Background and objectives: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer related mortality worldwide.The identification of new high-sensitivity and high-specificity markers for HCCis essential.Annexin A2 (ANXA2) plays an important role in the pathogenesis of multiple malignancies particularly HCCs and its expression strongly also affects the outcomes of HCC patients.This study aimed to investigate the clinical utility of hepatic and circulating Annexin A2 expression levels as a novel diagnostic marker of HCC and to correlate its level with alpha fetoprotein (AFP), the current marker ofHCC.Patients and methods: A total number of 40 patients( 6 patients with chronic hepatitis, 8 patients with liver fiberosis, 6 patients with liver cirrhosis, 8 patients with early HCC and 12 patients with late HCC).The same number of age and sex matched healthy people was enrolled as a control group.All patients and controls were subjected to full medical history, complete medical examination abdominal sonography, laboratory investigations including liver function tests, AFP, platelet count, Prothrombin time and concentration, HBsAg, anti-HCV and serum HCV RNA quantitation by real time PCR.Liver biopsies were done for all patients.Evaluation of serum ANXA2 level for all patient and controlgroups was detected by using a human ANXA2 ELISA kit.Analyzing the ANXA2 expression at mRNA and protein levels was detected for patient groups by using RT-PCR by immunohistochemistry staining, respectively.Results: Serum ANXA2was significantly increased in all patient groups (except for chronic hepatitis group) compared to the control group (P<0.01).The serological evaluation and expression of ANXA2 levels were significantly increased in early HCC compared to serum AFP.ANXA2 expression was localized in both cell membrane and cytoplasm in HCC tissue, not detected in normal tissues and limited to some hepatocytes in chronic hepatitis patients.Over expression of ANXA2 mRNA levelwas present in HCC tissues compared to other patient groups (P<0.001).There was a significant relation with HCV infection, (P<0.001) when comparing ANXA2 values among positive and negative HCV RNA in HCC patients.No correlations were found between serum ANXA2 levels with serum AST,ALT, platelet count, INR and HBsAgin comparison to controls.Conclusion: Our results demonstrated increased levels of ANXA2 in both of tissues and sera of HCC patients and also in both AFP-positive and -negative cases.Results of serumANXA2 was concomitant with hepatic ANXA2 expression by RT-PCR and immunocytochemistry staining.Remarkably, Combination of conventional serum marker AFP with serumANXA2 may complement and benefit for early HCC detection.
Background: BCG is the standard treatment for non-muscle invasive bladder cancer (NMIBC).However, the high recurrence rates and the significant local and systemic toxicity have led to increased interest in alternative intravesical therapies.Docetaxel has been shown to be a safe and effective intravesical therapy with no systemic absorption and minimal toxicity.Objectives: To compare the efficacy and safety of intravesical BCG and docetaxel for intermediate and high-risk NMIBC.Patients and methods: 82 patients with NMIBC were randomized into 2 groups; and treated with six weekly intravesical BCG (group I, 40 patients) and docetaxel (group II, 42 patients).Outcome measures were overall recurrence rate, progression rate, 1-year recurrence free and progression free survival.Treatment related toxicities were also evaluated.Results: No difference between the 2 groups in recurrence rate (32.5% vs. 42.9%),progression rate (20% vs. 28.6%),1-year recurrence free survival (72.5% vs. 61.9%),1-year progression free survival (80% vs.71.4%).No difference for intermediate and high risk patients in BCG group and their counterparts of docetaxel group in recurrence rate (16.7% vs. 42.9%)and (39.3% vs. 42.9%),progression rate (16.7% vs. 14.3%) and (21.4% vs. 35.7%),1-year recurrence free survival (83.3% vs. 76.9%) and (67.9% vs. 53.6%),1-year progression free survival (83.3% vs. 84.6%)and (78.6% vs. 65.5).Age, grade and multiplicity were independent predictive factors for recurrence while grade was the independent factor for progression.The adverse events of BCG group were more marked.Conclusions: Intravesical docetaxel demonstrate significant efficacy and minimal toxicity for the management of NMIBC.In comparison to BCG, there was no significant difference in terms of disease recurrence, progression or survival, and the decision to use either agent may be based on adverse events and cost.The results of this study support the role of intravesical docetaxel for intermediate risk patients and it can be of major concern for high risk patients, however, randomized multi-institutional trials should be considered.
