Journal of Oncology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Gallbladder Cancer in the 21st Century Tue, 01 Sep 2015 11:38:11 +0000 Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC. Rani Kanthan, Jenna-Lynn Senger, Shahid Ahmed, and Selliah Chandra Kanthan Copyright © 2015 Rani Kanthan et al. All rights reserved. Evaluation of AgNORs in Oral Potentially Malignant Lesions Mon, 31 Aug 2015 14:11:21 +0000 Oral squamous cell carcinoma (OSCC) is usually preceded by detectable mucosal changes, as leukoplakias and erythroplakia. Histologically, these lesions can range from hyperkeratosis and acanthosis to epithelial dysplasia and even OSCC. The aim of this study was to investigate the proliferative activity, using AgNORs quantification proteins, in low- and high-risk oral epithelial dysplasia, OSCC, and nondysplastic epithelium (inflammatory fibrous hyperplasia). The sample was divided into 4 groups: G1: 10 cases of inflammatory fibrous hyperplasia (IFH), G2: 11 cases of low-risk epithelial dysplasia (LD), G3: 10 cases of high-risk epithelial dysplasia (HD), and G4: 11 cases of OSCC. The quantitative analysis was performed using an image processing software in photomicrographs at 1000x magnification. The one-way ANOVA was used for comparison of the mean AgNORs counts between the study groups. The mean AgNORs count was significantly higher in OSCC when compared to IFH and the LD; however, it was not statistically different from HD. The mean number of LD was significantly lower than the HD and OSCC, with no difference related to IFH. AgNORs quantification can be an important and cheap method to help in the determination of the degree of epithelial dysplasia and, consequently, in the analysis of their potential for malignant transformation. Karin Berria Tomazelli, Filipe Modolo, and Elena Riet Correa Rivero Copyright © 2015 Karin Berria Tomazelli et al. All rights reserved. Cancer and Cardiovascular Disease: The Complex Labyrinth Tue, 04 Aug 2015 11:17:31 +0000 Susan Dent, Peter Liu, Christine Brezden-Masley, and Daniel Lenihan Copyright © 2015 Susan Dent et al. All rights reserved. Right Ventricular Dysfunction in Patients Experiencing Cardiotoxicity during Breast Cancer Therapy Mon, 03 Aug 2015 12:14:26 +0000 Background. Right ventricular (RV) dysfunction during cancer therapy related cardiotoxicity and its prognostic implications have not been examined. Aim. We sought to determine the incidence and prognostic value of RV dysfunction at time of LV defined cardiotoxicity. Methods. We retrospectively identified 30 HER2+ female patients with breast cancer treated with trastuzumab (± anthracycline) who developed cardiotoxicity and had a diagnostic quality transthoracic echocardiography. LV ejection fraction (LVEF), RV fractional area change (RV FAC), and peak systolic longitudinal strain (for both LV and RV) were measured on echocardiograms at the time of cardiotoxicity and during follow-up. Thirty age balanced precancer therapy and HER2+ breast cancer patients were used as controls. Results. In the 30 patients with cardiotoxicity (mean ± SD age 54 ± 12 years) RV FAC was significantly lower (42 ± 7 versus 47 ± 6%, ) compared to controls. RV dysfunction defined by global longitudinal strain (GLS < −20.3%) was seen in 40% (). During follow-up in 16 out of 30 patients (23 ± 15 months), there was persistent LV dysfunction (EF < 55%) in 69% (). Concomitant RV dysfunction at the time of LV cardiotoxicity was associated with reduced recovery of LVEF during follow-up although this was not statistically significant. Conclusion. RV dysfunction at the time of LV cardiotoxicity is frequent in patients with breast cancer receiving trastuzumab therapy. Despite appropriate management, LV dysfunction persisted in the majority at follow-up. The prognostic value of RV dysfunction at the time of cardiotoxicity warrants further investigation. Anna Calleja, Frédéric Poulin, Ciril Khorolsky, Masoud Shariat, Philippe L. Bedard, Eitan Amir, Harry Rakowski, Michael McDonald, Diego Delgado, and Paaladinesh Thavendiranathan Copyright © 2015 Anna Calleja et al. All rights reserved. Orthotopic Heart Transplantation and Mechanical Circulatory Support in Cancer Survivors: Challenges and Outcomes Mon, 03 Aug 2015 12:12:26 +0000 Chemotherapy-induced cardiomyopathy (CCMP) is a significant cause of morbidity and mortality. Compared to cardiomyopathy due to other causes, anthracycline-induced cardiomyopathy is