Gastrointestinal mixed adenoneuroendocrine carcinoma (MANEC): An immunohistochemistry study of 13 microsatellite stable cases

BackgroundMixed adenoneuroendocrine carcinoma (MANEC) is currently included in the category of neuroendocrine carcinomas but the therapeutically management is not yet defined.AimsTo present the immunohistochemical (IHC) features of the epithelial mesenchymal transition (EMT) of MANEC.Materials and methodsThe clinicopathological features of 13 consecutive cases of MANEC (6 gastric and 7 colorectal) were correlated with the IHC expression of the biomarkers E-cadherin, β-catenin, N-cadherin, vimentin, maspin, CD44 and S100. In all of the cases open surgery was performed.ResultsAll of the cases showed microsatellite stable status, expressed E-cadherin and membrane β-catenin in both components (neuroendocrine and adenocarcinoma) and were negative for N-cadherin, vimentin and S-100. The colorectal MANECs were negative for maspin. In gastric MANECs, maspin showed cytoplasm positivity in the neuroendocrine component and nuclear translocation in the adenocarcinoma cells. CD44 was positive in all of the cases, in both components. No tumor buddings were identified. Three of the 13 patients survived for at least 32 months, all of them showing lymphatic emboli but not lymph node metastases. Pure neuroendocrine lymph node metastases were seen in only four of the cases: one from stomach, two of the ascending colon and two cases of the upper rectum.ConclusionsGastrointestinal MANEC is a microsatellite stable tumor with nodular growth, which components might originate from a CD44-positive stem-like precursor cell. Lymph node status remains the most reliable prognostic parameter and agressivity seems to not be influenced by tumor budding degree or EMT-related features. The histologic aspect of metastatic component (neuroendocrine versus adenocarcinoma) should be included in the histopathological reports and might be used for establishing the proper-targeted therapy of MANEC.     

Arylsulfatases A and B: From normal tissues to malignant tumors

Arylsulfatases are lysosomal enzymes with important roles in the cell metabolism. Several subtypes of arylsulfatase are known, from A to K. Congenital deficiencies of arylsulfatases, especially A (ARSA) and B (ARSB), can induce metabolic disorders such as metachromatic leucodystrophy (ARSA deficiency) and Maroteaux-Lamy syndrome (ARSB deficiency). ARSA and ARSB pseudodeficiencies were recently described but their exact roles are far to be known. The aim of this review was to synthesize the literature data, combined with personal results, regarding the roles of ARSA and ARSB in non-tumor disorders but also carcinogenesis. Few than 50 published papers regard ARSA and ARSB expression in cancer. They suggest decreased activity of these arylsulfatases in most of carcinomas, compared with normal tissues. However, the clinical impact is still unknown. Further complex studies are necessary to be done, to understand the role of ARSA and ARSB expression in cancer.     

The relationship between TLR4 rs4986790 and rs4986791 gene polymorphisms and Helicobacter pylori infection in children with gastritis

BackgroundTLR4 is involved in H. pylori lipopolysaccharide recognition and its SNPs might be related to increased risk of developing premalignant conditions and gastric cancer. The objectives of the study were to evaluate the associations between both TLR4 rs4986790 and rs4986791 gene polymorphisms and H. pylori infection in children with gastritis.MethodsWe performed a cross-sectional study on 150 children admitted in a Tertiary Centre from Romania, between March 2016 and July 2018 in order to evaluate them regarding demographic, endoscopic, histopathological and TLR4 gene polymorphisms.ResultsOur final sample consisted of 50 children with H.pylori associated gastritis (group 1-Ghp group) and 97 children with gastritis without H.pylori infection (group 2). Poor socioeconomic status was a significant risk factor for H.pylori infection. We found no significant differences regarding the clinical symptoms and laboratory parameters between the two groups. Concordant results were found between the histopathological exam and rapid urease test. Variant genotypes of TLR4rs4986790 and TLR4rs4986791 gene polymorphisms acted as protective factors against H. pylori infection, without statistical significance.ConclusionsThe variant genotype of the TLR4 gene polymorphisms might be protective factors for H.pylori infection, while socioeconomic status is an risk factor for H. pylori infection. Urease test is a usefull diagnostic tool for H. pylori infection.     

