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Background: COVID-19 has spread widely among health care workers. Oral health care workers have an increased risk of being infected owing to dental practice characteristics. New, effective vaccines against COVID-19 have been approved for use. The authors aim was to evaluate intentions to be vaccinated against COVID-19 in a population of dentists and identify factors associated with their intentions. Methods: The authors conducted an anonymous online survey among 761 dentists enrolled at the Board of Physicians and Dentists of the District of Monza Brianza, Monza, Italy. The authors collected data on demographic characteristics, influenza vaccine uptake, COVID-19 history, vaccine attitudes, and specific reasons for their intentions to be vaccinated against COVID-19 or not. Results: Overall, 421 dentists completed the survey. More than 82% of the participants declared their intention to be vaccinated against COVID-19. The multivariate logistic regression model reported a positive association with receiving the influenza vaccine in the 2020-2021 influenza season (odds ratio, 5.15; 95% CI, 2.14 to 12.39) and a negative association with receiving a diagnosis of COVID-19 previously (odds ratio, 0.32; 95% CI, 0.15 to 0.66). The participants’ main reason for supporting vaccination was to protect their family and friends (87%) and their main reason for opposing vaccination was the lack of information (39%). Conclusions: It is fundamental to consider vaccine hesitancy in health care workers and address it properly because they must provide recommendations to patients and promote adherence to vaccination programs. Practical Implications: The vaccination of dental practitioners should be prioritized owing to the high risk related to dental practice.

Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1, 30% positive; and FGFR2, 65% positive) and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.

Background & Aims A therapeutically challenging subset of cells, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche. Methods CCA cells were cultured in 3D conditions to generate spheres. CCA sphere analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed. The in vitro and in vivo effect of CCA spheres on macrophage precursors was tested after culturing healthy donor cluster of differentiation (CD)14+ with CCA-sphere conditioned medium. Results CCA spheres engrafted in 100% of transplanted mice and revealed a significant 20.3-fold increase in tumor-initiating fraction (p = 0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA spheres were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. Next, fluorescence-activated cell sorting analysis showed that in the presence of CCA sphere conditioned medium, CD14+ macrophages expressed key markers (CD68, CD115, human leukocyte antigen-D related, CD206) indicating that CCA sphere conditioned medium was a strong macrophage-activator. Gene expression profile of CCA sphere activated macrophages revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated macrophages from CCA resections recapitulated a similar molecular phenotype of in vitro-educated macrophages. Consistent with invasive features, the largest CD163+ set was found in the tumor front of human CCA specimens (n = 23) and correlated with a high level of serum cancer antigen 19.9 (n = 17). Among mediators released by CCA spheres, only interleukin (IL)13, IL34 and osteoactivin were detected and further confirmed in CCA patient sera (n = 12). S

Background: MET amplification has been detected in ∼20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. Patients and methods: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. Results: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. Conclusions: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance

The American Association for the Study of Liver Diseases guidelines recommend the use of all available markers for improving the accuracy of the diagnosis of small hepatocellular carcinoma (HCC). To determine whether clathrin heavy chain (CHC), a novel HCC marker, is effective in combination with glypican 3 (GPC3), heat shock protein 70, and glutamine synthetase, we compared the performances of a three-marker panel (without CHC) and a four-marker panel (with CHC) in a series of small HCCs (≤2 cm) and nonsmall HCCs by core biopsy with a 20- to 21-gauge needle. The series included 39 nonsmall HCCs and 47 small HCCs (86 in all); the latter showed a well-differentiated histology [small grade 1 (G1)] in 30 cases (63.8%). The panel specificity was analyzed with the adjacent/extranodular cirrhotic liver (n = 30) and low-grade (n = 15) and high-grade dysplastic nodules (n = 16) as a control group. Absolute specificity (100%) for HCC was obtained only when at least two of the markers were positive (which two markers were positive did not matter). The addition of CHC to the panel increased the diagnostic accuracy for small HCCs (from 76.9% to 84.3%), and there was an important gain in sensitivity (from 46.8% to 63.8%). The four-marker panel had lower rates of accuracy (67.4%) and sensitivity (50%) for small G1 HCCs versus nonsmall G1 HCCs (93.9% and 88.2%, respectively). In seven cases (including six small G1 HCCs), there was no staining with any of the markers. Cirrhotic control livers were stained for CHC in four cases (13.3%) and for GPC3 in one case (3.3%). Conclusion: The addition of CHC to the panel supports the diagnosis of small HCCs in challenging nodules on thin core biopsy samples. Small G1 HCCs include a group of earlier tumors characterized by a more silent phenotype and the progressive acquisition of the markers under study. The search for additional markers for early HCC diagnosis is warranted. © 2011 American Association for the Study of Liver Diseases