associated with a worse survival. As cancer survival improves, patients with CCMP can be expected to comprise a significant proportion of patients who may require advanced therapies such as inotropic support, cardiac transplantation, or left ventricular assist device (LVAD). Distinct outcomes related to advanced therapies for end-stage heart failure in this patient population may arise due to unique demographic characteristics and comorbidities. We review recent literature regarding the characteristics of patients who have survived cancer undergoing orthotopic heart transplantation and mechanical circulatory support for end-stage heart failure. The challenges and outcomes of advanced therapies for heart failure related specifically to anthracycline-induced cardiomyopathy are emphasized. Nina Ghosh and John Hilton Copyright © 2015 Nina Ghosh and John Hilton. All rights reserved. Exercise Prevention of Cardiovascular Disease in Breast Cancer Survivors Mon, 03 Aug 2015 09:08:52 +0000 Thanks to increasingly effective treatment, breast cancer mortality rates have significantly declined over the past few decades. Following the increase in life expectancy of women diagnosed with breast cancer, it has been recognized that these women are at an elevated risk for cardiovascular disease due in part to the cardiotoxic side effects of treatment. This paper reviews evidence for the role of exercise in prevention of cardiovascular toxicity associated with chemotherapy used in breast cancer, and in modifying cardiovascular risk factors in breast cancer survivors. There is growing evidence indicating that the primary mechanism for this protective effect appears to be improved antioxidant capacity in the heart and vasculature and subsequent reduction of treatment-related oxidative stress in these structures. Further clinical research is needed to determine whether exercise is a feasible and effective nonpharmacological treatment to reduce cardiovascular morbidity and mortality in breast cancer survivors, to identify the cancer therapies for which it is effective, and to determine the optimal exercise dose. Safe and noninvasive measures that are sensitive to changes in cardiovascular function are required to answer these questions in patient populations. Cardiac strain, endothelial function, and cardiac biomarkers are suggested outcome measures for clinical research in this field. Amy A. Kirkham and Margot K. Davis Copyright © 2015 Amy A. Kirkham and Margot K. Davis. All rights reserved. The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada Sun, 02 Aug 2015 13:37:29 +0000 Background. While androgen deprivation therapy (ADT) reduces the risk of prostate cancer-specific mortality in high-risk localized prostate cancer, it adversely affects cardiovascular (CV) risk factor profiles in treated men. Methods. We retrospectively reviewed the charts of 100 consecutive men with intermediate- or high-risk localized prostate cancer referred to the British Columbia Cancer Agency for ADT. Data on CV risk factors and disease were collected and Framingham risk scores were calculated. Results. The median age of the study cohort was 73 years. Established cardiovascular disease was present in 25% of patients. Among patients without established CV disease, calculated Framingham risk was high in 65%, intermediate in 33%, and low in 1%. Baseline hypertension was present in 58% of patients, dyslipidemia in 51%, and diabetes or impaired glucose tolerance in 24%. Hypertension was more prevalent in the study cohort than in an age- and sex-matched population sample (OR 1.74, ); diabetes had a similar prevalence (OR 0.93, ). Conclusions. Patients receiving ADT have a high prevalence of cardiovascular disease and risk factors and are more likely to be hypertensive than population controls. Low rates of CV risk screening suggest opportunities for improved primary and secondary prevention of CV disease in this population. Margot K. Davis, Jennifer L. Rajala, Scott Tyldesley, Tom Pickles, and Sean A. Virani Copyright © 2015 Margot K. Davis et al. All rights reserved. An International Survey of Health Care Providers Involved in the Management of Cancer Patients Exposed to Cardiotoxic Therapy Sun, 02 Aug 2015 13:14:52 +0000 Cardiotoxicity is the second leading cause of morbidity and mortality in cancer survivors. The objective of this international cardiac oncology survey was to gain a better understanding of current knowledge and practice patterns among HCPs involved in the management of cancer patients exposed to potentially cardiotoxic drugs. Between 2012 and 2013, we conducted an email-based survey of HCPs involved in the management of cardiac disease in cancer patients. 