Translational Research in Pancreatic Cancer

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

This edition of the Gastroenterology Newsletter features a selection of the groundbreaking research examining the pathophysiology, genetics, diagnostics and treatment of pancreatic cancer and cystic disease. These studies represent a cooperative effort between the Divisions of Gastroenterology and Hematology-Oncology, the Abramson Cancer Center and the Departments of Medicine, Surgery, Pathology and Laboratory Medicine, and Oncology and Clinical Pharmacology at Penn Medicine.

Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer 

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDA) is defined by active suppression of the immune response concomitant to inflammatory cell-associated tumor development and progression. Recently, a team of researchers at Penn Medicine identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as an important regulator of inflammation and immune suppression in PDA.

The team, comprised of specialists from the Abramson Cancer Center, the Divisions of Hematology-Oncology and Gastroenterology, and the Departments of Medicine and Pathology and Laboratory Medicine, was led by Robert H. Vonderheide, MD, DPhil, with contributions from Ben Z. Stanger MD PhD.

The GM-CSF finding was the result of a wider investigation into the role of the antigens Gr-1 and CD11b in PDA. Both antigens are expressed as markers on myeloid-derived suppressor cells (MDSCs), which contribute to immunosuppression in PDA. Numerous in vitro studies have reported the expansion of Gr-1+ CD11b+ cells in implantable tumor models. However, the in vivo relevance of the T cell suppressive qualities remains controversial.

The Penn researchers focused on the KPC mouse model of spontaneous PDA to evaluate a mechanism of tumor-induced immune modulation critical to maintaining the local immune suppressive network characteristic of the disease. KPC mice develop primary PDA lesions that faithfully recapitulate features of the human disease, including progression from preinvasive pancreatic intraepithelial neoplasia (PanIN) to invasive cancer to metastatic disease.

The Penn researchers found that the dense desmoplasia and leukocytic infiltration classically observed in the tumor stroma of patients with PDA is reproduced in tumors of KPC mice. In addition, Gr-1+ CD11b+ cells were shown to accumulate in the spleen as well as the tumor in this model, where these cells maintained a close proximity to tumor cells and were prominently associated with metastatic lesions.

The authors noted that Gr-1+ CD11b+cells derived from tumor-bearing KPC mice suppressed the proliferation of splenic T cells from normal mice and that the cells exhibited high levels of arginase activity and nitrite, suggesting expression of inducible nitric oxide synthase (iNOS); both arginase and iNOS have been previously linked to immunosuppression by Gr-1+ CD11b+ cells in  tumorbearing mice.

Splenic cells proved to be the link to the potential origin of Gr-1+ CD11b+ cells in PDA. In the KPC murine model, splenocytes from tumor-bearing KPC mice exhibited a c-kit+ population similar in percentage to that of c-kit+ precursors found in bone marrow and higher than that found in splenocytes from normal mice. C-kit is a cell surface marker used to identify some types of hematopoietic progenitors in bone marrow.

When the researchers isolated c-kit+ Gr-1+ CD11b+ lineage cells from the spleens of tumor-bearing KPC mice and incubated them with conditioned media obtained from previously isolated cultured PDA tumor cells, c-kit+ cells expressed high levels of Gr-1 and CD11b, exhibited arginase and iNOS activity, and potently suppressed T cell proliferation in the OT-1 T cell suppression assay.

The Penn researchers hypothesized that a tumor-derived factor might drive the generation of Gr-1+ CD11b+ cells from c-kit+ cells in the spleen. To identify this factor, a set of secreted proteins from a panel of PDA tumor cell lines was measured in conditioned media and the results compared to those for conditioned media from benign pancreatic ductal cells from normal control mice. Conditioned media from every PDA line supported proliferation of c-kit+ cells into Gr-1+ CD11b+ cells, whereas media from none of the normal pancreatic ductal cells supported c-kit+ cell proliferation.

Among 11 proteins examined, only granulocyte-macrophage colony-stimulating factor was expressed at high levels by every PDA line but by none of the normal pancreatic ductal lines, suggesting that tumor-derived GM-CSF might be linked to Gr-1+ CD11b+ cell generation.

