Primary Carcinoma of the Frontal Sinus

A case of Primary Carcinoma of the Frontal Sinus is presented in which the diagnosis was difficult on the basis of clinical and radiological findings.     

ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma

Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal-regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients’ survival rates was assessed by Kaplan–Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P?ADAM17, AREG, EMMPRIN, and MMP-9 was significantly associated with stages, lymph node metastasis, differentiation, and parametrium invasion (P?ADAM17, AREG, EMMPRIN, and MMP-9 was significantly correlated with short progression-free survival and overall survival (P?ADAM17 expression were independent prognostic indicators for cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a molecular marker for predicting the progression and prognosis in cervical cancer.     

MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer

The molecular mechanism underlying cancer invasiveness and metastasis of gastric carcinoma remains elusive. Here, we reported significant decrease in microRNA (miRNA)-34a and significant increase in phosphorylated epidermal growth factor receptor (EGFR) and matrix metalloproteinase-7 (MMP7) in the resected gastric carcinoma from the patients, compared with adjacent normal tissue. Moreover, strong correlation was detected among these three factors. To examine whether a causal link exists, we used two human gastric carcinoma lines, SNU-5 and HGC27, to study the molecular basis of miRNA-34a, EGFR signaling, and MMP7 activation. We found that EGF-induced EGFR phosphorylation in SNU-5 or HGC27 cells activated MMP7 and consequently cancer invasiveness. Both an inhibitor for EGFR and an inhibitor for Akt significantly inhibited the EGF-induced activation of MMP7, suggesting a phosphatidylinositol 3-kinase (PI3K) signaling cascade dependent pathway. Moreover, miRNA-34a levels were not affected by EGF-induced EGFR phosphorylation. However, overexpression of miRNA-34a antagonized EGF-induced MMP7 activation without affecting EGFR phosphorylation in SNU-5 or HGC27 cells. Taken together, our data suggest that miRNA-34 inhibits EGFR signaling via downstream PI3K signaling cascades to regulate MMP7 expression in gastric carcinoma. Thus, miRNA-34a, EGFR, and MMP7 appear to be promising therapeutic targets for preventing the metastasis of gastric carcinoma.     

Comparison of dual-color in-situ hybridization and fluorescence in-situ hybridization in HER2 gene amplification in breast cancer

Background

HER2 is a prognostic factor in breast cancer, and is predictive of the effects of HER2-targeted drugs. HER2 tests are essential in invasive and metastatic breast cancer. Dual-color in-situ hybridization (DISH) is a novel genetic test, and we investigated its utility in HER2 testing in breast cancer.

Methods

Using DISH and two FISH methods (FISH method 1, FISH method 2) with representative slices of surgical specimens from 134 invasive breast cancer patients, we performed HER2 gene testing and compared the results for HER2 gene/CEP17 signal ratio and HER2 gene diagnosis.

Results

Of 134 patients, either the HER2 gene or the CEP17 signal could not be counted in 2 patients by DISH, in 1 patient by FISH method 1, and in 1 patient by FISH method 2. HER2 gene/CEP17 signal ratios were strongly correlated in DISH and FISH method 1 (R = 0.85, P < 0.05). Agreement of DISH and FISH method 1 for HER2 gene diagnosis was 98.5 % for all patients, irrespective of gene amplification (κ = 0.97). HER2 gene/CEP17 signal ratios were strongly correlated in DISH and FISH method 2 (R = 0.87, P < 0.05). Agreement of DISH and FISH method 2 for HER2 gene diagnosis was 94.1 % for gene amplification patients, 98.4 % for gene non-amplification patients, and 96.2 % for all patients (κ = 0.92).

Conclusions

DISH is useful for HER2 gene testing in breast cancer, and is recommended as a new option for assessing HER2 status.     

