Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete. AIM: To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients. METHODS: Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types. RESULTS: CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC-high cells were found to promote CCA progression through WNT signaling. MUC5B-high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13-high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis. CONCLUSION: Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

Pathological analysis of the superior mesenteric artery boundary in preoperative computed tomography of resectable pancreatic head adenocarcinoma.

The aim of the present study was to evaluate the biological and prognostic implications of the superior mesenteric artery (SMA) boundary on preoperative abdominal contrast-enhanced computed tomography (CE-CT) for resectable adenocarcinoma of the pancreatic head. A total of 121 patients treated over a 6-year period at Peking University Third Hospital (Beijing, China) were included in the present study. The pattern of the SMA boundary was investigated on preoperative CE-CT and detailed pathological analysis of the extrapancreatic plexus [the pancreatic head plexus II (PLX-II) located on the right edge of the SMA] was performed. The results revealed that the radiological SMA boundary was associated with the grade of parasympathetic neurogenesis (P=0.014) in PLX-II, and was predictive of postoperative disease-free survival (P=0.014) and liver metastasis (P=0.013). Therefore, it was proposed that extrapancreatic parasympathetic neurogenesis may account for the different patterns of the SMA boundary on preoperative abdominal CE-CT, and affect the prognosis, particularly for liver metastasis in resectable pancreatic head adenocarcinoma.

Extrapancreatic Neuropathy Correlates with Early Liver Metastasis in Pancreatic Head Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma has a devastatingly poor prognosis, and most prognostic factors reflected the tumor stage more than the tumors' biology. The peripheral nerve plexus is densely distributed in the tumor micro-environment, and there are interactions between tumor cells and these nerves. Perineural invasion is an important risk factor for tumor recurrence and metastasis in pancreatic head adenocarcinoma, but the concrete types of extrapancreatic neuropathy and its role in predicting prognosis are still not clear. OBJECTIVE: To clarify the role of extrapancreatic neuropathy in the early postoperative liver metastasis and tumor-related mortality in pancreatic head adenocarcinoma and to study the mechanism of tumor recurrence and liver metastasis in pancreatic head adenocarcinoma. METHODS: We reported a retrospective study of 60 patients with resectable pancreatic head adenocarcinoma, all of whom accepted radical pancreaticoduodenectomy. Plexus pancreaticus capitalis II (PLX-II) was the representation of extrapancreatic plexus in our study, and all of these plexus had immunohistochemical staining. We defined the postoperative tumor recurrence and tumor-related mortality within 6 months as the early prognostic indicators and analyzed the pathological alterations in PLX-II among different prognosis groups. RESULTS: There were 18 patients suffering early postoperative liver metastasis; these two groups differed significantly in the average number of nerve trunks (P<0.001), the proportion of neuritis (P=0.003), the content of sympathetic nerve fibers (P=0.004) and parasympathetic nerve fibers (P<0.001) per unit area of PLX-II. There were 15 patients suffering early postoperative mortality, and there were significant differences between these two groups in the average number of nerve trunks (P<0.001), the proportion of neuritis (P=0.009), the content of sympathetic nerve fibers (P=0.023) and parasympathetic nerve fibers (P<0.001) per unit area of PLX-II. CONCLUSION: The patterns of extrapancreatic neuropathy could reflect the biological behavior of resectable pancreatic head adenocarcinoma, and the pathological features of PLX-II were closely related to early liver metastasis and mortality.

TGF-ß signaling regulates DACT1 expression in intestinal epithelial cells.

DACT1, was first identified as a Dishevelled-associated antagonist of Wnt signaling pathway. It has been reported that DACT1 functions in embryonic development and tumorigenesis. However, the regulation of DACT1 still remains unclear. We found Wnt signaling has no effect on DACT1, but TGF-ß increases expression of DACT1 in intestinal epithelial cells. In addition, the minimal promoter is located in the region of -500bp to +1bp and the region between -3000bp to +1bp enhanced promoter activity. Site-directed mutation analysis was performed and indicated that potential regulatory elements was near -335bp. Our study provided the basic information for the exploration of DACT1 regulation and expression. Moreover, TGF-ß inhibits Wnt signaling to enhance the function of DACT1 inhibiting Wnt signaling.