393 survey responses were received, of which 77 were from Canadian respondents. The majority of respondents were cardiologists (47%), followed closely by medical oncologists. The majority of respondents agreed that cardiac issues are important to cancer patients (97%). However, only 36% of total respondents agreed with an accepted definition of cardiotoxicity. While 78% of respondents felt that cardiac medications are protective during active cancer treatment, only 51% would consider prescribing these medications up-front in cancer patients. Although results confirm a high level of concern for cardiac safety, there continues to be a lack of consensus on the definition of cardiotoxicity and a discrepancy in clinical practice between cardiologists and oncologists. These differences in opinion require resolution through more effective research collaboration and formulation of evidence-based guidelines. Jeffrey Sulpher, Shrey Mathur, Daniel Lenihan, Christopher Johnson, Michele Turek, Angeline Law, Ellamae Stadnick, Franco Dattilo, Nadine Graham, and Susan F Dent Copyright © 2015 Jeffrey Sulpher et al. All rights reserved. Multimodality Imaging in Cardiooncology Sun, 02 Aug 2015 12:29:02 +0000 Cardiotoxicity represents a rising problem influencing prognosis and quality of life of chemotherapy-treated patients. Anthracyclines and trastuzumab are the drugs most commonly associated with development of a cardiotoxic effect. Heart failure, myocardial ischemia, hypertension, myocarditis, and thrombosis are typical manifestation of cardiotoxicity by chemotherapeutic agents. Diagnosis and monitoring of cardiac side-effects of cancer treatment is of paramount importance. Echocardiography and nuclear medicine methods are widely used in clinical practice and left ventricular ejection fraction is the most important parameter to asses myocardial damage secondary to chemotherapy. However, left ventricular ejection decrease is a delayed phenomenon, occurring after a long stage of silent myocardial damage that classic imaging methods are not able to detect. New imaging techniques including three-dimensional echocardiography, speckle tracking echocardiography, and cardiac magnetic resonance have demonstrated high sensitivity in detecting the earliest alteration of left ventricular function associated with future development of chemotherapy-induced cardiomyopathy. Early diagnosis of cardiac involvement in cancer patients can allow for timely and adequate treatment management and the introduction of cardioprotective strategies. Fausto Pizzino, Giampiero Vizzari, Rubina Qamar, Charles Bomzer, Scipione Carerj, Concetta Zito, and Bijoy K. Khandheria Copyright © 2015 Fausto Pizzino et al. All rights reserved. Clinical Experience of Patients Referred to a Multidisciplinary Cardiac Oncology Clinic: An Observational Study Sun, 02 Aug 2015 11:08:58 +0000 Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors. The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in patients with early stage and advanced cancer who were referred to our multidisciplinary cardiac oncology clinic (COC). A total of 428 patients were referred to the COC between October 2008 and January 2013. The median age of patients at time of cancer diagnosis was 60. Almost half of patients who received cancer therapy received first-line chemotherapy alone (169, 41.7%), of which 84 (49.7%) were exposed to anthracyclines. The most common reasons for referral to the cardiac oncology clinic were decreased LVEF (34.6%), prechemotherapy assessment (11.9%), and arrhythmia (8.4%). A total of 175 (40.9%) patients referred to the COC were treated with cardiac medications. The majority (331, 77.3%) of patients were alive as of January 2013, and 93 (21.7%) patients were deceased. Through regular review of cardiac oncology clinic referral patterns, management plans, and patient outcomes, we aim to continuously improve delivery of cardiac care to our patient population and optimize cardiac health. Jeffrey Sulpher, Shrey Mathur, Nadine Graham, Freya Crawley, Michele Turek, Christopher Johnson, Ellamae Stadnick, Angeline Law, Jason Wentzell, and Susan Dent Copyright © 2015 Jeffrey Sulpher et al. All rights reserved. Clinical