Negative Epidermal Growth Factor Receptor Research Articles

Lower Plasma Amyloid Beta - 42 Levels Associated With Worse Survival in Patients With Glioma.

Glioma is often refractory. The accumulation of amyloid beta (Aβ) in the brain is commonly associated with Alzheimer's disease (AD), but there are studies suggesting that Aβ has tumor suppressor potential. The aim of this study was to identify a novel, non-invasive candidate biomarker for histological prediction and prognostic assessment of glioma. Serum was prepared from blood samples collected preoperatively from 48 patients with WHO grade II-IV glioma between October 2004 and December 2017 at a single tertiary institution. The concentration of Aβ42 was measured using the SMCxPRO immunoassay (Merck). The clinical and histological characteristics of the patients, including molecular subtypes, were reviewed. The mean age of the patients was 52.2±12.5 years. The mean value of serum Aβ42 concentration was 7.6±7.8 pg/ml in the anaplastic astrocytoma (WHO grade III) group and 6.4±6.5 pg/ml in the glioblastoma multiforme (WHO grade IV) group. The Negative epidermal growth factor receptor (EGFR) expression was associated with higher serum Aβ42 levels (p=0.020). Kaplan-Meier analysis demonstrated that patients with high serum Aβ42 (>11.78 pg/ml) had significantly longer progression-free survival (PFS) (p=0.038) and overall survival (OS) (p=0.018). This study investigated serum Aβ42 levels as a potential biomarker for glioma. The results showed that low serum Aβ42 levels were associated with EGFR expression and poor PFS and OS. Overall, these findings suggest a potential role of Aβ42 as a prognostic marker in astrocytomas.

Difference in Radiosensitivity Depending on the Presence and Absence of EGFR Mutations: Clinical and In Vitro Analyses

For stage IV non-small cell lung cancer (NSCLC), the treatment drug is selected based on the gene mutation status. However, the dose or field of radiation therapy is not change based on the genetic status. We evaluated both clinical and in vitro data, showing that the presence or absence of epidermal growth factor receptor (EGFR) mutations affects radiosensitivity in patients with brain metastases (BM) from NSCLC. Patients with BM from NSCLC who received whole brain radiotherapy (WBRT) were enrolled in this study. Patient characteristics are shown in the Table. EGFR mutations were observed in 13 (31.0%) patients. The prescribed dose was 30 Gy in 10 fractions (85.7%). The A549, VMRC-LCD, NCI-H1975, and HCC4006 cell lines were used for the in vitro study. EGFR mutation was negative in A549 and VMRC-LCD and positive in NCI-H1975 (exon21) and HCC4006 (exon19). After irradiation of these cell lines with 0, 2, 4, and 8 Gy, a colony formation assay was performed. DNA double-strand breaks (DSBs) were assessed 30 min and 24 h after 4 Gy irradiation using γH2AX. The median follow-up period was 4 months (range, 1-35). Intracranial recurrence was observed in 14 (33.3%) patients during the follow-up period. Thirty-nine (92.9%) patients died during the follow-up period. Patients with EGFR mutation-positive tumors had significantly better intracranial control rates than those with EGFR mutation-negative tumors (p = 0.0213). A similar tendency was observed in the analysis conducted, except for the cases in which tyrosine kinase inhibitor (TKI) was administered after WBRT. In the EGFR mutation-positive group, no significant difference was observed between patients who received TKI after WBRT and those who did not (p = 0.527). In the colony formation assay, EGFR mutation-positive cell lines showed a significantly lower number of colonies formed after irradiation with 2 and 4 Gy than mutation-negative cell lines (p = 0.00018 and 0.0000291, respectively). EGFR mutation-positive cell lines had significantly more DNA-DSBs remaining 24 h after irradiation than mutation-negative cell lines (p = 0.0000000312). Our data suggest that patients with EGFR mutation-positive NSCLC are more radiosensitive than those with negative EGFR mutations.