When recombinant GM-CSF was tested in in vitro assays, the researchers found that GM-CSF drove proliferation and differentiation of c-kit+ Gr-1+ CD11b+ splenocytes isolated from tumor-bearing mice into functional myeloid-derived suppressor cells. Further investigation concluded that GMCSF
is both necessary and sufficient for in vitro generation of functional, immunosuppressive Gr-1+ CD11b+cells, and that in vivo GM-CSF secreted by transformed pancreatic epithelial cells is critically involved in the regulation of inflammation associated with PDA.

When tumor-derived GM-CSF was abrogated in vivo, tumors failed to grow, rejected by an T cell response. Importantly, the investigators showed that GM-CSF is expressed by more than 95% of pancreatic tumors from patients, providing further rationale for novel strategies to inhibit GM-CSF in clinical trials.

This study was published in Cancer Cell.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide
RH. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor
Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer.
Cancer Cell. 2012 Jun 12;21(6):822-35.

Pancreatitis Research

The Rustgi lab is investigating the ways in which pancreatic development and regeneration and pancreatitis and cancer overlap. Funded by the NIH, the group pioneered the use of 3-dimensional cell culture model systems, and uses these with animal models and human tissues to identify key genes and pathways that drive these processes. A recent report from the group that explored the regulatory processes that overlap ductal development, acinarductal metaplasia and the progression of normal cells to pancreatic intraepithelial neoplasia appeared in Genes and Development.

Reichert M, Takano S, von Burstin J, Kim SB, Lee JS, hida-Stansbury K, Hahn C, Heeg S, Schneider
G, Rhim AD, Stanger BZ, Rustgi AK. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 2013; Jan 25.

EMT and Dissemination Precede Pancreatic Tumor Formation

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

Currently, two major paradigms have been proposed to explain the metastatic process. The first, or classical model, sees metastasis as the final step in a progressive sequence in which tumors acquire mutations that promote invasive behavior and dissemination late in tumor evolution. The alternative model envisions metastasis as an inherent feature of a tumor very early in its natural history.

This model is consistent with recent investigations in the field of breast cancer that suggest that cellular dissemination leading to metastasis (or metastatic seeding) may occur prior to the formation of an identifiable primary tumor among cells that would not meet a standard definition of cancer.

Recently, this alternative model has evoked the concept that pancreatic cancer cells precede the formation of tumors. Among the mysteries of pancreatic adenocarcinoma is that while it is often discovered after the cancer has matured and metastasized, it is rarely found in its nascent stages.

To examine the early events leading to pancreatic tumor formation, a team of researchers at Penn Medicine led by Ben Z. Stanger, MD, and Andrew Rhim, MD, developed a sensitive lineage-labeling system to tag (detect and isolate) cells of pancreatic epithelial origin during stochastic tumor progression in a mouse model.

An advantage of the labeling system was that it allowed the team to determine the kinetics of the epithelial-to-mesenchymal transition (EMT) and hematogenous dissemination during the natural evolution of pancreatic ductal adenocarcinoma (PDAC). It has been proposed that carcinoma cells undergo EMT, losing epithelial characteristics and acquiring invasive properties and stem-like features in the process.

Results
The Penn team discovered that tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial to mesenchymal transition (EMT).

Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.

This study was published in Cell.

Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert
M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and
dissemination precede pancreatic tumor formation. Cell. 2012 Jan 20;148(1-2):349-61.

Enrolling Clinical Trials: Autologous Whole Tumor Vaccines For Recurrent Ovarian Cancer

• Department of Obstetrics and Gynecology • Abramson Cancer Center
• Ovarian Cancer Research Center

Researchers at the Penn Ovarian Cancer Research Center (OCRC) are conducting clinical trials to examine the efficacy and safety of personalized tumor vaccines for the treatment of recurrent ovarian, fallopian tube, primary peritoneal and papillary serous endometrial cancers.

Cancer vaccines are designed to teach the immune system to attack and destroy cancer cells. Tumor cells often express distinct antigens known as tumor-associated antigens (TAAs). When the immune system is taught to recognize these antigens as foreign, an immune response is mounted against the tumor.

