Children's Cancer Hospital Newsletter - Spring 2012 by MD Anderson Cancer Center

NEWSLETTER

• • • • • • SPRING 2012

Focus on adolescents, young adults Cancer180, AYA Council cater to their needs

hey’re too old for the pediatric playroom and too young to relate to a waiting room of older patients. That’s the experience felt by many adolescent and young adult (AYA) cancer patients. About 72,000 teens and young adults are diagnosed with cancer each year in the United States, according to the National Cancer Institute. Their particular needs, both medical and developmental, make them misfits in either pediatric or adult centers. But that’s all changing, and MD Anderson is one of the leaders ensuring it. Not only does the institution focus on enhancing the care and experience for AYA patients, but it also works directly with patients and survivors to guide its programs.

• they feel alone; • they’ve rarely met or even seen another patient their own age going through what they are; • they’ve lost their independence and are relying on their parents again; • they’re isolated from friends due to treatment; • as survivors, their friendships may have changed through cancer; and • they find themselves with an experience that few of their peers can understand.

During the past two years, the Anderson Network, a program of MD Anderson’s Department of Volunteer Services, has designed a special initiative for young adult patients, survivors and their friends called Cancer180. The MD Anderson-based program got its name from a young caregiver who said that when cancer strikes,

life does a 180. Activities are open to all young adult patients and survivors, ages 18 to 39, regardless of where treatment is received. Throughout the year, social events such as bowling, pottery making, cooking classes and other activities are arranged to bring young adult patients and survivors together in a fun setting.

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Some of the most common remarks Elsa Morse, child life specialist who also works as a young adult specialist at MD Anderson Children’s Cancer Hospital, hears when visiting with young adult patients are that:

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It’s just not the same

Cancer180, AYA Council - continued “We’ve found that traditional support groups don’t always appeal to some in this age group. Providing the opportunity for them to connect in a more social, non-medical environment allows the story sharing to occur in a fun and natural way,” says Marisa Mir, program coordinator for the Anderson Network. “I like the camaraderie I get when I go to the Cancer180 events,” says Mark Gardner, a 28-year-old leukemia survivor. “It gives me a chance to see what other survivors are doing with their lives and catch up outside of the hospital. Plus, many of us share common issues as survivors, so we can discuss how we’re handling them.”

Patients know best Patients and their families are the experts about their bodies and should be viewed as partners, not recipients, when it comes to planning care.

“I like that our council actually has an impact on what services may be developed. I’ve also gained a better respect for the staff and what they’re trying to do.”

Believing in this concept, the Children’s Cancer Hospital began an initiative within the Division of Pediatrics and MD Anderson to show the importance of family- and patient-centered care as part of its daily operations.

Morse has been a member of the council since its inception and continues to value the insights she gains at monthly meetings.

Led by Patty Wells, director of family-centered care, a Family Advisory Council was formed in 2008 and includes parents of pediatric cancer patients and hospital staff. The success of that council spurred an idea to create a patient advisory council. The AYA Advisory Council began in 2009 with members — 12 young adult patients and 14 staff — from various areas throughout MD Anderson. “The AYA Council has been a way for me to explore the survivorship stage of cancer and the ups and downs that come with it,” says Chad Tremont, a 26-year-old lymphoma survivor and co-facilitator of the council.

Children’s Cancer Hospital • Spring 2012

“I like to hear the varying perspectives from our patients on active treatment to our survivors who have been off treatment for years,” she says. “When it comes to meeting the needs of this age group, there’s no ‘onesize-fits-all’ concept that applies. We must recognize that to develop better patient and survivor programs.” Although Morse is right that not every AYA program or service will meet all needs of MD Anderson’s AYA population, the institution is working hand in hand with patients to create programs and services for this unique age group. The hope: that no AYA patients will feel alone or without support through their cancer journey.

Division of Pediatrics

‘B’ is for basketball, not baby

Fertility discussion important for young patients When a 16-year-old male is diagnosed with cancer, he isn’t thinking of what he’ll name his first child. He just wants to know if he’ll live and how long it will be before he can return to workouts with his sports team. Fertility is the last thing on his mind. But it’s at the forefront for Anna Franklin, M.D. Franklin, assistant professor at MD Anderson Children’s Cancer Hospital, opened the institution’s fertility clinic in 2010. She is joined by nurse practitioner Donna Bell. Together, they consult with AYA patients about: • their personal risk of infertility due to cancer treatment,

Academic Office: 713-792-6620 Division Head Eugenie Kleinerman, M.D. Deputy Division Head Robert Wells, M.D. Adolescent/Young Adult Anna Franklin, M.D. Martha Askins, Ph.D. Michael Rytting, M.D. Bone Marrow Transplantation Laurence Cooper, M.D., Ph.D. Susan Kelly, M.D. Dean A. Lee, M.D., Ph.D. Demetrios Petropoulos, M.D. Laura Worth, M.D., Ph.D. Brain/Neural Tumors Vidya Gopalakrishnan, Ph.D. Soumen Khatua, M.D. Michael Rytting, M.D. Tribhawan Vats, M.D. Endocrinology Steven Waguespack, M.D. Anita Ying, M.D. Hematology Deborah Brown, M.D. Nidra Rodriguez, M.D. Trinh Nguyen, D.O. Leukemia/Lymphoma Robert Wells, M.D. Joya Chandra, Ph.D. Anna Franklin, M.D. Cesar Nunez, M.D. Michael Rytting, M.D. Patrick Zweidler-McKay, M.D., Ph.D. Nephrology Joshua Samuels, M.D. Joseph Angelo, M.D.

• options available for fertility preservation, and

Neurology/Neurofibromatosis Bartlett Moore, Ph.D. John Slopis, M.D.

• financial resources to help with out-of-pocket expenses for fertility preservation.

Non-Neural Solid Tumors Peter M. Anderson, M.D., Ph.D. Najat Daw, M.D. Nancy Gordon, M.D. Cynthia Herzog, M.D. Dennis Hughes, M.D., Ph.D. Winston Huh, M.D. Eugenie Kleinerman, M.D. Nidale Tarek, M.D. Shulin Li, Ph.D.

In addition, Franklin is developing studies that will track patients’ fertility status after treatment and investigate which methods prove to be more accurate predictors. By collecting better data, she hopes to form more precise risk assessments for patients before starting treatment.

Broadening access Recent technology has broadened fertility opportunities for patients, even those who haven’t reached puberty. Although some preservation techniques are still considered experimental, such as ovarian and testicular tissue banking, Franklin wants patients to be able to access those services through referrals from the clinic. “We hope that every physician initiates a discussion about fertility with a patient before treatment begins,” she says. “Beyond that first conversation, our clinic serves as a resource to help guide patients step by step through the planning process. We want them to know their options and help them make the best choice.”

Critical Care Jose Cortes, M. D. Rodrigo Mejia, M.D. Regina Okhuysen-Cawley, M.D. Sanju Samuel, M.D. Pediatric Surgery Mary Austin, M.D. Charles Cox, M.D. Andrea Hayes-Jordan, M.D. Kevin Lally, M.D. KuoJen Tsao, M.D. Orthopedic Surgery Valerae O. Lewis, M.D. Patrick P. Lin, M.D. Bryan Moon, M.D. Neurosurgery Fred Lang, M.D. Raymond Sawaya, M.D. Jeffrey Weinberg, M.D. Psychology Martha Askins, Ph.D. Bartlett Moore, Ph.D. Rhonda S. Robert, Ph.D. Survivorship Joann Ater, M.D. Winston Huh, M.D.

Drug shortages frustrate pediatric oncologists, patients By Sara Farris

Recent news stories have unveiled a growing concern among pediatric oncologists and health care institutions. Many predict we’re facing a nationwide drug shortage issue. Most recently, the injectable form of preservative-free methotrexate, commonly used to treat pediatric patients with leukemia and osteosarcoma, was at a critical supply level.

The bigger drug shortage picture

Drug shortages are an increasingly frequent and serious problem affecting health care organizations. “A number of contributing factors are causing these shortages, such as raw material unavailability, manufacturing difficulties and regulatory issues, voluntary recalls related to manufacturing problems, changes in medication formulation, and industry consolidations and economic decisions,” says Wendy Heck, Pharm.D., manager of drug information and drug use policy at MD Anderson. Regardless of the catalyst, drug shortages create great frustration for everyone involved, including purchasing agents, pharmacists, nurses, physicians and patients. Fortunately, MD Anderson can usually work around drug shortages due to its larger volume of stocked pharmaceutical agents. “We meet weekly to review current drug shortages. If a shortage does reach MD Anderson, our team works diligently to develop a management plan to minimize the impact on our patients,” says Joel Lajeunesse, vice president and head of the Division of Pharmacy. “For now, we have sufficient supplies of methotrexate.”

Managing methotrexate supply

Pediatric oncologists at MD Anderson Children’s Cancer Hospital work closely with pharmacists to manage the methotrexate supply for pediatric patients. The most recent concern involves the preservative-free form of injectable methotrexate. It’s commonly used for intrathecal, or spinal cord, injections because it lowers the risk for neurotoxicities, such as paralysis. The shortage was alleviated when the U.S. Food and Drug Administration allowed the temporary import of methotrexate and another scarce drug from countries abroad. Although helpful, many feel this is a band-aid approach to a larger issue. “We’ve been dealing with drug shortages in pediatric oncology for a while now, whether it stems from lack of development or discontinued production,” says Patrick Zweidler-McKay, M.D., Ph.D., section chief of leukemia at the Children’s Cancer Hospital. “It’s not as profitable for companies to make drugs for rarer cancers, such as childhood cancer. However, this situation involves vital standard-of-care drugs, and we can’t get a consistent supply of them. Something must be done for our patients’ sake.”

Children’s Cancer Hospital • Spring 2012

Advocating for a solution Advocacy groups, health care professionals and patients are uniting to bring a voice to the specific needs related to childhood cancer. Last March, families congregated on Capitol Hill as part of a special day hosted by the Children’s Oncology Group. Then, in September, Eugenie Kleinerman, M.D., head of the Children’s Cancer Hospital, and other leaders in pediatric oncology spoke before a Congressional panel on the need for drug development for childhood cancer. Val Marshall is one of thousands of parents who have lobbied on Capitol Hill with the Children’s Oncology Group. Her son, Addison, has spent the last three years undergoing treatment at the Children’s Cancer Hospital for acute lymphocytic leukemia, the most common cancer in children. Much of Addison’s treatment, both initially and after a relapse, has consisted of methotrexate, including intrathecal administration. He knows firsthand the fear that comes with a pending drug shortage. “It’s scary because you think if you can’t get the drug when you need it, the cancer will come back,” says the 18-year-old. Val plans to return to Capitol Hill in June to continue meeting with legislators and raising awareness about the needs of young cancer patients like her son. “This has been a band-aid solution, and band-aids are better than open wounds,” she says. “But it’s time we find a more long-term solution, and that’s why I’m going back to Washington.”

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Coordinators of care Mid-level providers play key role for patients By Lindsey Garner

Cole’s desmoplastic small round cell tumor diagnosis was originally treated with surgery and chemotherapy, but after returning home to St. Louis, Cole developed an infection at the incision site. Green, left, remained in constant communication with Owens and Cole’s local physicians. Acting as the intermediary between his specialists at CCH and physicians in St. Louis, Green helped coordinate a plan for Cole to get back on the road to recovery. As with Green’s experience, MLPs are often seen as the “glue” or“go-between” for other medical staff, patients and caregivers. But when one digs deeper, their impact on patient care is far-reaching. “Mid-levels play a vital role in helping to provide excellent patient care,” says Sarah Bottomley, mid-level provider manager for CCH. “Our focus and training bring a complementary perspective to help address the complex needs of our patients and their families.”

Growing in numbers and expertise During the past 10 years, the number of mid-level providers contributing to patient care at CCH has steadily increased to match the hospital’s childhood cancer patient population, which saw a 30% growth from 2005 to 2009. In 2001, there were no more than three MLPs at CCH. Today, there are three physician assistants and 11 nurse practitioners (NP). Green enjoys the intellectual challenge of her job and is inspired by the high caliber of doctors working at CCH, which allows her to continue to advance her skills. “Our mid-levels know how to provide the most delicate and specialized types of care,” says Riza Mauricio, an advanced practice nurse in the pediatric ICU at CCH.

Educators and advocates “As mid-levels, our training and experience provide us the opportunity to serve as educators and advocates for patients and their families, as well as other employees,” Bottomley says. MLPs provide care that looks beyond the disease process and is more holistic and family-centered. Including the family and caregivers in the treatment process is essential, Bottomley says. Complementing this strength is the keen ability of MLPs to address patient needs by incorporating other disciplines into the treatment process, such as support programs and psychological services. The theme of education continues in the relationships MLPs have with staff members. They collaborate with nurses, specialists and technicians to bolster their skills and knowledge base and provide educational opportunities.

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o Laura Owens, a mid-level provider is a “hero, champion and friend.” Mid-level provider (MLP) Holly Green, a physician assistant on the surgery team at MD Anderson Children’s Cancer Hospital (CCH), worked in depth with Owens to prepare her and son, Cole, for a surgical procedure. Mauricio knows firsthand how training can help staff. In 2005, she assessed and identified the needs of nurses and respiratory therapists in the ICU. This led her to collaboratively develop an annual three-day workshop, where experts from MD Anderson and nearby institutions present on the human body systems coupled with bedside training. “Every day presents an opportunity for all of us to learn something new,” Mauricio says. “But with this training, they’re empowered with knowledge and skills that give them confidence in the work they do.”

More than support Working in tandem with faculty, each MLP’s role differs slightly within each team at CCH. However, what’s similar is that they all act independently and interdependently within their teams. “We’re more than liaisons between our faculty, patients and their families,”says Mauricio. “We make sure that there’s movement and progress — we’re care coordinators.” Within the hospital, MLPs frequently participate in the development of protocols, policies and procedures to improve efficiency and standards of care for patients. This is true even for routine tasks, like drawing blood. Previously, volumes of blood drawn for lab tests were equivalent to those used for adult patients. Mauricio felt that this experience could be made more pediatric-friendly and created a task force with faculty, nurses and lab techs. As a team, they established a new policy for pediatrics on how to draw blood, minimizing the stress placed on patients and making the process more efficient.

Room to grow With a career in oncology that spans 25 years, Bottomley has seen the presence of MLPs in this specialty grow. She expects that the reliance on and need for MLPs will continue to increase because of likely future gaps in patient access to care. This is primarily due to factors such as health care reform, the decreased availability of medical residents and a growing patient population. With MLPs poised to take on more responsibilities, Bottomley finds reassurance in knowing that “our roles are nicely supported and valued within the institution, and I feel they will continue to be.” Owens values Green’s role in helping Cole get on the path to becoming cancer free. “Holly helped see us through every challenge,” she says. After overcoming many challenges, 10-year-old Cole is healthy, back to playing baseball, a straight A student and having fun “just being a kid” on his school breaks. The University of Texas MD Anderson Cancer Center • Division of Pediatrics

Research Highlights

from Children’s Cancer Hospital Laurence Cooper, M.D., Ph.D.

MD Anderson Children’s Cancer Hospital is focusing on understanding each cancer at the molecular level so that more targeted treatments with less toxicity can be found. As molecular pathways that are abnormal in different childhood cancers are defined, investigators can better determine which new therapies developed for adult cancers may apply to treating pediatric patients. In addition, the Children’s Cancer Hospital is investigating immunotherapies and cell therapies as treatments for metastases and for eliminating residual microscopic disease after conventional treatments.

Here’s a summary of Children’s Cancer Hospital research highlights for 2011. If you’re interested in learning more about any of these studies, call the Children’s Cancer Hospital, 713-792-5410, to speak directly with an investigator.

Children’s Cancer Hospital • Spring 2012

Dean Lee, M.D., Ph.D.

Shulin Li, Ph.D.

Cell Therapy Targeting Leukemias by CD123-specific Chimeric Antigen Receptor Finding: The specificity of T cells can be engineered to recognize a molecule of cancer stem cells Application: To develop potent immunotherapy for AML Source: Presented at American Society of Hematology (ASH) annual meeting Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Image-Guided T Cell Therapy Using Nanoparticles Complexed With PET Imaging Probes Finding: Positron emission tomography can be used to reveal the presence of T cells. Application: To assess whether infused T cells can migrate to sites of malignant disease Source: Presented at Gordon Research Conference Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Adoptive Transfer Therapy Using Expanded Melanoma-specific T Cells Programmed Ex Vivo for Improved Efficacy In Vivo Finding: A new culturing technique was developed to generate melanoma-specific T cells. Application: To improve our ability to generate clinical grade T cells for use in trials Source: Presented at American Society for Blood and Marrow Transplantation (ASBMT) annual meeting Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Assessing Potential Genotoxicity of Sleeping Beauty Transposition Events in T Cell Immunotherapy by Supercomputer-based High-throughput Profiling Finding: High-performance computing was coupled with high-throughput sequencing to understand the risks and benefits of a new approach to genetic engineering. Application: To improve our understanding of the gene therapy platform, which we are using to engineer T cells for use in ongoing clinical trials Source: Presented at ASH Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Improved In Vivo Persistence of CD19-specific T Cells Expressing a Membrane-bound Form of IL-15 Finding: Genetic engineering can be used to improve the ability of T cells to persist after infusion. Application: To generate T cells that not only can target B-cell tumors, but also exhibit improved persistence Source: Presented at Society for Immunotherapy of Cancer (SITC) annual meeting Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Digital Multiplexed Quantification of Both T Cell Receptor Beta-chain and Alpha-chain Diversity in T Cells Using the Nanostring Ncounter Assay System Finding: A new technique was developed that reveals the type of receptors T cells employ to recognize antigen. Application: To improve our understanding of how T cells recognize tumors Source: Presented at ASBMT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Genetic Reprogramming and Editing of T Cells Using the Sleeping Beauty System and Designer Zinc Finger Nucleases Finding: A genetic approach was harnessed to insert genes of interest, as well as to remove genes that interfere with T cell function. Application: To improve the broad application of T cell therapies Source: Presented at ASBMT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

The Hyperactive Sleeping Beauty Transposase SB100x Improves the Genetic Modification of T Cells to Express a Chimeric Antigen Receptor Finding: The gene transfer platform was modified to improve the ability to insert genes into T cells. Application: To improve the efficiency of gene transfer into T cells Source: Gene Therapy Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Reprogramming CD19-specific T Cells With IL-21 Signaling Can Improve Adoptive Immunotherapy of B-lineage Malignancies Finding: We found that IL21 might prevent activation-induced T cell death. Application: These data will lead to T cells that have improved persistence and therapeutic potential. Source: Presented at American Society of Gene and Cell Therapy (ASGCT) annual meeting Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Expansion, Purification and Functional Assessment of Human Peripheral Blood NK Cells Finding: Using a method involving K562 cells expressing membranebound IL21, we were able to produce rapid proliferation of natural killer (NK) cells without senescence, achieving a median 21,000-fold expansion in 21 days ex vivo. Application: Discovering a method that allows us to rapidly grow NK cells ex vivo will enhance our ability to further develop NK cell immunotherapies. Source: Journal of Visualized Experiments Primary/senior investigator: Dean Lee, M.D., Ph.D.

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Research Highlights Vimentin in Cancer and its Potential as a Molecular Target for Cancer Therapy Finding: This review looks at the expression and functions of vimentin in various types of cancer. Application: Vimentin’s overexpression in cancer and its association with tumor growth and metastasis makes it an attractive potential target for cancer therapy. Source: Cellular and Molecular Life Sciences Primary/senior investigator: Shulin Li, Ph.D.

WSX1 Expression in Tumors Induces Immune Tolerance Via Suppression of Effector Immune Cells Finding: The gene WSX1 plays a role in affecting crosstalk between tumor cells and their environment when highly expressed and promotes tumor growth. Application: This key observation reveals a new pathway of tumor-host interaction, which will ultimately lead to better strategies in immune therapy to reverse tumor tolerance. Source: PloS One Primary/senior investigator: Shulin Li, Ph.D.

Discovery of a Linear Peptide for Improving Tumor Targeting of Gene Products and Treatment of Distal Tumors by IL-12 Gene Therapy Finding: We studied a novel targeting approach to deliver IL-12 gene therapy using the linear peptide VNTANST. Application: These results show the promise of using VNTANST to improve IL-12 treatments and decrease systemic toxicity. Source: Molecular Therapeutics Primary/senior investigator: Shulin Li, Ph.D.

Enhancement of NK Cell Function and Proliferation Using L-MTP-PE Finding: Muramyl tripeptide (MTP-PE) caused a greater increase in NK cell cytotoxic activity when coincubated with monocytes, compared to its effect on NK cells alone. This could be a result of its impact on CD244, a surface receptor on NK cells. Application: MTP-PE appears to enhance cytotoxicity of NK cells in the presence of monocytes, presumably via cytokine secretion. Source: Presented at American Society of Pediatric Hematology/ Oncology (ASPHO) annual meeting Primary/senior investigator: Dean Lee, M.D., Ph.D.

Disruption of HLA Expression to Enable Allogeneic Cells to Escape Immune Recognition Finding: We found that by decoupling antigen targeting and T cell activation using designer zinc-finger nucleases, we can program T cells with a “universal” CAR to treat multiple conditions. Application: This data supports the concept of the development of “off-the-shelf” allogeneic cells that can be transplanted across HLA barriers on demand. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Cell Therapy Continued The University of Texas MD Anderson Cancer Center • Division of Pediatrics

Adoptive Transfer Therapy Using Expanded Melanoma-Specific T cells Programmed Ex Vivo for Improved Efficacy In Vivo Finding: We show that K562 cells can function as artificial antigenpresenting cells (aAPC) for propagating melanoma-specific T cells from both tumor-infiltrating lymphocytes (TIL)and peripheral blood. Application: This aAPC strategy not only shows a way to rapidly grow melanoma-specific T cells, but also offers a way to broaden T cell therapy to treat patients from whom TIL cannot be expanded. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

T Cells Genetically Modified to Express Chimeric Antigen Receptor Specific EGFR for Glioma Finding: We have found a way to introduce a chimeric antigen receptor to redirect the specificity of autologous T cells to EGFR, a clinical target for patients with diffuse intrinsic pontine glioma (DIPG). Application: Given our ability to manufacture clinical-grade CAR(+) T cells, we are proceeding with studies to enable EGFR to be targeted in children with DIPG. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Targeting B-cell Malignancies With Chimeric Antigen Receptor-modified γδ T Cells Finding: This study reports a clinically-appealing approach to generate large numbers of genetically modified T cells to target B-cell malignancies. Application: Using this approach provides a novel therapeutic option using T cells that are specially programmed to be effective killers. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Expression of Membrane Bound GD2 Peptide Mimic on K562 Cell Line Supports Antigen Specific Expansion of T Cells Modified With GD2 Chimeric Antigen Receptor Finding: This study is the first to describe the generation of an aAPC for the expansion of CAR-modified T cells in which the natural ligand for the CAR is not a protein antigen. Application: Based on this approach, we propose the expression of membrane-bound peptide mimics (such as GD2 used in the study) as a novel way to expand genetically modified T cells and NK cells. Source: Presented at ASGCT Primary/senior investigator: Dean Lee, M.D., Ph.D.

Generation of an HLA-negative K562 Clone as Proof of Principle for Targeting of HLA-C by a Novel Zinc-finger Nuclease Finding: We validated the ability of a zinc finger nuclease to functionally delete the HLA-C locus in the K562 cell line. Application: This is an important step in creating an artificial aAPC that is truly HLA-negative and validates the ZFN technology for this purpose. Source: Presented at ASGCT Primary/senior investigator: Dean Lee, M.D., Ph.D.

Children’s Cancer Hospital • Spring 2012

CELL THERAPY - continued Generating a Chimeric Antigen Receptor (CAR) to Redirect T Cell Specificity After Infusion Finding: We have developed a CAR that can be modified after expression to enable genetically modified T cells to target multiple antigens after T cell infusion through specific adapters. Application: This allows us the capability to make a generic T cell to treat multiple conditions. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

Improved Costimulation of CD19-Specific T Cells Transpresenting a Membrane-Bound IL-15 Finding: Our data shows that using IL-15 in the form of a membranebound molecule can prolong persistence of on CAR(+) T cells. Application: Using this form of IL-15 on the modified T cells enhances their proliferation and persistence during adoptive immunotherapy without the need for exogenous cytokine support. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

CD56-specific T Cells Can Distinguish Between Allogeneic and Autologous CD56+ Targets Finding: Our data demonstrates that we can express CD56-specific CAR on T cells despite their co-expression of CD56, and these modified T cells can target tumor cells while evading autolysis. Application: These data supports clinical potential for CD56RCD23(+) T cells against a multitude of CD56(+) tumors. Source: Presented at ASGCT Primary/senior investigator: Laurence Cooper, M.D., Ph.D.

IL-21 Has an Anti-Apoptotic Effect on NK Cells During Activation Finding: We found that IL21 might prevent activation-induced NK cell death through upregulation of anti-apoptotic factors through a CD160-mediated mechanism. Application: We can use these findings to further investigate and identify the mechanisms of suppressing apoptosis in this system. Source: Presented at ASGCT Primary/senior investigator: Dean Lee, M.D., Ph.D.

Herceptin Conjugates Linked by EDC Boost Direct Tumor Cell Death Via Programmed Tumor Cell Death Via Programmed Tumor Cell Necrosis – PloS One Finding: To our knowledge, our report is the first to reveal the capability of a tumor-targeted antibody to simultaneously induce programmed necrotic tumor cell death (PNCD) and overcome the resistance of tumor cells to antibody treatment. Application: Our study illustrates an independent approach and mechanism to overcome the tumor resistance to antibody treatment and to induce necrotic cancer cell death. The induction of necroptosis has great potential to treat apoptosis-resistant cancer cells. Source: PLoS One Primary/senior investigator: Shulin Li, Ph.D.

Joya Chandra, Ph.D.

Michael Rytting, M.D.

Patrick Zweidler-McKay, M.D., Ph.D.

Leukemia and Lymphoma Specific and Prolonged Proteasome Inhibition Dictates Apoptosis Induction by Marizomib and its Analogs Finding: This paper describes a series of next-generation proteasome inhibitors that have specific advantages over the original FDAapproved drug, bortezomib (Velcade). Application: We provide a mechanism and rationale for why second generation proteasome inhibitors, such as marizomib (NPI-0052), may be more effective for the treatment of T cell leukemias, and should be tested in a clinical trial for leukemias. Source: Chemico-Biologic Interactions Primary/senior investigator: Joya Chandra, Ph.D.

Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors Finding: The future of HDAC inhibitors may reside in combination therapies. Here, we reviewed potential candidates, such as inhibitors of DNA methyltransferases and histone demethylases, ROS-generating compounds, proteasome inhibitors and DNA-damaging agents. Application: The combination therapies reviewed have demonstrated enhanced efficacy when combined with HDAC inhibitors and may provide a therapeutic advantage in the clinic. Source: Journal of Biomedicine and Biotechnology Primary/senior investigator: Joya Chandra, Ph.D.

Absolute Lymphocyte Counts Refine Minimal Residual Disease-based Risk Stratification in Childhood Acute Lymphoblastic Leukemia Finding: In this study, researchers found that adding the absolute lymphocyte count to modern minimum residual disease-based risk classification was better able to determine which treatment a given child needed, whether that was more intense or less intense treatment. Application: Based on this study, the Children’s Oncology Group is monitoring the ALC in all children with high-risk acute lymphcytic leukemia (ALL) during the next 3-5 years (>2000 children), and will determine if it should be incorporated into future ALL risk classification strategies. Source: Pediatric Blood and Cancer Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

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Research Highlights

Targeting Glycolysis in Leukemia: A Novel Inhibitor 3-BrOP in Combination With Rapamycin Finding: This paper describes the first use of a novel glycolysis inhibitor across a panel of human leukemias. The MD Anderson-developed drug, 3-BrOP, was very effective in rapidly killing tumor cells, especially when combined with an mTOR inhibitor. Application: The researchers hope to initiate a clinical trial to test this novel inhibitor in children and adults with leukemias. Source: Leukemia Research Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

Notch/HES1-mediated PARP1 Activation: A Cell Type-specific Mechanism for Tumor Suppression Finding: Researchers show that Notch activation actually inhibits B-cell ALL, contrary to T cell ALL. In addition to showing the use of Notch-activating agents to kill B-ALL, this paper reveals the mechanism of this approach. Application: Notch-activating agents have a potential use as a novel therapeutic strategy for B-cell ALL. Source: Blood Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

Notch and PLK1: Targeting Novel Mechanisms in B-ALL Finding: These data reveal that multiple mechanisms of Notch/ HES1-mediated growth arrest in B-cell ALL may occur via a Polo-like kinase1 (PLK1). Application: Targeting Notch and PLK1 pathways in B-cell ALL may represent a novel therapeutic approach. Source: Presented at ASPHO Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

The Sun and the Sea: Balancing Ikaros in AML, T-ALL and B-ALL Finding: We demonstrate that IKAROS function has distinct effects on AML, B-cell ALL and T-cell ALL, which may suggest a cell type-specific role for IKAROS in these leukemias. Application: These results provide insight into the complexity of IKAROS in acute leukemias. Source: Presented at ASPHO Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

Acute Lymphoblastic Leukemia in Adolescents and Young Adults Finding: Chapter describing current management of the AYA patient with ALL Source: Leukemias: Principles and Practice of Therapy; Faderl S and Kantarjian H, eds. Primary/senior investigator: Michael Rytting, M.D.

Adolescents and Young Adults With Acute Lymphoblastic Leukemia Treated With Modified Berlin-Franfurt-Muenster Therapy Finding: Describes current clinical trial in AYA ALL at MD Anderson. Application: Ongoing trial. Excellent results for patients younger than 25. Source: Presented at ASH (poster) Primary/senior investigator: Michael Rytting, M.D. The University of Texas MD Anderson Cancer Center • Division of Pediatrics

Valerae Lewis, M.D.

Nancy Gordon, M.D.

Anita Mahajan, M.D.

Andrea Hayes-Jordan, M.D.

Michael Rytting, M.D.

Sarcomas and Solid Tumors Tumor Vessel Development and Expansion in Ewing’s Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials With Vascular-targeting Agents Finding: Recent insights have identified VEGF, SDF-1α and DLL4 as critical players in supplying a vascular system for Ewing’s sarcoma growth. Application: This will help us in selecting new strategies and drugs to treat Ewing’s sarcoma. Clinical trials using vascular targeting agents are under way. Source: Sarcoma Primary/senior investigator: Eugenie Kleinerman, M.D.

Advanced Atypical Teratoid/Rhabdoid Tumor (ATRT) Treated With Intensive Multimodal Approach Shows Continued Response to Sarcoma Type Salvage Therapy Finding: Sarcoma therapy works for ATRT. Application: Patients may have better survival when treated with standard ATRT therapy along with sarcoma therapy. Source: Pediatric Blood and Cancer Primary/senior investigator: Michael Rytting, M.D.

Osteosarcoma of the Jaw in Children and Young Adults Finding: We have seen excellent results in patients with osteosarcoma of the jaw by using more surgery and less chemotherapy. Application:Survival outcomes and better jaw function are directly correlated with the reconstructive experience of the head and neck surgeons. Source: Head and Neck Primary/senior investigators: Winston Huh, M.D., and Peter Anderson, M.D., Ph.D.

Children’s Cancer Hospital • Spring 2012

Dennis Hughes, M.D., Ph.D.

Peter Anderson, M.D., Ph.D.

Winston Huh, M.D.

Eugenie Kleinerman, M.D.

Gastric Adenocarcinoma in Children and Adolescents Finding: Gastric adenocarcinoma, though very rare in children, can have excellent results in various situations. Application: Novel therapies and surgeries are the key to successful outcomes. Patients with localized disease have shown the best results. Source: Pediatric Blood and Cancer Primary/senior investigator: Winston Huh, M.D.

Soft Tissue Sarcomas of the Popliteal Fossa: A Single-institution Retrospective Review Finding: Surgery is very difficult for this disease due to its location behind the knee (near nerve and vessels). This presents a challenge in controlling the primary tumor. Application: A combination of radiation and surgery is needed for limb salvage and a better outcome. Source: Cancer Primary/senior investigators: Winston Huh, M.D., and Valerae Lewis, M.D.

Pediatric Sarcomas and Related Tumors of the Head and Neck Finding: In the past, head and neck sarcomas have been difficult to treat using surgery and radiation. Application: New technologies, such as proton beam radiation, and a multidisciplinary approach will offer patients the best outcome with lower long-term risks. Source: Cancer Treatment Review Primary/senior investigators: Winston Huh, M.D., and Peter Anderson, M.D., Ph.D.

Liposarcoma in Children and Young Adults: A Multi-institutional Approach Finding: Liposarcoma is more common in adults and presents very differently in children. Application: Biomarkers and the role of adjuvant therapy will be increasingly important in improving outcomes for pediatric patients. Source: Pediatric Blood and Cancer Primary/senior investigator: Winston Huh, M.D.

Location of Pulmonary Metastasis in Pediatric Osteosarcoma is Predictive of Outcome Finding: Patients with central pulmonary metastases in osteosarcoma have a very poor prognosis, even after operative treatment, compared with those with peripheral disease. Application: Patients with central lesions may benefit from other nonsurgical treatment options. Source: Journal of Pediatric Surgery Primary/senior investigator: Andrea Hayes-Jordan, M.D.

The Diagnosis and Management of Desmoplastic Small Round Cell Tumor: A Review Finding: Persistent reduction in tumor burden and improved diseasefree survival is a result of a novel surgery (HIPEC), abdominal radiation and chemotherapy. Application: Aggressive surgery and a multidisciplinary approach is essential to provide long-term disease control. Source: Current Opinion Oncology Primary/senior investigators: Andrea Hayes-Jordan, M.D., and Peter Anderson, M.D., Ph.D.

Resection of Pulmonary Metastases in Pediatric Patients With Ewing’s Sarcoma Improves Survival Finding: This study compared the outcomes of Ewing’s sarcoma patients with pulmonary metastasis using various treatment strategies. Application: In addition to radiation, surgery is effective against pulmonary metastases. It can provide better hope for longer disease-free survival as opposed to patients who don’t have surgical pulmonary resections. Source: Journal of Pediatric Surgery Primary/senior investigator: Andrea Hayes-Jordan, M.D.

Effect of HDAC Inhibitor, SNDX-275, on Fas Signaling in Osteosarcoma Cells and the Feasibility of its Topical Application for the Treatment of Osteosarcoma Lung Metastases Finding: SNDX-275 can activate Fas signaling in osteosarcoma cells in vitro and in vivo. We also found that administering SNDX-275 by inhalation is feasible as a treatment for metastases. Application: With further investigation, this could be a potential mechanism to improve the effectiveness of chemotherapy. Source: Cancer Primary/senior investigator: Eugenie Kleinerman, M.D.

Genetically Modified T cells Targeting Interleukin-11 Receptor α-chain Kill Human Osteosarcoma Cells and Induce Regression of Established Osteosarcoma Lung Metastases Finding: The study demonstrated in human cell lines and mice that genetically modified T cells can be used to target and kill osteosarcoma cells in the lung with no organ toxicity. Application: This shows a new approach using immune therapy, similar to a cancer vaccine, for osteosarcoma lung metastases. Source: Cancer Research Primary/senior investigator: Eugenie Kleinerman, M.D.

CAPER-α Alternative Splicing Regulates the Expression of Vascular Endothelial Growth Factor (VEGF) in Ewing’s Sarcoma Cells Finding: Basic research shows a mechanism of growth factor production caused by Ewing’s sarcoma. Application: Understanding the roles of VEGF165 and CAPER-α may help in the selection of future drugs to treat Ewing’s sarcoma. Source: Cancer Primary/senior investigator: Eugenie Kleinerman, M.D.

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Research Highlights

SDF-1α Induces PDGF-B Expression and the Differentiation of Bone Marrow Cells Into Pericytes Finding: The bone marrow microenvironment can facilitate or inhibit cancer growth. Our findings show the importance of SDF-1α not only as a chemotactic factor for bone marrow cells, but also as a signaling molecule that can regulate the expression of growth factors such as PDGF-B. Application: Our findings emphasize the importance of understanding the different growth factors and signaling pathways that can control the differentiation of bone marrow cells into pericytes, which can ultimately affect tumor vascular morphology and function. Source: Molecular Cancer Research Primary/senior investigator: Eugenie Kleinerman, M.D.

Epigenetic Regulation of Apoptosis and Cell Cycle in Osteosarcoma Finding: Life and death of osteosarcoma cells is not always nature, but sometimes it’s nurture, a non-inherited genetic change. Application: Epigenetic alterations of genes involved in cell cycle regulation and apoptosis may contribute to the pathogenesis of osteosarcoma. Source: Sarcoma Primary/senior investigator: Eugenie Kleinerman, M.D.

Bone Marrow Cells Participate in Tumor Vessel Formation That Supports the Growth of Ewing’s Sarcoma in the Lung Finding: This study suggests that bone marrow cells participate in the vascular formation that supports the growth of Ewing’s sarcoma lung metastases. Application: Targeting this process may have therapeutic potential. Source: Angiogenesis Primary/senior investigator: Eugenie Kleinerman, M.D.

Metadherin Mediates Tumor Migration and Interaction With Non-cellular Matrix Stromal Elements in Osteosarcoma Finding: In an initial screen of HES1-regulated genes that might be responsible for Notch-mediated metastasis, we identified Metadherin as a candidate regulator of osteosarcoma invasion. Application: These data demonstrate an important role for Metadherin in osteosarcoma mediating migration and invasion, key elements of metastatic behavior. Other mechanisms should be evaluated to further define Metadherin’s role mediating tumor cell and endothelium interaction. Source: Presented at American Association for Cancer Research (AACR) Special Conference on Tumor Microenvironment Complexity Primary/senior investigator: Dennis Hughes, M.D., Ph.D.

Sarcomas and Solid Tumors Continued

The University of Texas MD Anderson Cancer Center • Division of Pediatrics

The Microenvironment Plays an Important Role in the Ability of Aerosol Gemcitabine and Liposomal 9-Nitrocamptothecin to Elicit Therapeutic Effect on Osteosarcoma Lung Metastases Finding: In this study, we demonstrated that corruption of the Fas pathway decreases therapeutic efficacy of aerosol GCB and L9-NC. Therapeutic efficacy of the two agents was completely abolished in the absence of FasL in the lung. Application: This underscores the potential importance of the tumor microenvironment in not only the ability of tumor cells to form metastases, but also in the therapeutic efficacy of chemotherapy against osteosarcoma lung metastases. Source: Presented at AACR Special Conference on Tumor Microenvironment Complexity Primary/senior investigators: Nancy Gordon, M.D., and Eugenie Kleinerman, M.D.

Whole Abdominopelvic Intensity-Modulated Radiation Therapy for Desmoplastic Small Round Cell Tumor After Surgery Finding: Whole abdominopelvic intensity-modulated radiation therapy (WAP-IMRT) with concurrent radiosensitizing chemotherapy was well tolerated after aggressive surgery for DSCRT. Enhanced bone sparing with IMRT probably accounts for the low hematologic toxicity (vs. conventional WAP-RT). Application: This modality, which is considered less toxic, should be considered as an additional local-regional control option for DSRCT. Source: International Journal of Radiation Oncology, Biology and Physics Primary/senior investigator: Anita Mahajan, M.D.

Miss Texas made a December visit to the Children’s Cancer Hospital along with 2011 Lombardi Award nominees. Thanks to the Rotary Club, numerous patients were also invited to the Lombardi Award dinner and ceremony.

Children’s Cancer Hospital • Spring 2012

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SARCOMAS and SOLID TUMORS - continued

Vidya Gopalakrishnan, Ph.D.

Dennis Hughes, M.D., Ph.D.

Patrick Zweidler-McKay, M.D., Ph.D.

Neuroblastoma Notch Pathway Activation Induces Neuroblastoma Tumor Cell Growth Arrest

Finding: Neuroblastoma cell lines express multiple Notch receptors, which are inactive. Activation of Notch via ligand binding results in growth arrest. HES gene expression could be induced with decitabine. Application: These findings support a tumor suppressor role for Notch signaling in neuroblastoma. Source: Journal of Pediatric Blood and Cancer Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

The Selective Trk Inhibitor AZ623 Inhibits Brain-derived Neurotrophic Factor-mediated Neuroblastoma Cell Proliferation and Signaling and Is Synergistic With Topotecan Finding: AZ623 treatment was found to inhibit brain-derived neurotrophic factor-mediated neuroblastoma cell proliferation. AZ623 inhibited tumor growth in mice and, when combined with topotecan, AZ623 results in the prolonged inhibition of tumor regrowth. Application: More preclinical development is needed to further explore the use of Trk inhibitors to treat neuroblastoma. Source: Cancer Primary/senior investigator: Patrick Zweidler-McKay, M.D., Ph.D.

Retinoic Acid Induces REST Degradation and Neuronal Differentiation by Modulating the Expression of SCF in Neuroblastoma Cells Finding: The results indicated that elevated transcription of REST compounded by its impaired degradation of SCF may contribute to the failure of neuroblastoma tumors to differentiate in response to retinoic acid. Application: These results are particularly important because mutations in the retinoic acid signaling pathways have not been demonstrated. Because REST is an important regulator of neuronal differentiation, it may be reasonable to hypothesize that patients who have elevated REST levels in their tumors may have a poorer prognosis. This will require validation through study of patient data. Source: Cancer Primary/senior investigator: Vidya Gopalakrishnan, Ph.D.

HER4 Confers Anoikis Resistance and Chemotherapy Resistance in Neuroblastoma Through Suppression of Cell Cycle Finding: HER4 plays a key role in how neuroblastoma cells resist chemotherapy. By blocking HER4, the neuroblastoma cells become more sensitive. This set of studies used a newer, 3D culture that forces cells to cling to one another in order to survive. Application: The new 3D technique of culturing cells makes it more like an in vivo environment, aiding in the study of cancer cells and their behaviors. HER4 expression is a major cell survival factor in neuroblastoma induced by 3D culture. Source: Presented at ASPHO Primary/senior investigator: Dennis Hughes, M.D., Ph.D.

Anita Ying, M.D. .

Steven Waguespack, M.D.

Endocrine Management of Medullary Thyroid Carcinoma and MEN2 Syndromes in Childhood Finding: Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia type 2 (MEN2) are rare, but increasing knowledge of their genotype-phenotype correlations have facilitated the development of guidelines for interventions. Application: The review shows that early diagnosis and surgery provide the best prognosis and chance for cure. With additional therapies on the horizon, it supports the need for these diseases to be treated at treated at tertiary centers with multidisciplinary care. Source: National Review of Endocrinology Primary/senior investigator: Steven Waguespack, M.D.

Many Children’s Cancer Hospital patients participated in Read Across America Day, which was hosted by the Pediatric Education and Creative Arts Program at MD Anderson. The annual literacy day celebrates the birthday of Dr. Seuss, inspiring more than 45 million young readers across the nation to pick up a book and read.

Gonadotropin-dependent Precocious Puberty: Neoplastic Causes and Endocrine Considerations Finding: This paper reviews the neoplastic and developmental causes of gonadotropin-dependent precocious puberty. Application: The review discusses the common CNS lesions and related tumors that cause sexual development early, the relationship between therapeutic radiation and gonadotropin-dependent precocious puberty and the therapies available for height preservation. Source: International Journal of Pediatric Endocrinology Primary/senior investigator: Steven Waguespack, M.D.

Random Postoperative Day-3 Cortisol Concentration as a Predictor of Hypothalamic-pituitary-adrenal Axis Integrity After Transsphenoidal Surgery (TSS) Finding: This study evaluated a potential predictor of adrenal sufficiency post-TSS. It found that a postoperative day-3 cortisol value can be a predictor. Application: Treatment decisions regarding corticosteroid replacement should be personalized, considering the postoperative day-3 cortisol level, the clinical context in which the measurement was obtained, and any evidence of concomitant pituitary dysfunction in the perioperative period. Source: Endocrine Practice Primary/senior investigator: Steven Waguespack, M.D.

Teddy Bear Clinic To help patients better understand and prepare for their treatment, child life specialists at the Children’s Cancer Hospital created the Teddy Bear Clinic. Patients and their siblings became doctors for the day as they put on their kid-sized white coats and got hands-on experience working with 22 departments at MD Anderson.

Predictors of Direct Costs of Diabetes Care in Pediatric Patients With Type 1 Diabetes Finding: Better metabolic control in patients with Type 1 diabetes was associated with lower direct medical costs and lower odds of hospitalization. Also, marital status of the primary caregiver, irrespective of type of insurance, impacts the patient’s health care costs and risk of hospitalization. Application: This cost analysis is informative for payers and providers focused on effective management and improving health care costs. Source: Pediatric Diabetes Primary/senior investigator: Anita Ying, M.D.

Research Highlights continued

Soumen Khatua, M.D.

Anita Mahajan, M.D.

Brain Tumors Inhibition of LSD1 Sensitizes Glioblastoma Cells to Histone Deacetylase Inhibitors Finding: Enzymes that control epigenetic alterations could be targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. This study looked at a potential combination therapy of lysine specific demethylase 1 (LSD1) and histone deacetylase (HDAC) inhibitors. Application: The study results indicate that LSD1 and HDAC inhibitors cooperate to regulate key pathways of cell death in glioblastoma cell lines, but not in normal counterparts. They also validate the combined use of LSD1 and HDAC inhibitors as a potential therapy for glioblastoma. Source: Neuro-Oncology Primary/senior investigator: Joya Chandra, Ph.D.

Diffuse Intrinsic Pontine Glioma-current Status and Future Strategies Finding: Average survival for patients with diffuse pontine glioma remains less than 12 months due to the tumor’s resistance to current therapies and the lack of ability to perform biopsies to gain knowledge of the disease’s biology. Application: This review validates the need for initiating biopsies or even encouraging families to allow autopsies to study the molecular biology. Continued advances should be pursued in neuro-imaging technology and in surgical approaches to enhance the local delivery of therapies. Source: Child’s Nervous System Primary/senior investigator: Soumen Khatua, M.D.

Treatment of Recurrent Diffuse Intrinsic Pontine Glioma: The MD Anderson Cancer Center Experience Finding: This retrospective study looked at the treatment of 31 patients with recurrent diffuse intrinsic pontine glioma using various treatment combinations. Application: The study found that repeat radiation resulted in the highest response rates and the longest progression-free survival. This provides a basis to test repeat radiation in a prospective clinical study. Source: Journal of Neuro-Oncology Primary/senior investigator: Anita Mahajan, M.D.

Children’s Cancer Hospital • Spring 2012

Michael Rytting, M.D. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

Joya Chandra, Ph.D.

John Slopis, M.D.

Palliative Reirradiation for Progressive Diffuse Intrinsic Pontine Glioma Finding: Patients with diffuse intrinsic pontine glioma experience severe neurologic deficits and morbidity from progression of their disease. We investigated reirradiation as a tool to manage symptoms of these patients. Application: From the study, we concluded that additional radiation in combination with chemotherapy may be feasible to improve symptoms and delay progression with minimal toxicity. Patients who are most likely to benefit may be those with prolonged response to initial therapy and a long interval since initial radiation. Source: American Journal of Clinical Oncology Primary/senior investigator: Anita Mahajan, M.D.

Low Early Ototoxicity Rates for Pediatric Medulloblastoma Patients Treated With Proton Radiotherapy Finding: This study investigated whether proton radiotherapy, which reduces radiation to the cochlea, would lower the rate of hearing loss for pediatric patients compared to conventional radiotherapy. Application: Rates of high-grade ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed in this study, may improve both quality of life and cognitive functioning for these patients. Source: Radiation Oncology Primary/senior investigator: Anita Mahajan, M.D.

Patterns of Electromagnetic Activity Recorded from Neoplastic Tissue Finding: This report is the first to demonstrate that magnetoencephalography (MEG) may differentiate between neoplastic tissue types. We found that meningioma and medulloblastoma cells may produce separate electromagnetic signatures. Application: The preliminary findings demonstrate that MEG can detect specific electromagnetic signatures, which may be used to differentiate between cells from primary brain tumors such as medulloblastomas and meningiomas. Source: Journal of Neuro-Oncology Primary/senior investigator: John Slopis, M.D.

Advanced Atypical Teratoid/Rhabdoid Tumor Treated With Intensive Multimodal Approach Shows Continued Response to Sarcoma Type Salvage Therapy Finding: A case of a patient with advanced, recurrent atypical teratoid/ rhabdoid tumor (ATRT) that responded to therapy usually used for highgrade sarcomas. Application: We cannot tell which parts of the treatment regimen, that is, the systemic chemotherapy or the intrathecal chemotherapy, were most effective individually for our patient, but the combination was effective. Use of IT cytarabine in combination with sarcoma-like systemic chemotherapy for advanced ATRT may be worth further investigation. Source: Pediatric Blood and Cancer Primary/senior investigator: Michael Rytting, M.D.

Research Highlights

Andrea Hayes-Jordan, M.D.

Rhonda Robert, Ph.D.

Other Diseases and Survivorship Outcomes in Pediatric Melanoma: Comparing Prepubertal to Adolescent Pediatric Patients Finding: This is the largest known study of prepubertal melanoma patients. Although overall survival and event-free survival didn’t differ between the two age groups, younger ages showed increased risk of lymph node metastasis and thicker tumors. Application: This suggests that the younger pediatric patients may have a disease that differs biologically from that of the older pediatric patients. More investigation is necessary to understand these differences. Source: Annals of Surgery Primary/senior investigator: Andrea Hayes-Jordan, M.D.

Quality of Life as a Population Health Outcome Evaluation Finding: The Pediatric Quality of Life (PedsQL) was sensitive in detecting difference between long-term survivors of pediatric cancer and other populations. It may also serve to measure the health of this particular population. Application: In terms of fatigue and pain, this quality of life measurement tool will allow clinicians to systemically assess a patient’s condition, allocate resources to better manage and treat the condition, and to measure efficacy of the interventions. Source: Presented at the International Society of Pediatric Oncology (SIOP) annual conference Primary/senior investigators: Joann Ater, M.D., and Rhonda Robert, Ph.D.

A Case Study on Gliosarcoma Presenting as Recurrent Spontaneous Intracranial Hemorrhage in a Child With Neurofibromatosis Type 1 Finding: We describe a child with NF1 who at the age of 18 months presented with optic glioma and progressive juvenile pilocytic astrocytoma of the optic chiasm and hypothalamus. This is a rare case of gliosarcoma described in the pediatric NF1 population. Application: This unique presentation raises the possibility of potential effect of genetic mutation in the sarcomatous transformation of CNS tumors in NF1 patients. Further exploration of this association will help determine future therapeutic options. Source: Presented at the Neurofibromatosis Conference 2011 Primary/senior investigator: John Slopis, M.D.

John Slopis, M.D.

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Joann Ater, M.D.

Comparison of Myocardial Strain (GPLSS) and Ejection Fraction (EF) for Follow-up of Childhood Cancer Survivors at Risk for Cardiac Late Effects Finding: We examined the concordance and discordance between EF and GPLSS, two measures of cardiac function in 94 childhood cancer survivors younger than 16. We found that GPLSS may be an earlier and more sensitive measure of cardiac dysfunction in childhood cancer survivors. Application: Our data suggests that GPLSS may be a useful test to help identify early cardiac dysfuction in childhood cancer survivors and help identify patients in need of long-term cardiac monitoring and possible treatment. Source: Presented at the European Symposium on Late Complications of Childhood Cancer 2011 Primary/senior investigator: Joann Ater, M.D.

Abnormal Myocardial Strain and Preserved Ejection Fraction in Children With Chemotherapy-related Carditoxicity Finding: In this cross-sectional study of 313 children who had echocardiograms during chemotherapy and in follow-up, we found that a significant proportion of the patients with abnormal strain had preserved ejection fraction, indicating that the parameter of strain may be able to identify early myocardial injury. Application: Our data suggests that myocardial strain may be able to identify early myocardial injury and thus enable timely intervention. Source: Presented at the European Symposium on Late Complications of Childhood Cancer 2011 Primary/senior investigator: Joann Ater, M.D.

Treatment of Progressive Hypothalamic/Optic Pathway Gliomas in Children With NF1: A Report From the Children’s Oncology Group Finding: We found that children with NF1 and progressive intracranial optic pathway tumors had higher response rate and better event-free survival when treated with carboplatin and vincristine than children with the same tumors without NF1. However, children with NF1 were at higher risk for a second malignant neoplasm if they received treatment with temozolomide after carboplatin and vincristine for progression. Application: Carboplatin and vincristine are good front-line therapies for children with NF1 who have progression of their tumors. However, for those who progress after this chemotherapy, alternatives are needed. Temozolomide is not recommended in this population. Source: Presented at the Neurofibromatosis Conference 2011 Primary/senior investigator: Joann Ater, M.D.

The University of Texas MD Anderson Cancer Center • Division of Pediatrics

The Children’s Cancer Hospital Newsletter

is an educational resource for physicians and others interested in the treatment, research and prevention of pediatric cancers, produced quarterly from the Division of Pediatrics at The University of Texas MD Anderson Cancer Center.

The University of Texas MD Anderson Cancer Center Division of Pediatrics 1515 Holcombe, Unit 087 Houston, Texas 77030 ADDRESS SERVICE REQUESTED

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Division Administrator: Karen Broussard Managing Editor: Gail Goodwin We welcome your questions and suggestions.

Change of address or other communication regarding this newsletter may be directed to Karen Broussard at 1515 Holcombe Blvd., Unit 087, Houston, TX 77030; 713-792-6620.

George Foreman Pediatric and Adolescent Inpatient Unit Robin Bush Child and Adolescent Clinic Kim’s Place R.E. (Bob) Smith Research Facility

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Our Mission

To cure cancer in children and young adults within a caring, life-affirming environment.

Our Vision

We will offer children and young adults hope and an opportunity to lead full and productive lives. We will lead the efforts worldwide to cure cancers through the excellence and compassion of our people, research-driven innovative therapies, education programs and active collaboration with patients, families and communities.

• • • • • Contact us at 713-792-5410 8 a.m.–5 p.m. (M–F) and after hours at 713-792-7090. Request the on-call pediatric oncology attending.

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