Imbalance between MMP-2, 9 and TIMP-1 promote the invasion and metastasis of renal cell carcinoma via SKP2 signaling pathways

S-phase kinase-associated protein-2 (Skp2) is overexpressed in human cancers and acted as an oncogenic protein associated with poor prognosis by enhancing tumor metastasis. The present study has demonstrated that Skp2 overexpresses stable transfectants from 786-0 human renal cancer cells. We found that these stable transfectants exhibited increased migratory and invasive abilities. In addition, expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was upregulated and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was downregulated. In contrast, RNA interference-mediated knockdown Skp2 expression suppressed the ability of ACHN cells to migratory and invasive. Skp2 depletion increased P27 and decreased cyclin E activity, and then induced cell cycle arrest in the G0/G1 phase. Skp2 depletion also downregulated MMP-2 and MMP-9, while upregulated the TIMP-1 activity and expression. The results suggest that Skp2 signaling pathways promoted the ability to metastasize, by stimulating cell proliferation and increasing the ratio of MMP-2 and MMP-9/TIMP-1. So, in conclusion, we provide the first evidence that the imbalance of MMP/TIMP, including upregulation of MMP-2 and MMP-9 and downregulation of TIMP-1, is one of the mechanisms by which Skp2 promotes cell invasion.     

Comparison of ERCP,EUS, and ERCP combined with EUS in diagnosing pancreatic neoplasms: a systematic review and meta-analysis

In the current study, we performed a systematic review of literature pertaining to the diagnostic value of endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography (EUS), and combined ERCP plus EUS to pancreatic cancer. We searched MEDLINE, OVID, and the Cochrane Library for studies evaluating diagnostic validity of ERCP, EUS, and ERCP plus EUS between January 1989 and May 2014. We obtained pooled estimates of sensitivity, specificity, and summary receiver operating characteristic curves (SROC). A total of 10 studies that included 669 patients who fulfilled all of the inclusion criteria were considered for inclusion in the analysis. The pooled sensitivities of EUS, ERCP, and EUS plus ERCP were 76.7, 57.9, and 79.9 %, respectively. The pooled specificities were 91.7, 90.6, and 94.2 %, respectively. The *Q index estimates were 0.828, 0.862, and 0.896, respectively. The *Q indices for EUS and EUS plus ERCP were significantly higher compared with ERCP (P?=?0.010 and 0.008, respectively). Our meta-analysis showed that ERCP plus EUS was associated with a high diagnostic value for the detection of pancreatic neoplasms compared with ERCP and EUS alone.     

Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Purpose

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo.

Methods

MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography.

Results

Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts.

Conclusions

These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.     

Abrogating phosphorylation of eIF4B is required for EGFR and mTOR inhibitor synergy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive disease. They have a high rate of relapse and often develop resistance to standard chemotherapy. Many TNBCs have elevated epidermal growth factor receptor (EGFR) but are resistant to EGFR inhibitors as monotherapy. In this study, we sought to find a combination therapy that could sensitize TNBC to EGFR inhibitors. Phospho-mass spectrometry was performed on the TNBC cell line, BT20, treated with 0.5 μM gefitinib. Immunoblotting measured protein levels and phosphorylation. Colony formation and growth assays analyzed the treatment on cell proliferation, while MTT assays determined the synergistic effect of inhibitor combination. A Dual-Luciferase reporter gene plasmid measured translation. All statistical analysis was done on CalucuSyn and GraphPad Prism using ANOVAs. Phospho-proteomics identified the mTOR pathway to be of interest in EGFR inhibitor resistance. In our studies, combining gefitinib and temsirolimus decreased cell growth and survival in a synergistic manner. Our data identified eIF4B, as a potentially key fragile point in EGFR and mTOR inhibitor synergy. Decreased eIF4B phosphorylation correlated with drops in growth, viability, clonogenic survival, and cap-dependent translation. Taken together, these data suggest EGFR and mTOR inhibitors abrogate growth, viability, and survival via disruption of eIF4B phosphorylation leading to decreased translation in TNBC cell lines. Further, including an mTOR inhibitor along with an EGFR inhibitor in TNBC with increased EGFR expression should be further explored. Additionally, translational regulation may play an important role in regulating EGFR and mTOR inhibitor synergy and warrant further investigation.     