Vaccinating patients with personalized tumor vaccines, which are derived from the patient’s tumor tissue, has the benefit of conditioning the immune system to mount an immune response against the patients’ unique tumor antigens, as well as target multiple unknown antigens simultaneously. This approach also ensures that every patient has an opportunity to be vaccinated, as the number of molecularly defined TAAs in ovarian cancer is limited.

Penn researchers at the Ovarian Cancer Research Center have created vaccines from dendritic cells (DC), a subset of bone marrow-derived leukocytes, which can be isolated from tumor tissue collected at the time of surgery. These vaccines boost a patient’s pre-existing anti-tumor immune response and are capable of inducing an immune response against new tumor antigens in patients lacking spontaneous immunity.

Recently, Penn investigators have improved the vaccine platform and created a more immunogenic vaccine by treating patients’ tumor cells with an oxidizing agent that enhances the ability of dendritic cells to recognize and engulf tumor cells (Figure 1). To date, this new and improved therapeutic vaccine, called oxidized tumor cell-dendritic cell (OC-DC) vaccine, has been administered to 25 patients with recurrent ovarian cancer at Penn Medicine.

Preliminary results demonstrate that the vaccine is safe and immunogenic with immune response correlating with clinical benefit in most patients. Patients with clinical benefit have favorable immune parameters and some patients have achieved prolonged progression-free survival and remission.

Following vaccination, patients have the option to enroll in a second study where they receive their own vaccine-primed T cells. Using a technique developed at Penn, patient’s T cells are grown in the laboratory to expand the number of cells and then reintroduced into the patient after a lymphodepleting chemotherapy regimen (Figure 2). Because the T cells have already been primed via the personalized dendritic cell vaccine to attack the tumor cells, the adoptive T cell transfer amplifies the anti-tumor immune response.

To date, both the vaccination and adoptive T cell therapy approaches in use at Penn Medicine have demonstrated clinical benefit in about 75% of patients.

Clinical trials in autologous OC-DC immunotherapy now enrolling patients at Penn Medicine’s Ovarian Cancer Research Center:

Autologous OC-DC Vaccine in Ovarian Cancer

This is a four cohort sequential clinical trial for patients with recurrent ovarian, fallopian tube, primary peritoneal or papillary serous endometrial cancer to determine the feasibility, safety and immunogenicity of OC-DC. The current cohort involves a combination of OC-DC with intravenous bevacizumab, cyclophosphamide and oral aspirin.
Future cohorts will include more combinatorial strategies.

Principal Investigator: Janos Tanyi, MD, PhD
Sponsor: George Coukos, MD, PhD
Contact: Melissa Moore 215-615-7447; or OCRC.Trials@uphs.upenn.edu
Study ID Number: UPCC 19809
ClinicalTrials.gov Identifier: NCT01132014

Autologous T-Cells Combined With Autologous OC-DC Vaccine in Ovarian Cancer

This is a phase-I clinical trial in patients with recurrent ovarian cancer, fallopian tube or primary peritoneal cancer who previously underwent induction vaccination with dendritic cell vaccine. The objective of the trial is to determine, in patients who have had cyclophosphamide/fludarabine lymphodepletion, the feasibility and safety of adoptive transfer of vaccine-primed, ex vivo CD3/CD28-costimulated peripheral blood autologous T cells, followed by intradermal vaccination with OC-DC in combination with bevacizumab.  

Principal Investigator: Janos Tanyi, MD, PhD
Sponsor: George Coukos, MD, PhD
Contact: Melissa Moore 215-615-7447; or OCRC.Trials@uphs.upenn.edu
Study ID Number: UPCC 26810
ClinicalTrials.gov Identifier: NCT01312376

Faculty Team

The Penn Ovarian Cancer Research Center (OCRC) is a joint effort of the research and clinical facilities of the Perelman School of Medicine at the University of Pennsylvania, the Abramson Cancer Center and the Department of Obstetrics and Gynecology.

