreactivity was significant according to liver involvement ( P < 0.001), TNM staging ( P < 0.001), and Nevin staging ( P < 0.001). Multivariate analysis of ROBO1 immunoreactivity showed that SLIT immunoreactivity and TNM stage (adjusted R = 0.203) or SLIT immunoreactivity and Nevin stage (adjusted R = 0.195) were independent predictors of ROBO1 expression. pN classification, liver involvement, perineural invasion, and pathologic stage are significant prognostic factors for gallbladder cancer survival. SLIT expression is associated with cholelithiasis and liver involvement, and ROBO1 expression is associated with liver involvement and pathologic stage. In addition, SLIT expression and pathologic stage predict ROBO1 expression independently. [ABSTRACT FROM AUTHOR]