Cancer

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Educational Attainment and Special Education Use Among Long-Term Survivors of Childhood Cancer: Planning of a Childhood Cancer Survivor Study Project
(2017-03-14) Bashore, Lisa; Bowman, W. Paul; Hamby, Tyler; Shah, Deep; Basha, Riyaz; Robison, Leslie; Armstrong, Greg; Krull, Kevin; Merchant, Zahra
Purpose: Childhood cancer survival rates have increased dramatically in recent years. Because of this, long-term complications are becoming more apparent. Survivors have previously been shown to have lower educational attainment and more special education use than their siblings. The proposed study will expand upon the extant literature by examining specific predictors of special education usage and educational attainment in cancer survivors. In particular, we will address the following aims: 1) Describe the usage of special education and educational attainment in a large cohort of survivors of childhood cancer diagnosed between 1970-1999, 2) Compare patterns of special education services and educational attainment by decade of diagnosis, 3) Determine predictors of use of special education and educational attainment, 4) Examine associations between use of special education services and educational attainment with chronic health conditions. Methods: This is the first Cook Children’s initiated project to utilize the Childhood Cancer Survivor Study (CCSS), a retrospective longitudinal cohort funded by the National Cancer Institute (CA55727). Proposing and performing studies within the CCSS is a multi-step process. First, potential topics are discussed with a Working Group Chair who oversees the specific content. Second, an application of intent must be written with an identified CCSS mentor. Then, an initial analysis concept proposal must be written and approved by the Chair. Once approved, a full analysis concept proposal must be written and approved by a multidisciplinary publication committee. This proposal identifies the specific variables required to attain the outcomes of interest and maps out the analyses and tables to be used in the manuscript. Statisticians within the CCSS analyze the data and provide populated tables to the authors to interpret and write up the results and discussion. Results/Conclusions: Because of the length of this process and CCSS’s policy of using their own statisticians, we do not yet have the results of our study. We have submitted a protocol to the CCSS and have worked with our mentor there. As we approach a final draft, our protocol will be reviewed by a larger publication committee. Then it will be sent to the statisticians for analysis. The proposed poster presentation will describe the CCSS population and study methods designed to capture meaningful data on survivors’ educational attainment and special education use.
A Small Molecule Derivative as a Targeting Agent for Sp1 and Survivin Effectively Suppresses Pancreatic Cancer Cell Growth
(2017-03-14) Sankpal, Umesh; Mahammad, Shahela; Chhabra, Jaya; Brown, Deondra; Gurung, Raj; Holder, Alvin; Basha, Riyaz; Hurtado, Myrna Ms
Background: Pancreatic cancer has one of the most fatal malignancies due to its poor prognosis. It currently has a one-year survival rate of 20%. Current standard forms of treatment contain a high level of toxicity, thus preventing an increase in dosage or frequency. This issue poses the need for more effective, yet less toxic agents for treatment. Tolfenamic acid (TA) is most commonly used to treat migraines but has recently been demonstrated to contain anti-cancer properties. It is known to downregulate the Specificity Protein (Sp) transcription factor, Sp1. Sp1 regulates several genes involved in cell proliferation and apoptosis, including survivin, an inhibitor of apoptosis protein. Interestingly, a recent discovery proposed that a copper(II) complex with TA as a ligand can result in higher therapeutic response; however its efficacy was not tested in gastro-intestinal cancers. Purpose: In this study, we assessed the therapeutic efficacy of a Cu(II)- containing complex of TA (Cu-TA) using human pancreatic cancer cell lines. Methods: MIA PaCa-2 and Panc1 cells were treated with increasing concentrations of DMSO (vehicle), equimolar CuCl2 (negative control), TA or Cu-TA and the cell viability was measured at 24 and 48 h post-treatment using CellTiter-Glo kit. CuTA was further tested for its effect on Sp1 and survivin expression by Western blot and quantitative PCR. The activation of apoptosis was determined by measuring the activity of effector caspases using the Caspase 3/7-Glo kit and the apoptotic cell population through flow cytometric analysis using Annexin-V staining. Cell cycle arrest was assessed by flow cytometry with propidium iodide staining. Results: While both TA and Cu-TA inhibited pancreatic cancer cell growth in a dose/time-dependent manner. Cu-TA was highly effective in inhibiting Sp1 and survivin protein expression and showed similar trend for inducing apoptotic markers and causing cell cycle arrest in G2/M phase. The results of qPCR demonstrated that the expression of survivin mRNA was significantly lower following both Cu-TA and TA treatment; however, the mRNA expression of Sp1 remained unchanged. This indicates that TA and Cu-TA could be affecting Sp1 by a similar mechanism. Conclusions: These results demonstrate that Cu-TA is more effective than TA and potentially useful for pancreatic cancer treatment after clinical testing. Studies to understand precise underlying mechanisms are currently under investigation.