and Microbiological Profile of Pathogens in Febrile Neutropenia in Hematological Malignancies: A Single Center Prospective Analysis Tue, 28 Jul 2015 07:33:44 +0000 Background. Febrile neutropenia is the consequence of treatment of hematological disorders. The first-line empirical treatment should cover the prevalent microorganism of the institute. The aim of study was to establish the effectiveness of current practices used at the institution and to review the culture sensitivity pattern of isolated microorganisms. Patients and Methods. Data was recorded and analyzed prospectively for 226 hospitalized patients of febrile neutropenia from January 2011 till December 2013. Results. Out of 226 cases, 173 were males and 53 were females. Clinically documented infections were 104 (46.01%) and microbiologically documented infections were 80 (35.39%), while 42 (18.58%) had pyrexia of undetermined origin. Gram negative infections accounted for 68 (85%) and Escherichia coli was the commonest isolate. Gram positive microorganisms were isolated in 12 (15%) cases and most common was Staphylococcus aureus. First-line empirical treatment with piperacillin/tazobactam and amikacin showed response in 184 patients (85.9%) till 72 hours. Conclusion. There is marked decline in infections due to Gram positive microorganisms; however, Gram negative infections are still of great concern and need further surveillance. In this study the antibiogram has shown its sensitivity for empirical antibiotic therapy used; hence, it supports continuation of the same practice. M. Taj, T. Farzana, T. Shah, S. Maqsood, S. S. Ahmed, and T. S. Shamsi Copyright © 2015 M. Taj et al. All rights reserved. Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia Wed, 10 Jun 2015 13:38:02 +0000 Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I. Christophe Nicot Copyright © 2015 Christophe Nicot. All rights reserved. Do Diametric Measurements Provide Sufficient and Reliable Tumor Assessment? An Evaluation of Diametric, Areametric, and Volumetric Variability of Lung Lesion Measurements on Computerized Tomography Scans Sun, 10 May 2015 11:10:35 +0000 Diametric analysis is the standard approach utilized for tumor measurement on medical imaging. However, the availability of newer more sophisticated techniques may prove advantageous. An evaluation of diameter, area, and volume was performed on 64 different lung lesions by three trained users. These calculations were obtained using a free DICOM viewer and standardized measuring procedures. Measurement variability was then studied using relative standard deviation (RSD) and intraclass correlation. Volumetric measurements were shown to be more precise than diametric. With minimal RSD and variance between different users, volumetric analysis was demonstrated as a reliable measurement technique. Additionally, the diameters were used to calculate an estimated area and volume; thereafter the estimated area and volume were compared against the actual measured values. The results in this study showed independence of the estimated and actual values. Estimated area deviated an average of 43.5% from the actual measured, and volume deviated 88.03%. The range of this variance was widely scattered and without trend. These results suggest that diametric measurements cannot be reliably correlated to actual tumor size. Access to appropriate software capable of producing volume measurements has improved drastically and shows great potential in the clinical assessment of tumors. Its applicability merits further consideration. Aaron Frenette, Joshua Morrell, Kirk Bjella, Edward Fogarty, James Beal, and Vijay Chaudhary Copyright © 2015 Aaron Frenette et al. All rights reserved. Comparison of Enoxaparin and Warfarin for Secondary Prevention of Cancer-Associated Stroke Thu, 07 May 2015 06:11:29 +0000 Background. The aim of this study was to determine which anticoagulant is superior for secondary prevention of cancer-associated stroke, using changes in D-dimer levels as a biomarker for recurrent thromboembolic events. Methods. We conducted a retrospective, single center observational study including patients with cancer-associated stroke who were treated with either enoxaparin or warfarin. Blood samples for measuring the initial and follow-up D-dimer levels were collected at admission and a median of 8 days after admission, respectively. Multiple logistic regression analysis was conducted to evaluate the