Liquid biopsy for detecting epidermal growth factor receptor mutation among patients with non-small cell lung cancer treated with afatinib: a multicenter prospective study

BackgroundThis study aimed to determine the effectiveness of liquid biopsy in detecting epidermal growth factor receptor (EGFR) mutations at diagnosis, disease progression, and intermediate stages.MethodsThis prospective, multicenter, observational study included 30 patients with non-small cell lung cancer treated with afatinib, harboring a major EGFR mutation confirmed by tumor tissue biopsy. We collected blood samples for liquid biopsy at diagnosis, intermediate stage, and progressive disease. Tissue and liquid biopsies were examined using Cobas ® EGFR Mutation Test v2.ResultsLiquid biopsy detected EGFR mutations in 63.6% of the patients at diagnosis. The presence of metastasis in the extrathoracic, brain, and adrenal glands correlated positively with the detection of EGFR mutations. Patients with positive EGFR mutations at diagnosis had significantly shorter overall and progression-free survival than patients with negative EGFR mutations. Four of the 18 patients (22.2%) who reached progressive disease had positive EGFR T790M mutations. Three of 10 patients (30.0%) with progressive disease were positive and negative for T790M using tumor re-biopsy and liquid biopsy, respectively. The results of EGFR mutation by tissue re-biopsy were the same as those of liquid biopsy in the three patients who were positive for significant EGFR mutations but negative for the T790M mutation using liquid biopsy at progressing disease. Only two patients were positive for major EGFR mutations at intermediate levels.ConclusionsLiquid biopsy can be a prognostic factor in EGFR-tyrosine kinase inhibitor treatments at diagnosis. Tumor re-biopsy can be omitted in patients with positive EGFR mutations by liquid biopsy at PD.

Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response.

Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.

Prognostic Impact of Low-Level p53 Expression on Brain Astrocytomas Immunopositive for Epidermal Growth Factor Receptor.

Although the expression of p53 and epidermal growth factor receptor (EGFR) is associated with therapeutic resistance and patient outcomes in many malignancies, the relationship in astrocytomas is unclear. This study aims to correlate p53 and EGFR expression in brain astrocytomas with overall patient survival. Eighty-two patients with astrocytomas were enrolled in the study. Semi-quantitative p53 and EGFR immunohistochemical staining was measured in tumor specimens. The mean follow-up after astrocytoma surgery was 18.46 months. The overall survival rate was 83%. Survival was reduced in EGFR-positive patients compared with survival in EGFR-negative patients (p < 0.05). However, no significant differences in survival were detected between patients with high and low p53 expression. In patients with low p53 expression, positive EGFR staining was associated with significantly worse survival compared with patients with negative EGFR staining (log-rank test: p < 0.001). Survival rates in positive and negative EGFR groups with high p53 protein expression were similar (log-rank test: p = 0.919). The IC50 of an EGFR inhibitor was higher in GBM cells with high p53 protein expression compared with the IC50 in cells with low p53 expression. Combined EGFR and p53 expression may have prognostic significance in astrocytomas.

Observational Study of Paclitaxel-Carboplatin versus Pemetrexed-Carboplatin for Advanced Pulmonary Adenocarcinoma at Single-Centre in Indonesia