Prognostic significance of K-ras mutations in pancreatic cancer: a meta-analysis.

BACKGROUND: K-ras gene mutations are common in patients with pancreatic cancer (PC); however, their prognostic value for PC remains inconclusive. This meta-analysis was performed to quantitatively evaluate the association between K-ras mutations and survival in patients with pancreatic cancer. METHODS: We performed a comprehensive search of electronic sources including MEDLINE (via PubMed), Web of Science, and the Cochrane Library. The search covered a publication period from inception to November 2015. RESULTS: Seventeen studies with a total of 2249 patients with pancreatic cancer were included in the tissue detection of this study. The meta-analysis indicated a significant association between mutant K-ras genes and overall survival (OS) (HR = 1.51, 95% CI 1.32-1.72, P < 0.001). Moreover, further subgroup analyses by ethnicity, publication year, therapy method, cancer resectability, and gene detection method all revealed that pancreatic cancer patients with the K-ras mutation had significantly poorer OS (P < 0.05). And results from four studies with 225 patients focused on plasma K-ras mutations enhanced such association (HR = 2.23, 95% CI 1.69-2.95, P < 0.001). CONCLUSIONS: As a prediction of poor prognosis, the detection of K-ras mutations may be a useful prognostic factor for pancreatic cancer patients.

Strategies for diagnosis of xanthogranulomatous cholecystitis masquerading as gallbladder cancer.

BACKGROUND: Patients with xanthogranulomatous cholecystitis sometimes exhibit imaging and intraoperative findings that are similar to those of advanced gallbladder cancer, thus these patients are easily misdiagnosed. The present study aimed to investigate the characteristics of xanthogranulomatous cholecystitis masquerading as gallbladder cancer that could potentially aid in the correct diagnosis of this condition. METHODS: The clinical, serological, radiological and operative features of twelve patients with obviously wall-thickening or mass-forming xanthogranulomatous cholecystitis were retrospectively analyzed. Additionally, the patient preoperative features were compared to those of 36 patients with advanced gallbladder cancers. RESULTS: Twelve patients with xanthogranulomatous cholecystitis exhibited one to three episodes of acute cholecystitis within 0.5 to 7 months prior to admission to the hospital. Five of these patients exhibited concomitant choledocholithiasis, whereas no concomitant choledocholithiasis was identified in patients with advanced gallbladder cancer. The incidence of abdominal pain (χ(2) = 6.588, P = 0.010), acute cholecystitis (χ(2) = 29.176, P = 0.000), acute cholangitis (χ(2) = 6.349, P = 0.012), choledocholithiasis (χ(2) = 16.744, P = 0.000), carcinoembryonic antigen test (P = 0.007), CA125 (P = 0.001), and diffuse gallbladder wall thickening (χ(2) = 6.031, P = 0.014), continued mucosal line (χ(2) = 15.745, P = 0.000), homogeneous enhancement of mucosal line (χ(2) = 19.947, P = 0.000), submucosal hypoattenuated nodules or band (χ(2) = 18.607, P = 0.000) in computed tomography demonstrated statistically significant differences between cases of xanthogranulomatous cholecystitis and gallbladder cancer. Furthermore, all the twelve patients with xanthogranulomatous cholecystitis exhibited at least one positive computed tomography imaging feature aside from past acute cholecystitis episode, and no patient with advanced gallbladder cancer simultaneously exhibited past acute cholecystitis episode and at least one positive computed tomography imaging feature. CONCLUSIONS: The accurate preoperative diagnosis of xanthogranulomatous cholecystitis includes an integrated review of past acute cholecystitis episode, choledocholithiasis, and positive computed tomography imaging features. Besides, we present an algorithm for intraoperative diagnosis.