Identification of Homer1 as a Potential Prognostic Marker for Intrahepatic Cholangiocarcinoma

Background: The aim of the present study was to analyze whether Homer1 is a potential prognostic markerfor intrahepatic cholangiocarcinoma (ICC). Materials and Methods: The expression of Homer1 in ICC tissuewas detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated byWestern blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance.Results: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant differencebetween ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologicdifferentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion(p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expressionof Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was anindependent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63-21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC. Conclusions: Homer1promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The currentstudy shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection,and it provides an important basis for screening/treating high-risk patients.     

TGF-β-activated Kinase-1: A Potential Prognostic Marker for Clear Cell Renal Cell Carcinoma

Background: TGF-β-activated kinase-1 (TAK1) has been found to be over-expressed in a variety of solidmalignancies and related to tumor growth. The aim of this study was to evaluate the expression level of TAK1in clear cell renal cell carcinoma (ccRCC) and assess its value as a novel prognostic marker. Methods: TAK1mRNA was assessed in 51 paired ccRCC tissues and adjacent normal tissues (ADTs) by real-time PCR. TissueTAK1 protein was also assessed in 91 ADTs and 177 samples of ccRCC immunohistochemically for evaluationof relationships with clinical characteristics. Results: RT-PCR showed that TAK1 RNA level was significantlyhigher in ccRCC tissues than in the paired ADTs and immunohistochemistry confirmed higher expression ofTAK1 protein in ccRCC samples compared with ADTs. TAK1 protein expression in 177 ccRCC samples wassignificantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, but not ageand gender. Patients with low TAK1 levels had a better survival outcome. TAK1 expression and N stage wereindependent prognosis factors for the overall survival of ccRCC patients. Conclusions: Overexpression of TAK1predicts a poor prognosis in patients with ccRCC, so that TAK1 may serve as a novel prognostic marker.     

Neutrophil–Lymphocyte Ratio as a Prognostic Factor in Laryngeal Carcinoma

Aim of this study; investigate whether neutrophils/lymphocyte ratio (NLR) could be used as a prognostic factor in larynx cancer. The correlation between preoperative peripheral blood NLR and age, gender, smoking, alcohol use, clinical stage and differentiation degree was examined. One hundered fourty-four patients in Dicle University Department of Otorhinolaryngology between the years of 2005 and 2014 were included in the study. Clinical and preoperative laboratory data of patients were screened retrospectively from archive files of otorhinolaryngology and the pathology results were screened retrospectively from archive files of pathology. The study was approved by the local ethics committee of the department and carried out in accordance with the declaration of Helsinki as amended in 2013. Statistical analyses were performed using the SPSS 15.0 software package for Windows (SPSS inc., Chicago, IL, USA). There was a significant difference between NLR and clinical stage (p = 0.003) smoking (p = 0,001) and alcohol use (p = 0.001). When NLR was analyzed in detail according to the degree of tumor differentiation; significant differences were observed between G1 and G2 (p = 0.007) and between G1 and G3 (p = 0.001). Light of these findings, NLR is a cheap and easily accessible marker which can be used as a prognostic faxtor in laryngeal cancer. It is thougkt to shed light on the studies which will be conducted with more patients.     

Urinary Cell-Free DNA IQGAP3/BMP4 Ratio as a Prognostic Marker for Non–Muscle-Invasive Bladder Cancer

BackgroundDisease monitoring in non–muscle-invasive bladder cancer (NMIBC) patients is crucial for early identification of disease recurrence and progression. High IQGAP3/BMP4 and IQGAP3/FAM107A ratios in urinary cell-free DNA (ucfDNA) are a diagnostic biomarker for bladder cancer. We aimed to investigate whether the levels of these biomarkers in ucfDNA can be used to monitor disease recurrence or progression in patients with NMIBC.Patients and MethodsA total of 103 patients with NMIBC (pTa-pT1) were enrolled. The IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were measured by real-time PCR, and the results were compared with clinical outcome by Kaplan-Meier curves and Cox regression analyses.ResultsOverall, 55 patients (53.4%) experienced recurrence and 29 (28.2%) experienced disease progression during a median follow-up of 42.7 months (range, 6.1-172.2 months). Kaplan-Meier analysis revealed that NMIBC patients with a high IQGAP3/BMP4 ratio had worse recurrence-free survival and progression-free survival (PFS) (P = .001 and < .001, respectively), and those with a high IQGAP3/FAM107A ratio had worse PFS (P = .006). Multivariate Cox regression analysis revealed that the IQGAP3/BMP4 ratio was independently associated with recurrence-free survival (hazard ratio, 2.462; P = .003) and PFS (hazard ratio = 3.871; P = .004), whereas the IQGAP3/FAM107A ratio was not an independent factor for PFS (P = .079).ConclusionThe IQGAP3/BMP4 ratio in ucfDNA might be a valuable novel biomarker for predicting disease recurrence and progression in patients with NMIBC.     