Decreased expression of lncRNA loc285194 as an independent prognostic marker in cancer: A systematic review and meta-analysis

BackgroundSeveral studies have indicated that lncRNA loc285194 is aberrantly expressed in many types of cancer. This meta-analysis was performed to elucidate the potential role of lncRNA loc285194 as a prognostic marker in malignant tumors.MethodsAn electronic search of PubMed, Medline, Embase, and Web of Science was performed to identify all eligible papers related to the prognostic impact of lncRNA loc285194 expression in cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted from the included studies to explore the association between lncRNA loc285194 expression and patient overall and disease-free survival (OS & DFS). The odds ratios (ORs) were also calculated to assess the association between lncRNA loc285194 expression and clinicopathological parameters.ResultsA total of 14 eligible articles with 1215 patients were included in this meta-analysis. Meta-results revealed that low expression of lncRNA loc285194 was significantly correlated with poorer overall survival (OS; HR = 2.34; 95% CI, 1.78–3.06; P < 0.001) and disease-free survival (DFS; HR = 2.66; 95% CI, 1.95–3.64; P = 0.001) rates in cancer patients. Low lncRNA loc285194 expression was also found to be significantly associated with lymph node metastasis (LNM; OR = 2.17; 95% CI, 1.23–3.83; P = 0.007), and distant metastasis (DM; OR = 2.49; 95% CI, 1.26–4.91; P = 0.009).ConclusionsThis study demonstrated that decreased level of lncRNA loc285194 was associated with poor clinical outcomes for patients with different types of cancer, supporting a promising potential biomarker for prognosis and metastasis in human cancers.     

The expression of C-MYC in gastric adenocarcinoma is associated with PD-L1 and FOXP3 expression: C-MYC overexpression is a good prognostic factor

BackgroundC-MYC appears to initiate and maintain tumorigenesis through modulation of immune regulatory molecules such as PD-L1. The aim of our research was to evaluate the clinical implication of C-MYC expression in gastric adenocarcinoma in relation to the expression of the immune regulatory molecules PD-L1 and FOXP3.MethodsTissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected at Kyung Hee University Hospital at Gangdong from 2006 to 2012. Immunohistochemical staining for C-MYC, PD-L1, CD8 and FOXP3 was done.ResultsC-MYC overexpression showed a significant correlation with smaller tumor size, lower T category, lower N category, lower recurrence rate, and less lymphatic invasion. And C-MYC overexpression was negatively correlated with PD-L1 expression. The tumoral FOXP3 was positively correlated with C-MYC overexpression and Tregs count. PD-L1 expression was positively correlated with Tregs, CD8 + T cells, and tumor infiltrating lymphocytes (TIL). Tregs count was positively correlated with CD8 + T cells and TIL. CD8 + T cells was positively correlated with TIL.ConclusionWe discovered that the immune regulatory effect of C-MYC and PD-L1, and the tumor suppressor function of tumoral FOXP3 had a significant influence on the tumor microenvironment (Tregs, CD8 + T cells, and tumor infiltrating lymphocytes) in a complex manner. The C-MYC overexpression is a good prognostic factor in gastric adenocarcinoma.     

The academic-industry divide in health communication: A call for increased partnership

ObjectiveHealthcare communication research, teaching, and practice is in a period of innovation and disruption from new technologies, consumerization, and emerging models of care delivery. The goal of this commentary is to discuss perceived barriers and provide baseline metrics of academic-industry partnership in health communication.MethodsWe coded industry affiliations of authors published in Patient Education and Counseling (PEC) in 2018, and attendees and authors of accepted submissions at the 2018 International Conference on Communication in Healthcare (ICCH). We examined perceived barriers to collaboration by summarizing a roundtable discussion between industry and academic participants at the 2018 ICCH conference.ResultsIn 2018, less than 5% of contributions to PEC, 16 abstracts (3.1%) and only 7 attendees (1.4%) at ICCH had industry affiliations. Roundtable participants identified actual or perceived motivational differences, publication challenges, and distinct metrics/outcomes as key barriers to collaboration.ConclusionThese rough estimates provide a benchmark for current industry collaboration in our professional society. We discuss potential benefits of increased partnerships, suggest approaches to reduce barriers, and highlight recent progress.Practice implicationsAs individuals and professional organizations, we should promote ethical, multidisciplinary, and high impact research, teaching, and practice in partnership with our colleagues in industry.     