factors that influenced D-dimer levels after treatment. Results. Although the initial D-dimer levels did not differ between the two groups, the follow-up levels were dramatically decreased in patients treated with enoxaparin, while they did not change with use of warfarin (3.88 μg/mL versus 17.42 μg/mL, ). On multiple logistic regression analysis, use of warfarin (OR 12.95; ) and the presence of systemic metastasis (OR 18.73; ) were independently associated with elevated D-dimer levels (≥10 μg/mL) after treatment. Conclusion. In cancer-associated stroke patients, treatment with enoxaparin may be more effective than treatment with warfarin for lowering the D-dimer levels. Future prospective studies are warranted to show that enoxaparin is better than warfarin for secondary prevention in cancer-associated stroke. Hyemin Jang, Jung Jae Lee, Mi Ji Lee, Sookyung Ryoo, Chang Hyo Yoon, Gyeong-Moon Kim, Chin-Sang Chung, Kwang Ho Lee, Oh Young Bang, and Suk Jae Kim Copyright © 2015 Hyemin Jang et al. All rights reserved. Evolving Concepts: Immunity in Oncology from Targets to Treatments Tue, 28 Apr 2015 11:02:09 +0000 Cancer is associated with global immune suppression of the host. Malignancy-induced immune suppressive effect can be circumvented by blocking the immune checkpoint and tip the immune balance in favor of immune stimulation and unleash cytotoxic effects on cancer cells. Human antibodies directed against immune checkpoint proteins: cytotoxic T lymphocytes antigen-4 (CTLA-4) and programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), have shown therapeutic efficacy in advanced melanoma and non-small-cell lung cancer and other malignancies. Immune check point blockade antibodies lead to diminished tolerance to self and enhanced immune ability to recognize and eliminate cancer cells. As a class these agents have immune-related adverse events due to decreased ability of effector immune cells to discriminate between self and non-self. Seventy percent of patients participating in clinical trials have experienced anticancer activities and varying degrees of immune mediated dose-limiting side effects. Hina Khan, Rasim Gucalp, and Iuliana Shapira Copyright © 2015 Hina Khan et al. All rights reserved. TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis Wed, 25 Mar 2015 11:16:35 +0000 Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers. Panagiotis Papageorgis Copyright © 2015 Panagiotis Papageorgis. All rights reserved. Fractal Dimensions of In Vitro Tumor Cell Proliferation Wed, 25 Mar 2015 09:07:44 +0000 Biological systems are characterized by their potential for dynamic adaptation. One of the challenges for systems biology approaches is their contribution towards the understanding of the dynamics of a growing cell population. Conceptualizing these dynamics in tumor models could help us understand the steps leading to the initiation of the disease and its progression. In vitro models are useful in answering this question by providing information over the spatiotemporal nature of such dynamics. In the present work, we used physical quantities such as growth rate, velocity, and acceleration for the cellular proliferation and identified the fractal structures in tumor cell proliferation dynamics. We provide evidence that the rate of cellular proliferation is of nonlinear nature and exhibits oscillatory behavior. We also calculated the fractal dimensions of our cellular system. Our results show that the temporal transitions from one state to the other also follow nonlinear dynamics. Furthermore, we calculated self-similarity in cellular proliferation, providing the basis for further investigation in this topic. Such systems biology approaches are very useful in understanding the nature of cellular proliferation and growth. From a clinical point of view, our results may be applicable not only to primary tumors but also to tumor metastases. George I. Lambrou and Apostolos Zaravinos Copyright © 2015 George I. Lambrou and Apostolos Zaravinos. All rights reserved. The Regulatory Role of MicroRNAs in EMT and Cancer Wed, 25 Mar 2015 08:51:49 +0000 The epithelial to mesenchymal transition (EMT) is a powerful process in tumor invasion, metastasis, and tumorigenesis and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells. It is now well known that miRNAs are important regulators of malignant transformation and metastasis. The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated. The metastasis suppressive role of the miR-200 members is strongly associated with a pathologic EMT. This review describes the most recent advances regarding the influence of miRNAs in EMT and the control they exert in major signaling pathways in various cancers. The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed. Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways. The link between cancer stem cells and EMT is also reported and the most recent developments regarding clinical trials that are currently using anti-miRNA constructs are further discussed. Apostolos Zaravinos Copyright © 2015 Apostolos Zaravinos. All rights reserved. Epithelial Plasticity in Cancer: Unmasking a MicroRNA Network for TGF-β-, Notch-, and Wnt-Mediated EMT Wed, 25 Mar 2015 07:50:31 +0000 Epithelial-to-mesenchymal transition (EMT) is a reversible process by which cancer cells can switch from a sessile epithelial phenotype to an invasive mesenchymal state. EMT enables tumor cells to become invasive, intravasate, survive in the circulation, extravasate, and colonize distant sites. Paracrine heterotypic stroma-derived signals as well as paracrine homotypic or autocrine signals can mediate oncogenic EMT and contribute to the acquisition of stem/progenitor cell properties, expansion of cancer stem cells, development of therapy resistance, and often lethal metastatic disease. EMT is regulated by a variety of stimuli that trigger specific intracellular signalling pathways. Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT. In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways. Interestingly, in this process, we identified a “signature” of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease. Eugenio Zoni, Gabri van der Pluijm, Peter C. Gray, and Marianna Kruithof-de Julio Copyright © 2015 Eugenio Zoni et al. All rights reserved. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA Wed, 11 Mar 2015 10:52:05 +0000 One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application. Sharad Sawney, Rashi Arora, Kamal K. Aggarwal, and Daman Saluja Copyright © 2015 Sharad Sawney et al. All rights reserved. Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck Thu, 05 Mar 2015 09:42:41 +0000 Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs. Kentaro Kikuchi, Toshiyuki Ishige, Fumio Ide, Yumi Ito, Ichiro Saito, Miyako Hoshino, Harumi Inoue, Yuji Miyazaki, Tadashige Nozaki, Masaru Kojima, and Kaoru Kusama Copyright © 2015 Kentaro Kikuchi et al. All rights reserved. Dental Treatment in Patients with Leukemia Sun, 15 Feb 2015 09:15:59 +0000 Dental treatment of patients with leukemia should be planned on the basis of antineoplastic therapy which can be chemotherapy with or without radiotherapy and bone marrow transplantation. Many are the oral manifestations presented by these patients, arising from leukemia and/or treatment. In addition, performing dental procedures at different stages of treatment (before, during, or after) must follow certain protocols in relation to the haematological indices of patients, aimed at maintaining health and contributing to the effectiveness of the results of antineoplastic therapy. Through a literature review, the purpose of this study was to report the hematological abnormalities present in patients with leukemia, trying to correlate them with the feasibility of dental treatment at different stages of the disease. It is concluded in this paper that dental treatment in relation to haematological indices presented by patients with leukemia must follow certain protocols, mainly related to neutrophil and platelet counts, and the presence of the dentist in a multidisciplinary team is required for the health care of this patient. Caroline Zimmermann, Maria Inês Meurer, Liliane Janete Grando, Joanita Ângela Gonzaga Del Moral, Inês Beatriz da Silva Rath, and Silvia Schaefer Tavares Copyright © 2015 Caroline Zimmermann et al. All rights reserved. Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma Thu, 05 Feb 2015 07:50:07 +0000 Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease-free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma. Jun Osugi, Yuka Kimura, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Satoshi Muto, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Athushi Yonechi, Mika Hoshino, Mitsunori Higuchi, Yutaka Shio, Hiroyuki Suzuki, and Mitsukazu Gotoh Copyright © 2015 Jun Osugi et al. All rights reserved. Hematopoietic Stem-Cell Transplantation in the Developing World: Experience from a Center in Western India Tue, 03 Feb 2015 09:56:45 +0000 We describe our experience of first 50 consecutive hematopoietic stem-cell transplants (HSCT) done between 2007 and 2012 at the Apollo Hospital, Gandhinagar, 35 autologous HSCT and 15 allogeneic HSCT. Indications for autologous transplant were multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia, and indications for allogeneic transplants were thalassemia major, aplastic anaemia, chronic myeloid leukemia, and acute lymphoblastic and myeloid leukaemia. The median age of autologous and allogeneic patient’s cohort was 50 years and 21 years, respectively. Median follow-up period for all patients was 39 months. Major early complications were infections, mucositis, acute graft versus host disease, and venoocclusive disease. All of our allogeneic and autologous transplant patients survived during the first month of transplant. Transplant related mortality (TRM) was 20% (N = 3) in our allogeneic and 3% (N = 1) in autologous patients. Causes of these deaths were disease relapse, sepsis, hemorrhagic complications, and GVHD. 46% of our autologous and 47% of our allogeneic patients are in complete remission phase after a median follow-up of 39 months. 34% of our autologous patients and 13% of our allogeneic patients had disease relapse. Overall survival rate in our autologous and allogeneic patients is 65.7% and 57.1%, respectively. Our results are comparable to many national and international published reports. Chirag A. Shah, Arun Karanwal, Maharshi Desai, Munjal Pandya, Ravish Shah, and Rutvij Shah Copyright © 2015 Chirag A. Shah et al. All rights reserved. Corrigendum to “Cucurbitacin B Causes Increased Radiation Sensitivity of Human Breast Cancer Cells via G2/M Cell Cycle Arrest” Mon, 02 Feb 2015 13:40:38 +0000 Suwit Duangmano, Phorntip Sae-lim, Apichart Suksamrarn, Pimpicha Patmasiriwat, and Frederick E. Domann Copyright © 2015 Suwit Duangmano et al. All rights reserved. Role of Rebiopsy in Relapsed Non-Small Cell Lung Cancer for Directing Oncology Treatments Thu, 29 Jan 2015 14:29:27 +0000 Background. Currently, few rebiopsies are performed in relapses of advanced non-small cell lung cancer. They are not customary in clinical practice of lung cancer. However, it is not possible to properly target treatments in cases of relapse without knowing the nature of new lesions. Design. This paper comprehensively summarizes the available literature about rebiopsy and broadly discusses the importance of rebiopsy in advanced non-small cell lung cancer. Results. Altogether 560 abstracts were used as material for further analysis. 19 articles were about clinical rebiopsy in lung cancer and were reviewed in detailed manner. Conclusions. This review shows that rebiopsy is feasible in non-small cell lung cancer, and success rates can be high if rebiopsy is accompanied by adequate evaluation before biopsy. Its use may resolve the difficulties in sampling bias and detecting changes in cancer characteristics. In cases where treatment was selected based on tissue characteristics that then change, the treatment selection process must be repeated while considering new characteristics of the tumor. Rebiopsy may be used to predict therapeutic resistance and consequently redirect targeted therapies. Such knowledge may resolve the difficulties in sampling bias and also in selecting preexisting clones or formulating drug-resistant ones. Rebiopsy should be performed more often in non-small cell lung cancer. Antti P. Jekunen Copyright © 2015 Antti P. Jekunen. All rights reserved. Survival Outcomes and Tumor IMP3 Expression in Patients with Sarcomatoid Metastatic Renal Cell Carcinoma Tue, 20 Jan 2015 06:53:12 +0000 Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy (), immunotherapy (), cytotoxic chemotherapy (), and no treatment (). Median OS was 8.2 months (95% CI 3.8–14.