Surgical Intervention for Hepatocellular Carcinoma with Bile Buct Thrombi

Objective: To summarize the experience of surgical intervention for hepatocellular carcinoma(HCC) with bile duct thrombi (BDT), and to evaluate the influence on prognosis. Methods: From 1994 to 2002, 15 patients with HCC and BDT who underwent surgical intervention were retrospectively analyzed.Results: The operative procedures included hepatectomy with removel of BDT (n=7), hepatectomy com-bined with extrahepatic bile duct resection (n=4), thrombectomy through choledochotomy (n=3), piggy back orthotopic liver transplantation (n=1). The 1-and 3-year survival rates were 73.3% and 40%, respec-tively. Two patients survived over 5 years. Conclusion: Surgical intervention was effective for patients with HCC and BDT. Operation for recurrent lesion can prolong survival period. Liver transplantation is a new treatment worthy of further investigation.     

Clinical Significance of the Serum Crosslinked N-Telopeptide of Type I Collagen as a Prognostic Marker for Non–Small-Cell Lung Cancer

IntroductionLung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix.Patients and MethodsWe measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non–small-cell lung cancer (NSCLC).ResultsThis study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close association between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level < 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level ≥ 22 nmol BCE/L (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.36-2.99; log-rank P = .00037).ConclusionsWe have revealed that a high serum NTx level (> 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.     

Polymorphism of Promoter Region of TNFRSF1A Gene (−610 T &gt; G) as a Novel Predictive Factor for Radiotherapy Induced Oral Mucositis in HNC Patients

Every year, about 650 thousand new cases of Head and Neck Cancer (HNC) are diagnosed globally. Apart from surgery, radiotherapy (RTH), chemotherapy (CHT) or its combination is used in the treatment of HNC. One of the most frequent complications and, at the same time, limitations of RTH is oral mucositis (OM). Proinflammatory cytokines (including TNF-α) play a key role in the development of OM. Genetic alterations, i.e. single nucleotide polymorphisms (SNPs) within genes encoding for receptors for TNF (ie. TNFRSF1A) may change their function. The aim of this study was to investigate relationship between a polymorphism of TNFRSF1A and occurrence and severity of acute reaction after RTH for HNC patients. Data from 58 HNC patients (stages I-IV) were analyzed. All of them were irradiated using IMRT technique with doses 50-70Gy. Oral mucositis (OM) was evaluated according to RTOG/EORTC guidelines. DNA from HNC patients were isolated from whole blood and genotypes were determined by sequencing method. Patients with TT or GT genotype demonstrated higher risk of manifestation of grade 3 OM in 5th week of RTH (p=0.041; OR=9.240; 95% CI: 1.101–77.581) compared to GG carriers. Similarly, high risk of grade 3 OM in patients with T allele presence was noted in 6th week (p=0.030; OR=10.50; 95%CI:1.257–87.690) and in 7th week (p=0.008; OR=5.625; 95% CI: 1.584–19.975) of treatment compared to patients with GG homozygote. Our results indicate an association between SNP of TNFRSF1A (rs4149570) gene and risk of more severe OM related to radiation therapy for HNC patients.     

Elevated Renin Levels in Patients with Liver Cirrhosis and Hepatocellular Carcinoma

Liver fibrosis is the common consequence of chronic liver injury of any etiology, disrupting the normalarchitecture,and causing hepatocellular dysfunction and portal hypertension. Since the renin-angiotensin system(RAS) may be involved in chronic liver diseases, in the present study we assayed renin levels using ELISA in groupsof Egyptian patients with liver cirrhosis (N=32) and hepatocellular carcinoma (HCC) (N=67), for comparisonwith twenty five healthy controls. The results showed significant differences between the control and liver cirrhosispatients (P<0.001) and also the controls and HCC patients (P<0.001), without significant variation between thepatient groups. Furthermore, in HCC patients, it was found that the renin levels negatively correlated with serumalbumin and prothrombin time (P=0.003 for each) and positively with α-fetoprotein (P=0.04). Thus, it is concludedthat renin levels are elevated in patients with liver cirrhosis and HCC and suitable medical intervention shouldbe placed for management of such alteration. Moreover, further studies are warranted to explore its prognosticsignificance.     

