International Journal of Cancer Research and Molecular Mechanisms

2

Authors: Habip Gedik

Hyperammonemia syndrome is one of the causes of metabolic encephalopathy that is rarely observed after high dose chemotherapy for the treatment of hematologic malignancies. Two cases, who developed neurologic symptoms and coma due to hyperammonemia subsequent to chemotherapy for Burkitt’s lymphoma and acute myeloid leukemia, respectively are being presented in this report. In case respiratory alkalosis, unexplained neurological symptoms and mental status changes develop after intensive chemotherapy, hyperammonemia should come into mind, and the serum ammonium level should be measured to implement ammonium-lowering therapy.

5

Authors: Koul R

Introduction: Overall incidence rate of all brain tumors to be 10.82 (95% CI: 8.63–13.56) per 100,000 person-years. Glioblastoma accounts for up to 60% of all malignant primary brain tumors in adults, occurring in 2-3 cases per 100,000 in Europe and North America. In 2005 maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma. We adopted this as the standard of care in 2009 in the province of Saskatchewan, Canada. Material and methods: A cohort of 393 consecutive patients with pathologically proven glioblastoma, who had been registered in the Province of Saskatchewan from 2000 to 2010, was examined. Survival analysis was performed using Kaplan-Meier curves and log-rank test for comparing subgroups. The independent effect of factors that predicted survival at the bivariate level was determined using a Cox proportional hazard model. Results: Median age at diagnosis was 67 years in females and 63 years in males. The median overall survival was 13.8 months (95% CI: 12.6, 15.1 months). Based on a literature review and after the univariate analysis, the following variables were included in the Cox’s multivariable model: age at diagnosis, ECOG status (dichotomous variable created), type of surgery (complete vs. sub-total), and whether chemotherapy and radiotherapy were given after surgery. Patients who treated with chemotherapy and chemotherapy had a better median survival of 18.1 months vs. 11.3 months without chemotherapy. Patients younger than 50 years did better as compared to elderly population. For fit elderly patients >70 years, 11.0 months median survival was achieved. Contrary to common belief in literature, patients with headache do not have a worse survival and patients who presented with seizure survived better. Conclusion: Our series demonstrates improved survival outcomes for patients <50 years old quite consistent with literature. However for elderly patients with excellent performance status in the western Canadian province, a median survival of <70 years 16.1 months (95% CI 13.6- 18.1 months) ≥ 70 years 11.7 months (95% CI: 10.4-13.0 months) was achieved which is better than other series in the current literature. The landscape of treatment options for GBM patients has changed substantially over the past decade and with further information still amassing in ongoing clinical trials in GBM population the suggestion is to base treatment options based on patient age and KPS. Until further treatment advances are made for GBM in general, utilizing the current therapeutic options of surgery, RT, and TMZ appropriately according to patient age, performance status, and patient preferences represents optimal management.

8

Authors: Sita Aggarwal

Conjugates of membrane disrupting lytic peptides with a 15-amino acid segment of the β chain of chorionic gonadotropin (CG) or luteinizing hormone releasing hormone (LHRH) target and destroy cancer cell xenografts in nude mouse model. Follicle stimulating hormone receptors (FSHR) have been detected in tumor neo-vascular endothelial cells of a variety of cancers and tumor tissue in prostate and ovarian cancers. In the present study, we have conjugated a lytic peptide (Phor18) to each of three segments of the β chain of FSH that bind to FSHR, and tested these conjugates (FSH90-95-Phor18, FSH81-95-Phor18 and FSH33-53-Phor18) for their ability to target and inhibit growth of prostate cancer cells in vivo. We found that intravenous administration of FSH90-95-Phor18, FSH81-95-Phor18 and FSH33-53-Phor18 significantly (p<0.05) inhibited the growth of prostate cancer (PC-3) xenografts in nude mice. The minimal effective dose of FSH81-95-Phor18 was 0.1 mg/kg and 1 mg/kg for FSH90- 95-Phor18 and FSH33-53-Phor18. Immunohistochemical analyses of tumor sections at necropsy showed dense expression of FSHR on vascular endothelial cells in control mice, reduced expression in tumors of mice treated with FSH90-95-Phor18, FSH81-95-Phor18 or FSH33-53-Phor18. FSH81- 95-Phor18 had the most potent anti-angiogenic activity of the three conjugates tested. These data show that a lytic peptide conjugated to FSH β chain segments bind to FSHR and are capable of inhibiting prostate cell tumor growth by targeting and destroying endothelial cells that express FSH receptors.