Combination of Vincristine and Tolfenamic Acid induces Anti-proliferative activity in Medulloblastoma Cells.
(2017-03-14) Sankpal, Umesh; Hafeez, Areeba; Bowman, W. Paul; Basha, Riyaz; Patil, Shruti
Background: Medulloblastoma (MB) is the most common pediatric malignant brain tumor and usually originates in the cerebellum. These tumors have the propensity to disseminate throughout the central nervous system and are often difficult to treat. Chemotherapy is widely accepted as part of the multimodality treatment approach for MB. However, it is associated with debilitating toxicity and potential long term disabilities. Vincristine, a commonly used chemotherapeutic agent for MB treatment, is known to induce some toxic effects including peripheral neuropathy. Reducing the dose of the drug to minimize the toxic effect also reduces the cytotoxic efficacy of the drug. Purpose: The aim of this study was to test a combination treatment involving vincristine and an anti-cancer non-steroidal anti-inflammatory drug, Tolfenamic acid (TA) against MB cell lines. Previously, we showed that TA inhibited MB cell proliferation and tumor growth in mice by targeting the transcription factor specificity protein-1 (Sp1) and an inhibitor of apoptosis protein, survivin. The overexpression of survivin is associated with aggressiveness and poor prognosis in several cancers. Methods: DAOY and D283 cells were treated with vehicle (DMSO) or low dose of vincristine (DAOY: 2ng/ml; D283: 1ng/ml) or TA (10 µg/ml) or combination of vincristine + TA and the cell viability was measured at one and two days post-treatment using Cell-TiterGlo kit. Flow cytometry was employed to analyze apoptotic cells using Annexin-V staining and cell cycle phase distribution using propidium iodide staining. The activation of apoptotic pathways was further investigated by assessing the levels of effector caspases with Caspase 3/7-Glo kit and the expression of apoptotic markers [c-PARP, Bcl2, and survivin] by Western blot (WB) analysis. The expression of key proteins associated with cell cycle [Cyclin A, B, D CDK4/6 and p21] was also determined by WB analysis. Results: When compared to individual agents, the combination of TA and vincristine increased MB cell growth inhibition which is accompanied by an induction of apoptotic markers and the modulation of proteins associated with cell cycle phase distribution. Conclusions: These results suggest that vincristine and TA combination treatment is effective for inducing anti-proliferative response in MB cells. The experiments to evaluate the effect of this combination in animal model for MB are currently under study.
Photophysical characterization of oligopeptide linked FRET system in PVA matrix and buffer to detect levels of matrix metalloprotease-9.
(2017-03-14) Mandecki, Wlodeck; Li, Ji; Gryczynski, Zygmunt; Borejdo, Julian; Gryczynski, Ignacy; Fudala, Rafal; Shah, Sunil Ajit
Purpose: Matrix metalloproteinases (MMP’s) are a group of zinc dependent peptidases which can be classified based on their structural differences. So far, over 26 MMP’s have been identified. Out of these, MMP-9 is of particular interest in many biomedical applications. MMP-9, also known as gelatinase B, plays an important role in degrading the basement membrane of the extracellular matrix (ECM). Levels of MMP-9 have been found to be upregulated in several types of cancer, including breast, bladder, colon, ovarian etc. and are generally associated with poor prognosis. The basement degradation activity of MMP-9 allows for tumor growth. Thus, the overall goal of this project is to develop applications for detecting MMP-9 enzyme levels. This would result in rapid, non-invasive detection, and possibly early treatment for several cancers. Approach: We can use Forster resonance energy transfer (FRET) to come up with a custom peptide that is cleaved by MMP-9 enzyme, leading to easy detection and diagnosis. FRET is a well-known phenomenon being used today in studying molecular interactions. Briefly; FRET is the energy transfer between two fluorophores when they are within 1-10nms of each other. The fluorophore with emission at the shorter wavelength acts as the donor, and instead of emitting florescence, transfers its energy to an acceptor molecule, whose emission is generally at a longer wavelength. It is a very sensitive technique which can be used as a precise measurement and detection tool. Materials and Methods: We were able to successfully demonstrate FRET with a custom peptide whose partial sequence was recognized and selectively cleaved by MMP-9 enzyme. The probe uses 5,6 TAMRA and HiLyte 647 as a donor and acceptor respectively. The target peptide sequence is Lys-Gly-Pro-Arg-Ser-Leu-Ser-Gly-Lys-NH2, and was optimized by Kridel et al. The fluorophores were attached to the peptide at the Ser-Leu bond, labeled on the ε-NH2 groups of lysine with donor (5, 6 TAMRA) and acceptor (HiLyte647) dye. Peptide labelled with 5,6-TAMRA only was used as the donor control, and free HiLyte 647 was used as the control for acceptor. The probe and donor control were dissolved in 10% (w/w) poly-vinyl alcohol, and dried on glass slides. This produced films 200 microns in thickness. Furthermore, the probe was dissolved in buffer and upon addition of MMP-9 enzyme, showed a gradual decrease in energy transfer over time. These measurements were done by using a 1cmx1cm quartz cuvette and a square geometry set-up with 470nm as the excitation wavelength. Results: Absorption spectra and other steady state measurements indicate successful energy transfer between donor and acceptor fluorophores which gradually reduces over time as it gets cleaved by MMP-9. This showed that the peptide is functional, and also being recognized and cleaved by MMP-9 enzyme. Conclusions: It is possible to synthesize a functional FRET probe that is selectively cleaved by the enzyme MMP-9, which shows elevated levels in several cancers due to its role in basement degradation. We successfully demonstrated using FRET as a precise technique to detect and measure MMP-9 enzyme activity.