Apolipoprotein E is a predictive marker for assessing non-small cell lung cancer patients with lymph node metastasis

BackgroundApolipoprotein E (APOE) modulates lipid homeostasis in the systemic circulation and induces inflammatory immune responses in the tumor microenvironment. We evaluated APOE expression in order to assess tumor progression in non-small cell lung cancer (NSCLC).MethodsImmunohistochemical staining for APOE was performed on tissue microarray blocks from 148 patients who had undergone surgery for NSCLC. The staining intensity and the proportion of APOE-positive tumor cells (based on distinct membranous and cytoplasmic staining) were scored. The relationships between APOE expression and clinical (age, sex, and smoking history) and pathological (TNM stage and histological type) factors were evaluated.ResultsPositive APOE staining was observed in 93 (64.6%) patients. APOE expression patterns differed among NSCLC histological types (p-value = 0.016). Negative APOE expression was significantly associated with lymph node metastasis in NSCLC (p-value = 0.040). Both cases of N2 (stage IIIA) disease showed negative APOE expression.ConclusionsAPOE is a useful marker for assessing NSCLC patients with lymph node metastasis.     

Gastric adenocarcinoma with enteroblastic differentiation should be differentiated from hepatoid adenocarcinoma: A study with emphasis on clear cells and clinicopathologic spectrum

BackgroundIn gastric cancer, clear cells are preferentially found in gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The distinction between GAED and HAC is difficult because of their rarity and histologic overlap.MethodsTo elucidate identification of gastric adenocarcinoma with clear cells as GAED or HAC, survival analyses were performed in 28 GAED, 26 HAC, and 1107 conventional adenocarcinoma cases. Cells of origin were assessed by investigating the expression of oncofetal proteins (α-FP, glypican-3, SALL4), in addition to gastric (MUC5AC, MUC6), and intestinal (MUC2, CD10, CDX-2) cell markers.ResultsClinically, HAC showed frequent (57.5%) distant metastasis (mostly in the liver) at the time of diagnosis compared to GAED (P < 0.001). On pathology, all 28 GAED had a predominantly tubulopapillary growth pattern while 24 HAC displayed a predominantly hepatoid growth pattern. In survival analyses, patients with HAC had significantly shorter overall and recurrence-free survival (mean: 25 months, and 53 months, respectively) compared to those with GAED (mean: 107 months, and 118 months, respectively) (P < 0.001).HAC with clear cells showed diffuse and strong expression of all oncofetal proteins (α-FP, glypican-3, and SALL4), were highly positive for CDX-2, and were negative for CD10, MUC6, MUC5AC, and MUC2, suggesting an intestinal mucin phenotype and hepatoid features. In contrast, GAED showed focal expression of one or two oncofetal proteins and commonly expressed CD10, CDX-2, and MUC6 but not MUC2 and MUC5AC, suggesting both gastric antral/intestinal mucin phenotype and focal enteroblastic differentiation. SALL4 was diffusely and strongly positive in HAC, while it was heterogeneously expressed in GAED.ConclusionsIn conclusion, although rare, HAC with clear cells should be differentiated from GAED based on the poor prognosis, diffuse and strong oncofetal protein expression, and intestinal mucin phenotype.     

Ultrasound images in hepatic alveolar echinococcosis and clinical stage of the disease

PurposeHepatic alveolar echinococcosis (AE) is a parasitic disease caused by the larval stage of the tapeworm Echinococcus multilocularis. Ultrasonography is the method of choice in the initial diagnosis of AE. The aim of the study is to present the most frequent sonomorphological patterns of lesions in hepatic AE based on the analysis of ultrasound findings in patients treated for AE at the University Centre of Maritime and Tropical Medicine (UCMMiT; Gdynia, Poland), and to establish whether there is a relationship between the clinical stage of AE and the occurrence of a specific sonomorphological pattern of hepatic lesions.Patients and methodsWe analysed the results of ultrasound examinations of 58 patients hospitalized in the UCMMiT with probable or certain diagnosis of AE. Liver lesions were assessed according to the classification developed by researchers from the University Hospital in Ulm (Germany). Statistical analysis was based on the relationship between the occurrence of a specific sonomorphological pattern of hepatic lesions and the clinical stage of AE.ResultsThe most frequently observed patterns of AE lesions in the liver were the hailstorm and the pseudocystic patterns. There was no correlation between the clinical stage of the disease and the ultrasonographic appearance of lesions. There was no statistically significant relationship between the more frequent occurrences of specific ultrasonographic patterns of lesions in the liver and radical or non-radical surgery.ConclusionsThe ultrasonographic appearance of the lesion in liver AE cannot determine the therapeutic management. Treatment plan should be established based on the PMN classification.     