Epidermal growth factor induces FoxO1 nuclear exclusion to activate MMP7-mediated metastasis of larynx carcinoma

The molecular mechanism underlying cancer invasiveness and metastasis of larynx carcinoma remains elusive. Here we reported a strong correlation between phosphorylated epidermal growth factor receptor (EGFR) and matrix metalloproteinase-7 (MMP7) levels in larynx carcinoma patients. To examine whether a causal link exists, we used a human larynx carcinoma line, Hep-2, to study the molecular basis of EGFR signaling and MMP7 activation. We found that EGF-induced EGFR phosphorylation in Hep-2 cells resulted in activation of MMP7 and, consequently, an increase in cancer invasiveness. An EGFR inhibitor efficiently blocked this EGF-induced activation of MMP7. Moreover, an inhibitor for PI3 kinase (PI3K)/Akt, but not an inhibitor for mitogen-activated protein kinase (MAPK) or an inhibitor for c-Jun N-terminal kinase (JNK), significantly inhibited the EGF-induced activation of MMP7, suggesting that PI3K/Akt signaling cascades may be responsible for EGF-activated MMP7. Further dissection of the pathway revealed that nuclear exclusion of Akt downstream target, FoxO1, was induced by EGF-induced Akt activation and could be inhibited by either the EGFR inhibitor or by the PI3K/Akt inhibitor. Expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP7 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI3K/Akt to induce FoxO1 nuclear exclusion, which activates MMP7 to promote larynx carcinoma metastasis. Thus, Akt and FoxO1 appear to be promising therapeutic targets for preventing the metastasis of larynx carcinoma.     

Limited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers

Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 (BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients (N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher’s exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14 %, whereas it dropped to 3 % in non-TNBCs with adequate family history (OR 5.31, 95 % CI 1.38–23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing.     

miR-195 Targets HDGF to inhibit proliferation and invasion of NSCLC cells

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related death worldwide. MicroRNAs (miRNAs) play critical roles in the development and progression of NSCLC. miR-195 acts as a tumor suppressor in several cancers, however, its role in NSCLC is not well understood. Herein, we found that miR-195 was significantly decreased in both NSCLC tissues and cell lines. Forced expression of miR-195 significantly suppressed proliferation, migration, and invasion of NSCLC cells. Hepatoma-derived growth factor (HDGF) was identified as a target of miR-195 in NSCLC cells. Overexpression of HDGF dramatically abolished the tumor suppressive role of miR-195 in NSCLC cells. Our results demonstrated a tumor suppressive role of miR-195 in NSCLC, and suggested a potential therapeutic target for NSCLC.     

Recent advances in radiation oncology: intensity-modulated radiotherapy,a clinical perspective

Radiotherapy plays an important role in the treatment of various malignancies, and intensity-modulated radiotherapy (IMRT) is an attractive option because it can deliver precise conformal radiation doses to the target while minimizing the dose to adjacent normal tissues. IMRT provides a highly conformal dose distribution by modulating the intensity of the radiation beam. A number of malignancies have been targeted by IMRT; this work reviews published data on the major disease sites treated with IMRT. The dosimetric advantage of IMRT has resulted in the significant reduction of adverse effects in some tumors. However, there are few clinical trials comparing IMRT and three-dimensional conformal radiotherapy (3D-CRT), and no definite increase in survival or the loco-regional control rate by IMRT has been demonstrated in many malignancies. IMRT also requires greater time and resources to complete compared to 3D-CRT. In addition, the cost–effectiveness of IMRT versus 3D-CRT has not yet been established.     