5

Authors: Ellinor IB Peerschke

Background: gC1qR is a multifunctional cellular protein that has been linked to inflammation and cancer. gC1qR is highly upregulated in adenocarcinomas as compared to normal tissue counterparts, and soluble gC1qR (sgC1qR) has been detected in vitro in the pericellular milieu of proliferating malignant cells. Aim: The present study explored the tissue expression of gC1qR in pancreatic cancer by immunohistochemistry, and the presence of sgC1qR in vivo, by examining blood and malignant effusions from patients with metastatic pancreatic adenocarcinoma. Methods: Tissue expression of gC1qR by pancreatic adenocarcinoma was visualized by immunohistochemistry. SgC1qR was quantified in serum from healthy volunteers (n=20) and pancreatic cancer patients (n=34), as well as in malignant pleural (n=23) and peritoneal effusions (n=27), using a newly developed, sensitive immunocapture sandwich ELISA. Results: Overexpression of gC1qR was confirmed in pancreatic adenocarcinoma compared to nonmalignant pancreatic tissue. Moreover, increased serum levels of sgC1qR (0.29 + 0.22 ng/ml) were noted in patients with metastatic pancreatic cancer compared to healthy controls (0.15 + 0.10 ng/ml) (mean + S.D.) (p=0.035). In 11 of 16 patients for whom sequential samples were available, serum sgC1qR levels rose with disease progression, and paralleled changes in tumor biomarkers, CEA and CA19.9. In addition to blood, sgC1qR was detected in malignant pleural (0.55 + 0.47 ng/ml) and peritoneal effusions (0.57 + 0.38 ng/ml). Conclusion: This study provides the first evidence for the presence of sgC1qR in vivo. The ability to detect sgC1qR in blood and body fluids will enable further studies to elucidate its pathophysiology in malignancy.

6

Authors: Paul B. Tchounwou

Cis-diamminedichloroplatinum (II) (cisplatin) is the most widely used chemotherapeutic drug for various cancers, but its effectiveness is limited by tumor cell resistance and the severe side effects it causes. Since high level of cisplatin is cytotoxic to both cancer and normal cells, the goal of the present study was to explore the effectiveness of prolonged low doses of cisplatin in the management of leukemia. To achieve our goal, human leukemia (HL-60) cells were treated with different doses (1, 2, or 3 µM) of cisplatin for 24, 48, 72 and 96 hours. Cell viability was assessed by MTS assay. Both oxidative stress damage and genotoxicity were estimated by antioxidants, lipid peroxidation, and comet assays, respectively. Data obtained from the MTS assay demonstrated that cisplatin treatment decreased the number of viable tumor cells by direct cell killing or by simply decreasing the rate of cellular proliferation in a dose- and time-dependent fashion. The results of the lipid peroxidation showed a significant increase (p<0.05) of malondialdehyde levels with increasing cisplatin doses. Results obtained from super oxide dismutase and catalase assays showed a gradual increase in antioxidant enzyme activity in cisplatin-treated cells compared to control cells. Data generated from the Comet assay demonstrated a significant dose-dependent increase in genotoxicity with respect to DNA damage as a result of cisplatin treatment. Taken together, our research demonstrated that cisplatin-induced cytotoxicity in HL-60 cells is mediated at least in part via induction of oxidative stress and oxidative damage.