Introduction Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy. Methods Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR). Results DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS. Conclusions We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.
BACKGROUND:Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and African-American women. METHODS:We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education. RESULTS:Our logistic regression identified 3 significant apoptosis-related SNPs in whites (APAF-1, rs1007573; CD40 rs3765459, and CD40 rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1, rs513349; TNF, rs1800629; TP63, rs6790167; TP63, rs7613791, TP63, rs35592567 and TP63, rs3856775) in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, APAF-1 (rs1007573), CD40 (rs3765459) and CD40 (rs1535045) were all found to be significant by FPRP. In African-Americans, TP63 SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI: 1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI: 3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and TP63 rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in African-Americans. CONCLUSION:In whites, only SNPs APAF-1 rs1007573 and CD40 rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only TP63 rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies.
In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.
We tried to evaluate tubular differentiation in the paraffin sections of 130 Libyan breast cancers to distinguish the less aggressive variants of infiltrating breast cancer from other variants and to found the relationship with clinicopathological features. We also compared our results with corresponding results on Finnish, and Nigerian female breast cancer patients. Methods: Histological samples from 130 patients of Libyan breast cancer were retrospectively studied by estimated the fraction of fields with tubular differentiation (FTD). The samples were screened at x10 magnification and the presence or absence of malignant tubular structures in each microscopic field was registered. They were compared with different clinicopathological features, and patient's survival. Results: The mean (±SD) value of FTD in Libya 23.4±21.6%, was higher than in Nigeria. but lower than reported in European breast cancer. There was statistically significant correlation between the FTD and some clinicopathological features, with the strongest association observed for large tumor (p < 0.0001). There was also correlation between FTD and histological grade (p = 0.001) and lymph node (LN) status (p = 0.007). The correlation with tumor staging was almost significant (p = 0.07). Conclusions: The results indicated that FTD are reliable prognostic indicators in Libyan female breast carcinomas, as they were among Finnish and Nigerian females. The FTD is a good parameter for identifying the aggressive tumor phenotype and provide significant prognostic support. The cut-offs (30% and 50%) might be applied as quantitative criterium for Libyan breast cancer to separate the patients into good, moderate and bad prognosis groups. The survival analysis indicated that short survival time was associated with low FTD values.
However, the most common mechanism of resistance is the active efflux of drugs by ATP-binding cassette (ABC) transporters including P-glycoprotein (ABCB1/P-gp), ABCC1/ MRP1 and ABCG2 [6].These transporters play a key role in the energy-dependent cellular efflux of toxic agents.They are capable of recognizing and extruding a broad range of functionally and structurally unrelated compounds, thereby causing the MDR phenotype in various cancer types.An obvious strategy to restore drug sensitivity in MDR cancer cells caused by ABC drug transporters is to block transporter-mediated drug efflux.Over the past decade, tremendous efforts have been made to discover and synthesize such inhibitors/modulators.Numerous clinical trials have been performed to evaluate the combination of ABCB1/P-gp modulators with standard chemotherapy regimens in enhancing anticancer efficacy [7].However, none of them has been successfully put into clinical use, partly because of their low potency and lack of specificity
Background: There is increasing evidence that cancer cachexia patients have high cytokine levels, and bacterial translocation (BT) could increase cytokine secretion.Thus, we sought to investigate the relationship between BT and cancer cachexia. Methods:We studied colon cancer patients in our ward and healthy outpatient controls.Cancer patients were considered cachectic if they had lost > 10% of their pre-illness stable weight within 6 months and had serum CRP > 10 mg/L.Polymerase chain reaction (PCR) was used to detect bacterial DNA in serum from cancer patients and healthy controls.Cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA).Results: Bacterial DNA fragments were detected in 12 of 50 patients with cachexia (24.0%) and in 4 of 50 non-cachectic patients (8.0%).None of 89 healthy controls had bacterial DNA fragments in their serum.A statistically significant difference was found between cachectic and non-cachectic patients (p = 0.037, < 0.05) and healthy controls (p = 0.62×10-5, < 0.05).BT(+) cachectic patients had significantly higher levels of IL-1α, IL-6, IL-8, and TNF-α than healthy controls and BT(-) cachectic patients.CD3+ T, CD4+ T, CD4+ T/CD8+ T, and NK cell numbers were significantly lower in colon cancer patients than in healthy controls (p < 0.05), but CD8+ cell numbers were significantly higher in healthy controls than in cancer patients. Conclusions:Our results suggest for the first time that BT may contribute to cancer cachexia.