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant (IMP3 negative 14.2 versus IMP3 positive 4.9 months; HR 0.46, 95% CI 0.16–1.21; ). The study was limited by small sample size. Srinivas K. Tantravahi, Daniel Albertson, Archana M. Agarwal, Sowmya Ravulapati, Austin Poole, Shiven B. Patel, Jamil S. Hawatmeh, Alli M. Straubhar, Ting Liu, David D. Stenehjem, and Neeraj Agarwal Copyright © 2015 Srinivas K. Tantravahi et al. All rights reserved. Phosphoglycerate Dehydrogenase: Potential Therapeutic Target and Putative Metabolic Oncogene Tue, 09 Dec 2014 08:56:12 +0000 Exemplified by cancer cells’ preference for glycolysis, for example, the Warburg effect, altered metabolism in tumorigenesis has emerged as an important aspect of cancer in the past 10–20 years. Whether due to changes in regulatory tumor suppressors/oncogenes or by acting as metabolic oncogenes themselves, enzymes involved in the complex network of metabolic pathways are being studied to understand their role and assess their utility as therapeutic targets. Conversion of glycolytic intermediate 3-phosphoglycerate into phosphohydroxypyruvate by the enzyme phosphoglycerate dehydrogenase (PHGDH)—a rate-limiting step in the conversion of 3-phosphoglycerate to serine—represents one such mechanism. Forgotten since classic animal studies in the 1980s, the role of PHGDH as a potential therapeutic target and putative metabolic oncogene has recently reemerged following publication of two prominent papers near-simultaneously in 2011. Since that time, numerous studies and a host of metabolic explanations have been put forward in an attempt to understand the results observed. In this paper, I review the historic progression of our understanding of the role of PHGDH in cancer from the early work by Snell through its reemergence and rise to prominence, culminating in an assessment of subsequent work and what it means for the future of PHGDH. Cheryl K. Zogg Copyright © 2014 Cheryl K. Zogg. All rights reserved. Absence of HPV Infection Is Associated with Smoker Patients with Squamous Cell Carcinoma of the Oropharynx Tue, 30 Sep 2014 11:12:57 +0000 The purpose of this study was to evaluate the survival of patients with SCC of the oropharynx, according to the presence of HPV and tobacco consumption. A total of 37 patients were followed up for at least 5 years after being diagnosed with SCC of the oropharynx. The biopsy tissue was submitted to the polymerase chain reaction (PCR) and in situ hybridization (ISH) methods for broad determination of HPV presence, to identify the presence of high-risk viruses (16 and 18). 12 of the 37 (32.4%) samples were HPV positive, whereas the two specific types of virus were identified in two samples for HPV-16 and in no samples for HPV-18. We observed no significant effect of the virus in survival analysis, irrespective of tobacco consumption. The level of tobacco consumption was significantly higher in the group of HPV-negative patients (), in which all the patients in this group were smokers. Therefore, HPV did not change the survival of patients with SCC of the oropharynx in this study, indicating that factors other than tobacco need to be studied in conjunction with it, and the level of tobacco consumption is significantly higher in the group of HPV-negative patients. Gláucia Resende Soares, Adriana Demathé, Neivio José Mattar, Éder Ricardo Biasoli, and Glauco Issamu Miyahara Copyright © 2014 Gláucia Resende Soares et al. All rights reserved. Comparison of Short and Continuous Hydration Regimen in Chemotherapy Containing Intermediate- to High-Dose Cisplatin Wed, 24 Sep 2014 08:04:59 +0000 Aim. The efficacy of the short hydration regimen was reported in chemotherapy containing intermediate- to high-dose cisplatin, and the use of outpatient chemotherapy containing cisplatin with short hydration has been widespread in recent years. Methods. We compared patients with gastric cancer, lung cancer, and urothelial cancer who received outpatient chemotherapy containing cisplatin (≥60 mg/m2/cycle) with the short hydration regimen since April 2012 with those who received hospital chemotherapy with continuous hydration between April 2011 and March 2013 in our hospital. Results. Grade 2 or higher acute kidney injury occurred in 2 patients in the continuous hydration group and in no patient in the short hydration group; 1 patient discontinued treatment on account of nephrotoxicity. There was no difference between the 2 groups in maximum creatinine increment and maximum clearance decrement. Relative dose intensity in the short hydration group was higher than that in the continuous hydration group (89.5% versus 80.3%; ). Conclusions. The short hydration regimen in outpatient chemotherapy containing intermediate- to high-dose cisplatin is as safe as the continuous hydration regimen and increased the efficacy of chemotherapy. Akira Ouchi, Masahiko Asano, Keiya Aono, Tetsuya Watanabe, and Takehiro Kato Copyright © 2014 Akira Ouchi et al. All rights reserved.