8

Authors: Susan Kadlubar

Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole is subject to direct glucuronidation catalyzed by UDP-glucuronosyltransferase1A4 (UGT1A4). Interindividual variability in anastrozole glucuronidation may be affected by UGT1A4 SNPs. Interplay between drug metabolizing genes such as UGT1A4 and transporter genes may also be affected by genetic variability. Thus, we hypothesize that genetic variability in MRPs could influence anastrozole glucuronidation. The correlation between UGT1A4 and MRP2 or MRP3 transporter gene expressions and the correlation between MRP2 or MRP3 mRNA and anastrozole glucuronidation were analyzed in normal human liver samples. MRP2 and MRP3 mRNA levels were significantly correlated with UGT1A4 mRNA, with anastrozole glucuronidation and with each other (p<0.05). The data also demonstrated that MRP2 SNPs are positively correlated with MRP2 mRNA expression, while there was no association between MRP3 SNPs from this study and MRP3 expression. Significant correlations (p<0.05) between certain MRP2 SNPs (3972C>T, 2366C>T and -24C>T) and anastrozole glucuronidation were observed. There were no observed correlations between MRP3 SNPs and anastrozole glucuronidation. MRP2 polymorphisms have been identified as playing a role in the disposition of other drugs, and the data presented here indicate for the first time that MRP2 SNPs could influence anastrozole metabolism and contribute to interindividual variation in treatment responses.

3

Authors: Persinger MA

Aim: Discern if there is a specific proportion of mixture of normal and malignant cells that increase photon emissions from cell cultures. Method: Different proportions of B16-B6 mouse melanoma cells and HEX cells were mixed and allowed to proliferate. Photon emissions were measured from the different mixtures of cells by digital photomultiplier units and then analyzed for Spectral Power Density (SPD). Results: Mixtures of the malignant and non-malignant cells that were more than 10% of one component displayed photon emission flux densities that were significantly less than the photon emissions for either cell type when measured as pure samples. Only 1% proportion of the malignant cell in 99% of non-malignant cells produced the strongest photon emissions. Spectral density profiles of power flux density variations indicated elevated power around 22 Hz that was even greater than this signature for malignant cells only. Conclusion: Only 1% of malignant cells in a normal aggregate, representative of the early stages of cancer development, resulted in conspicuously increased numbers of photon emissions and spectral power spectra that often reflect a total malignant cell population. This combination of photon flux density and spectral power profiles may be a potentially useful (nanotechnology) tool to detect the minute changes in cell activities relevant to oncology.

5

Authors: Sergei V Jargin

After the Chernobyl accident appeared many publications exaggerating its medical consequences. Some of them are discussed in this minireview, which is a continuation of a preceding discussion. Among the motives for the overestimation were anti-nuclear resentments, widespread among the Green movement; however, their attitude has not been entirely wrong: nuclear facilities should have been prevented from spreading to overpopulated countries governed by unstable regimes and regions where conflicts and terrorism cannot be excluded. Nevertheless, we believe that certain Green activists have worked in the interests of the fossil fuel producers. The Chernobyl accident has been exploited to strangulate worldwide development of nuclear energy. Today, there are no alternatives to nuclear power: nonrenewable fossil fuels will probably become more expensive in the long run, contributing to the excessive population growth in the oil-producing countries and poverty in the rest of the world. Worldwide use of nuclear energy will become possible only after a concentration of authority within an efficient international executive based in the most developed countries. This will enable construction of nuclear power plants in optimally suitable places, considering all sociopolitical, geographic, geologic, and other preconditions, quality of working of local workforce, etc.

