BACKGROUND Celiac disease (CD) is one of the most prevalent chronic disorders. The clinical manifestations of CD are diverse and may present with gastrointestinal findings, extra-intestinal findings or no symptoms. Although there has been a marked increase in the prevalence of CD in the past 30 years, up to 95% of patients with CD remain undiagnosed. As most cases have atypical signs or no symptoms, the diagnosis of CD is either missed or delayed. In addition, one of the most important reasons for the delay in diagnosis may be the poor knowledge of healthcare professionals (HCPs) regarding CD. AIM To evaluate the knowledge of HCPs, patients and their caregivers (parents) regarding CD. METHODS The current study was carried out between June 2021 and February 2022 prospectively, as part of the Focus IN CD project. Patients with CD and their caregivers participated in the study from 6 different cities in Turkey. General practitioners, pediatricians, pediatricians with other subspecialities and pediatric gastroenterologists from different cities participated in the study. RESULTS The questionnaire was completed by 348 HCPs, 34 patients with CD, and 102 mothers and 34 fathers of patients with CD. Most of the participants were general practitioners (37.07%). There were 89 (25.57%) pediatricians and 72 (20.69%) pediatric gastroenterologists in the study. The highest score in all categories was achieved by pediatric gastroenterologists. There were significant differences between the four groups of HCPs in terms of the subsections of overall mean score, epidemiology and clinical presentation, treatment and follow-up. No significant difference was found between the groups (patients with CD, mothers of patients with CD and fathers of patients with CD) in terms of the questionnaire subsections. CONCLUSION The level of knowledge on CD among HCPs, patients and their caregivers was unsatisfactory. We consider that it is necessary to increase awareness and to develop e-learning activities on CD among HCPs, patients and their caregivers. Consequently, they may benefit from e-learning programs similar to the one created as part of the EU-funded project Focus IN CD (https://www.celiacfacts.eu/focusincd-en).

Knowledge regarding celiac disease among healthcare professionals, patients and their caregivers in Turkey

A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment

BACKGROUND
 Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that pathological evaluation of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may be crucial in determining tumor behavior in the gastrointestinal tract. Regarding gastric adenocarcinoma (GAC), although some results suggest that TB and TILs may be effective in determining the course of the disease, the data do not agree. Moreover, very few studies have investigated the relationship between DR and survival. At present, the associations between tumor TB, DR and TILs in GAC patients have not been determined.
 AIM
 To establish the relationships between TB, DR, and TILs in patients with GAC and to assess their influence on prognosis.
 METHODS
 Our study group comprised 130 patients diagnosed with GAC. The definition of TB was established based on the International TB Consensus Conference. The DR was categorized into three groups according to the level of tumor stroma maturation. The assessment of TILs was conducted using a semiquantitative approach, employing a cutoff value of 5%. The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27.
 RESULTS
 A significant correlation between peritumoral budding (PTB) and intratumoral budding (ITB) was noted (r = 0.943). Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs (P < 0.01). PTB and ITB were associated with histological subtype, lymph node metastasis (LNM), and stage (P < 0.01). ITB, PTB, LNM, DR, and stage were significant risk factors associated with poor prognosis. The multivariate Cox regression analysis identified ITB, PTB, and LNM as independent prognostic variables (P < 0.05). In intestinal-type adenocarcinomas, a positive correlation between PTB and ITB was noted (r = 0.972). While univariate analysis revealed that LNM, stage, PTB, ITB, and DR were strong parameters for predicting survival (P < 0.05), only PTB and ITB were found to be independent prognostic factors (P < 0.001).
 CONCLUSION
 TB may be a potential prognostic marker in GAC. However, further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.

Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma

Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64Cu2+ is an anticancer radiopharmaceuticals targeting the copper requirement of cancer cells. However, intravenously injected 64Cu2+ ions primarily accumulate in the liver. Ligand complexation of 64Cu2+ would be a promising method for increasing tumor delivery by reducing liver uptake. Herein, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64Cu2+ ions and compared their in vivo tumor and liver uptake using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis for these compounds. 64Cu2+-Tren and 64Cu2+-Dien showed higher tumor uptake than 64Cu2+-TPMA and 64Cu2+ ions in TFK-1 tumors. Among the three 64Cu2+ complexes and 64Cu2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake and nuclear delivery was the highest for 64Cu2+-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64Cu2+ complexes of tripodal amine ligands and 64Cu2+ ions. These results provide useful information for the future development of anticancer 64Cu radiopharmaceuticals. 

&lt;sup&gt;64&lt;/sup&gt;Cu&lt;sup&gt;2+ &lt;/sup&gt;Complexes of Tripodal Amine Ligands on In Vivo Tumor and Liver Uptake and Intracellular Cu Distribution in the Extrahepatic Bile Duct Carcinoma Cell Line TFK-1: A Basic Comparative Study

The identification of proteins as new cancer diagnostic and prognostic biomarkers continues to attract considerable attention in the oncology literature, especially in the context of invasion and metastasis activation process [...]

Biomarkers of Tumor Metastasis and Invasiveness

Simple Summary Extrahepatic cholangiocarcinoma (EHCC) is an aggressive tumor. The five-year survival rate for patients who undergo surgical resection is only 20–40% due to recurrences. Therefore, elucidating the molecular mechanisms underlying invasion and metastasis in EHCC is crucial for developing adjuvant therapy. The epithelial–mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. The association between CCR7 expression and clinicopathological features and EMT status was examined via the immunohistochemical staining of tumor sections from 181 patients with perihilar cholangiocarcinoma. This association was then investigated in two EHCC cell lines. CCR7 mediates cell invasion and migration in EHCC by inducing EMT, which was abrogated by a CCR7 antagonist. CCR7 may be a potential target for adjuvant therapy in EHCC. Abstract The epithelial–mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. However, the association between EMT and CCR7 in extrahepatic cholangiocarcinoma (EHCC) remains unknown. This study aimed to elucidate the prognostic impact of CCR7 expression and its association with clinicopathological features and EMT in EHCC. The association between CCR7 expression and clinicopathological features and EMT status was examined via the immunohistochemical staining of tumor sections from 181 patients with perihilar cholangiocarcinoma. This association was then investigated in TFK-1 and EGI-1 EHCC cell lines. High-grade CCR7 expression was significantly associated with a large number of tumor buds, low E-cadherin expression, and poor overall survival. TFK-1 showed CCR7 expression, and Western blotting revealed E-cadherin downregulation and vimentin upregulation in response to CCL19 treatment. The wound healing and Transwell invasion assays revealed that the activation of CCR7 by CCL19 enhanced the migration and invasion of TFK-1 cells, which were abrogated by a CCR7 antagonist. These results suggest that a high CCR7 expression is associated with an adverse postoperative prognosis via EMT induction and that CCR7 may be a potential target for adjuvant therapy in EHCC.

/pdf/ccr7-mediates-cell-invasion-and-migration-in-extrahepatic-3bbubm7t.pdf

CCR7 Mediates Cell Invasion and Migration in Extrahepatic Cholangiocarcinoma by Inducing Epithelial–Mesenchymal Transition

Postoperative Prognosis According to Pathologic Categorization of Desmoplastic Reaction in Patients with Extrahepatic Cholangiocarcinoma

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CCR7 Mediates Cell Invasion and Migration in Extrahepatic Cholangiocarcinoma by Inducing Epithelial–Mesenchymal Transition

Postoperative Prognosis According to Pathologic Categorization of Desmoplastic Reaction in Patients with Extrahepatic Cholangiocarcinoma