The goal of the OCRC is to identify new methods to detect, prevent and treat ovarian cancer and to improve the quality of life for women with the disease. The Faculty of the Penn Ovarian Cancer Research Center includes world-renowned clinicians and researchers with a commitment to the investigation of novel, advanced approaches to the diagnosis and treatment of ovarian cancer.

Gynecologic Oncology

Janos L. Tanyi, MD, PhD
Principal Investigator of Immunotherapy Trials
Assistant Professor of Gynecologic Oncology

Division of Gynecologic Oncology
University of Pennsylvania

Christina S. Chu, MD
Associate Professor of Obstetrics and Gynecology

George Coukos, MD, PhD
Celso-Ramon Garcia Professor of Reproductive Biology

Stephen C. Rubin, MD
Chief, Gynecologic Oncology

Franklin Payne Professor of Gynecologic Oncology

Lana Kandalaft, PharmD, PhD, MTR
Research Assistant Professor of Obstetrics and Gynecology and Director of Clinical Immunotherapy Development

Download a pdf of this Clinical Briefing:

Enrolling Clinical Trials: Intrapleural Adenoviral-Mediated Interferon-Alpha Gene Transfer for Malignant Pleural Mesothelioma

Pulmonary, Allergy and Critical Care Division • Abramson Cancer Center
• Mesothelioma and Pleural Program  

Researchers at the Perelman School of Medicine are conducting a clinical trial to evaluate a promising new gene therapy approach to malignant pleural mesothelioma (MPM).

A cancer of the mesothelial lining of the pleura, peritoneum and pericardium, mesothelioma is typically caused by asbestos exposure and is invariably fatal. The disease is resistant to standard approaches to cancer treatment, including surgery, radiation and chemotherapy. However, because mesothelioma typically presents as a localized tumor in an accessible cavity, it is an appealing target for gene therapy, a new approach to treatment.

Among a number of experimental clinical trial initiatives now in development at the Penn Mesothelioma and Pleural Program (PMPP), gene therapy seeks to treat MPM by delivering genetic information to targeted cells at the disease site to induce an immune reaction. The adenoviral vector is an attractive gene delivery method for MPM for its capacity to transfect various target cell types with high efficiency and to accomplish significant, but transitory, gene expression on target cells.

In published findings, [1] more than half of MPM patients treated with adenoviral-mediated interferon-alpha gene transfer had disease stability and/or tumor regression within two months of initiation of treatment.

A significant percentage of patients evaluated had anti-tumor humoral immune responses. These data demonstrate that Ad.IFN-alpha-2b generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor sites and thus has a potential therapeutic benefit in MPM.

A pilot and feasibility trial is now underway at Penn to evaluate a recombinant, replication-defective adenovirus altered to express high levels of the powerful immune system stimulant interferon-alpha (Ad.IFN-alpha-2b). Injected directly into the affected chest cavity, the virus provokes an anti-tumor immune response by promoting high levels of interferon production within the mesothelioma tumor and pleural space.

A pilot and feasibility trial evaluating two different chemotherapy regimens in combination with intrapleural adenoviral-mediated interferon-alpha gene transfer for malignant pleural mesothelioma
This is a single-center, open-label pilot and feasibility study of intrapleural Ad.hIFN-alpha-2b in combination with pemetrexed/cisplatin or gemcitabine/carboplatin chemotherapy in the first-line or second-line treatment of subjects with malignant pleural mesothelioma. 

The primary goals of this study are to determine the safety of combining intrapleural Ad.hIFN-alpha- 2b with systemic chemotherapy and to establish an estimate of the clinical response of this regimen in patients with malignant mesothelioma. 

All patients will receive two (Day 1 and Day 4) fixed doses of intrapleural Ad.hIFN-alpha-2b (3e11 vp) and Celebrex 400mg BID for 14 days, followed by four to six cycles of pemetrexed (500mg/m2) and cisplatin (75mg/m2) or gemcitabine (1000mg/m2) and carboplatin (AUC 5) chemotherapy every 21 days. 