Comparison of the efficacy of an education program for people with diabetes and insulin pump treatment (INPUT) in a randomized controlled trial setting and the effectiveness in a routine care setting: Results of a comparative effectiveness study

ObjectiveTo compare the efficacy of an education program for people with diabetes and insulin pump treatment (INPUT) in a randomized controlled trial (RCT) to the effectiveness in an implementation trial (IT).Methods135 people with diabetes on insulin pump treatment (CSII) underwent structured education with INPUT under RCT-conditions, 191 people with diabetes on CSII underwent structured education with INPUT under IT-conditions. Baseline characteristics and treatment outcomes at the 6-month follow-up were compared.ResultsAt baseline, RCT-participants were younger (42.7 ± 14.2 vs. 47.2 ± 14.1 years, p = 0.005), had higher HbA1c-values (8.3 ± 0.8% vs. 7.8 ± 1.2%, p = 0.001) and had more diabetes-related distress (27.8 ± 16.4 vs 22.4 ± 14.4, p = 0.002). At follow-up, INPUT results were comparable under the RCT and IT settings. After adjustment for baseline HbA1c, reduction of HbA1c in the IT was significantly greater than in the RCT (Δ0.17%; 95% CI 0.023–0.319%, p = 0.024). Participants with higher HbA1c-levels, more diabetes-related distress and more hypoglycemia problems were most likely to benefit from INPUT regardless of the trial setting.ConclusionsEfficacy of the INPUT program for people with CSII was demonstrated under RCT- and routine care conditions.Practice implicationsEducation with the INPUT program is effective not only under standardized RCT conditions but also under conditions of routine care.     

Strategies for the measurements of expression levels and half-lives of HLA class I allotypes

HLA class I molecules are highly polymorphic cell surface proteins that trigger immune responses by CD8⁺ T cells and natural killer (NK) cells. Most humans express six different HLA class I proteins encoded by the HLA-A, HLA-B and HLA-C genes. HLA class I molecules bind to peptide antigens and present these antigens to T cell receptors (TCR) of CD8⁺ T cells. HLA class I expression levels also regulate NK cell activation. The presence of individual HLA class I genes is linked to many different disease, transplantation and therapy outcomes. An understanding of HLA class I expression and stability patterns is fundamentally important towards a better understanding of the associations of HLA class I genes with disease and treatment outcomes, and towards HLA class I targeting for vaccine development. Quantitative flow cytometry allows for assessments of variations in expression levels of HLA class I molecules in cells from a single blood donor over time, as well as averaged measurements across donors for the same allotype. Since all HLA class I molecules are structurally-related, cellular measurements of the HLA class I expression levels and stabilities of individual variants in human cells require careful choices of donors and antibodies, which are discussed here.     

Implementation,participation and satisfaction rates of a web-based decision support tool for patients with metastatic colorectal cancer

ObjectiveTo examine implementation and patients’ and providers’ participation and satisfaction of a newly developed decision support tool (DST) for patients with metastatic colorectal cancer (mCRC) in palliative setting.MethodsOur DST consisted of a consultation sheet and web-based tailored information for mCRC treatment options. We conducted an implementation trajectory in 11 Dutch hospitals and evaluated implementation, participation and satisfaction rates.ResultsImplementation rates fluctuated between 3 and 72 handed out (median:23) consultation sheets per hospital with patients’ login rates between 36% and 83% (median:57%). The majority of patients (68%) had (intermediate)-high participation scores. The median time spent using the DST was 38 min (IQR:18–56) and was highest for questions concerning patients’ perspective (5 min). Seventy-six% of patients were (very) satisfied. The provider DST rating was 7.8 (scale 1–10) and participation ranged between 25 and 100%. Remaining implementation thresholds included providers’ treatment preferences, resistance against shared decision-making and (over)confidence in shared decision-making concepts already in use.ConclusionWe implemented a DST with sufficient patient and oncologist satisfaction and high patient participation, but participation differed considerably between hospitals suggesting unequal adoption of our tool.Practice implicationsRequirements for structural implementation are to overcome remaining thresholds and increase awareness for additional decision support.     

Mast cells: A key component in the pathogenesis of Neuromyelitis Optica Spectrum Disorder?

Neuromyelitis Optica Spectrum Disorder (NMOSD) is characterized as an autoimmune, inflammatory and demyelinating disease of the Central Nervous System (CNS). Its pathogenesis is due to the presence of anti-aquaporin 4 immunoglobulin G1 antibodies (anti-AQP4IgG), with presence of lymphocytes T Helper 1 and 17 (TH1 and TH17), in addition to previous neuroinflammation.The Mast cell (MC) is a granular cell present in all vascularized tissues, close to vessels, nerves, and meninges. In CNS, MCs are in the area postrema, choroid plexus, thalamus and hypothalamus. MC has ability to transmigrate between the nervous tissue and the lymphoid organs, interacting with the cells of both systems. These cells reach the CNS during development through vessel migration. Most MCs reside on the abluminal side of the vessels, where it can communicate with neurons, glial cells, endothelial cells and the extracellular matrix.Considering the role of MCs in neurodegenerative diseases has been extensively discussed, we hypothesized MCs participate in the pathogenesis of NMOSD. This cell represents an innate and adaptive immune response regulator, capable of faster responses than microglial cells. The study of MCs in NMOSD can help to elucidate the pathogenesis of this disease and guide new research for the treatment of patients in the future. We believe this cell is an important component in the cascade of NMOSD neuroinflammation.     