Relationship between Microsatellite Alterations of RASSF1A Gene and Development of Cervical Carcinoma

Objective： To explore the relationship between microsatellite alterations of RASSFIA gene and the development of cervical carcinoma, and its relationship with HPV16 infection. Methods： Two sites of microsatellite polymorphism of RASSFIA gene were selected. Polymerase chain reaction （PCR） technique was used to detect LOH and MSI in 50 cases of cervical carcinoma and 40 cases of cervical intraepithelial neoplasia （CIN）, and to detect the infection state of HPV16. Results： At D3S1478 and D3S4604, the LOH rates of cervical carcinomas were 32.6% （14/43） and 48.9% （23/47）, the MSI rates were 14% （6/43） and 19.1% （9/47）, respectively. The LOH rates of CINs were 31.4% （11/35） and 39.5% （15/38）, the MSI rates were 11.4% （4/35） and 15.8% （6/38）, respectively. There were no significant differences between cervical carcinomas and CINs in respect to their positive rates of LOH and MSI at D3S1478 and D3S4604 （P〉0.05）. There were significant differences in LOH rates at D3S1478 and D3S4604 between the stage Ⅰ-Ⅱ and Ⅲ-Ⅳ cervical carcinomas and between the well/moderately differentiated cervical carcinomas and the poorly differentiated cervical carcinomas （P〈0.05）. The positive rates of LOH and MSI for CIN Ⅲ and noninvasive cervical carcinomas were higher than those in CIN Ⅰ-Ⅱ. The rates of infection of HPV16 in cervical cancer was obviously higher than that in CIN and in normal cervical tissues （P〈0.05）, and the incidence of LOH of RASSFIA gene was higher in HPV16（＋） than that in HPV16（-） （P〈0.05）. Conclusion： The RASSFIA gene change is a relatively late event in cervical carcinomas. The detection of LOH and MSI of RASSFIA gene might be helpful to the early diagnosis and the screening of cervical carcinoma. It might also be useful for predicting the prognosis of cervical carcinoma.     

Synchronous Hepatocellular Carcinoma and Gastric Carcinoma—A Case Report with Review of the Literature

Purpose

The study was designed to investigate the clinicopathological correlations, relationship to apoptotic index, and prognostic significance of estrogen receptor beta expression in colorectal carcinoma.

Methods

The study was carried out on 40 patients with newly diagnosed colorectal cancer. The patients?? data were collected prospectively and the 2?years overall survival was the endpoint. Estrogen receptor beta expression was assessed by immunohistochemistry. Apoptotic body index was calculated by counting apoptotic cells using the modified TUNEL assay.

Results

Estrogen receptor beta positivity was detected in 65% of colorectal cancer cases, while estrogen receptor alpha positivity was found in only 7% of cases. The rate of estrogen receptor beta immunoreactivity was significantly higher in low-grade colorectal tumors. The median apoptotic index in estrogen receptor beta positive cases was significantly higher than in estrogen receptor beta negative cases (6% versus 3%; p?=?0.01). The median overall survival was higher in estrogen receptor beta positive cases (22 versus 18?months); however, the difference was not statistically significant.

Conclusions

The study results reinforce the importance of the estrogen receptor beta rather than the estrogen receptor alpha in colorectal cancer. Lack of estrogen receptor beta expression is associated with loss of differentiation and decreased apoptosis. Future studies should include validation of estrogen receptor beta as a prognostic marker and exploration of its role as a target in the management of colorectal cancer.     

Hepatocellular Carcinoma with Bone Metastases: Incidence,Prognostic Significance,and Management—Single-Center Experience

Background

Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer-related deaths worldwide, with rising incidence in the USA. Bone metastases with HCC, in particular, have an extremely poor prognosis. We present prevalence, treatment, and survival of patients with bone and more specifically spinal metastases from HCC.

Methods

A retrospective analysis was done at a single tertiary care institution of patients with bone metastases from HCC between January 2005 and December 2015.

Results

Among 1017 patients with HCC, 20 were found to have bone metastases of which 11 had spinal metastases. Seventeen (85%) were male, with median age of 58 years at time of HCC diagnosis. Systemic chemotherapy and sorafenib were used in 12 (60%) patients, and 12 (60%) received radiation therapy. Among patients who did not receive therapy, median survival was 76 days. Median survival after diagnosis of metastasis in patients on sorafenib and radiation were 106 and 100 days, respectively.

Conclusion

Bone metastases in HCC are very rare and aggressive. Due to its rarity, optimal treatment strategies are not well defined. Early diagnosis is important for optimal therapy and improved survival.