The Therapeutic Role of rHDL Nanoparticles with Saquinavir in Fighting High Risk Neuroblastoma
(2017-03-14) Panchoo, Marlyn; Sabnis, Nirupama; Lacko, Andras G.; Maharaj, Anshumaan
Hypothesis: Our hypothesis is to determine how effective rHDL nanoparticles with saquinavir are in killing neuroblastoma cells. Specifically, we are looking to see how they effect specific cell lines that do express the SR-B1 receptor versus cell lines that do not express the SR-B1 receptor. We are also measuring the effect of rHDL with saquinavir versus free saquinavir in killing neuroblastoma cells. Materials and Methods: The rHDL-saquinavir nanoparticles were prepared by cholate dialysis method, and their biochemical composition was determined using standard assay kits for the different components of the nanoparticle. The average size of the particles was measured using DeLsa Nano particle size analyzer. The cytotoxic effect of the rHDL-saquinavir combination versus free saquinavir was measured against a HRNB cell line, SMS-KCNR, using a CCK-8 kit. Results: The most pertinent result came from the cytotoxicity assay, which showed that free saquinavir was more effective than rHDL with saquinavir in killing neuroblastoma cells from the SMS-KCNR cell line, which has low expression of SR-B1. This is contrary to the previous experiment (from last years data on this same project) which showed that rHDL wth saquinavir was more effective than free saquinavir in killing neuroblastoma cells from the IMR-5 and SJNKP cell lines, which have high expression of SR-B1. Conclusions: From this project, we were able to conclude several things. First was that saquinavir was successfully incorporated into rHDL capsules to form a viable nanoparticle. The particle was also small enough to be incorporated into the cells. The biggest and main conclusion was that the SR-B1 receptor plays a key role in regulating uptake of the rHDL nanoparticles. Cells lines that had high expression of SR-B1 showed more uptake of the nanoparticles, and therefore more cell death. Cell lines that had low levels of expression of SR-B1 showed less uptake of the nanoparticles, and therefore less cell death. Free saquinavir showed more effective killing of cancer cells than encapsulated saquinavir when SR-B1 levels were low. Ergo, cancers that express high levels of SR-B1 can be targeted with encapsulated chemotherapeutic agents such as rHDL. Overall, rHDL nanoparticles are a novel therapeutic treatment strategy that can potentially be used in patients with high risk neuroblastoma as well as other forms of cancer.
Ewing Sarcoma of the Pelvis in a Young Woman
(2017-03-14) Hamby, Tyler; Cope-Yokoyama, Sandy; Bowman, W. Paul; Dorsett, Landry
Purpose: The goal of this project is to improve the management and clinical decision making for patients with Ewing sarcoma. It is also a goal to explore opportunities for earlier diagnoses, which could enhance treatment outcomes. Ewing sarcoma is a malignant tumor most often arising in the medullary cavity of bones and with greatest frequency in the pelvis, femur, and humerus. These patients present with pain at the site of the tumor, but there is often a delay in diagnosis that results in a more difficult course of treatment. The current 5-year survival rate is 75% with long-term cure rate of 50%. The outlook is worse for adolescent and young adult (AYA) patients, especially those with evidence of metastasis at diagnosis. Methods: A retrospective analysis of this patient’s medical history and treatment as it pertains to Ewing sarcoma was conducted. Results: A healthy 18-year-old female presented to her family physician 10 months after the initial onset of hip pain with the chief complaint of constipation and general abdominal discomfort. The pain was progressively worsening and began to radiate down her anterior right thigh. It was exacerbated with exercise, walking, sitting, and caused difficulty sleeping. It was alleviated with bending forward and lying down. There were no reports of numbness, tingling, muscle weakness, or other symptoms in the right leg. On physical exam, her family physician palpated a mass in the right lower quadrant, which was confirmed by ultrasound to be approximately 12cm in diameter. A pelvic MRI confirmed a 9.2 x 13.9 x 12cm soft tissue mass of the right ileum. After 8 weeks of chemotherapy, the tumor showed a significant decrease in size, and she received proton-beam radiation therapy at 14 weeks. On six occasions, chemotherapy had to be delayed by one week to allow for platelet or white blood cell count recovery. At the conclusion of her chemotherapy regimen, the patient was considered to be cancer-free, in remission, and began off-therapy surveillance. This case is significant because it assesses the importance of a prompt diagnosis in the outcome of Ewing sarcoma patients, and the difficulties that can arise during a compressed interval treatment. Conclusions: Despite the large period of time between onset of symptoms and diagnosis, the combination of chemotherapy and radiation achieved a remission. It will be important to follow this patient closely to monitor for risk of relapse and late effects of cancer treatment.
Investigating the affinity of human plasma lipoproteins and albumin to the anti-cancer drug valrubicin
(2017-03-14) Sabnis, Nirupama; Prabhulkar, Shradha; Lacko, Andras G.; Dossou, Akpedje
Background: Reconstituted lipoproteins and albumin are promising targeted drug delivery agents. Valrubicin is a hydrophobic anti-cancer drug currently approved for the treatment of in situ BCG –resistant bladder carcinoma through intra-vesical instillation. An injectable formulation with the patients’ own lipoproteins or albumin as carriers would not only make valrubicin an attractive therapy candidate for other types of cancer, but also limit immunological response and off-target effects including cardiotoxicity. Purpose: This study aimed to assess the binding of valrubicin to human plasma lipoproteins and serum albumin (HSA) under different incubation conditions. We hypothesize valrubicin will preferentially associate with high density lipoprotein (HDL) due to its high hydrophobicity index. Materials and Methods: A solution of valrubicin in dimethyl sulfoxide was incubated for up to 24 hours with either pooled whole human plasma or with individual plasma components at room temperature (RT) or 37 degrees Celsius. Plasma component fractions were separated by ultracentrifugation. A 45 mg/mL albumin solution was used for individual incubation. Absorbance at 490 nm was used to estimate valrubicin concentration in low density lipoprotein (LDL), HDL and HSA. Results: Incubation for 2 hours at RT yielded the highest valrubicin concentration in plasma components. Overall, valrubicin association with plasma components moderately increased with the amount of valrubicin added prior to incubation. For instance, 0.185 mg and 1.121 mg of valrubicin was recovered with respectively 1 mg and 5 mg of valrubicin initially added to 1 mL of plasma. About 4%, 10% and 86% of the initial valrubicin added to whole plasma were respectively distributed in the LDL, HDL and the HSA –containing plasma fractions after ultracentrifugation. The incorporation of valrubicin in HDL increased-though not proportionally- with 10 fold concentration of HDL. However, prolonged incubation of valrubicin with 45mg/mL HSA resulted in the dissociation of valrubicin and HSA. Conclusions: Our preliminary data suggests differential interaction of valrubicin with plasma components with preferential binding to HSA. The optimization of the HSA/ valrubicin complex will be required to develop an efficient drug transport formulation. HSA stabilizing agents such as sodium acetyltryptophanate and sodium caprylate could potentially facilitate and stabilize the binding of valrubicin to HSA.
Cell Ghost Coated Polymeric Nanoformulation For Brain Metastasized Triple Negative Breast Cancer
(2017-03-14) Van Treuren, Timothy; Ranjan, Amalendu; Chaudhary, Pankaj; Vishwanatha, Jamboor; Kumar, Piyush
Background: Nanoparticle-mediated targeted delivery has become the buzzword in cancer therapy due to its small size and ease in modulation. Cell ghost derived from cancer cells that mimic the cellular environment can be used for specific targeting of tumor in personalized therapy. Purpose: The purpose of this study is to design drug delivery system for personalized medicine to check the brain metastasized Triple Negative Breast Cancer (TNBC). We speculate that cell ghost derived from the tumor of the cancer patient can also be used as a personalized treatment of metastatic cancer. Methods: Cell ghost isolated from brain metastasized TNBC cells was coated on polymeric nanoparticles. Dynamic Light Scattering & Zeta Size analyzer (Malvern Instruments, USA) were used to determine the hydrodynamic size & surface charge of the cell ghost coated nanoparticles(CGNP) respectively. SDS-PAGE was used for comparative analysis of proteins in the cell ghost & CGNP. The Cell uptake of the dye-loaded CGNP was studied using the confocal microscope (Zeiss microscope USA). Results: We have successfully formulated cell ghost coated polymeric nanoparticles (CGNP).The size & surface charge of the CGNP are in desirable range to cross the blood-brain barrier to target brain metastasized TNBC. The SDS-PAGE analysis confirmed that protein contents of cell ghost are stable in CGNP. Confocal microscopic image analysis showed that maximum cellular uptake of these nanoparticles by TNBC cell line. Conclusions: In summary, we concluded that cell ghost isolated from TNBC cells could be used as targeting agents for brain metastatic TNBC. These nanoparticles have maximum cellular uptake and retain the protein contents of cell ghost on nanoformulation infers its possible role in generating personalized medicine for the brain metastasized TNBC treatment.
Cholesterol Metabolism in High Risk Neuroblastoma. Contributions by the SR-B1 Receptor and Cholesterol Ester Accumulation
(2017-03-14) Spolitu, Stefano; Deligia, Stefania; Batetta, Barbara; Lacko, Andras G.; Panchoo, Marlyn
Background: Cancer cells promote their survival by reprogramming metabolic pathways. Alterations in cholesterol metabolism have been observed as one of these mechanisms, including reduced levels of high-density lipoprotein (HDL) cholesterol in cancer patients. In high-risk neuroblastoma (HRNB), an extra cranial pediatric cancer, activation of genes associated with cholesterol synthesis has been reported. However, it is unclear whether modification in exogenous sources of cholesterol also occur in HRNB. An external source of cholesterol is from lipoproteins via the scavenger receptor class B type 1 (SR-B1) lipoprotein receptor that mediates the selective uptake of cholesteryl esters (CE) into the cell. In neuroblastoma high expression of SR-B1 correlates with poor prognosis. Objective: Our goal was to examine whether the accumulation of cholesteryl ester occurs in HRNB cells and whether this process is correlated with SR-B1 expression. Methods and Results: Human neuroblastoma cell lines expressing wild type p53; SH-SY-5Y, SMS-KCNR, and mutated p53; SK-N-BE (2), and BE (2) C were cultured. Western blot analysis confirmed the presence of the HDL receptor, SR-B1, and the multidrug resistant protein 1 (MDR1). Fluorescence staining of lipid droplets was performed using Nile Red. The neutral lipid content in SH-SY-5Y and SMS-KCNR, was higher at 24 hours than 72 hours suggesting that at 24 hours either increased accumulation or synthesis of neutral lipids occurred. To examine cholesterol esterification, cells were incubated with 14C-oleate. Cells were collected, lipids extracted with cold acetone and neutral lipids separated by thin layer chromatography. The results indicated notable reduction in cholesterol esterification in p53-mutated cells as compared to the wild type cells. However, triglyceride synthesis seems unaffected by p53 mutation when compared with the wild type. Conclusions: We confirm that there is accumulation of cholesteryl esters and high expression of SR-B1 in HRNB. These findings present a more in depth understanding of molecular mechanisms that drive progression of HRNB and may provide unique molecular targets to combat HRNB and other cancers. Future plans will include investigating cholesteryl ester accumulation and SR-B1 expression as a function of cell proliferation in HRNB. Additionally, human neuroblastoma tissue samples will be used to investigate the association between overexpression of SR-B1 and tumor aggressiveness.
CRISPR deletion of MIEN1 in Triple Negative Breast Cancer
(2017-03-14) Desai, Priyanka; Vishwanatha, Jamboor; Van Treuren, Timothy
Purpose/Objective: Triple negative breast cancer (TNBC), which accounts for 15-20% of all breast cancer diagnoses, is the most aggressive subtype of breast cancer. The propensity of TNBC to metastasize to vital organs, such as lung, brain and bone, early in the disease progression is its most devastating feature, which leads to the high mortality rates seen among women diagnosed with TNBC. Efforts to identify specific factors that are able to predict disease progression to aggressive TNBC have proved to be fruitless thus far. In addition, the standard treatments for TNBC are radiation therapy, systemic chemotherapy and/or resection surgery since there are currently no target-based therapies for TNBC. In an effort to address these knowledge gaps, the objective of this project is to knock-out (KO) the oncogene Migration and Invasion Enhancer 1 (MIEN1), implicated in TNBC disease progression, in MDA-MB-231 TNBC cells using CRISPR genome editing technology in order to assess MIEN1’s ability to mediate migration and invasion. Methods: Single-guide RNAs (sgRNAs) were designed to delete the C-terminal end of exon 2, along with exon 3 and 4 of the MIEN1 gene. Following transient transfection of CRISPR plasmids containing sgRNA/Cas9/GFP, MDA-MB-231 cells were FACS sorted into 96-well plates at a concentration of 1 cell/well. Colonies were then identified, genotyped and screened via western blot to confirm MIEN1 protein KO. Downstream signaling pathways were also analyzed via western blot. Various in vitro migration assays were performed to evaluate functional consequence of MIEN1 KO in TNBC cells. Results: 22.2% of MDA-MB-231 single-cell colonies screened showed deletion of at least one MIEN1 allele. 10.3% of colonies screened showed complete KO of MIEN1 protein. In addition, western blots showed a reduction in downstream signaling through Akt/NF-kB as a result of MIEN1 KO. MIEN1 KO also resulted in reduced migratory phenotype in vitro. Conclusions: Designed CRISPR sgRNAs effectively target the MIEN1 gene. MIEN1 KO in TNBC cells results in reduction of pro-metastasis signaling and cell migration.
The Use of Positron Emission Tomography-Computed Tomography in the Early Response Assessment of Nodular Sclerosing Hodgkin Lymphoma: A Case Series
(2017-03-14) Bowman, W. Paul; Forner, Elizabeth
Purpose: Positron Emission Tomography-Computed (PET-CT) is increasingly being incorporated into the management of pediatric lymphomas. Clinical trials are currently using “interim” PET/CT to assess early response and are seeking to establish whether its’ predictive value can successfully be used to direct individual treatments with the purpose of improving outcomes and decreasing treatment-associated toxicities. This review presents three cases of pediatric Hodgkin’s Lymphoma (HL) seen at Cook Children’s Medical Center (CCMC) to demonstrate the role that PET/CT is currently playing in the management of high-risk HL patients. Methods: A literature review was first performed in regards to the current protocol for PET-CT imaging in pediatric malignancies. It was found that the utility of PET-CT in this population is not yet a standard of care but there is support in the literature for its’ use in risk-stratification and treatment modulation. A review of the cases of three pediatric HL patients at CCMC receiving PET-CT imaging during their initial treatment was performed. The clinical decisions made by practitioners were examined to determine whether the PET-CT imaging that was done in addition to standard CT imaging changed treatment decisions among these three patients. This was based on examining whether the radiologic reports from the PET-CT studies provided additional information about treatment response in comparison to the CT imaging that was performed. It was also examined whether this additional information that was provided by the PET-CT studies was used to guide clinical decisions as demonstrated by changes in treatment plans. Results: In each of these three cases, PET-CT imaging provided the practitioner with additional information over the CT imaging alone. Patient 1 was found to have residual bulky disease on CT imaging. The PET-CT imaging provided the additional information that the lesions were not metabolically active. This demonstrated that the malignancy was responding well to the chemotherapy treatment. This patient was able to avoid radiation therapy due to the additional information that the PET-CT imaging provided. Patient 2 also showed residual bulky disease on CT imaging but a marked decrease in metabolic activity on PET-CT imaging similar to patient 1. This patient, however, had such extensive involvement at diagnosis that the protocol they are enrolled on required involved site radiation therapy (ISRT) regardless of PET-CT negativity. This case demonstrates a patient that may have been able to avoid radiation therapy if using PET-CT is the sole standard of treatment response assessment in the future. Patient 3 had one region that was found to still be metabolically active on PET-CT and was subjected to ISRT of this region specifically. Other previously involved regions avoided radiation therapy as they were determined by PET/CT to be responsive to chemotherapy. Conclusions: PET-CT has become a valuable resource in evaluating the response to chemotherapy in this population. PET-CT played a pivotal role in the risk-stratification among these three patients and kept one of them completely off of radiation therapy and allowed the others to receive ISRT and allowed avoidance of full body radiation. It provides a promising means by which pediatric patients with high-risk HL can avoid unnecessary chemotherapy and radiation related toxicities.
A Bioinformatics Approach to the Design and Engineering of Biomimetic Personalized Nanoparticle Therapy for Bone Metastatic Prostate Cancer
(2017-03-21) Ranjan, Amalendu; Lin, Victor; Lampe, Jana B.; Vishwanatha, Jamboor; Gdowski, Andrew
Purpose: Bone metastatic prostate cancer remains a challenge to treat clinically due to lack of therapies prolonging overall survival and off target side effects of current treatments. In this study, we employ a bioinformatics approach for target validation and design of biomimetic cancer-coated nanoparticles (CCNP) for treatment of bone metastatic prostate cancer. Our goal is to personalize this targeted therapy by utilizing a patient’s own cancer cells to coat the nanoparticles. We hypothesize that this approach will be an effective strategy to deliver drugs to the site of metastasis. Methods: A bone metastatic prostate cancer target was identified utilizing The Cancer Genome Atlas (TCGA) database from a study of 130 patients with metastatic prostate cancer who underwent next-generation sequencing of their tumors. We used this information and stimulated prostate cancer cells to increase expression of this targeted cell membrane protein. These membranes where purified and used to coat nanoparticles. Nanoparticles were characterized with TEM, DLS, and zeta potential. Membrane purification was validated with coommassie stain and western blot. Membrane orientation on nanoparticle surface was verified with an immuno-conjugation assay. Nanoparticle cancer cell uptake was quantified through immunofluorescence and flow cytometry. Cell viability was performed with MTT assay. Results: Nanoparticles were successfully coated with stimulated cancer cell membranes. Nanoparticle size and zeta potential both increased after coating with membrane. After membrane purification, only markers for cell membranes were identified. Immuno-conjugation assay demonstrated that the cell membrane coating was correctly oriented on the nanoparticle surface. Immunofluorescence results showed when nanoparticles were coated with the cell membrane, there was increased nanoparticle uptake. This was verified by flow cytometry. Stimulated nanoparticles showed decreased cell viability in MTT assay. Conclusions: We successfully engineered cancer coated nanoparticles and validated the manufacturing process. This novel approach to target identification and personalized coating of nanoparticles has tremendous potential as a strategy for treating bone metastasis in prostate cancer patients. Future experiments will study in vivo targeting of bone metastatic lesions with these biomimetic nanoparticles.
Hemophagocytic Lymphohistiocytosis Secondary to Malignancy and Chemotherapy in Pediatric Patients
(2017-03-14) Kaheri, Mahdi; Ray, Anish; Haloot, Justin
Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon yet potentially devastating systemic disease arising from uncontrolled activation of the immune system. While the primary form of this disease can be caused by genetic mutation(s), the secondary form maybe triggered by infection, hematologic, malignant and metabolic conditions. Here, we present 3 cases of HLH secondary to malignancy and chemotherapy in pediatric patients. Purpose: The diagnosis of HLH remains a clinical challenge due to nonspecific symptoms such as fever, skin rash, cytopenias and splenomegaly found at presentation. Proper diagnosis is significantly more difficult among patients with acute leukemia who have received chemotherapy and present with fever and pancytopenia. The objective of this study is to describe three unique cases of secondary HLH, describe the specific treatment for this entity, and improve the awareness of this condition Methods: Three patients were diagnosed with HLH at Cook Children’s Medical Center (CCMC) between June 2006 and June 2016. They were treated per HLH-2004 guidelines. Medical records of these patients were reviewed at CCMC. Data collected included timeline of diagnosis of HLH in relation to primary diagnosis and treatment, laboratory values, pathology studies, outcome of HLH after treatment, and overall survival. Conclusions: Two patients with acute myeloid leukemia (AML) and one with acute lymphoblastic leukemia (ALL) were diagnosed with HLH, having fulfilled the criteria as outlined in HLH 2004 protocol. They then received HLH specific treatment. One patient passed from refractory HLH, one from primary disease (i.e. AML) and one patient remains alive 22 months from her allogeneic bone marrow transplant. The diagnosis of HLH requires the presence of any of the five following criteria: fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK cell activity, hyperferritinemia, and elevated soluble interleukin 2 receptor level. Due to its heterogeneous presentation, it remains imperative that treating clinicians remain cognizant about HLH so that prompt diagnosis may allow appropriate treatment. Two out of 3 patients in our study were in remission with regard to HLH, while 1 patient succumbed to refractory disease. We hope to improve awareness of HLH among pediatric oncologists that will lead to improved survival and better outcome for these patients.
Dietary Intake of Calcium, Magnesium and Risk of Breast Cancer
(2017-03-14) Tao, Menghua; Li, Furong
Objective: Magnesium (Mg) is the second most abundant intracellular cation in the body, and is essential for DNA synthesis and repair, and associated with DNA mutations leading to carcinogenesis. Calcium (Ca) plays an important role in various cellular activities including cell proliferation, differentiation, and apoptosis. Magnesium and calcium antagonizes each other in (re)absorption, cell cycle regulation, inflammation and many other physiologic activities. However, results on the relationships between dietary intake of magnesium and calcium remain mixed, and few studies have evaluated the interaction between calcium and magnesium intake on breast cancer incidence. We aim to test whether the associations of breast cancer risk with intakes of calcium and magnesium differ by the dietary Ca to Mg intake ratio. Materials and Methods: The Swedish Women’s Lifestyle and Health Cohort Study included 49,259 women in Sweden who were aged 30-50 years between 1991 to 1992. Complete follow-up for breast cancer incidence was performed until December, 2012 through linkage to national registries. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer risk. Results: During follow-up, 1909 primary, incident breast cancer cases were diagnosed. After adjusting for known risk factors of breast cancer, intakes of energy, vitamin D, magnesium, higher dietary intake of calcium was associated with reduced breast cancer risk (HR: 0.98; 95%CI: 0.98-0.99 for highest versus lowest quartile; p trend = 0.01), and dietary intake of vitamin D was also associated with reduced breast cancer risk (HR: 0.46; 95%CI:0.25,0.86) for highest versus lowest quartile. Conclusions: In this preliminary analysis, we found that dietary calcium and vitamin D intake may be protective factors of breast cancer for women.
Colorectal Cancer Knowledge and Screening Habits among Refugee Populations in DFW
(2017-03-14) Raines-Milenkov, Amy; Baker, Eva; Subedi, Radhika; Thein, Emelda; Qureshi, Iram; Kwentua, Victoria
Purpose: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Although resources are available to screen for and to treat CRC, refugees living in the United States report low levels of screening. Over the past several years, Texas has resettled the largest numbers of refugees, yet little research has investigated the need for colorectal cancer screening in refugee populations. This study aimed to assess local refugees’ current knowledge of and experience with colon/rectal cancer and screening. This information is needed to guide effective CRC education and screening efforts among this underserved population. Methods: Refugees, previously enrolled in a community-based refugee health program, the Building Bridges Initiative (BBI), were contacted by bilingual lay health educators to complete a 23-question phone interview on their familiarity with CRC. The survey was translated into Nepali and Karen by a professional translator, and included detailed descriptions of colon cancer and available screening methods. Descriptive statistics were compiled using statistical analysis software. Results: Twenty-nine of the 43 eligible participants (ages 50-75) agreed to participate. 72% of participants were unaware of colon cancer, and 97% wanted more education on the subject. Familiarity with the screening process and physician recommendation were strong motivators to complete a CRC screening. Conclusions: Local refugee populations are receptive to CRC screening. Programs such as BBI have the structure in place to provide culturally and linguistically appropriate education and tailored evidence-based interventions, which are necessary to reduce health disparities when it comes to CRC screening.
Case Study: Long-Term Effects of Treatment in a Survivor of Stage IV Neuroblastoma
(2017-03-14) Bowman, William; Bell, Hailie
Purpose: Neuroblastoma is a tumor of the sympathetic nervous system and adrenal medulla that most frequently affects the paravertebral area of the abdomen and the posterior mediastinum of children with a median age of 18 months at diagnosis [1]. It accounts for 8% of pediatric cancers, yet it is responsible for 15% of deaths from pediatric cancer [2]. Although great strides have been made in the treatment of this disease over the last several decades, children diagnosed with high-risk neuroblastoma still have an unfavorable 5-year survival rate of 40%[1]. While extensive literature exists on the progression of neuroblastoma, not much can be found on the long-term effects of those who have survived high risk disease. Methods: An 8-year-old female was diagnosed in 2005 with localized stage II neuroblastoma of her upper abdominal paraspinal region. The localized tumor was resected and she appeared to be cancer-free. However, she relapsed 3 months later with metastatic stage IV disease that had progressed to widespread bone marrow involvement. After approximately 3 years of undergoing multiple protocols of chemotherapy along with radiation, I-MIBG (metaiodobenzylguanidine) therapy and hematopoietic stem cell transplantation, this young girl was found to be tumor-free. She has been in continuous remission for 10 years but her survivorship has not been without great obstacles. Results: While long term survival of stage IV neuroblastoma is a remarkable feat, the patient has continued to face obstacles resulting from late effects of treatment. She has had recurring bouts of thrombocytopenia, delayed-onset puberty with amenorrhea, primary ovarian failure and high frequency hearing loss, all of which resulted from her exposure to chemotherapeutic agents and radiation at a young age. She has faced these challenges with courage and a commitment to live as normally as possible; however, she must continue to be monitored closely for any long-term residual effects that could still manifest, in order to manage these effectively. Conclusions: This is a unique case of a child diagnosed at an older than expected age with stage IV neuroblastoma who survived the high-risk cancer and has remained in remission for many years after her treatment. She has encountered and overcome many hardships during her remission. This case highlights the importance of studying the long-term effects of treatment that survivors of childhood cancer face as they enter adulthood.

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