ABO genotyping of various hematopoietic cell lines to select model cells for research purposes

Various cells from humans and animals have been established as cell lines, and their features, characteristics, and origins have been reported. Many laboratories use cell lines as model cells, which are selected to suit research purposes.We attempted to identify the ABO genotypes of 31 human leukemia and lymphoma cell lines stored in our laboratory using three methods: the PCR amplification of specific alleles (PASA), PCR-restriction fragment length polymorphism (RFLP), and the direct DNA sequencing of PCR products.We distinguished 31 human leukemia and lymphoma cell lines examined into six major ABO genotypes: A/O (A101/O01: n = 1, A101/O12: n = 4, A101/O26: n = 1, A101/O49: n = 1, A102/O01: n = 3), A/A (A101/A101: n = 1, A102/A102: n = 2), B/O (Bw29/O01: n = 1), B/B (B101/B101: n = 2), O/O (O01/O01: n = 9, O01/O02: n = 1, O01/O26: n = 1, O02/O03: n = 1), and A/B (A102/B101: n = 3).To the best of our knowledge, this is the first study to identify the ABO genotypes of various cell lines. The ABO genotypes of cell lines are important when selecting an experimental model cell for an ABO blood group study, and are essential information for cell lines. These results may be employed by research and clinical laboratories as well as in the forensic field.     

Markers of the pre-metastatic niche "knock on the door" of metastasis-free cervical lymph nodes in patients with oral cancer

AimTo assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients.MaterialsLNs from metastatic-free neck dissections (LN0/N0, N = 43) and metastatic-free LNs in the vicinity of metastasis-containing LNs (LN0/N+, N = 30) were immuno-histochemically stained for lysyl oxidase (LOX), fibronectin (FN), vascular-endothelial growth factor receptor (VEGFR)-1 and matrix metalloproteinase (MMP)-9. Staining was assessed as 0 (no or weak staining), 1 (strong stain in 25% cells or extracellular area), 2 (same as 1 but in up to 50%) and 3 (same as 1 but in > than 50% of cells/area). Assessment was performed in the lymph node capsule (CAP), sub-capsular sinus (SCS) and medullary sinus (MS). In addition, sections were stained with picrosirius red and examined with polarized microscopy for assessing the distribution of polarization colors of the collagen fibers in the LN capsular area.ResultsAll examined LNs were positive for markers of the PMN. In general, the distribution and intensity of the immunoreactivity was similar between the LN0/N0 and LN0/N+, with only a few differences regarding expression of LOX in the capsule (p = 0.002) and VEGFR1 and MMP9 in the SCS (p = 0.023 and p < 0.001, respectively). Picrosirius red stain and polarized microscopy revealed a disrupted arrangement and distribution of the collagen fibers in both LN0/N0 and LN0/N + .ConclusionMarkers for PMN were shown for the first time to be expressed in cervical LN0/N0 from patients with oral cancer, suggesting the increased permissive pathway remotely paved by the primary oral tumor for the incoming metastatic cells.     

KMT2C modulates migration and invasion processes in osteosarcoma cell lines

In this study we investigated the role of KMT2C (a chromatin-modifying and remodelling protein) in osteosarcoma progression through cell migration and invasion assays in osteosarcoma primary and metastatic cell lines. Wound healing and transwell assays were used to detect changes of cell migration and matrigel assay was used to evaluate changes of cell invasion in primary and metastatic osteosarcoma cell lines after KMT2C siRNA transfection. We found that primary osteosarcoma cell lines showed the highest capacity of migration before mRNA KMT2C silencing and the highest capacity of invasion after mRNA KMT2C silencing; on the contrary, osteosarcoma metastatic cell line showed the highest capacity of migration after mRNA KMT2C silencing and the highest capacity of invasion before mRNA KMT2C silencing.Our study supports data in favour of selective enhancer changes, KMT2C-mediated, in metastatic osteosarcoma probably due to the different microenvironment between primary and metastatic sites.