     

Aryl Hydrocarbon Receptor in Breast Cancer—A Newly Defined Prognostic Marker

Aryl hydrocarbon receptor (AhR) has been reported to exert various anticancer effects upon breast carcinoma cells in vitro but its details have remained largely unknown. Therefore, we first examined the AhR status in 90 invasive ductal carcinoma patients using immunohistochemistry. We then performed in vitro studies including wound healing assay, invasion assay, and matrix metalloproteinase (MMP) protein array in order to further elucidate the roles of AhR signaling in breast carcinoma. The status of AhR immunoreactivity was inversely correlated with histological grade (P?=?0.0135) and Ki-67 labeling index (LI; P?=?0.0087) of the patients. In addition, results of both uni- and multivariate analyses revealed that AhR in carcinoma cells turned out an independent prognostic factor with a protective relative risk (P?=?0.0179). An administration of 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR, significantly decreased Ki-67 LI in an AhR-dependent fashion in MCF-7, T47D, ZR75-1, and MDA-MB-231. Wound healing and invasion assays performed in T47D and ZR75-1 further demonstrated that 10 nM TCDD inhibited estrogen-induced migration and invasion of cells. MMP proteins associated with AhR in breast carcinoma cells were also firstly identified. These results demonstrated that AhR in breast carcinoma cells is considered a newly defined histological prognostic parameter of the breast cancer patients and effects of AhR activation on proliferation and MMPs expression may be related to the relatively good clinical outcome of AhR-positive breast cancer patients.     

Predictive Value of Interferon γ Receptor Gene Polymorphisms for Hepatocellular Carcinoma Susceptibility

Background: Recent reports suggested relation between Interferon Gamma (IFN-γ) gene polymorphism and the risk of development of HCC on top of hepatic cirrhosis. The aim of this study was to address the predictive value of Interferon Gamma gene receptor (IFN-γR) polymorphisms for the occurrence of hepatocellular carcinoma on top of liver cirrhosis. Patients and Methods: This is a case control study performed on patients selected from the outpatient hepatology clinic, specialized medical hospital, Mansoura University, Egypt, from August 2017 to February 2019. The included patients were categorized into two groups; 60 patients with HCC on top of cirrhosis and 20 patients with hepatic cirrhosis. For all patients IFN-γR polymorphism was identified by RFLP. Results: Our study showed that HCC patients had male predominance. Additionally, diabetes mellitus (DM) was found in 28.3% of total HCC patients. Half of HCC patients in this study were from rural areas (50%). The frequency of AA at position -611 in the IFN-γR (-611 IFN-γR) was significantly higher in the HCC group as compared to cirrhotic group (P=0.021). Moreover; the frequency of CC and CT genotypes of IFN-γR -56 was not significantly different in HCC group as compared to control group (P>0.05). The IFN-γR (-611 IFN-γ) AA genotype significantly increased risk of HCC (OR= 0.78, 95% CI= 0.10-6.39; P= 0.042). Conclusion: The analysis of IFN-γR -611 single nucleotide gene polymorphism could be a valuable marker for predicting subgroup of cirrhotic patients with high risk of developing HCC.  Cirrhotic patients have AA genotype of IFN-γR-611 recommended to be under close follow up.     

Prognostic significance of cyclin A and B1 in pediatric embryonal tumors

Embryonal tumors constitute the most common malignant brain tumor group in children. Although patient prognosis has been substantially improved over recent decades, identification of prognostic markers would be of obvious significance. In the present study we evaluated the prognostic significance of cyclin A and B1 in correlation with Ki-67 index in pediatric embryonal tumors. We retrospectively evaluated 53 children with embryonic tumors who were treated surgically in our institute. All patients had regular follow-up examinations. The streptavidin–biotin–horseradish peroxidase (HRP) method was performed on paraffin sections for detection of Ki-67/MIB-1, and cyclin A and B1. There were 42 cases of medulloblastoma (MB), 9 cases of atypical teratoid/rhabdoid tumor (AT/RT), and 2 cases of supratentorial primitive neuroectodermal tumor (PNET). In MB patients, Ki-67 index >50% was associated with worse survival (P = 0.003). Cyclin A index >40% was associated with significantly poorer survival (P = 0.023). Patients with cyclin B1 index >15% exhibited a trend towards poorer survival (P = 0.068). On multivariate analysis, only Ki-67 index was identified as a factor with independent prognostic power. In AT/RT and PNET, there was high expression of Ki-67 and variable expression of cyclin A and B1. Apart from Ki-67 index, cyclin A may have a prognostic role. Study of the above indices at diagnosis could alter or intensify treatment methods, so as to improve disease outcome. There is obviously a need for future studies with larger number of patients to confirm our preliminary observations.