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Epidermal growth factor receptor (EGFR) signaling has a central role in the regenerative response of the liver upon injury and is involved in cellular transformation linked to chronic damage. Hepatic EGFR expression, trafficking, and signaling are regulated by growth hormone (GH). Chronically elevated GH levels are associated with liver cancer development and progression in mice. Studies in different in vivo experimental models indicate that EGF and GH mutually crossregulate in a complex manner. Several factors, such as the extent of exposure to supraphysiological GH levels and the pattern of GH administration, are important variables to be considered in exploring the interplay between the two hormones in connection with the progression of hepatic tumors.

Background: EGFR over-expression plays a key role in the development and progression of lung cancer. However, its status as a prognostic biomarker for survival outcomes is unclear. Objectives: To evaluate the prognostic utility of serum EGFR mRNA expression in Non-Small cell lung cancer (NSCLC) for treatment response and survival. Methods: EGFR mRNA levels were determined in serum using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Based on ROC curve, a cut off value of 16.0-fold increase was selected to categorize patients into low EGFR (≤ 16.0) and high EGFR (> 16.0) groups. Results: A total of 350 subjects were included (78.3% males), with mean (± SD) age of 57.1 (± 11.2) years, and including 247 (70.6%) adenocarcinoma (ADC). Majority (73.1%) had metastatic (stage IV) disease. Patients had higher pre-treatment serum EGFR mRNA levels than controls [median fold-increase (min, max), 16.2 (1.9, 66.7). Serum EGFR mRNA levels significantly reduced in those who achieved objective response and disease control. Significantly longer OS and PFS was observed in subjects having baseline EGFR mRNA expression ≤ 16.0 fold- increase compared to those with > 16.0 fold- increase [median (95% CI) OS: 25.0 (14.9, NR) versus 7.7 (6.3, 8.9) months; HR (95% CI) 2.9 (2.3, 4.0), p < 0.001; and PFS: 9.9 (7.1, 11.5) versus 6.0 (4.1, 7.5) months; HR (95% CI) 1.8 (1.3, 2.4), p < 0.001]. Conclusion: Serum EGFR mRNA expression is a useful parameter for predicting treatment response and survival outcomes in NSCLC.

Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy.

Introduction:Squamous cell carcinoma of the oral cavity is one of the most common head and neck cancers with an aggressive course and high mortality rates.The aimof the study was to determine the EGFR expression levels in tumor tissues in patients with squamous cell carcinoma of the tongue and oral mucosa depending on the efficacy of the therapy.Material and methods:The study included 60 patients with squamous cell carcinoma of the tongue and oral mucosa T3-4N0-1M0. The main group included 30 patients receiving chemotherapy (cisplatin/fluorouracil) in combination with targeted therapy with cetuximab. The control group included 30 patients receiving chemotherapy without cetuximab. Both groups were divided into two subgroups: sensitive and resistant.Results:In treatment-resistant patients of the main group with cetuximab, the average EGFR expression was twice lower than the initial levels (p = 0.0080) and 1.7 times higher than in treatment-resistant patients of the control group (p = 0.0157). In treatment-sensitive patients, the average EGFR expression was 19.8 times lower (p = 0.0020) than initial values and 14.9 times higher (p = 0.0067) than in treatment-sensitive controls.Conclusions:A natural decrease in the EGFR expression in tumor tissues due to the targeted therapy was revealed. However, some patients were resistant to cetuximab, which dictates the need to search for predictors of targeted therapy efficacy in patients with locally advanced squamous cell carcinoma of the tongue and oral mucosa.

Background and Aim: Glioblastoma multiforme (GBM) is the most common malignant and invasive tumor of the brain. The relation between prognosis and survival of GBM patients with Epidermal Growth Factor Receptor (EGFR) expression is challenging. Thus, we aimed to evaluate the prognosis and survival of patients with GBM and its relationship with EGFR expression. Materials and Methods: This single-arm cohort study was conducted on 70 patients with GBM during 2012-2018 in Shahid Rahnemoon and Mortaz hospitals. The immunohistochemistry technique was applied to paraffin blocks of brain tumors for examining EGFR expression. Other data were extracted from medical records. To determine the survival rate, the Kaplan–Meier curves were used. A chi-square test was used for the analysis of data. Statistically, p-value 0.05). Conclusion: Based on our study, it seems that the GBM tumor was associated with poor prognosis and a low survival rate. It was also found that the expression of the EGFR gene did not affect the survival rate of patients with GBM. Therefore, its use as a predictor factor for survival and prognosis is questionable.