Treatment naïve patients will receive the standard “front-line” chemotherapy of pemetrexed/cisplatin. Patients previously treated with pemetrexed-based therapy who have progressive disease will receive chemotherapy with gemcitabine and Carboplatin. Patients will be followed up for six months.

Principal investigator: Daniel H. Sterman, MD . All inquiries should be directed to Susan Metzger, RN, BA, at 610.209.2971, or at susan.metzger@uphs.upenn.edu.

1. Sterman DH, Haas A, Moon E, Recio A, Schwed D, Vachani A, Katz SI, Gillespie CT,
Cheng G, Sun J, Papasavvas E, Montaner LJ, Heitjan DF, Litzky L,Friedberg J, Culligan
M, June CH, Carroll RG, Albelda, SM. A trial of intrapleural adenoviral-mediated
interferon-alpha-2b gene transfer for malignant pleural mesothelioma. Am J Respir Crit Care Med. 2011; 184:1395-1399. 

 

Mesothelioma Clinical Trials at Penn Medicine

For information about mesothelioma clinical trials at Penn Medicine, please visit: pennmedicine.org/mesotheliomatrialspennmedicine.org/mesotheliomatrials.

Faculty Team

The Penn Mesothelioma and Pleural Program is a multidisciplinary center dedicated to providing the best treatments for patients with mesothelioma and other pleural diseases. In addition to providing patients with the best treatments currently available, the PMPP strives through in-house and collaborative research to develop the best future treatments for mesothelioma and other diseases of the pleura.

PMPP researchers have performed clinical trials in gene therapy for mesothelioma almost continuously since 1995, beginning with early-phase proof of principle studies and continuing today with trials that combine gene therapy with standard chemotherapy. The resulting treatment program is among the largest in the world.

Thoracic Surgery

Joseph S. Friedberg, MD
Co-Director, Penn Mesothelioma and Pleural Program
Chief, Thoracic Surgery, Penn Presbyterian Medical Center
Associate Professor of Surgery

Pulmonary Medicine

Daniel Sterman, MD
Co-Director, Penn Mesothelioma and Pleural Program
Associate Professor of Medicine and Surgery

Steven M. Albelda, MD
Professor of Medicine

Anil Vachani, MD
Assistant Professor of Medicine

Andrew R. Haas, MD, PhD
Assistant Professor of Medicine

Interventional Pulmonology

Anthony R, Lanfranco, MD
Assistant Professor of Clinical Medicine

Endocrine and Oncologic Surgery

Giorgos C. Karakousis, MD
Assistant Professor of Surgery

Hematology-Oncology

Corey J. Langer, MD
Professor of Medicine

Evan W. Alley, MD, PhD
Clinical Associate Professor, Medicine

Pathology

Franz Fogt, MD
Professor of Pathology and Laboratory Medicine

Bo Jian, MD
Assistant Professor of Clinical Pathology and Laboratory Medicine

Leslie A. Litzky, MD
Professor of Pathology and Laboratory Medicine

Anna M. Moran, MD
Clinical Assistant Professor of Pathology and Laboratory Medicine

Radiology

Sharyn I. Katz, MD
Assistant Professor of Radiology

Harvey Nisenbaum, MD, FACR
Associate Professor of Radiology

Radiation Oncology

Keith Cengel, MD, PhD
Assistant Professor of Radiation Oncology

Charles B. Simone II, MD
Assistant Professor of Radiation Oncology

Stephen M. Hahn, MD
Professor of Radiation Oncology

Clinical Research & Operations

Melissa Culligan, RN, BSN
Director, Clinical Operations

Mona S. Jacobs-Small, BS, RRT, CCRC

Sally I. McNulty, RN
Clinical Research Nurse, Radiation Oncology

Susan Walker, CRNP, MSN, AOCN
Advanced Practice Nurse (Hematology/Oncology)

Patient Navigator

Karen D Mudrick
Associate Director of Operations & Patient Navigator

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   Penn Mesothelioma and Pleural Program
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   51 North 38th Street
   Philadelphia, PA 19104

   Philadelphia Heart Institute Building
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   38th & Market Streets
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Penn Lung Center
Perelman Center for Advanced Medicine
West Pavilion, 1st Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

