Cancer
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Item A Literature Review of Exercise in the Pediatric Oncology Population(2018-03-14) Nguyen, Peter; Salem, Yasser; Liu, Howe; Becnel, KelseyTitle: A Literature Review of Exercise in the Pediatric Oncology Population The advances in treatment of children with cancer have been improved in recent years. This has resulted in an increase in the number of pediatric cancer survivors. Several research studies have shown that the medical condition and its related disorders is associated with impaired growth and development, decreased strength, fatigue, cognitive dysfunction, cardiopulmonary compromise, impaired physical fitness, musculoskeletal complications and decreased quality of life. There is growing evidence that lack of participation in physical activity in children with disability including children with pediatric oncology may result in several negative effects and decrease quality of life. In recent years, several exercise programs have been implemented for pediatric oncology. Purpose The purpose of this literature review is to examine evidence regarding the potential benefits of exercise for children with pediatric oncology. Safety, benefits, and application are addressed. Methods This systematic review identified 18 articles that met our inclusion criteria. Electronic databases used were PubMed, Physiotherapy Evidence Database (PEDro), CINAHL, Rehabilitation Oncology Journal, and Scopus. Key words included pediatric, children, oncology, exercise, and rehabilitation. Our initial search yielded 271 potential articles, which we screened for selection criteria. In total, 751 children with cancer were studied in our final research articles. Results In total, 18 research studies were examined and met our inclusion criteria for aerobic exercise in pediatric oncology patients. Of the included articles, 12 were randomized controlled trials, 2 were quasi-experimental design, 3 were cohort studies, and 1 were clinical trial. Across all 18 studies, 751 children with pediatric oncology were participants. Sample size for each study ranged between 7 and 150 children. All studies showed beneficial effects of exercise training for children with pediatric cancer. Discussion and Conclusion This systematic review adds to the body of literature that supports exercise training for individuals with pediatric oncology. Studies included support the beneficial effects of exercises for children with cancer. Further studies are needed to determine long term effects of any intervention. Available literature on exercise in children with pediatric oncology suggests that there are beneficial effects without adverse outcomes.Item Anti-cancer activity of biogenic silver nanoparticles against Neuroblastoma cells(2018-03-14) Umesh, Sankpal; Ravikumar, Nulakachandanam; Bharathkumar, Bukkapatnam; Basha, Riyaz; Rajasekhar, MaramABSTRACT Purpose: Neuroblastoma (NB) is one of the solid tumors diagnosed in young children. Due to severe side effects associated with the current therapeutic options, it is important to identify less toxic therapies for treating NB patients. Nanoparticles (NPs) are widely used in various medical applications; however, the particle size and preparation methods play critical roles in their activity. Recently use of plant extracts as stabilizing or reducing agents is gaining significance due to higher stability and activity. Biogenic silver nanoparticles (BSNPs) have been tested for their activity in wound healing mechanism and preventing microbial diseases. The objective of this investigation was to prepare BSNPs using plant extracts and silver nanoparticles and evaluate their anti-cancer activity against neuroblastoma (NB) cell lines. BSNPs were prepared using two different plant extracts and characterized. SHSY5Y and LA155n cells were treated with increasing concentrations of BSNPs for 48 h and dose curves obtained. The effect of BSNPs on apoptosis and cell cycle arrest was evaluated to understand the underlying mechanisms. Method: BSNPs were synthesized using silver NPs and herbal reducing agents. These particles were characterized by Atomic Force Microscope and Transmission Electron Microscope. Fourier-transform infrared spectroscopy was used to identify the active herbal compounds along with silver nanoparticles. The cell viability of NB cells was measured using Cell Titer-Glo kit. Apoptotic cells distribution were determined by Flow cytometry using annexin V staining The expression of cleaved Poly (ADP-ribose) Polymerase (cPARP) was evaluated by western blot. Results:. The characterization of BSNPs revealed alkynes, amines and alkylhalides as reducing agents and particles were ranged 20-100 nm in size. BSNPs caused significantly more cell growth inhibition when compared to silver NPs which is accompanied by an increase in apoptotic markers, c-PARP expression and annexin-v staining. Conclusion: These preliminary data using different reducing agents suggest the potential anti- proliferative effect of BSNPs against NB cells.Item Blocking LLT1-CD161 interaction enhances natural killer cell-mediated lysis of triple-negative breast cancer cells(2018-03-14) Mathew, Stephen O.; Chaudhary, Pankaj; Mathew, Porunelloor A.; Marrufo, Armando M.Purpose: Triple-negative breast cancer (TNBC) accounts for 20 percent of all breast cancer cases and is known to be the most invasive form of breast cancer. TNBC’s absence of estrogen, progesterone, and human epidermal growth factor-2 receptors makes utilizing hormonal treatments ineffective in suppressing tumor growth. TNBC is associated with poorer prognosis and higher incidences of relapse. Therefore, natural killer cell-mediated immunotherapy shows potential as a treatment option for TNBC. Natural killer cells (NK) are innate lymphoid cells that serves its role in the immune system to eradicate infected and tumor cells. NK cell function is regulated through its receptors interacting with activating and inhibitory ligands on target cells. Lectin-like Transcript-1 (LLT1, CLEC2D) is a counter-receptor that interacts with CD161 (NKRP1A) and inhibits NK cell activation. Our study demonstrated that by blocking TNBC’s LLT1 interaction with CD161 with antibodies increases lysis of TNBCs by NK cells. Methods: We have identified the expression and function of LLT1 on TNBC cell lines MDA-MB-231 and MDA-MB-436 by flow cytometry, western blot, immunofluorescent microscopy, and chromium-release assay. LLT1 expression at the cell surface was decreased through gene knockdown with small interference RNA (siRNA) transfection. Primary NK cells were isolated from peripheral blood mononuclear cells from healthy individuals and then were co-incubated with chromium-labeled TNBCs for quantification of specific lysis of TNBCs by NK cells. Results: Our results have demonstrated a higher expression of LLT1 on TNBCs than non-tumorigenic breast cell line MCF10A. We have shown that blocking LLT1 interaction with CD161 with antibodies on TNBCs have increased lysis of TNBCs by primary NK cells. We have also shown that gene knockdown of LLT1 decreases cell surface expression of LLT1 on TNBCs and increases lysis of TNBCs by NK cells. Conclusions: LLT1 expressed on TNBCs is a ligand that interacts with NK receptor CD161 and sends an inhibitory signal to the NK cell thus serving its role for TNBCs to evade immunosurveillance. Respectively, blocking LLT1 with antibodies on TNBCs and decreasing expression of LLT1 by gene knockdown increases susceptibility of TNBCs to NK cell-mediated lysis. Blocking interaction between LLT1 and CD161 with antibodies activates lysis by NK cells and will open a possible new immunotherapeutic strategy for patients diagnosed with TNBC.Item Bone Sectioning Technique for 3D Confocal Image Resolution and Capture of Dye-Loaded Nanotherapeutics(2018-03-14) Gdowski, Andrew; Ranjan, Amalendu; Vishwanatha, Jamboor; Lampe, Jana B.ABSTRACT Purpose:Capturing detailed images of bone architecture has unique challenges and conventional procedures have proved to be insufficient for molecular 3D imaging. Furthermore, traditional 2D immunohistochemistry provides limited information for assessing therapeutic localization in the bone. In addition, techniques such as thin paraffin sections visualized by immunofluorescence microscopy or transmission electron microscopy, require prolonged exposure to damaging decalcification reagents. These chemicals have destructive effects on bone morphology and limit the capture of proteins. The objective of this project was to develop an adapted protocol for bone tissue preparation prior to sectioning and immunohistochemical (IHC) staining. This method enables ultra-thick sections for enhanced Z-stacking, enables the generation of high-resolution 3D images that map the bone tissue, and provides oseo-spatial detection of our dye-loaded nanotherapeutics. Methods:Bones were decalcified then incubated in cryoprotectant before emersion in the embedding solution. Samples were frozen at -80. Ultra-thick sections were made on a Thermo Fisher Cryostar NX70 Cryostat (75 – 100 m) and placed on polar slides. Immunohistochemical staining was applied to the slides, which were imaged with a Zeiss LSM 510 confocal microscope. Our therapeutic was labeled with near fluorescent dye.Results:High-fidelity, 3D images of mouse tibia and femur were imaged. Furthermore, visualization of nuclear staining, bone epithelial cells, and the fluorescently labeled therapeutics were easily detected. Thick sectioning provided us with a more robust, tomographic image, allowing for more thorough mapping and analysis of the nanotherapeutics in the bone. Conclusions:Our modified protocol for processing and imaging bone is an effective approach to bone handling, confocal imaging, and detecting bone and dye-labeled nanotherapeutics. This approach will provide benefits for facilitating our understanding of the significance that drug localization has on the bone microenvironment and its impact on therapeutic efficacy.Item Cell surface PCNA is a marker of pancreatic and colon cancer stem cells and inhibits NK cell effector function.(2018-03-14) Mathew, Porunelloor A.; Malaer, JosephPurpose: Cancer stem cells (CSC), a unique subset of tumor cells, possess a stem-cell-like phenotype and are thought to facilitate metastasis by escaping NK cell effector function. There are numerous markers used to identify CSC; of which include surface markers CD44 and CD133, and transcription factors NANOG, SOX2, and Oct-4. NK cells participate in the innate immune response against cancer without prior sensitization. NK cell function depends on a balance of signals transmitted from activating and inhibitory receptors interacting with ligands on the surface of target cells. Cancer cells may evade NK-mediated killing by expressing or secreting ligands for NK cell inhibitory receptors. NKp44 can function as an activating receptor that induces NK cell cytotoxicity or an inhibitory receptor depending on ligand interaction. Proliferating cell nuclear antigen (PCNA) associates with Human Leukocyte Antigen I (HLA I) and forms the inhibitory ligand for NKp44, resulting in the inhibition of NK function. We hypothesize surface PCNA is a marker for CSC in pancreatic and colon cancer. Methods: Pancreatic (Panc-1) and colon (HCT 116) cancer cells were labeled with antibodies against PCNA, CD44, and CD133 and flow cytometry was performed to determine surface expression. Cells were labeled and sorted for cell surface PCNA expression via fluorescence activated cell sorting; NANOG, SOX2, and Oct-4 were analyzed by qRT-PCR from sorted cells. NK receptor-ligand interactions were blocked by incubating cells with anti-PCNA or control antibodies and a chromium release killing assay was performed. Results: In both Panc-1 and HCT 116 cells, a PCNA+CD44+CD133+ population was detected. Furthermore, cell sorting and qRT-PCR confirmed cells with cell surface PCNA have increased expression of CSC transcription factors compared to PCNA- cells. Blocking the interaction of NKp44 and PCNA enhanced the specific lysis of cells by primary NK cells. Conclusions: Cell surface PCNA is associated with co-expression of CD44 and CD133 as well as increased CSC transcription factor expression. Collectively these data demonstrate that surface PCNA is a marker of pancreatic and colon CSC. Additionally, cell surface PCNA on CSC facilitate escape from NK cell killing by interacting with NKp44 and transmission of an inhibitory signal. Our research implicates that blocking NKp44-PCNA interaction may provide novel immunotherapeutic targets for pancreatic and colon cancer stem cells and prevent metastasis.Item Challenges of Medical Decision-Making in an Autistic Pediatric Patient with Retinoblastoma and Osteosarcoma: A Case Study(2018-03-14) Rapisand, Stefanie; Hamby, Tyler; Bowman, Paul; Shum, KathyBackground: In oncology, one of the most crucial decisions is whether it is appropriate to discontinue chemotherapy before the full course of treatment. Medical professionals must consider the risks versus the benefits, the patient’s quality of life, the appropriate role of chemotherapy, and the patient’s preference. The decision is difficult in pediatric patients who have encountered multiple malignancies while suffering from the untoward effects of chemotherapy. It is especially difficult in malignancies such as osteosarcoma where successful treatment involves the full course of systemic chemotherapy. Case Information: A 9-year-old autistic male with a history of retinoblastoma presented with pain in the right leg and an abnormal gait. A biopsy confirmed the diagnosis of high grade osteosarcoma. Neoadjuvant chemotherapy (protocol AOST 0331) was initiated with the administration of Cisplatin and Adriamycin, but was complicated by nausea, vomiting, febrile pancytopenia, and multiple life threatening infections. Nausea and vomiting was so severe that a feeding tube was placed for feedings and medication administration. After hip disarticulation amputation, chemotherapy was resumed, but was suspended at week 15 of treatment due to multiple life-threatening complications such as nephrotoxicity, endocarditis, and staphylococcus and streptococcus mitis infections. Discussion: The decision to discontinue chemotherapy early was not an easy one. The patient suffers from severe autism, is non-verbal, blind, intellectually disabled, and suffered many complications from his first and second pediatric malignancies. After considering the patient’s long battle with two pediatric malignancies and the numerous challenges he has had from undergoing chemotherapy, the patient’s parents and physicians agreed to discontinue chemotherapy. The patient is now receiving palliative care. Conclusion: Our case illustrates the importance of an individualized treatment plan when working with complicated patients. When physicians are faced with challenging medical decisions, it is important to remember, that with the help of their medical team and open communication with patients and their family members, making these decisions may not be as difficult and may be beneficial to everyone involved.Item Combination of Mithramycin and Standard Chemotherapeutic Agents Induces Anti-proliferative activity in Ewing Sarcoma cell lines(2018-03-14) Hunter, Abigail; Lout, Holly; Dunlap, Elissa; Sankpal, Umesh; Bowman, W. Paul; Basha, Riyaz; Ray, Anish; Albeer, LinaBackground/Hypothesis: Ewing sarcoma (ES) is a small, round, blue cell tumor found primarily in bones of adolescents. The EWS-FLI1 transcription factor is associated with proliferation of cancer cells and is over-expressed in [greater than] 85% of Ewing sarcoma cases. Mithramycin (MIT) is an antibiotic with antineoplastic properties and has been shown to inhibit EWS-FLI1. A recent trial of MIT treatment in ES patients found that hepatotoxicity precluded the administration of MIT at a dose required to inhibit EWS-FLI1 ([greater than]50nmol/L). We hypothesize that the efficacy of adjunct treatment can be enhanced if MIT is used along with standard chemotherapeutic agents such as Vincristine (VIN) and Etoposide (ETO). Combination treatment will reduce the effective dose of both Mithramycin and the standard agent thereby decreasing the therapeutic dose range and side effects. Methods: ES cells, CHLA10 and TC205 were cultured in the presence of vehicle or MIT or VIN or ETO or in combinations (MIT+VIN or MIT+ETO). After 2 days, cell viability was measured using The CellTiter-Glo® Luminescent Cell Viability Assay kit. The apoptosis induced by each of the above-mentioned treatments on the ES cells was measured by Flow cytometry using Annexin V Apoptosis Detection Kit. The expression of cleaved-Poly (ADP-ribose) polymerase (c-PARP), a marker for apoptosis was determined by Western blot analysis. Results: While all treatments showed ES cell growth inhibition, the combination treatment of MIT+ETO was more effective (significant at p Conclusion: The combination MIT+ETO caused more cell growth inhibition when compared to individual treatments in the TC205 and CHLA10 cell lines. These results demonstrate that MIT in combination with standard chemotherapeutic agents potentially increases therapeutic efficacy in ES. However, these results are limited to in vitro studies and need to be tested in an animal model to determine reproducibility and assess the toxicity.Item Copper Tolfenamic acid induces anti-proliferative activity effective against Medulloblastoma cells(2018-03-14) Sankpal, Umesh; Bowman, W. Paul; Basha, Riyaz; Arechiga, BiancaPurpose: Medulloblastoma (MB) is the most common pediatric malignant brain tumor, comprising 20% of all childhood brain tumors. Between 250-500 children per year are diagnosed in the US alone. Standard therapies result in severe long-term morbidities. Therefore, there is an urgent need for inventing novel effective treatment strategies with lower side-effects. Our laboratory showed anti-cancer activity of Tolfenamic acid (TA) in pre-clinical model for MB. Recent studies showed higher pharmacological effect of TA when synthesized as a complex with copper (Copper-TA, Cu-TA). Our aim was to investigate the anti-cancer activity of Cu-TA against MB cell lines. We hypothesize that Cu-TA presents higher anti-cancer activity and is more effective than TA to induce cytotoxicity against MB cells. Methods: DAOY and D283 cells were obtained from ATCC and grown following standard cell culture conditions. Cells were treated with TA or Cu-TA and the cell viability was measured at 24 and 48 h post-treatment using a CellTiter-Glo kit. The induction of apoptosis was investigated by studying caspase activation using the Caspase 3/7-Glo kit. In addition, reactive oxygen species (ROS) involvement was measured by flow cytometry. Results: Both Cu-TA and TA treatment resulted in decreased cell viability. However, when compared to TA, Cu-TA was more effective at inducing anti-proliferative activity in MB cells. Cu-TA induces increased production of ROS. The anti-proliferative activity of Cu-TA was accompanied by an increase in Caspase 3/7 activity, suggesting the induction of apoptosis. Conclusions: Cu-TA was more effective than TA. Therefore, it has potential as an effective anti-cancer agent for inhibiting MB cell growth. Further studies are needed to better understand Cu-TA’s mechanism of action.Item Current landscape of immunotherapy clinical trials in prostate cancer(2018-03-14) Gdowski, Andrew; Lampe, Jana B.; Ranjan, Amalendu; Vishwanatha, Jamboor; Gorman, BrendanPurpose The number of immunotherapies that have been approved in recent years has generated a lot of enthusiasm in the field of oncology. This success has come on the results of approvals for immunotherapy drugs and the expansion of indications for a variety of hematological and solid malignancies. However, very few immunotherapies have demonstrated improved overall survival in treating patients with prostate cancer. This is due to several factors including tumor heterogeneity, limited prostate tumor-associated antigens, and an immunosuppressive environment. Despite these challenges, numerous clinical trial efforts are ongoing to determine outcomes of immunotherapies in prostate cancer, and many are in the context of combination strategies. The purpose of this project was to identify and categorize the current landscape of immunotherapies that are in clinical trials for prostate cancer. Methods An extensive evaluation of the all currently registered clinical trials in the United States of immunotherapies in the setting of prostate cancer was performed utilizing www.clinicaltrials.gov on 1-20-18. The following search parameters were used: Condition/disease: “prostate cancer” Other terms: “immunotherapy”, “CAR-T cell therapy”, “monoclonal antibody”, “checkpoint inhibitors”, and “vaccine”. Results The query resulted in a total of 215 registered clinical trials. Most of these trials (84%) were in the context of vaccine therapy against prostate cancer, 12% of trials involved checkpoint inhibitors, and 4% were testing CAR-T cell therapy. Only 6% of the trials were in the phase 3 setting while 32% and 60% were in phase I or phase II, respectively (the remainder were not categorized into a phase). The majority of these trials used combination strategies. Conclusion The slow-growing nature of prostate cancer in many patients makes this cancer uniquely suitable for utilizing immunotherapies that may need time to allow for an immune response to mount against cancer cells. There is a tremendous amount of clinical trials that are currently being performed on prostate cancer with a variety of immunotherapeutic strategies. Although more research needs to be done, the potential of a durable and sustained response with immunotherapies is encouraging in the setting of prostate cancer.Item Diffuse Large B cell Lymphoma presenting as Acute Pancreatitis(2018-03-14) Mohanaselvan, Arvind; Patel, Aman; Makhni, Manmeet; Jipescu, DanielBackground: Diffuse large B cell Lymphoma (DLBCL), not otherwise specified (NOS) is the most common type of lymphoma in the world accounting for 25–30% of Non-Hodgkin lymphomas (NHL). It is more common in the elderly but occurs in all age groups and predominantly affect the male.Most common sites of involvement include lymph nodes or extranodal sites (bone, skin, thyroid, gastrointestinal tract and lung).1 Only 1.25% to 2.2% of all patients with NHL have pancreatic involvement at presentation.2,3 Primary pancreatic lymphoma (PPL) rarely presents with the typical B symptoms observed in lymphoma (ie, weight loss, fever, or night sweats).4–6 Here we report an unusual and rare case of PPL which was first diagnosed as acute biliary pancreatitis that was later found to be Pancreatic Adenocarcinoma and later confirmed on biopsy as DLBCL-NOS. Case Report: An 80-years-old caucasian male presented to the ER with complaints of abdominal pain for one day, generalized weakness and shortness of breath for two weeks. ROS otherwise unremarkable. Vitals showed elevated blood pressure otherwise unremarkable. Physical exam was positive for epigastric tenderness radiating to the back without any signs of peritonitis and labs showed TBili-5.4, DBili-3.6, AST-440, ALT-502, AlkPhos-372, LDH-388, Amylase-268, Lipase-4403. Beta-2-microglobulin-2.4, AFP-1.5, CEA-0.7, CA 19-9-178. Patient had a prior history of Prostate CA status-post radiation. CT Abdomen showing a pancreatic mass with biliary and duodenal obstruction suggestive of a tumor. CT Abdomen and pelvis with contrast was suggestive of Pancreatic Adenocarcinoma. Patient was diagnosed with acute biliary pancreatitis and was started IVF and pain medication. He subsequently underwent placement with a biliary drain to relieve obstruction. Biopsy was suggestive of DLBCL-NOS. Patient was started on CHOP-R regimen and advised to have a close follow up with oncologist as an outpatient. As treatment progresses, biliary drain will be replaced by indwelling stents to relieve the obstructions. Discussion: PPL is a rare neoplasm that can mimic pancreatic adenocarcinoma in many aspects. Arriving to a proper diagnosis using both biochemical and tissue biopsy is very essential as it carries excellent prognosis if diagnosed early. The best therapeutic option as per the study by Behrns et al and many other recent studies is chemotherapy CHOP-R with or without surgical resection and radiotherapy depending on the Ann Arbor staging and is associated with increased long-term survival of PPL.7-8Item Documentation of Substance Use in Adolescent and Young Adult Cancer Patients(2018-03-14) Galagoda, Anika; Hamby, Tyler; Hoeft, Alice; Heath, Corey; Albritton, Karen; Lout, HollyTitle: Documentation of Substance Use in Adolescent and Young Adult Cancer Patients Anika Galagoda, OMS-II, Holly Lout, OMS-II, Corey Heath, PhD, Karen Albritton, MD, Alice Hoeft, MS, Tyler Hamby, PhD Background: Cancer remains the leading cause of disease-related death in the Adolescent and Young Adult (AYA) population, ages 15-39. One psychosocial circumstance influencing the management of this population is substance use. Substance use can impair judgement which may affect patient adherence to treatment protocol. Substance use may lead to poorer health outcomes and can increase the risk for secondary malignancies. It is important for clinicians to ask about substance use in AYA patients so they can prevent these adverse effects. Purpose: The purpose of this study was to examine the quality of the documentation of substance use behaviors among this population at Cook Children’s Medical Center (CCMC) before and after the implementation of an AYA program at CCMC in 2011. Methods: This study used a retrospective analysis of patient charts aged 15-35 years old at the time of diagnosis who were treated at CCMC between 2008 and 2014. Patients with brain and thyroid tumors were excluded. Quality of documentation was compared before and after the AYA program was started. The variables collected include documentation of tobacco, alcohol, and illicit drug use before and during treatment. Chi-square analyses and odds ratios (OR) were used to compare rates of documentation. Results: There were 169 patients who met inclusion criteria. Clinician documentation of history of substance use was highest with tobacco use (72%) followed by alcohol use (32%) and drug use (30%). Additionally, documentation was significantly better after the implementation of the AYA program for tobacco use before (pppppp=.10; OR=1.75), treatment. Conclusions: Providers were more likely to document tobacco use than alcohol or drug use. Documentation improved after a programmatic focus on AYA care was established. Despite this, most charts reviewed did not document alcohol or drug use, so thorough and consistent documentation is still needed in order to see if there is a relationship between these variables and the outcomes of AYA patients.Item Does Skin Cancer Differ by Metropolitan Status by Gender?(2018-03-14) Frauendorfer, Megan; Spencer, Shawna; Hartos, Jessica; Bram, HannahPurpose: Skin cancer is a major health concern in the general population, but there are conflicting findings regarding its relationship to where people live. The purpose of this study was to determine whether skin cancer differs by metropolitan status in adults aged 18 and older by gender. Methods: This cross sectional analysis used 2015 BRFFS data for males and females aged 18 years and older from Florida, North Carolina, and Tennessee. Multiple logistic regression analysis was used to assess the relationship between skin cancer and metropolitan status while controlling for cancer diagnosis, general health, educational level, employment status, income level, ethnicity, age, and gender. Results: Few participants in the target population reported ever being diagnosed with skin cancer (9-16%), and 4-35% reported living in a rural region, while 22-58% reported living in a suburban area and 38-49% living in an urban area. After controlling for health, socioeconomic and demographic factors, skin cancer and metropolitan status were significantly related. Skin cancer also differed by ethnicity and age (moderate to large effect sizes) for both genders. Conclusions: This study found that skin cancer was significantly related to suburban metropolitan status amongst adults aged 18 and older in the general population. Limitations to this study include a broad definition of skin cancer and no lifestyle variables specific to sun exposure. It is recommended that general practitioners screen, educate, and provide referral services as necessary.Item Does the Relationship Between Skin Cancer and Obesity Differ Between Young Adult Males Versus Elderly Males?(2018-03-14) Ly, Ashley; Chuen, Joyce; Dao, Alejandra; Hartos, Jessica; Hamid, KanwalPurpose: Obesity is an established risk factor for several cancer types, but there are conflicting findings about the relationship between obesity and skin cancer especially in males. Therefore, the purpose of this study was to explore whether the relationship between obesity and skin cancer differs between young adult males and elderly males. Methods: This cross-sectional analysis used 2015 BRFSS data for males ages 18-40 and ages 65 and older from Alabama, Kentucky, Tennessee, and West Virginia. Multiple logistic regression analysis was used to assess the relationship between skin cancer and obesity while controlling for age, White ethnicity/race, educational level, tobacco use, alcohol use, healthy eating, and routine checkups. Results: Few participants reported ever being diagnosed with skin cancer (13-17%) and about one-third reported being obese (28-33%). Results of adjusted analysis indicated that skin cancer and obesity were not significantly related in any state, but skin cancer differed by age and ethnicity/race (large effect sizes) in all four states. Conclusions: Overall, obesity was not related to skin cancer in any of the four states in young and elderly males, but skin cancer differed by age and ethnicity/race in all four states. Although this study was restricted to a single time-point survey, the broad range of the BRFSS survey allows the results to generalize to the general population in the primary care setting. Due to the low to moderate prevalence of obesity, primary care providers should educate patients on its harmful effects while the low prevalence of skin cancer indicates providers should only screen patients with symptoms. Since there is no association between obesity and skin cancer, these conditions should be considered separately.Item Evaluation of Metformin as an anti-cancer agent in Medulloblastoma(2018-03-14) Basha, Riyaz; Bowman, W. Paul; Sankpal, Umesh; Payne, KristenEvaluation of Metformin as an anti-cancer agent in Medulloblastoma Purpose: Medulloblastoma (MB) is the most common malignant brain tumor in children under 16 years of age. Standard treatment, including surgery, chemotherapy, and radiation, is successful for most; however, survivors often suffer from long-term neurocognitive and growth potential related sequelae. Therefore, there is a need to understand the molecular processes regulating MB growth to find less toxic therapies. Survivin is a protein in the Inhibitor of Apoptosis Protein (IAP) family that inhibits caspase activity. Survivin is highly expressed in MB and associated with a poor prognosis. Specificity protein 1 (Sp1) is a transcription factor regulating survivin expression and is overexpressed in many cancers. Interestingly, the use of Metformin (MET), an anti-diabetic drug, correlated with decreased occurrence of several cancers. Previous studies have demonstrated its anti-cancer activity in breast cancer cells as well. The objective of this study is to test the effect of MET on MB cells in vitro. Hypothesis: We hypothesize that MET treatment decreases the growth of MB cells in a dose and time-dependent manner, possibly inhibiting the expression of survivin via downregulating Sp1. Methods: DAOY (MB cell line from American Type Culture Collection) cells were treated with increasing concentrations of MET (0, 1, 5, 10, and 20 mM). Cell viability was assessed at 24 and 48 hours post-treatment using the CellTiter-Glo cell viability assay. Survivin and Sp1 expression in MET treated cells was determined by Western blot analysis. Potential mechanism of cell proliferation inhibition was investigated by measuring the induction of reactive oxygen species (ROS) through Flowcytometry. Results: MET treatment resulted in decreased cell viability in a dose and time dependent manner. MET treatment also decreased Sp1 and survivin expression indicating that the effect of MET is mediated via Sp1 transcription factor. We also observed MET induced cellular ROS formation, which could be a potential anti-cancer mechanism. Conclusion: Our data demonstrates that MET can inhibit MB cell growth, possibly via targeting Sp1 to down-regulate survivin and inducing ROS. We conclude that MET has the potential to be used in the treatment of MB. Due to limitations of using Metformin alone as an anti-cancer agent, additional experiments are underway to determine its use in conjunction with MB specific chemotherapeutic agents.Item Evaluation of Stability and Anti-cancer activity of Copper(II) Tolfenamic Acid with an emphasis on Pancreatic(2018-03-14) Sankpal, Umesh; Patel, Rafid; Chhabra, Jaya; Brown, Deondra; Gurung, Raj; Holder, Alvin; Rajasekhar, Maram; Basha, Riyaz; Hurtado, MyrnaPurpose: Tolfenamic acid (TA) acts as an anti-cancer agent in several cancer models via down-regulating transcription factors Sp1 and Sp3, and an inhibitor of apoptotic protein, survivin. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, Cu-TA has been synthesized and tested for enhanced therapeutic activity. In this study, Cu-TA was investigated for its stability and anti-cancer activity using several cancer cell lines and mouse model for pancreatic cancer (PC). Method: Cu-TA was synthesized and characterized by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR). Anti-proliferative activity was evaluated against twelve cell lines representing six (breast, colon, glioblastoma, medulloblastoma, pancreatic and prostate) cancers using the CellTiter-Glo kit and compared with TA. Further studies were performed using PC cells. The expression of Sp1, Sp3 and survivin was determined by Western blot and qPCR. The stability of Cu-TA was determined using 8-12 month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Athymic mice were injected with PC cells and treated with vehicle (control) or 25 or 50 mg/kg of Cu-TA 3 times/week and the effect on tumor growth was monitored for 4 weeks Animals body weight changes were also observed to determine overt toxicity. Results: Cu-TA significantly more effective than TA against all tested cancer cells. The IC50 values of Cu-TA were 30 to 80% less when compared with TA. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cells showed similar IC50values ( Conclusion: These in vitro and in vivo studies demonstrate that Cu-TA is more effective than TA and potentially useful as an effective anti-cancer agent.Item MIEN1 Regulates Breast Cancer Cell Migration and Invasion by Altering Cytoskeletal Dynamics Through Focal Adhesion Kinase and N-WASP Signaling(2018-03-14) Chaudhary, Pankaj; Kpetemey, Marilyne; Vishwanatha, Jamboor; Van Treuren, TimothyPurpose: Triple negative breast cancer (TNBC), accounts for approximately 15-20% of all breast cancer diagnoses. This is the most aggressive breast cancer subtype and is characterized by a lack of known receptors associated with, making prognosis and treatment difficult in patients with TNBC. TNBC has a propensity to metastasize to vital organs, including lung, brain and bone. This can occur early in the disease progression and usually leads to the elevated mortality rate in TNBC patients. Research efforts to identify molecular markers within TNBC for prognosis and therapy have not been fruitful. Migration and Invasion Enhancer 1 (MIEN1) has been implicated in the disease progression of many cancers, including TNBC. We determined to further understand the molecular mechanisms by which MIEN1 regulates cell motility and invasion in the context of TNBC. This knowledge will provide a basis to pursue MIEN1 as a potential marker for future treatment and evaluation of TNBC cases. Methods: Wild-type MIEN1 (MIEN1-WT) or Immunoreceptor tyrosine-based activation motif (ITAM)-mutant MIEN1 MIEN1-Y39/50F) was overexpressed in MDA-MB-231 cells to evaluate the role of ITAM signaling in MIEN1 mediated migration and invasion. Migration speed and persistence toward a chemoattractant was assessed using microfluidic chambers. Invasion was evaluated by embedding cell aggregates in a 3D collagen matrix and examining the spread of the cells. MIEN1 influence on migration was mediated by actin cytoskeletal dynamics. This mechanism was further delineated by looking at actin polymerization as well as focal adhesion adaptors and signaling molecules using western blotting as well as confocal microscopy. An in vitro kinase assay was also used to evaluate activators of MIEN1. Results: MIEN1-WT over-expression in MDA-MB-231 cells resulted increased migratory and invasive capabilities compared to wild-type cells. Additionally, over-expression of the MIEN1-Y39/50F ITAM mutant inhibited the cells’ ability to migrate towards a chemoattractant as well as invade through a collagen matrix. MIEN1 co-localized to the cell membrane with FAK (focal adhesion kinase) and facilitated signaling through N-WASP to alter cytoskeletal dynamics and increase filamentous actin accumulation. Conclusion: MIEN1 regulates migration and invasion of TNBC cells by altering cytoskeletal dynamics through activation of FAK and N-WASP, which results in increased actin polymerization and cell motility.Item Novel therapeutic formulation for the anticancer drug valrubicin using human serum albumin and D-alpha-tocopheryl polyethylene glycol 1000 succinate(2018-03-14) Raut, Sangram; Lacko, Andras G.; Dossou, AkpedjePurpose: Human serum albumin (HSA) and the bioavailability enhancer D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) are recognized as versatile biocompatible ingredients in drug nanoformulation. Due to its lipophilicity, the anticancer drug valrubicin is currently solubilized in cremophor EL which does not favor systemic delivery. Hence, even though valrubicin is less toxic and more potent than its widely used anthracycline parent compound doxorubicin, its administration and use are respectively restricted to intravesical route and bladder cancer. Since HSA is able to transport endogenous lipophilic compounds in the blood, and TPGS forms micelles, HSA and/or TPGS could increase the solubility of valrubicin in a preparation and extend its administration to alternative administration routes including systemic delivery. Thus, the goal of this study is to characterize and compare three formulations: HSA-Valrubicin (Val), TPGS-Val and HSA-TPGS-Val. Methods: The formulations were prepared using 0.5mg/mL Val, 50mg/mL HSA and different concentrations of TPGS. Each formulation was continuously stirred at room temperature for 2 hours. Centrifugation and filtration were used to remove unbound valrubicin. The particle size was estimated by dynamic light scattering while the amount of valrubicin incorporated was derived from absorbance reading at 490 nm. Results: Whereas only 61.5% of the feeding valrubicin was incorporated in the HSA-Val formulation, the amount of Val dissolved in TPGS followed the ratio of 1:6 (mol/mol). Addition of increasing amount of TPGS to HSA increased the amount of Val incorporated in HSA-TPGS-Val formulations. The mixture of 50mg/mL HSA, 0.5 mg/mL TPGS and 0.5 mg/mL Val showed 76% of Val incorporation and also displayed the lowest particle size with the highest homogeneity (56 nm±15.3, polydispersity index (PDI) 0.148). Conclusion: Although TPGS concentration could be a limiting factor for drug loading efficiency in TPGS-Val preparations, the combination of TPGS and HSA show the promise of an acceptable formulation. Perhaps, the optimization of HSA-TPGS-Val preparations can be achieved by reducing disulfide bridges in HSA to uncover more hydrophobic sites on the molecule.Item Nutrition Intervention in Pediatric Acute Lymphoblastic Leukemia Patients with Down Syndrome(2018-03-14) Hamby, Tyler; Hill, Rachel; Bricker, MadeleineAbstract: Purpose: Children and adolescents with Down Syndrome (DS) are more likely to become overweight or obese than those without DS. Additionally, children with DS develop acute lymphoblastic leukemia (ALL) at higher rates than the general population, and pediatric ALL treatment is associated with excessive weight gain. Despite DS-ALL patients’ increased risk for obesity and its complications, there remains a lack of research on preventing weight gain in this specific population. Our objective was to determine if a three-visit nutritional intervention in maintenance therapy was effective at reducing weight gain in DS-ALL patients. Methods: In a retrospective analysis, medical records of the intervention group were compared to historical controls on the same ALL treatment protocol. Anthropometrics were collected throughout intensive therapy and at every monthly visit during the 12 months of maintenance therapy. Results: Nine patients met the inclusion criteria: 5 males, 7 Caucasian and 2 Hispanic, and 5 on high risk protocols. The median age was 4.07 years (range, 1.60-14.26). Three and five patients had unhealthy BMIs at diagnosis and month 12 of maintenance, respectively. When comparing patients who had healthy BMIs at diagnosis, the intervention group had smaller increases in BMI than the control group. However, patients who had unhealthy BMIs at diagnosis had unhealthy BMIs at month 12 of maintenance therapy, regardless of intervention. Conclusions: These results provide evidence that DS patients do tend to gain weight during treatment for ALL, but the data were insufficient to determine whether the nutrition intervention was successful for this population. To our knowledge, this is the first study to investigate obesity prevention in DS-ALL patients. One approach for future studies is an inter-institutional collaboration to obtain a sample size large enough to draw conclusions using inferential statistics.Item Prevalence and Risk Factors for Malnutrition during Pediatric Acute Lymphoblastic Leukemia Induction Therapy(2018-03-14) Ali, Mir; Hill, Rachel; Hamby, Tyler; Johnson, Danielle; Ray, Anish MD; Boren, CharlesPurpose It is well documented that pediatric patients with acute lymphoblastic leukemia (ALL) often experience significant weight gain during induction therapy and later struggle with obesity. However, some patients experience unintended weight loss during induction therapy; since this issue is not well reported, it often goes unnoticed or undertreated. Although malnutrition is reported to be associated with decreased survival, increased risk of infection and loss of lean body mass, there remains a scarcity of in depth analysis of prevalence and risk factors that contribute to this problem. Our study attempts to address this critical yet unmet need. Our aim was to identify the clinical risk factors and outcomes associated with weight loss during induction therapy for pediatric ALL. Design/Method This was a retrospective chart review of patients between 