Platinum-based chemotherapy regimens with two types of drugs, such as paclitaxel-carboplatin and pemetrexedcarboplatin, are first-line therapy for pulmonary adenocarcinoma patients with negative epidermal growth factor receptor (EGFR) mutation. This study aimed to determine the efficacy, toxicity, and cost profile of paclitaxel-carboplatin compared to pemetrexed-carboplatin. This is a cross-sectional study. Pulmonary adenocarcinoma negative EGFR mutation naïve patients treated with paclitaxel-carboplatin or pemetrexed-carboplatin were included. Effectiveness was assessed based on the overall response rate (ORR) according to the response evaluation criteria in solid tumours (RECIST). A pharmacoeconomic analysis is performed based on clinical outcomes consisting of effectiveness and direct medical costs. Medical records from 21 patients with paclitaxel-carboplatin and 21 patients with pemetrexedcarboplatin were successfully evaluated. The effectiveness of the two chemotherapy regimens was not significantly different (OR, 1.25; 95% confidence interval, 0.34 to 4.64; p = 0.739). Frequent haematological toxicities experienced in the two groups were grade 1-2 anaemia, neutropenia, leukopenia. Grade 3 anaemia, leukopenia, and neutropenia were more common in the paclitaxel-carboplatin group. The two groups’ nonhematological toxicities were nausea vomitus and hair loss, with peripheral neuropathy more experienced by the paclitaxel-carboplatin group. Costminimization analysis reveals that the average cost per patient with pulmonary adenocarcinoma negative EGFR mutation with paclitaxel-carboplatin regimen was cheaper IDR 10,986,257.55 or 50.25%, compared to pemetrexedcarboplatin. In conclusion, there was no significant difference in the effectiveness of the two regimens. The most common adverse effects in both regimens were haematological toxicities. The average cost per patient with a paclitaxel-carboplatin regimen was cheaper compared to pemetrexed-carboplatin.

Study of Programmed Death Ligand 1 and EGFR/HER2 Expression in Non-Small-Cell Lung Carcinoma With a Clinicopathological Spectrum.

Non-small-cell lung carcinoma (NSCLC) is a disease characterized by the upregulation of programmed death ligand 1 (PD-L1) along with alterations in epidermal growth factor receptor (EGFR) and HER2-neu (HER2) amplification in addition to EGFR mutation. In the present study, the expression of PD-L1 and EGFR and HER2-neu in NSCLC was studied and their expression in relation to various clinicopathological parameters was analysed. We studied 49 core biopsy specimens of NSCLC for PD-L1, EGFR and HER2-neu expressions using immunohistochemistry. Scoring was based on the intensity and percentage of tumour cells expressing the immunomarkers. PD-L1, EGFR and HER2-neu expression was seen in 20.4%, 32.7% and 14.2% of NSCLC, respectively. The analysis showed no significant difference in PD-L1 expression in relation to any clinicopathological parameters. Low or negative EGFR expression was significantly associated with positive lymph node status (P=0.04). HER2-neu expression showed a significant difference in relation to tumour histology (adenocarcinoma; P=0.01). Also, there was no difference noted with PD-L1 expression in relation to EGFR and HER2-neu expression. As our study has a small number of cases, the validation of the predictive and prognostic value of these markers in lung cancer patients requires further studies.

Triple-Negative Metaplastic Breast Carcinoma: Association of Epidermal Growth Factor Receptor Expression With Prognostic Parameters and Clinical Outcome.