6

Authors: Jennifer Wu

Cholangiocarcinoma is a potentially lethal cancer of biliary epithelium with variable incidence rates across the world. Given patients often have advanced disease at the time of diagnosis and limited therapeutic options, the prognosis of patients with cholangiocarcinoma remains poor. There are efforts to develop new treatments for cholangiocarcinoma as current standard chemotherapy offers limited benefit. In vitro and in vivo models of cholangiocarcinoma have been studied to unveil underlying molecular mechanisms of cholangiocarcinogenesis. Recent advances in understanding of different pathways underlying cholangiocarcinogenesis will guide the development of potential therapeutic molecular targets. We will do a detailed review of the pathogenesis of cholangiocarcinoma and its relevance in molecular targets for potential therapies in cholangiocarcinoma. Clinical trials using targeted therapies and proposals for potential clinical trials using novel targets will be discussed.

4

Authors: Chun-Shuo Hsu

It is rare to have three synchronous neoplasms including neuroendocrine carcinoma, squamous cell and glandular neoplasia in a uterine cervix. Here, we present the case of a 35-year-old woman with Cervical Polypoid Neuroendocrine Carcinoma (NEC), High-Grade Squamous Intraepithelial Lesion (HSIL), and Endocervical Adenocarcinoma In Situ (AIS). DNA in situ hybridization of high-risk HPV (types 16, 18, 31, 33, and 51) DNA shows more intense signals over the HSIL and underlying Squamous Intraepithelial Lesion (SIL)-related atypical endocervical glands and less intensity over AIS and NEC. The heterogeneity of NEC is exhibited by various immunohistochemical staining patterns of chromogranin A, cytokeratin 7, CD56, CD44, c-kit, and vimentin, as well as histomorphology. CK7 immunostaining is observed over HSIL and AIS, CK5 over HSIL and underlying SIL-related atypical glands, P63 over HSIL, and Hep Par1 over AIS. In conclusion, this cervical NEC with tumor heterogeneity has unusually polypoid gross feature and fatal outcome. She died due to metastatic neuroendocrine carcinoma 21 months later. The special characters of SIL-related atypical endocervical glands, which show CK5 immunostaining, loss of expression of estrogen and progesterone receptors, and intense HR-HPV DNA hybridization, disclose the discrepancy between morphology and CK5 immunostaining result, which might be an early evidence of neoplastic transformation.

6

Authors: Akash Verma

Aim: Assess timeliness of lung cancer management, causes for delays, and whether length of delays affected the prognosis. Method: A retrospective study of patients diagnosed with lung cancer between January 2012 - September 2014. Results: The median (range) delay in CT scan from first presentation to health care setting, “CT scan-to-first diagnostic procedure,” “first diagnostic procedure to confirmed diagnosis,” “confirmed diagnosis-to-start of treatment” was 13 (1-399), 7 (1-490), 3 (1-176), and 35 (1-150) days respectively. The median length of the journey from “CT scan-to-start of treatment,” and “first presentation to healthcare-to-start of treatment” was 56 (6-192), and 74 (2-438) days respectively. Thirty six percent waited more than 2 months to start definitive treatment from the time of their CT scan. Less-timely care correlated with those who underwent transthoracic needle aspiration, elderly males, and had non-small cell carcinoma. It also correlated with better survival 272 (18-965) vs. 97 (2-1615) days (p=0.01) due to more number of early stage lung cancer in this group (43.1% vs. 27.1%, p=0.05). Common causes of less-timely care were misdiagnosis of cancer as TB, failure of first diagnostic procedure to provide diagnosis, delay in patient`s decisions regarding initiation of therapy, and development of inter-current illness while waiting for therapy. Conclusions: Delay in the management of early stage lung cancer patients was seen. CT guided biopsy (transthoracic needle aspiration), advanced age, male gender, and NSCLC were the predictors of delay. Limited (twice weekly) availability of CT guided biopsy, misdiagnosis as TB, delayed patients` decision, and development of inter-current illness were the main causes of delay. Correlation between less timely care and better survival, attributable to the early stage indicates risk for progression of the disease and merits measures for more efficient resource allocation.