Prediction of thyroid extracapsular extension with cervical lymph node metastases (ECE-LN) by CEUS and BRAF expression in papillary thyroid carcinoma

The aim of our study was to find a specific imaging (contrast-enhanced ultrasound, CEUS) to detect extracapsular extension and cervical lymph node metastases (ECE-LNM) that associated with BRAF protein expression in papillary thyroid carcinoma (PTC). Preoperative utrasonography (US) or CEUS was performed in the diagnosis of extracapsular extension (ECE) in 317 patients with 369 PTC. BRAF protein status was tested on the primary tumor and lymph node involvement. The diagnostic accuracy of CEUS and US was evaluated after thyroid surgery. The association between CEUS and BRAF expression were then analyzed to investigate the diagnostic value of ECE-LNM in PTC. The sensitivity and specificity of CEUS were higher than those in US in the diagnosis of ECE in patients with PTC (91.1, 86.5 vs 49, 55 %). BRAF protein overexpression were significantly associated with ECE (P?=?0.0003) and lymph node metastasis (LNM) positive cases (P?=?0.0014). The results of CEUS, not US, have a significant correlation with BRAF expression status in PTC samples (P?BRAF protein expression status, the routine preoperative CEUS could have a good value in the diagnosis of ECE-LNM in PTC and facilitate a surgeon to improve further clinical management.     

Immunopathology of nasal polypi

Thirty patients operated for nasal polypi and 15 age and sex matched controls were taken for study. Estimation of albumin, IgG, IgA, IgM and IgE was done in serum and nasal polyp fluid. Histopathology of polypi was undertaken in order to divide polypi into allergic and inflammatory groups and to study the immunoglobulin profile in these two groups. Allergic polypi were found to be more common than inflammatory polypi. The inflammatory polyp fluid IgA level (208.19 ± 59.33 mg/dl) was significantly raised (p<0.05) as compared to serum (160.58 ±40.28 mg/dl) suggesting the protective role of IgA against entry of antigens. Allergic polyp fluid IgE level (5342.80 ±2540.77 LU, ml.) was roughly twice that of serum (2461.25±1546.25 I.U./ml.) suggesting local production of IgE, rather than that explained by simple filtration process. Also local production of IgE correlated with the tendency to sneeze and was found to be in excess in polypi infiltrated by eosinophils thereby suggesting the role of allergy in production of allergic polypi.     

Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway,obesity, and breast cancer disease-free survival

Obesity-related hormones and cytokines alter PI3 K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I–II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant, or recessive) after correcting for false discovery rate (FDR = 0.10) were included in Cox proportional hazards multivariable analyses. After adjusting for race/ethnicity, age at diagnosis, tumor stage, and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS, and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by the type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. In this study, germline SNPs in the PI3 K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3 K-AKT-mTOR pathway in breast tumors.     

Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers

Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan–Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.     

CXCL10 mRNA expression predicts response to neoadjuvant chemoradiotherapy in rectal cancer patients

Chemoradiotherapy has been commonly used as neoadjuvant therapy for rectal cancer to allow for less aggressive surgical approaches and to improve quality of life. In cancer, it has been reported that CXCL10 has an anti-tumor function. However, the association between CXCL10 and chemoradiosensitivity has not been fully investigated. We performed this study to investigate the relationship between CXCL10 expression and chemoradiosensitivity in rectal cancer patients. Ninety-five patients with rectal cancer who received neoadjuvant chemoradiotherapy (NCRT) were included. Clinical parameters were compared with the outcome of NCRT and CXCL10 messenger RNA (mRNA) expression between the pathological complete response (pCR) group and non-pathological complete response (npCR) group. CXCL10 mRNA and protein expressions between groups were analyzed using the Student’s t test and chi-square test. The mean mRNA level of CXCL10 in the pCR group was significantly higher than that in the npCR group (p?=?0.010). In the pCR group, 73.7 % of the patients had high CXCL10 mRNA expression, and 61.4 % of the patients in the npCR group had low CXCL10 mRNA expression. Subjects with high CXCL10 mRNA expression demonstrated a higher sensitivity to NCRT (p?=?0.011). The receiver operating characteristic curve showed that the diagnostic performance of CXCL10 mRNA expression had an area under the curve of 0.720 (95 % confidence interval, 0.573–0.867). There were no differences between the pCR and npCR groups in CXCL10 protein expression (p?>?0.05). High CXCL10 mRNA expression is associated with a better tumor response to NCRT in rectal cancer patients and may predict the outcome of NCRT in this malignancy.