Purpose Gd-encapsulated carbonaceous dots (Gd@C-dots) have excellent stability and magnetic properties without free Gd leakage, therefore they can be considered as a safe alternative T1 contrast agent to commonly used Gd complexes. To improve their potential for cancer diagnosis and treatment, affibody-modified Gd@C-dots targeting non-small-cell lung cancer (NSCLC) EGFR-positive tumors with enhanced renal clearance were developed and synthesized. Materials and methods Gd@C-dots were developed and modified with Ac-Cys-ZEGFR:1907 through EDC/NHS. The size, morphology, and optical properties of the Gd@C-dots and Gd@C-dots-Cys-ZEGFR:1907 were characterized. Targeting ability was evaluated by in vitro and in vivo experiments, respectively. Residual gadolinium concentration in major organs was detected with confocal imaging and inductively coupled plasma mass spectrometry (ICP-MS) ex vivo. H&E staining was used to assess the morphology of these organs. Results Gd@C-dots with nearly 20 nm in diameter were developed and modified with Ac-Cys-ZEGFR:1907. EGFR expression in HCC827 cells was higher than NCI-H520. In cell uptake assays, EGFR-expressing HCC827 cells exhibited significant MR T1WI signal enhancement when compared to NCI-H520 cells. Cellular uptake of Gd@C-dots-Cys-ZEGFR:1907 was reduced, when Ac-Cys-ZEGFR:1907 was added. In vivo targeting experiments showed that the probe signal was significantly higher in HCC827 than NCI-H520 xenografts at 1 h after injection. In contrast to Gd@C-dots, Gd@C-dots-Cys-ZEGFR:1907 nanoparticles can be efficiently excreted through renal clearance. No morphological changes were observed by H&E staining in the major organs after injection of Gd@C-dots-Cys-ZEGFR:1907. Conclusion Gd@C-dots-Cys-ZEGFR:1907 is a high-affinity EGFR-targeting probe with efficient renal clearance and is therefore a promising contrast agent for clinical applications such as diagnosis and treatment of NSCLC EGFR-positive malignant tumors.

Background Despite advanced treatments could inhibit progression of colorectal carcinoma (CRC), the recurrence and metastasis remain challenging issues. Accumulating evidences implicated that AVL9 played a vital role in human cancers, but it’s biological function and mechanism in CRC remain unclear. Aim To investigate the biological role and mechanism of AVL9 in colorectal carcinoma. Results AVL9 expression was significantly upregulated in tumor tissues than that in matched normal tissues both at mRNA and protein levels. High expression of AVL9 was closely correlated with M status, stages and poor prognosis of colorectal carcinoma (CRC) patients. Functionally, AVL9 overexpression promoted cell migration rather than cell proliferation in vitro, whereas AVL9 knockdown exhibited the contrary results. Mechanistically, AVL9 regulated EGFR expression, and knockdown of EGFR restrained AVL9-induced cell migration. Conclusion These findings demonstrated that AVL9 contributed to CRC cell migration by regulating EGFR expression, suggesting a potential biomarker and treatment target for CRC.

Introduction: Nasopharyngeal carcinoma (NPC) is a lymphoepithelial malignancy of the nasopharynx, one of the etiologies is the infection of Epstein–Barr virus in undifferentiated type of nasopharyngeal carcinoma. The Epstein-Barr virus Nucleus Antigen-1 (EBNA-1) is Epstein–Barr virus-encoded proteins as regulatory virus transcription. Epithelial Growth Factor Receptor (EGFR) consist of a single polypeptide chain of amino acid, ErbB members, tyrosine kinase receptor, a transmembrane glycoprotein encoded by gen location in the short arms of a chromosome and overexpression in epithelial tumors. EGFR plays a central role in signal transduction pathways which regulate key cellular functions in epithelial malignancies. and may also present in NPC. Objective: To investigate this relation of expression patterns of EBNA-1 and EGFR in a histological type of undifferentiated nasopharyngeal carcinoma. Method: Observational, analytical study with a cross-sectional method of 34 formalin-fixed within inclusion criteria are EBNA-1 and positive staining of EGFR expression (30 patients) and exclusion criteria of negative staining of EGFR (4 patients). All biopsy samples work with paraffin embedded and resulted in hematoxylin-eosin undifferentiated histological types of the advanced stage in nasopharyngeal carcinoma. EBNA-1 and EGFR expression used immunohistochemistry staining. Result: EBNA-1 and EGFR expression level were detection and correlated with the advanced stadium of nasopharyngeal undifferentiated carcinoma. Conclusion: EBNA-1 is significantly related to EGFR expression in the advanced stadium of undifferentiated nasopharyngeal carcinoma. Overexpression of EGFR is mostly found in advanced NPC but not in all ages. Male is dominated and overall age below 55 years old. Screening of EGFR with immunohistochemistry is highly considered before anti-EGFR treatment

There are few studies investigating the biomarker signatures and their relations with prognosis of pulmonary artery sarcoma patients. In the present study, we performed a cohort study on 16 cases of pulmonary artery sarcoma in an attempt to identify the potential diagnostic markers and molecular therapeutic targets of that vascular sarcoma. Patients who had undergone pulmonary artery sarcoma tumorectomy over 7 ½ years in our hospital were enrolled in this retrospective study. The resected tumors were analyzed by histopathology, the expression and mutation of Murine Double Minute 2 (MDM2), Epidermal Growth Factor Receptor (EGFR), and Platelet-Derived Growth Factor Alpha (PDGFRA) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlations between patients’ outcomes and tumor histological, IHC and FISH features were statistically analyzed. MDM2 immunostaining was seen mainly in intimal sarcoma. At univariate analysis, MDM2 expression had a positive correlation with shorter progression free survival (PFS). MDM2 and EGFR co-expression also had a positive correlation with shorter PFS and tumor metastasis. This study investigated MDM2, EGFR, and PDGFRA as potential biomarkers for diagnosis of pulmonary artery sarcoma and therapeutic targets.

Cancer patients contracting SARS-CoV-2 encounter additional challenges due to inflammatory bursts and lymphopenia, which may aggravate breast cancer prognosis. In this in silico analysis, we identified the potential of miRNAs as new therapeutic targets to treat breast cancer patients infected with COVID-19 via the regulation of ADAM17 and EGFR expression microRNAs.

Introduction. Head and neck tumors (HNT) are tumors that normally occur at the head and neck region of the body. Epidermal growth factor receptor (EGFR) has been found to be highly expressed in breast and other tumors; therefore, there is the need to investigate the level of EGFR expression among patients with head and neck tumors in Ghana. Method. The level of EGFR expression was determined in head and neck tumor and control head and neck tissues with quantitative real-time PCR and immunohistochemistry analysis. Results. The level of EGFR expressions was high in tumor tissues than in the control tissues. There was a significant difference of p value 0.025 among the ages >40 and ≤ 40 when the high and low level of EGFR was compared in the head and neck malignant tumor. The area under the curve for the high expression of EGFR among the malignant head and neck tumors was 0.901 with a specificity of 86.4%. Conclusion. EGFR can serve as a prognostic marker in monitoring patients with HNT as well as a molecular therapeutic target.

Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, antiepidermalgrowth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novelnanobioconjugate based on a poly(b-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carriesanti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrinreceptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide(AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR fortumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) forendosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissueaccumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging)and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detectedby western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFRsynthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation.Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1) [P = 0.03 vs. controls;P,0.05 vs. nanobioconjugate variant (2)]. Lead nanobioconjugate (1) also showed stronger inhibition of EGFR expressionand Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumorgrowth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugaterepresents a new generation of nanodrugs for treatment of TNBC.

Purpose One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. Patients and methods PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. Results Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750–1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. Conclusion Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Background Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations. Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available. This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications. Methods The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene. Mutation frequency, genomic location distribution, functional impact, and clinical targeted therapy implication were compared among different cancer types, and their associations with patient survival were analyzed. Results EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types. The overall mutation frequency in all cancers combined was relatively low. Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain. Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin‐like domain where targeted therapy was less effective. Low‐grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome. Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival. Squamous cell carcinoma regardless of their sites (the head and neck, lung, or esophagus) exhibited similar characteristics with an alteration frequency of about 5.0%, was dominated by gene amplification, and had increased EGFR expression generally associated with short patient survival. DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers. Conclusions EGFR aberration type, frequency, distribution in functional domains, and expression vary from cancer to cancer. While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR‐driven tumors.

Background: Oral cancer is a leading cause of cancer in India and contributes to 12% deaths worldwide. The identification of high-risk oral premalignant lesions such as leukoplakia and intervention at premalignant stages could result in significant loss of mortality and morbidity among these patients. The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias and the available studies show wide variations in their expression. Materials and Methods: A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of squamous cell carcinomas (SCCs). Results: There was a significant correlation between the expression of markers p53 and EGFR in leukoplakia and SCC. The expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant (P ≤ 0.001). Similarly, EGFR expression was significant (P ≤ 0.001) between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases. Similarly, in SCCs, it was observed that lesser the differentiation, more is the expression of both p53 and EGFR. Similarly, a definite correlation was observed between p53 and EGFR (P ≤ 0.001) but not with c-erbB2 (P ≤ 1.000). Conclusion: Thus, the author concludes that p53 and EGFR are useful biomarkers for the diagnosis of leukoplakia and their risk of malignant transformation.

// Fei Miao 1 , Mengmeng Zhang 1 , Yuechao Zhao 1 , Xiaolu Li 1 , Rongyan Yao 1 , Fan Wu 1 , Rong Huang 1 , Kai Li 1 , Shiying Miao 1 , Changwu Ma 4 , Hongge Ju 2, 3 , Wei Song 1 , Linfang Wang 1 1 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China 2 Department of Pathology, Baotou Medical College, Baotou 014040, China 3 Department of Pathology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China 4 Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng 024000, China Correspondence to: Changwu Ma, email: docmachangwu@126.com Hongge Ju, email: juhongge1088@163.com Wei Song, email: songwei@ibms.pumc.edu.cn Keywords: colorectal cancer, EGFR, RHBDD1, AP-1, c-Jun Received: September 02, 2016 Accepted: January 24, 2017 Published: February 25, 2017 ABSTRACT Our previous study showed that RHBDD1 can activate the EGFR signaling pathway to promote colorectal cancer growth. In the present study, EGFR was decreased when RHBDD1 was knocked down or inactivated. Further analysis found that c-Jun and EGFR protein expression was decreased in RHBDD1 knockdown and inactivated cells. c-Jun overexpression in RHBDD1-inactivated cells rescued EGFR expression in a dose-dependent manner. RHBDD1 overexpression in RHBDD1-inactivated cells restored EGFR expression, but this effect was counteracted by c-Jun knockdown. Furthermore, EGFR and c-Jun were attenuated in the RHBDD1 knockdown and inactivated groups in animal tumor models. Tissue microarray assays demonstrated a correlation between RHBDD1 and EGFR in colorectal cancer patients. Therefore, our findings indicate that RHBDD1 stimulates EGFR expression by promoting the AP-1 pathway.

Background: Expression of the epidermal growth factor receptor (EGFR) and human papillomavirus (HPV) DNA can serve as independent prognostic factors in squamous cell carcinoma (SCC) of the larynx. EGFR correlation with the course of disease and its effect on survival makes EGFR expression a negative prognostic factor, whereas HPV DNA is a positive prognostic factor. Aim: To assess the association of EGFR expression with clinical outcome of laryngeal HPV SCC. Materials and methods: This retrospective study included 196 SCC patients operated on at the Department of ENT, Head and Neck Surgery, Split University Hospital Center in Split, Croatia, between 1 January 2000 and 31 December 2009. Results: The association of HPV infection and EGFR expression was found to be statistically significant, and so was the difference in survival between patient groups with different HPV to EGFR expression ratio. Conclusions: The group of laryngeal HPV SCC patients with increased EGFR expression had shorter survival, confirming EGFR as a major component in predicting patient prognosis and survival. Significance: This article confirms the importance of EGFR expression as a biomarker in laryngeal SCC.

The epidermal growth factor receptor (EGFR) located in dorsal root ganglion has been found as a new target for chronic pain treatment. However, it is not clear whether the change of EGFR expression in the dorsal root ganglion contributes to neuropathic pain development. In this study, we used a chronic compression of unilateral lumbar dorsal root ganglions (CCD)-induced rat neuropathic pain model and found that CCD caused the upregulation of both phosphorylated EGFR and total EGFR expression in compressed lumbar 4/5 (L4/L5) dorsal root ganglions by western blotting and immunohistochemistry methods. Either inhibition of EGFR activation by EGFR inhibitor or knockdown of EGFR expression by EGFR small interference RNA (siRNA) relieved CCD-induced pain hypersensitivities to mechanical, thermal, and cold stimuli in rats. Moreover, EGFR knockdown reversed CCD-induced the increase of intracellular mammalian target of rapamycin (mTOR) expression as well as the activation of the satellite glial cells in the ipsilateral compressed L4/L5 dorsal root ganglions. These findings suggest that not only activated EGFR but also total EGFR contribute to CCD-induced neuropathic pain by enhancing intracellular mTOR signaling.

e15033 Background: Cardioesophageal cancer is a common tumor affecting the cardiac stomach and lower esophagus. Tumor heterogeneity is important, since it can cause the ineffectiveness of chemotherapy and radiotherapy due to individual characteristics of the neoplasm in different patients, as well as the intensification of invasion and metastasis. Our purpose was to analyze the relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression in orthotopic patient-derived xenografts of cardioesophageal cancer. Methods: The model of cardioesophageal cancer was created in Balb/c Nude mice with surgical bioptates of adenocarcinoma obtained from donors. The relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression were determined by Real-Time qPCR. Results: A PDX model of cardioesophageal cancer was successfully created by transplanting a moderately differentiated adenocarcinoma from a patient diagnosed with infiltrative ulcerative cancer of the lower third of the esophagus with a transition to the cardiac stomach into the distal esophagus of Balb/c Nude mice. The EGFR expression was elevated in patient tumor samples, compared to healthy tissues (p = 0.021) and gastric cancer xenografts (p = 0.07). Molecular genetic analysis demonstrated an association between an increased EGFR expression and changes in the relative copy numbers of TP63, YAP1, and KMT2D in donor samples compared to gastric cancer xenografts (p = 0.02, p = 0.026 and p = 0.042). Conclusions: The relative copy numbers of TP63, YAP1, and KMT2D were associated with intensified EGFR expression and changed with each new generation of orthotopic xenografts.

e21018 Background: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are proteins that negatively regulate immune responses. Increased expression of PD-L1 in cancer cells leads to inhibition of the immune response against cancer, and causes cancer development and metastasis. Epidermal growth factor receptor (EGFR) activation upregulates PD-L1 expression in lung cancer cells and contribute to escape from immune response. In this study, we aimed to investigate the circulating T lymphocyte subsets and, PD-1 and EGFR expression levels of these cells in non-small cell lung cancer (NSCLC) progression. Methods: 40 NSCLC patients with 63.8 ± 8.0 mean age and 40 healthy controls with 60.9 ± 14.6 mean age were included in the study. In the peripheral blood samples of the patients taken at the time of diagnosis and controls, CD4+ T helper (Th) subsets (Th1, Th2, Th9, Th17, Th1Th17, CD4+ follicular T [Tfc] and peripheral T cells [Tpcs]), CD8+ cytotoxic T cell (CTL) subsets (CD8+ Tfcs and Tpcs), EGFR and PD-1 expression levels of T cells were determined by flow cytometric analysis. Results: Total lymphocyte ratio was decreased in patients with NSCLC compared to control (11.5 ± 5.2 in patients and 17.6 ± 6.1 in controls, p = 0.001), but there was no significant difference in CD3+ total T, Th and CTLs as well as their subsets (p < 0.05). Increased PD-1 expression level (mean fluorescence intensity-MFI) on total lymphocyte (p = 0.001), CD3+ T (p = 0.001), CD4+ Th (p = 0.001), CTL (p = 0.016), CD4+ Tpc (p = 0.002) and CD8+ Tpc subsets (p = 0.017) were determined in the patients compared with controls. EGFR expressions were also increased on total lymphocyte, CD3+ T, Th and Th2 cells (p = 0.034, p = 0.020, p = 0.030, respectively). 19 NSCLC patients were metastatic, while 21 patients were non-metastatic. There was no significant difference in mean age between metastatic and non-metastatic NSCLC patients. Reduced total lymphocytes and Th cells, increased Th1Th17 cells were found in metastatic NSCLC patients (p = 0.003, p = 0.046 and p = 0.022, respectively). The percentage of EGFR in CD3+ T cell and Th17 cells decreased in metastatic patients. Conclusions: This study showed the increased PD-1 and EGFR expression levels of T lymphocytes in patients with NSCLC. Cancer cells may upregulate PD-1 expression by inducing EGFR activation on lymphocytes to suppress immune responses, leading to programmed cell death of lymphocytes and a decrease in the percentage of these cells in NSCLC. Therapeutic approaches focused on changing EGFR need to be considered for the distribution of T cell subsets and EGFR expressions.

We studied epidermal growth factor receptor (EGFR) expression profile in urothelial bladder carcinoma (UBC) which is a complex and heterogeneous disease with a large spectrum of histological aspects and deadly potential. Using immunohistochemistry (IHC), all GI tumors and pTa cases showed a low expression profile of EGFR. However, we note that when the stage of disease is advanced, tumors over-express EGFR. Indeed, 5% and 25% of GII and GIII tumors over-expressed EGFR, respectively. Further, 0% of pTa, 9,5% of pT1, 15% of pT2, 50% of pT3, and 90% of pT4 tumors were shown to be high EGFR expression (HEE). Moreover, we found a statistically significant correlation between the EGFR over-expression and grade and stage (P < 0.05). Thus, EGFR over-expression could be a potential prognostic marker to predict poor outcome in Tunisian patients with UBC.

The majority of borderline ovarian tumours (BOTs) behave in a benign fashion, but some may show aggressive behavior. The reason behind this has not been elucidated. The epidermal growth factor receptor (EGFR) is known to contribute to cell survival signals as well as metastatic potential of some tumours. EGFR expression and gene status have not been thoroughly investigated in BOTs as it has in ovarian carcinomas. In this study we explore protein expression as well as gene mutations and amplifications of EGFR in BOTs in comparison to a subset of other epithelial ovarian tumours. We studied 85 tumours, including 61 BOTs, 10 low grade serous carcinomas (LGSCs), 9 high grade serous carcinomas (HGSCs) and 5 benign epithelial tumours. EGFR protein expression was studied using immunohistochemistry. Mutations were investigated by Sanger sequencing exons 18-21 of the tyrosine kinase domain of EGFR. Cases with comparatively higher protein expression were examined for gene amplification by chromogenic in situ hybridization. We also studied the tumours for KRAS and BRAF mutations. Immunohistochemistry results revealed both cytoplasmic and nuclear EGFR expression with variable degrees between tumours. The level of nuclear localization was relatively higher in BOTs and LGSCs as compared to HGSCs or benign tumours. The degree of nuclear expression of BOTs showed no significant difference from that in LGSCs (mean ranks 36.48, 33.05, respectively, p=0.625), but was significantly higher than in HGSCs (mean ranks: 38.88, 12.61 respectively, p< 0.001) and benign tumours (mean ranks: 35.18, 13.00 respectively, p= 0.010). Cytoplasmic expression level was higher in LGSCs. No EGFR gene mutations or amplification were identified, yet different polymorphisms were detected. Five different types of point mutations in the KRAS gene and the V600E BRAF mutation were detected exclusively in BOTs and LGSCs. Our study reports for the first time nuclear localization of EGFR in BOTs. The nuclear localization similarities between BOTs and LGSCs and not HGSCs support the hypothesis suggesting evolution of LGSCs from BOTs. We also confirm that EGFR mutations and amplifications are not molecular events in the pathogenesis of BOTs.

Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.

The digestive system is an important energy supply system in human body. It can transform the nutrients in food into the energy of human life activities. In special cases, it can convert nutrients into body fat for storage. The appearance of digestive system tumor is a bad disease. It can lead to the loss of tongue coating cells and various complications[1]. According to the experimental theory of medicine, by observing the expression of EGFR in the exfoliated cells of tongue coating and the content of EGF in saliva of patients with tumor of digestive system, we can find the relationship between EGF and the changes of tongue coating cells of patients. Through the way of experiment, we can draw the corresponding conclusion. I think this conclusion will also provide theoretical help for the treatment of cancer-related diseases of digestive system in medicine.