Background : To assess feasibility of sparing the neural stem cell compartment (NSC), hippocampus, and limbic circuit during partial brain radiotherapy (PBRT) for pediatric intracranial tumors.Methods : Treatment plans were generated for the following pediatric intracranial tumors: low and high grade gliomas, low grade brainstem glioma, optic nerve glioma, hypothalamic glioma, localized ependymoma, skull base sarcoma, central nervous system (CNS) germinoma (involved field radiotherapy [IFRT] and whole ventricular radiotherapy [WVRT] ), and craniopharyngioma.For each pathology, standard intensity-modulated radiotherapy (IMRT) plans were generated using helical tomotherapy, as well as IMRT plans which spared limbic circuit, hippocampus, and NSC.Biologically equivalent dose for late effects (BED late effects ) was generated for limbic circuit, hippocampus, and NSC.Percent reduction in mean, maximum, and minimum physical dose and BED was calculated between plans. Results :We reduced mean physical dose and BED late effects to these critical structures by 44% and 47.9% respectively (range 5.4-78.8%and 7-80.3%).Greatest benefits in relative dose reduction were seen in high grade hemispheric glioma cases; least relative dose reduction was seen in WVRT cases.Dosimetric coverage of treatment target (PTV) was equivalent in all cases as assessed by D95 and V100 metrics.Integral dose to uninvolved brain was reduced by mean of 7.6% (range -19.3% to +0.3%) in sparing plans.Discussion and Conclusions : It is possible to spare limbic circuit, NSC, and hippocampus during PBRT for primary pediatric intracranial tumors using helical tomotherapy.This approach reduces integral dose delivered to uninvolved normal brain and may reduce late cognitive sequelae of cranial radiotherapy.
Background: To review the presentation and management of renal cell carcinoma metastatic to the parotid gland.Methods: Case report and review of the literature. Results:There have been 45 cases of renal cell carcinoma metastatic to the parotid gland reported in the English literature.A parotid lesion can be the initial clinical presentation of this malignancy (even before primary site identification).A case of patient with a parotid mass noted 4 years after undergoing a nephrectomy for renal cell carcinoma is presented.Superficial parotidectomy with facial nerve monitoring demonstrated metastatic renal cell carcinoma with negative margins on pathology.Conclusions: Metastatic renal cell carcinoma should be considered in the differential diagnosis a vascular parotid mass in patients have a history of prior diagnosis of renal cell carcinoma.After diagnosis is established, a systemic assessment should be performed given that solitary parotid metastases are uncommon.Due to the limited number of cases reported in the literature, clinical outcomes are difficult to predict.
Background:The risk of TRD with adjuvant chemotherapy for early breast cancer is unknown in Malaysia despite its widespread usage.This study aims to determine this rate in a large cohort of patients treated in UMMC.Patients & Methods: Patients who were treated with neoadjuvant or adjuvant chemotherapy for early breast cancer stages I, II or III from 2000-2007 in UMMC were identified from our UMMC Breast Cancer Registry.The TRD rate and 5 years overall survival (OS) were determined.TRD is defined as death occurring during or within 30 days of completing chemotherapy as a consequence of the chemotherapy treatment.OS was defined as death from any cause from the date of diagnosis to the date of death.OS was determined using the Kaplan-Meier method and differences between AJCC stages were compared by log-rank test.Results: A total of 1317 were identified for analysis.The median age at diagnosis was 49 years with a range of 24 to 74 years.The rate of TRD was 0.1%.The 5 years OS rate was 77.3% with a median follow up of 62 months.The 5 years OS according to AJCC stage were 90.7% for stage I, 83.9% for stage II and 62.2% for stage III disease.The commonest chemotherapy regimen used was the FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) regimen accounting for approximately 90% of the cases. Conclusion:Adjuvant chemotherapy for early breast cancer with the FEC regimen is safe with a TRD rate of 0.1% in our centre.