IntroductionMetaplastic breast carcinoma (MBC) is one of the rare special subtypes of breast carcinoma associated with poor prognostic features compared with invasive ductal carcinoma. Moreover, therapeutic options are limited in MBC owing to frequent triple-negative profiles of these tumors. Epidermal growth factor receptor (EGFR) is a proto-oncogene that is overexpressed in many human cancers, and is a potential therapeutic target. Therefore, in this study, we evaluated the expression of EGFR in MBC by immunohistochemistry, and its association with clinicopathological and prognostic parameters.MethodsWe conducted a retrospective observational study in the Department of Histopathology at Liaquat National Hospital and Medical College, Pakistan, over a period of seven years. A total of 61 cases with a histopathological diagnosis of MBC were included in the study. All slides were reviewed by histopathologists for diagnostic confirmation. Histopathological parameters, such as tumor size, grade, and nodal metastasis, were recorded. The representative tissue blocks were also retrieved and immunohistochemical studies were performed for cytokeratin 5/6 (CK5/6), Ki67, and EGFR.ResultsThe mean age of the patients was 44.48 ± 13.01 years. The mean tumor size was 5.72 ± 2.72 cm, with most of the cases belonging to tumor (T)-stage T3. Axillary metastasis was present in 57.4% cases, and the perinodal extension was present in 11.5% cases. Most tumors were grade III (85.2%), with a mean Ki67 index of 39.67% ± 20.38%. Most of the cases were nonbasal (83.6%), owing to the absent CK5/6 expression. Tumor recurrence was noted in 14.8% cases, with a median follow-up of 43 (13-83) months and median disease-free survival of 36 (12-60) months. Positive EGFR expression was noted in 52.5% cases. A significant association of EGFR expression was noted with tumor grade, mean Ki67 index, axillary metastasis, and nodal (N)-stage. Cases with positive EGFR expression were found to have higher grade (grade III), with higher Ki67 index, higher frequency of axillary metastasis, and higher N-stage. Moreover, cases with positive EGFR expression had lower disease-free survival compared to cases with negative EGFR expression.ConclusionWe found that a significant proportion of triple-negative MBC expressed EGFR. Moreover, EGFR overexpression was associated with poor pathological parameters and lower disease-free survival. Therefore, EGFR can be considered a potential prognostic biomarker and therapeutic target in triple-negative MBC; however, the correlation between gene amplification and protein overexpression is required to better uncover the role of EGFR as a therapeutic target.

Epidermal Growth Factor Receptor Mutation Status and Response to Tyrosine Kinase Inhibitors in Advanced Chinese Female Lung Squamous Cell Carcinoma: A Retrospective Study.

BackgroundThe frequency of epidermal growth factor receptor (EGFR) mutations and the efficacy of tyrosine kinase inhibitor (TKI) in Chinese female patients with lung squamous cell carcinoma (SCC) are unknown. This study was designed to investigate the incidence of EGFR mutations and the role of targeted therapy in advanced Chinese female lung SCC patients.MethodsAdvanced female patients diagnosed with lung SCC at the Shanghai Chest Hospital between January 2013 and December 2018 were retrospectively analyzed.ResultsA total of 4223 advanced lung SCC patients were screened, and there were 154 female lung SCC patients who had underwent EGFR mutation detection. Positive EGFR mutations were found in 29.9% (46/154) of female lung SCC patients, including twenty-three 19del mutation (14.9%), twenty-one 21L858R mutation (13.6%) and other mutations (1.4%, 21861Q and 20ins). For 45 EGFR positive mutation female SCC patients, the median progression-free survival (PFS) of patients who received EGFR-TKI therapy (n=38) was 8.0 months (95% CI, 5.4-10.7 months), which was significantly longer than patients who were treated with chemotherapy (8.0 vs. 3.2 months, p=0.024), and the median overall survival (OS) was also longer (24.9 months vs. 13.9 months, p=0.020). The objective response rate (ORR) was 44.7% (17/38), and the disease control rate (DCR) was 81.6% (31/38). For 105 female SCC patients with EGFR negative mutation, the median OS was 18.6 months (95% CI, 14.2-22.9 months) and it was no different from that of EGFR positive mutation patients (18.6 vs. 22.8 months, p=0.377).ConclusionFor advanced Chinese female lung SCC patients with EGFR positive mutations, targeted therapy could confer longer PFS and OS than chemotherapy, but the survival was similar with patients who were negative EGFR mutations.

Clinical utility of plasma EGFR mutation detection with quantitative PCR in advanced lung cancer: A meta-analysis

ObjectivesTo assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients. Materials and MethodsWe performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFR + detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNA + and ctDNA- subgroups. ResultsSix randomized clinical trials included 1058 tEGFR + patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22−0.36, p < 0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28−0.49, p < 0.00001; p-interaction = 0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25–9.07, p < 0.00001 vs 6.44; 95 % CI 4.21–9.87, p < 0.00001) and overall survival (HR 0.82; 95 % CI 0.70–1.04 vs HR 0.77; 95CI% 0.59–1.00) similarly favoured EGFR-TKI in both ctDNA + and ctDNA- subgroups respectively. ConclusionOur findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration.

Prognosis and Survival Study in Patients with Glioblastoma Multiform and Its Relationship with EGFR Expression

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 &lt;0.05 was assumed significant. Results: The mean survival of patients with GBM was 22.3 ± 2.5 months (95% CI=17.41 - 27.10). In addition, 1, 2- and 5-year survival rates were 90%, 30% and 5%, respectively. The mean survival of patients with negative and positive EGFR was 27.4±7.3 and 20.6±2.4 months, respectively. Besides, 11.1% and 14.3% of patients in negative and positive EGFR groups were alive. There was no significant difference in patient’s survival in terms of EGFR expression (p=0.36). No significant difference was seen between the two groups (EGFR positive and negative groups), regarding the frequency of age, sex, tumor’s anatomical location, and place of living (p&gt;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.

Survival differences between smokers and nonsmokers with EGFR mutated non-small cell lung cancer.

e21509 Background: Patients with epidermal growth factor receptor (EGFR) mutated lung cancer have an excellent prognosis compared to other non-small cell lung cancer (NSCLC) with no driver mutation, however, there is a wide range of survival between even a cohort with an EGFR driver mutation. Given that many patients with EGFR mutations are never smokers, it is possible that those with a smoking history have tumors with other oncogenic mutations and therefore as their tumors are less dependent on the EGFR driver, they may derive less benefit from targeted therapy. Methods: Pathology specimens of NSCLC sent for EGFR testing between January 1 2012 and December 31 2016 at Beaumont Hospital, Michigan were reviewed. If a tumor harbored a targetable EGFR mutation, the chart was queried. Inclusion criteria were EGFR exon 19 or 21 mutations, stage IV disease, at least 2 time points of follow up. Exclusion criteria included small cell histology, negative EGFR test, or inadequate information in the chart. The primary endpoint of the study was median survival. Results: Out of 329 cases identified, 40 were positive for EGFR exon 19 or 21 mutations. Of the 40 positive cases, 26 fit all inclusion criteria. Median duration of follow up was 14 months (range 0-80). Smokers represented 13/26 (50%) of cases. Death occurred in 9/13 (69%) of smokers vs 7/13 (54%) in non-smokers. Median survival was 8 mo (0-26) vs 20 mo (1-80) respectively for smokers vs non-smokers. Conclusions: This data suggests there may be a clinically relevant difference in the survival between smokers and nonsmokers who have NSCLC with an EGFR driver mutation. This may be due to the relatively low burden of alternative driver oncogene mutations in the nonsmoker’s tumors resulting in a lower likelihood of an escape mechanism for the tumor to survive. Further analysis of larger datasets with complete molecular analysis of the tumors would be informative in exploring this hypothesis. This would aid in risk stratifying patients more effectively for future clinical trials targeting the EGFR mutation and refining the prognosis in this otherwise good prognosis group.

Serum MiRNA as Predictive and Prognosis Biomarker in Advanced Stage Non-small Cell Lung Cancer in Indonesia

Background and objectiveLung cancer is the most common cause of death in men in the world and in Indonesia where non-small cell carcinoma lung cancer (NSCLC) constitutes 85% of all lung cancer cases. The high mortality rate is due to a poor prognosis and is often diagnosed as having advanced stages. If it is known at the initial stage, the prognosis of lung cancer will be better. Prognosis can be predicted with a marker of prognostic biology, one of which is micro RNA (miRNA). This study aims to prove that serum miRNA can be predictive biological marker and prognosis in NSCLC patients in Indonesia.MethodsThis study was cohort retrospective among 52 subjects in "Dharmais" Hospital National Cancer Center. Sample was obtained from patients' serum. MiR-34, miR-148, miR-155 and miR-222 serum are measured through Real-Time PCR (qPCR). Data were analyzed and interpreted with descriptive analysis, bivariate analysis (Mann Whitney-U for two type of variables or Kruskal-Wallis for more than two type of variables. Kaplan-Meier analysis was used to know association between characteristic which are sociodemographic, performance status, clinico-pathology, and survival rate in miRNA expression.ResultsFrom this study, miRNA expression: miR-34 (46.15%), miR-148 (23.08%), miR-155 (40.38%) and miR-222 (32.69%). Performance status score was statistically significant correlation with miR-148 (P=0.049) and miR-222 (P=0.018). High miR-34 is associated with multiple M1b metastatic type (P=0.020), cancer cell type (adenocarcinoma, P=0.009) and adenocarcinoma epidermal growth factor receptor (EGFR) mutation (negative, P=0.031). There was a significant correlation between the high miR-222 as a poor prognosis in advanced stage NSCLC with M1b metastasis (Median Survival/MS: 27 d, P=0.049) and positive EGFR mutations (MS: 74 d, P=0.049) and correlation of miR-155 with adenocarcinoma (MS: 69 d, P=0.034) and positive EGFR gene mutations (MS: 58 d, P=0.023).ConclusionHigh miR-34 expression in advanced stage NSCLC is the predictive factor for multiple metastatic, adenocarcinoma cell type and adenocarcinoma negative EGFR mutation. High expression of miR-155 and miR-222 are poor prognoses, especially high miR-222 found in metastasis M1b and positive EGFR mutation and miR-155 found in adenocarcinoma and positive EGFR gene mutations. Further studies regarding correlation between miRNA and survival rate are needed.

Impact of Nuclear Interleukin-1 Alpha and EGFR Expression on Recurrence and Survival Outcomes in Oral Squamous Cell Carcinomas.

Interleukin-1 alpha (IL-1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas. Although IL-1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL-1α expression in patient outcomes are poorly understood. This study is aimed at investigating the prognostic value of nuclear and cytoplasmic immunohistochemical IL-1α expression in oral squamous cell carcinomas (OSCCs). Tissue microarrays containing 146 OSCCs were analyzed for IL-1α and epidermal growth factor receptor (EGFR) expression by immunohistochemistry. IL-1α and EGFR expression scores were correlated with clinicopathological parameters and survival outcomes. IL-1α expression was observed in the nuclear and/or cytoplasmic compartments in 98% of evaluable tumors and 78% of tumors expressed IL-1α in both compartments. There were no differences observed in overall survival or progression-free survival between high, moderate, or negative IL-1α nuclear/cytoplasmic expression scores. When IL-1α nuclear/cytoplasmic expression scores were stratified by positive or negative EGFR expression, tumors with a combined EGFR-positive and high nuclear IL-1α expression profile were significantly more likely to possess perineural invasion and were significantly associated with a high risk of tumor recurrence and worse progression-free survival compared to all other EGFR and combined IL-1α/EGFR expression profiles. Altogether, nuclear IL-1α expression may enhance the prognostic value of EGFR in OSCC and warrants further study as a prognostic biomarker for recurrence.

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

BackgroundEpidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters.MethodsThe study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks.ResultsMean age of the patients included in the study was 69.05 ± 8.68 years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p = 0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression.ConclusionWe found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma.

EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced gut barrier dysfunction and liver injury

Recent study indicated that glutamine prevents alcoholic tissue injury in mouse gut and liver. Here we investigated the potential role of Epidermal Growth Factor Receptor (EGFR) in glutamine-mediated prevention of ethanol-induced colonic barrier dysfunction, endotoxemia and liver damage. Wild-type and EGFR*Tg transgenic (expressing dominant negative EGFR) mice were fed 1–6% ethanol in Lieber-DeCarli diet. Gut permeability was measured by vascular-to-luminal flux of FITC-inulin, and junctional integrity assessed by confocal microscopy. Liver injury was evaluated by plasma transaminases, histopathology and triglyceride analyses. Glutamine effect on acetaldehyde-induced tight junction disruption was investigated in Caco-2 cell monolayers. Doxycycline-induced expression of EGFR* blocked glutamine-mediated prevention of ethanol-induced disruption of colonic epithelial tight junction, mucosal permeability and endotoxemia. Ethanol activated cofilin and disrupted actin cytoskeleton, which was blocked by glutamine in an EGFR-dependent mechanism. Ethanol down-regulated antioxidant gene expression and up-regulated cytokine and chemokine gene expression, which were blocked by glutamine in wild-type mice in the presence or absence of doxycycline, but not in EGFR*Tg mice in the presence of doxycycline. Histopathology, plasma transaminases, triglyceride and expression of chemokine and antioxidant genes indicated ethanol-induced liver damage, which were blocked by glutamine in an EGFR-dependent mechanism. Src kinase activity and extracellular ligand binding domain of EGFR are required for glutamine-mediated protection of barrier function in Caco-2 cell monolayers. Glutamine released metalloproteinases into the medium, and metalloproteinase inhibitors blocked glutamine-mediated protection of barrier function. Results demonstrate that EGFR plays an important role in glutamine-mediated prevention of alcoholic gut permeability, endotoxemia and liver damage.

Clinical significance of epidermal growth factor receptor and thymidylate synthase expression in primary liver cancer

Objective: To investigate epidermal growth factor receptor (EGFR) and thymidylate synthase (TS) expression in primary liver cancer, and analyze its clinicopathological features and prognostic significance. Methods: Immunohistochemistry was performed using EnVision method to detect EGFR and TS expression in 41 cases of liver cancer. Correlation coefficient between EGFR and TS was calculated by Spearman method. Fisher's exact probability method or χ(2) test was used to analyze the clinicopathological features of EGFR and TS. Kaplan-Meier method was used to calculate the survival rate of patients in conjunction with the log-rank test.COX proportional hazard regression model was used to analyze the prognostic factors of patients. ROC curve was used to analyze the predictive accuracy of EGFR and TS for prognosis. Results: The positive rates of EGFR and TS in liver cancer tissues were 34.15% and 39.02%, respectively. There was a positive correlation between EGFR and TS expressions, and the difference was statistically significant (P < 0.05). EGFR was associated with tumor size and tissue differentiation (P < 0.05) in HCC patients, whereas TS was associated with tissue differentiation (P < 0.05). There was no significant difference in prognostic effect of EGFR on survival rate (P > 0.05). TS prognostic effect on survival rate was statistically significant (P < 0.05). HR of EGFR was 0.210 with 95% CI, 0.052-0.852, P = 0.029; indicating that the risk of death in patients with negative EGFR was 0.210 times higher than that in patients with positive EGFR. HR of TS was 2.496, with 95% CI, 1.325-4.701, P = 0.005, indicating that the risk of death increased by 2.496 times with the same level of EGFR. The area under the EGFR curve was 0.553 and its approximate reference confidence interval was 95% (0.355, 0.751), indicating that EGFR was a risk factor for death and the area under the TS curve was 0.695, and its approximate reference confidence interval was 95% (0.513, 0.878), indicating that TS was a risk factor for death. Conclusion: EGFR and TS were equally expressed in primary liver cancer, and EGFR and TS expressions were positively correlated. EGFR and TS had an effect on the degree of tissue differentiation in patients with liver cancer. EGFR and TS were risk factors for prognosis, and TS may assist EGFR.