There is substantial data that suggests an abnormality of innate immunity in patients with primary biliary cholangitis (PBC) which includes the transcription factor nuclear factor-kB (NF-kB) and well as downstream inflammatory signaling pathways. In addition, Immuno-Chip analysis has identified a novel PBC-associated locus near the receptor activator of NF-kB ligand (RANKL) gene. Based on these observations, we investigated the role of the RANKL axis in the liver of patients with PBC compared to controls. We used immunohistochemistry to quantitate liver expression of RANKL, its receptor (RANK), and importantly the decoy receptor osteoprotegerin (OPG), including a total of 122 liver samples (PBC = 37, primary sclerosing cholangitis = 20, autoimmune hepatitis = 26, chronic hepatitis B = 32 and unaffected controls = 7). In addition, we studied RANKL-RANK-OPG co-localization in CD4 and CD8 T cells, B cells, dendritic cells, macrophages, NK, NKT cells, hepatocytes, and cholangiocytes. We report herein that RANK is constitutively expressed by cholangiocytes in both unaffected and diseased liver. However, cholangiocytes from PBC express significantly higher levers of RANK than either the unaffected controls or liver diseased controls. CD4, CD8 and CD19 cells with in the portal areas around bile ducts in PBC express significantly higher levels of RANKL compared to controls. Importantly, the overall hepatic RANKL level and the ratio of hepatic RANKL/OPG correlated with disease severity in PBC. In conclusion, our data indicate a role of RANK-RANKL axis in the innate immune activation in PBC and we hypothesize that the damaged cholangiocytes, which express high levels of RANK, lead to the recruitment of RANKL positive cells and ultimately the classic portal tract infiltrates.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. METHODS: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. RESULTS: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. CONCLUSIONS: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.

The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, against which some antitumoral drugs have been developed. There is a lack of information as to EGFR expression in malignant pleural mesothelioma (MPM), an aggressive and fatal cancer poorly responsive to current oncological treatments. Our aim was to: (a) compare EGFR immunohistochemical expression with mRNA levels measured by real time PCR; (b) assess the relationships between EGFR expression and clinico-pathological data including survival; (c) analyze the EGFR mutations. We developed an immunohistochemical method of EGFR evaluation based on the number of immunoreactive cells and staining intensity in 61 MPMs. EGFR immunoreactivity was documented in 34/61 (55.7%) cases. A significant correlation between EGFR protein and mRNA levels (p = 0.0077) was found, demonstrating the reliability of our quantification method of EGFR membrane expression. Radically resected patients (p = 0.005) and those with epithelial histotype (p = 0.048) showed an increased survival. No statistical correlation between EGFR immunoreactivity and patients survival was observed. No EGFR mutation was documented. This study documents EGFR overexpression in MPM at the protein and the transcriptional levels; it proposes a reliable method for EGFR expression evaluation in MPM. EGFR levels are not associated with clinico-pathological features of patients, including survival. © 2005 Elsevier Ireland Ltd. All rights reserved.

Background: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. Methods: Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. Results: In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. Conclusions: These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment.