Department of Surgery Research: Pediatric Surgery

The section of Pediatric Surgery continues to run diverse, broad ranging basic science research programs in areas relevant to gastrointestinal, cardiopulmonary, trauma, and tumor physiology and pathophysiology in the fetus, infants and children. The section continues to be nationally recognized for its clinical research especially in ECMO, fetal diagnosis and treatment, pediatric trauma, inflammatory bowel disease, congenital diaphragmatic hernia, intestinal failure, Hirschsprung disease, abnormalities of sexual development, weight reduction surgery, and esophageal atresia.

Dr. Ronald Hirschl has developed a basic science and clinical program in the application total liquid ventilation in the setting of respiratory failure including the use of perflurocarbons to induce lung growth in newborns with congenital diaphragmatic hernia. A series of projects related to prevention of lung injury and treatment of ARDS with liquid ventilation are being conducted. In addition, basic science experiments are being carried out in the laboratory to study the pathophysiology of lung injury and respiratory failure including the development of artificial lungs to provide chronic support for gas exchange.

Peter Ehrlich
Associate Professor of Surgery Current Research Activities A. Cancer Research – Children's Oncology Group

Wilms tumor- Vice Chair Renal Tumors Studies Committee Surgical Principal investigator on all Studies

Active Studies

Evaluation of the Effect of Hepatic Metastases on Therapy in Patients with Nephroblastoma

Hypothesis 1:

Children with Wilms' tumor metastatic to the liver have outcomes similar to those with pulmonary metastasis alone (stratified by anaplastic and favorable biology histologies. We would compare the event-free survival (EFS) and overall survival (OS) of patients who had pulmonary metastases alone with those with both hepatic metastases with or without pulmonary metastases.

Hypothesis 2:

Survival for children with Wilms' tumor and hepatic metastasis is equivalent with or without resection of the hepatic tumors. (Stratified by anaplastic and favorable histology.) We would assess the therapy and outcome of patients with regard to treatment of their hepatic metastases. We would place patients into two cohorts: those who underwent resection of the liver lesions compared with those who received only chemotherapy, and those who received chemotherapy and radiotherapy. We would analyze outcome by these two modalities.

Hypothesis 3:

Resection of hepatic metastasis from Wilms' tumor is associated with a significant risk of surgical complications (ie. 15%). We would analyze the timing of the surgical resection, whether done primarily or after initial chemotherapy. I doubt the numbers will be adequate to address whether there was any difference in the survival of those patients by timing of resection, but we would like to look at the complications of liver resection in these two groups. Permission to perform this existing data chart review is requested.

AREN03B2: Renal Tumors Classification, Biology, and Banking Study

  1. To classify patients with renal tumors by histological categorization, surgico-pathological stage, presence of metastases, age at diagnosis, tumor weight, and LOH for chromosomes 1p and 16q. This classification will define eligibility for a series of therapeutic studies.
  2. To maintain a biological samples bank to make specimens available to scientists to evaluate additional potential biological prognostic variables and for the conduct of other research by scientists. Secondary
  3. To monitor outcome for those patients who are not eligible for a subsequent therapeutic study.
  4. To describe whether the pulmonary tumor burden correlates with outcome in Stage IV patients.
  5. To describe the sensitivity and specificity of abdominal computed tomography (CT) by comparison with surgical and pathologic findings for identification of local tumor spread beyond the renal capsule to adjacent muscle and organs, lymph node involvement at the renal hilum and in the retroperitoneum, preoperative tumor rupture and metastases to the liver.
  6. To compare the sensitivity and specificity of pre-operative abdominal CT and MRI for the identification and differentiation of nephrogenic rests and Wilms tumor in children with multiple renal lesions.
  7. To correlate the method of conception (natural versus assisted reproductive technology) with the development of Wilms tumor.

D5. AREN0532-Treatment for Very Low, Low, and Standard Risk Favorable Histology (FH) Wilms Tumor

    Objectives:
  1. To evaluate whether a treatment regimen containing cyclophosphamide, carboplatin, and etoposide alternating with vincristine, doxorubicin, cyclophosphamide improves the EFS of patients with diffuse AHWT and MRT compared to historical controls.
  2. To evaluate, in a phase II "window" study, the anti-tumor activity of a combination of vincristine and irinotecan against metastatic diffuse AHWT and metastatic/unresectable MRT.
  3. To maintain the excellent event-free survival of patients with stage I CCSK without the use of abdominal irradiation.

D5. AREN0532-Treatment for Very Low, Low, and Standard Risk Favorable Histology (FH) Wilms Tumor

    Objectives:
  1. To demonstrate that very low risk patients treated by nephrectomy and observation alone will have a 4 year EFS ÿ 85% and 4-year OS ÿ 95%; very low risk is defined as stage I favorable histology Wilms tumor of weight <550 g with patient age < 2 years at diagnosis.
  2. To document continued excellent outcome (4-year EFS ÿ 85% and OS ÿ 95%) for patients with stage III FH Wilms tumor without LOH of 1p and 16q treated with vincristine, dactinomycin, doxorubicin, and radiotherapy (Regimen DD4A).
  3. To improve the current 4 year Event Free Survival for patients with Stage I and II Favorable Histology Wilms tumor with LOH of 1p and 16q by adding doxorubicin but not radiotherapy (modified Regimen DD4A) to the standard dactinomycin and vincristine backbone.

D6. AREN0533- Treatment for Higher Risk Favorable Histology Wilms Tumor

    Primary Objectives:
  1. To demonstrate that patients with Stage IV FHWT with pulmonary metastases who have complete resolution of the pulmonary lesions after 6 weeks of DD4A chemotherapy (vincristine, dactinomycin, and doxorubicin) will have at least an 85% 4 year EFS after therapy without whole lung irradiation.
  2. To demonstrate that Stage IV FH patients who do not have resolution of pulmonary metastases by Week 6 will have a 4 year EFS of 85% with the addition of cyclophosphamide and etoposide to a modified Regimen DD4A (Regimen M).
  3. To improve the 4 year EFS to 75% for patients with Stage III or IV FH Wilms tumor with loss of heterozygosity (LOH) for chromosomes 1p and 16q.

AREN0534- Treatment for Patients with Bilateral, Multicentric, or Bilaterally-Predisposed Unilateral Wilms Tumor

    Primary Objectives:
  1. To improve 4 year EFS to 73% for patients with bilateral Wilms tumor (BWT).
  2. To salvage both kidneys in at least 50% of patients with BWT by using pre-nephrectomy 3-drug chemotherapy induction with vincristine, dactinomycin and doxorubicin.
  3. To evaluate the efficacy of chemotherapy in preserving renal units in children with diffuse hyperplastic perilobar nephrogenic rests (DHPLNR) and preventing Wilms tumor development.
  4. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with unilateral tumors and aniridia, Beckwith-Wiedemann Syndrome (BWS), hemihypertrophy or other overgrowth syndromes, by using pre-nephrectomy 2-drug chemotherapy induction with vincristine and dactinomycin.

AREN0631-Treatment of Children with Recurrent Favorable Histology Wilms Tumor, in development)

    Objectives:
  1. To compare the EFS for children with high-risk recurrent FHWT who have achieved a response to induction chemotherapy randomized to consolidation therapy with conventional chemotherapy versus high-dose chemotherapy and autologous stem cell transplant.
  2. To describe if a topotecan-containing regimen will improve the EFS for children with high-risk recurrent FHWT compared to historical controls.
  3. To measure at five time-points the health related quality of life (HRQL) by the Peds QL generic and cancer modules and the Health Utilities Index (HUI 2 and 3) in North American high risk Wilms tumor patients who participate in the AREN0631 randomized trial of autologous stem cell transplantation (ASCT) versus chemotherapy alone.
  4. To determine the impact treatment regimens (chemotherapy versus ASCT) have on single domain/attribute scores of the PedsQL (generic and cancer modules) and the HUI 2 and 3 as measures of morbidity burden.
    B. Hodgkin's Disease- Surgical Principal Investigator
    Studies
    Active Studies
    1. Intermediate Risk Hodgkin's Lymphoma ADOODO31 Children's Oncology Group/National Cancer Institute,Surgical PI
    2. Lymphocyte Predominate Hodgkin's Lymphoma- Surgery Only
    AHOD03P1
    Children's Oncology Group/National Cancer Institute, Amount: Surgical PI
    3. Low Risk hodgkins Lymphoma AHODO431

B. Trauma Research

  1. Pancreatic Trauma Assessment of clinical outcomes and complications in children
  2. Screening for Alcohol Use and Alcohol-Related Risk Taking Behaviors in Injured Adolescents
  3. Trauma Recidivism in 11-17 year old patients
  4. Use of Cervical CT scanning in pediatric trauma

Grants

  1. A Novel Approach to Injury Prevention, Motivational Intervention for Seat Belt Use Source: American Pediatric Surgical Association Foundation Scholar, Amount 10,000

    Role PI
  2. Maternal and Child Health EMSC-NDDP program 09/01/06-09/01/09 1U03 MC 00003-01 EMSC Network Development Demonstration Project Percent effort 10% PI Ronald Maio Direct Costs 1,762,918
  3. MS 3 Project Grant –Education G00291 2/01/06 to 02/28/16. This grant funds new surgical education initiatives by faculty Role Investigator/ Facilitator $2500 per year
  4. 2006 Co- Investigator Consultant 05/01/06-05/01/08 International Collaborative Alcohol & Injury Research Training Program in Poland Fogarty Center 1D43TW007569-01 Fred Blow PI
  5. 2006 A Clinical Decision Rule to Identify Children with Intra-abdomial Injuries 1 R49 CE001002-01, 450,000/ yr Project period: 9/01/06 - 8/31/09 Role Consultant 1,200 per year
  6. 2007 Development of a novel objective measure to monitor bicycle helmet use in children. Office of the Vice Provost for Research University of Michigan 14,699 Role Principal Investigator
  7. Safe Kids Buckle Up Annual Grant funded by General Motors 6,660

Daniel Teitelbaum, M.D.

Professor, Department of Surgery

Dr. Teitelbaum's laboratory is concerned with the interactions of the intestinal intraepithelial lymphocytes (IEL) population and epithelial cells. In particular, his lab studies how changes in epithelial growth, apoptosis and alterations in epithelial barrier function are modulated by the IEL expression of cytokines and growth factors. The laboratory utilizes mouse models to study this influence including administration of total parenteral nutrition (to study villus atrophy) and creation of a short bowel syndrome (to examine villus hypertrophy).

Another major focus in his laboratory is in the growth of intestine with the use of linearly applied distractive forces. His laboratory has collaborated with the School of Mechanical Engineering to develop a number of mechanical devices which are implanted into the lumen of the small bowel. We have achieved over a 3-fold increase in intestinal growth in a 2 week period of time. Development of such a device will hopefully lead to a clinical treatment of short bowel syndrome.

Dr. Teitelbaum's laboratory has also developed a new approach for the treatment of inflammatory processes of the gastrointestinal tract. This approach uses angiotensin converting enzyme inhibitors delivered to the gastrointestinal mucosa in a fashion which prevents systemic side-effects of these agents, but results in a marked prevention of epithelial cell apoptosis and a reduction in the expression of mucosally-derived pro-inflammatory cytokines.

James D. Geiger, M.D.

Associate Professor of Surgery

Dr. James D. Geiger continues to investigate novel methods for immunotherapy of cancer. Currently the laboratory is focused on optimizing the generation and function of dendritic cells generated from peripheral blood as well as the ability of dendritic cells to sensitize T-cells to tumor antigen. The first clinical trial utilizing dendritic cells in pediatric solid tumor patients has been completed and he currently is recruiting patients for a Phase I Clinical Trial exploring the use of tumor lysate-pulsed dendritic cell vaccine in solid tumor patients post stem cell transplantation. In addition, Dr Geiger is the director of the newly formed Medical Innovation Center. A joint effort between the University of Michigan Medical School, the College of Engineering, School of Dentistry and the Samuel Zell & Robert H. Lurie Institute for Entrepreneurial Studies at the Ross School of Business, this program looks to foster innovation and enable new medical technologies by integrating clinicians, scientists, engineers and business professionals through education and research to ultimately improve health.

PEDIATRIC SURGERY: IMMUNOTHERAPY IN PEDIATRIC SOLID TUMORS

James D. Geiger

Associate Professor of Surgery,

Section of Pediatric Surgery

University of Michigan Medical Center

Investigators:

James D. Geiger, M.D.

Techniques

  • Immunofluorescence staining
  • ELISA assay
  • Elispot
  • Lymphocyte proliferation assay
  • Lymphocyte cytotoxicity assay
  • T-cell stimulation and culture
  • preparation of single cells from solid tumors
  • preparation of dendritic cells

Equipment

  • CO2 incubators
  • laminar airflow hoods
  • Inverted microscopes
  • light microscopes
  • table top centrifuge
  • floor centrifuge
  • cytospin II
  • MACS cell separator
  • FACScan flow cytometer
  • BD LSR Cytometer
  • Revco - 80 freezer
  • Liquid nitrogen storage

Pilot study of tumor lysate-pulsed dendritic cell vaccine for immune augmentation for high-risk solid tumor patients following autologous stem cell transplantation

Collaborators: John E. Leving, M.D., Raymond J Hutchinson, M.D. Funding: The University of Michigan Medical School, The Brian Morden Foundation, the Shriver Foundation, The Berry Patch Foundation

The aims of this project are to evaluate the ability of tumor lysate-pulsed DC to augment the anti-tumor immune response in pediatric and young adult patients with solid tumors. This study will furhter the understanding of immune responses to solid tumors and the ability of DC tumor vaccine to modulate the anti-tumor immune response in the post-HSCT lymphopenic environment.

Other Studies

Other investigations will involve evaluating the use of CD 4( T- helper ) cells in adoptive immunotherapy. Optimal methods for expanding CD 4 cells and maintaining antigen specificity are being explored.

The laboratory continues to explore the best method to generate dendritic cells from peripheral blood and stem cells (CD 34). Chemokines and cytokines are being used to optimize the function of dendritic cells in both antigen processing and presentation. In addition, we are actively trying to identify tumor specific antigens in pediatric solid tumors that might be utilized as targets for immunotherapy.

The laboratory is also looking at ways to generate tumor lysate for presentation to DC. Established methids include freeze-thaw and heating, we have recently explored the use of focused ultrasound to ablate tumors and generate tumor lysate. DC are pulsed with lysate generated from ultrasound ablation and injected into mice for immunization against cancer. This technology is new and studies are in the very early stages.

Completed Studies:

Dendritic Cell Vaccines in The Treatment of Pediatric Solid Tumors

Collaborators: James J. Mule, Ph.D., Raymond Hutchinson, M.D.
Funding: NIH
The aims of this project are to investigate the use of dendritic cells as potent antigen presenting cells in a tumor vaccine to treat neuroblastoma and childhood sarcomas that have failed standard therapy. This therapy will be compared to vaccines consisting of tumor pulsed dendritic cells combined with chemokine secreting fibroblasts. Chemokines are essential for leukocyte function and trafficking and also enhance dendritic cell function. Pre-clinical studies will be performed to evaluate the capacity of dendritic cells with and without chemokines to detect T-cell specific responses to autologous neuroblastoma and sarcoma.

Grant Support

Past

Research Advisory Committee, Department of Surgery, University of Michigan Medical Center: Enzyme Linked Immuno-spot assay (ELISPOT) analyzer.

  • $20,000 1999

University of Michigan, Internal Support, Section of Pediatric Surgery;

  • 07/01/96 - 06/30/97 ($30,000)
  • 07/01/97 - 06/30/98 ($30,000)
  • 07/01/98 - 06/30/99 ($30,000)

National Cancer Institute, R-29, CA 77471-01, Vaccine Therapy of Pediatric Malignancies Utilizing Dendritic Cells

  • Principle Investigator (50% effort)
  • Annual direct cost $70,000
  • Total cost $532,000
  • 4/01/98-3/31/04

Current

Children's Oncology Group #A NBL00P2, Perinatal Neuroblastoma: Expectant Observation РA Children's Oncology Group Pilot Study

  • Co-Investigator
  • 7/1/01-6/30/05

Children's Oncology Group #A RST03P1, A Pilot Phase II Study for Children with Infantile Fibrosarcoma

  • Co-Investigator
  • 7/01/04-06-30-09

University of Michigan Medical School, Student Biomedical Research Program

  • 1998-2002
  • $10,000

The Brian Morden Foundation

  • 3/1/05-2/28/07
  • Funds given in support of submitted grant: Dendritic Cell Vaccine Therapy of Sarcoma Patients Post Stem Cell Transplantation Principle Investigator (20% effort) $50,000

The Role of Virtual Reality Simulation in Integrated Operating Room Design

  • Co-Investigator (10% effort)
  • Total direct cost $ 117,601
  • (This grant is pending funding from the Stryker Corporation)

UM-Faculty Group Practice - Geiger (PI)

  • Clinical Research Initiatives Program-University of Michigan
  • 3/1/05-2/28/07
  • Pilot study of dendritic cell vaccine therapy of solid tumor patients post stem cell transplant
  • Pilot study evaluating the ability of dendritic cell vaccines to generate anti-tumor specific T-cell responses in pediatric patients with solid tumors following antilogous hematopoetic stem cell transplant.

The Director's Leadership Gift Fund of the University of Michigan Comprehensive Cancer Center

  • 7/1/06 - 6/30/07
  • Funds given in support of submitted proposal: High Intensity Focused Ultrasound and Cancer Immunotherapy
  • Co-investigator $35,000

The Elsa U. Pardee Foundation

  • 10/2006 - 10/2007
  • Funds given in support of submitted grant: High Intensity Focused Ultrasound and Tumor Immunotherapy
  • Principle Investigator $85,000