Differential Claudin 3 and EGFR Expression Predicts BRCA1 Mutation in Triple-Negative Breast Cancer

BRCA-1 mutation-associated triple-negative breast cancer (TNBC) has been hypothesized to exhibit a phenotype that is distinct from non-mutation carriers. We have analyzed immunohistochemically detected cytokeratins 5 and 14, epidermal growth factor receptor (EGFR), claudin (CLDN) 3, 4, and 7, and E-cadherin in 57 TNBC (32 BRCA1 and 8 BRCA2 tumors, 17 WT tumors). Positive staining of CLDN3 and negative EGFR expression in TNBC are associated with a BRCA1 mutation. EGFR and CLDN3 expression was able to predict the presence of BRCA1 mutation (area under curve 0.802, p < 0.001). This could help in guiding the decision for BRCA testing.

Expression of epidermal growth factor receptor (EGFR) in cholangiocarcinomas: predictive factors and survival.

to evaluate the expression of the epithelial growth factor receptor (EGFR) by immunohistochemistry, and to verify its association with prognostic factors and survival of patients operated by cholangiocarcinoma. we verified the immunohistochemical expression of EGFR in 35 surgical specimens of cholangiocarcinoma (CCA). We obtained survival curves with the Kaplan-Meier method. we found significant EGFR expression in ten (28.6%) of the 35 CCAs, eight with score 3 and two with score 2. Advanced stages (III and IV) presented higher EGFR expression (p=0.07). The clinical characteristics that were most associated with positive EGFR expression were female gender (p=0.06) and absence of comorbidities (p=0.06). Overall survival at 12, 24, 36 and 48 months was 100%, 82.5%, 59% and 44.2%, respectively. The survival of EGFR positive patients at 12, 24, 36 and 48 months was 100%, 75%, 50% and 0%, whereas for negative EGFR patients it was 100%, 87.5%, 65.6% and 65.6%, respectively. EGFR expression occurred in 28.6% of the cases studied and was associated with lower survival.

Lactobacillus plantarum prevents and mitigates alcohol-induced disruption of colonic epithelial tight junctions, endotoxemia, and liver damage by an EGF receptor-dependent mechanism.

Pathogenesis of alcohol-related diseases such as alcoholic hepatitis involves gut barrier dysfunction, endotoxemia, and toxin-mediated cellular injury. Here we show that Lactobacillus plantarum not only blocks but also mitigates ethanol (EtOH)-induced gut and liver damage in mice. L. plantarum blocks EtOH-induced protein thiol oxidation, and down-regulation of antioxidant gene expression in colon L. plantarum also blocks EtOH-induced expression of TNF-α, IL-1β, IL-6, monocyte chemotactic protein 1 ( MCP1), C-X-C motif chemokine ligand ( CXCL)1, and CXCL2 genes in colon. Epidermal growth factor receptor (EGFR) signaling mediates the L. plantarum-mediated protection of tight junctions (TJs) and barrier function from acetaldehyde, the EtOH metabolite, in Caco-2 cell monolayers. In mice, doxycycline-mediated expression of dominant negative EGFR blocks L. plantarum-mediated prevention of EtOH-induced TJ disruption, mucosal barrier dysfunction, oxidative stress, and inflammatory response in colon. L. plantarum blocks EtOH-induced endotoxemia as well as EtOH-induced pathologic lesions, triglyceride deposition, oxidative stress, and inflammatory responses in the liver by an EGFR-dependent mechanism. L. plantarum treatment after injury accelerated recovery from EtOH-induced TJ, barrier dysfunction, oxidative stress, and inflammatory response in colon, endotoxemia, and liver damage. Results demonstrate that L. plantarum has both preventive and therapeutic values in treatment of alcohol-induced tissue injury, particularly in alcoholic hepatitis.-Shukla, P. K., Meena, A. S., Manda, B., Gomes-Solecki, M., Dietrich, P., Dragatsis, I., Rao, R. Lactobacillus plantarum prevents and mitigates alcohol-induced disruption of colonic epithelial tight junctions, endotoxemia, and liver damage by an EGF receptor-dependent mechanism.