2 and 20 years of age diagnosed with ALL at Cook Children’s Medical Center from 4/1/14 to 3/31/17. For each patient, we collected height, weight, age, body mass index (BMI) z-scores at diagnosis and end of induction therapy, risk stratification, and whether consolidation was delayed. Patients with a BMI z-score [greater than] 85th percentile at diagnosis were categorized as being overweight or obese. Using logistic regression analyses, we examined which variables predicted whether the patient had an increase or decrease in BMI z-score throughout induction. A critical alpha level of 0.05 indicated statistical significance. Results Ninety-six patients met our inclusion criteria. Of these, 40% experienced a decrease in BMI during induction therapy. Compared to patients whose BMI increased during induction, patients with a decrease in BMI were more likely to be overweight or obese at diagnosis (55% vs. 22%; p Conclusion This research highlights a risk not previously identified in the literature that may impact outcomes. Patients treated on high- or very-high-risk protocols, who are overweight or obese at diagnosis, and who are ≥10 years old at diagnosis should be monitored closely for weight loss during induction therapy. Patients who experience weight loss should receive prompt intervention. It is our hope that this information can be used for future prospective studies and help develop evidence-based guidelines.Item Recurrence of Sub-Acute Methotrexate Neurotoxicity in a 16-year-old Female Undergoing Therapy for Precursor B-cell ALL(2018-03-14) Torres, Jordan; Chaphekar, Anita V.Introduction: Methotrexate, an anti-folate, is commonly used in treatment for acute lymphoblastic leukemia. Neurotoxicity is a known complication of methotrexate and can present as acute, sub-acute, and long-term neurotoxicities. Sub-acute methotrexate neurotoxicity can be seen as late as two weeks after methotrexate administration and can present as stroke-like symptoms, seizures, aphasia, and encephalopathy.Patients who develop methotrexate neurotoxicity can be safely re-challenged with the drug, although there are reports of recurrent neurotoxicity occurring. Patients who develop methotrexate neurotoxicity often have MRI findings of white matter hyper-intensities known as leukoencephalopathy. These changes are usually transient and can be present in an asymptomatic patient being treated with methotrexate. Case Presentation: This case was identified and reviewed using electronic medical records and imaging. Details of the case were also supplied by the patient herself during interview. A 16-year-old female presented to her outside pediatrician with several months of headaches, one week history of loose stools, and two-day history of bruising to the back of the hands. A complete blood count revealed anemia, thrombocytopenia, and leukocytosis. The patient was sent to Cook Children’s Emergency Room. A diagnosis of precursor B-cell Acute Lymphoblastic Leukemia, High Risk was established. Patient was enrolled in the COG protocol AALLO8B1 for biology and tissue banking and treatment protocol AALL1131. Induction began as planned. The patient was given intrathecal methotrexate on day 8 and 29 without problems. However, her minimal residual disease at the end of induction was 0.2%. Due to this, the patient was switched to the very high-risk arm of protocol AALL1131.The Consolidation phase consisted of weekly intrathecal methotrexate, intravenous cyclophosphamide, intravenous cytarabine, and 6-mercaptopurine. During the first few days of consolidation the patient began complaining of trouble with concentration and memory. Approximately eleven days after intrathecal methotrexate administration, the patient reported to the Cook Children’s Emergency Department with complaints of pain in her mouth, difficulty swallowing, and a fever of 101.9 degrees Fahrenheit. The patient also had weakness in her right upper extremity, slurred speech, and she could not write with her right hand. Physical exam in the emergency department was remarkable for right facial hemiparesis and asymmetry. She was somnolent and lethargic. The right upper extremity had decreased tone and strength compared to the left upper extremity. The patient exhibited aphasia. Cranial nerve seven demonstrated a right central palsy, but all other cranial nerves were intact. Blood cultures were negative. The patient had to be intubated and transferred to the PICU due to loss of gag reflex and inability to keep her airway open. MRI showed bilateral periventricular white matter and centrum semiovale diffusion restriction with no mass effect consistent with acute methotrexate toxicity. Decadron and Leucovorin were started. She was extubated on PICU day 4. The patient returned to the oncology clinic a few days after discharge and was doing well overall. During this clinic visit, she received a re-challenge of 15 mg of intrathecal methotrexate. Approximately one week after this methotrexate administration, the patient returned to the emergency department with recurrent methotrexate encephalopathy. She complained of a left lower facial palsy, left arm weakness, and difficulty with speech. She was afebrile and physical exam did not show any major neurological abnormalities, An MRI of the brain showed diffusion restriction in bilateral centrum semiovale and supratentorial periventricular white matter with right more than left side. This was deemed to be consistent with methotrexate neurotoxicity. MRA showed no vascular deficit. The patient was switched from intrathecal methotrexate to intrathecal cytarabine for maintenance therapy. She tolerated this well, although she did have some delayed clearance of the methotrexate requiring a longer hospital stay. Conclusion: Although re-challenge is considered safe, it is important to be aware of the possibility of a second episode of methotrexate neurotoxicity occurring as seen in this patient. The patient had stroke-like symptoms that resolved in a few days in both instances. Additionally, her MRI findings are consistent with leukoencephalopathy. She continues to receive intravenous methotrexate but is given intrathecal cytarabine rather than intrathecal methotrexate.