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Enrolling Clinical Trials: Adoptive Immunotherapy for Chemotherapy Resistant or Refractory CD-19+ Leukemia and Lymphoma

Researchers at Penn have initiated a clinical trial to evaluate the efficacy and safety of CTL-019 (formerly CART-19) for adoptive immunotherapy in patients with relapsed or chemotherapy-refractory chronic lymphocytic leukemias (CLL) and acute lymphoblastic leukemias (ALL) clinicaltrials.gov identifier: NCT01029366. In the near future this trial will be open to patients with relapsed or refractory CD19+ non-Hodgkin’s lymphoma.

Current treatments for B cell malignancies include chemotherapy, radiation therapy, and bone marrow and peripheral blood stem cell transplantation. The only curative therapy for patients with relapsed or refractory disease is allogeneic stem cell transplant, but this is associated with extensive morbidity and mortality, and often very high relapse rates.

Among the highly attractive therapeutic targets for the treatment of leukemia and lymphoma today is CD19, an antigen that is expressed only on the surface of B cells (both normal and malignant) and can thus be used to target B cell lymphomas and leukemias, including ALL, CLL and most non-Hodgkin’s lymphomas.

The virtual absence of CD19 in normal tissues and pluripotent blood stem cells limits the potential for induction of autoimmune disease and irreversible myelotoxicity among therapies targeting CD19.

Researchers Carl June, MD, and David Porter, MD, at Penn Medicine are conducting a clinical trial to assess the efficacy and safety of CTL-019, an agent comprised of autologous T cells engineered to express an antibody against CD19.

The cells are genetically modified with a chimeric antigen receptor (CAR) that contains an extracellular single chain antibody (scFv) against CD19 and a potent intracellular signaling domain (the CD3-zeta domain and the 4-1BB fragment of CD137 co-stimulatory receptor) that induce potent T cell activation. Preliminary results have been published in NEJM_2011;365:725-733 and Sci Transl Med 10 August 2011;3:95ra73.

The primary objective of the trial is to determine the safety and survival of the redirected autologous T cells transduced with the anti-CD19 lentiviral vector. Study participants will include adult patients aged >18 with CD19+ B cell malignancies and no available curative treatment options (such as autologous or allogeneic stem cell transplantation) who have limited prognosis (several months to less than 2 years survival) with currently available therapies.

 About Referring Patients to the CTL-019 Trial

The principal investigators for the CTL-019 trial are Noelle Frey, MD, and David Porter, MD. Patients may be referred by contacting Drs. Frey or Porter directly at 215-662-2867.

For more information about this trial, and other trials for patients with CLL, ALL and NHL, visit:
www.pennmedicine.org/Tcelltherapy.


 
 Case Study

Mr. C, 65-year-old male, was diagnosed with CLL four years before he came to Penn. During that time, he had six treatments, all with partial responses, and was now refractory to purine analogs. At Penn, his lab work revealed a white count of 30,000, extensive marrow infiltration and diffuse adenopathy. After a consultation, Mr. C agreed to the CTL-019 treatment regimen.

Mr. C first received a lymphodepleting conditioning regimen consisting of cyclophosphamide (250 mg/m2/d x 3 days) and fludarabine (25 mg/m2 x 3 days) prior to adoptive transfer of T cells. Subsequently, he was administered CTL-019. He then experienced flu-like symptoms, fever, rigor, transient hypertension and tumor lysis syndrome for 14 days. These symptoms resolved over the next two weeks.

Lab tests at his first disease assessment on day 31 revealed that his CTL-019 cell count had expanded by 3 logs; his white cell count was normal; his bone marrow revealed no CLL by deep sequencing (a technology with the capacity to detect the one cell in 100,000 that is cancerous); and his adenopathy had resolved. He was judged to be in complete remission. It is known now that remissions can be sustained for at least two years, and the CTL-019 cells are still circulating in the body at this time. At six months, Mr. C had no signs of disease.
 
Faculty Team

Investigators with Penn Hematology/Oncology are focused on translating laboratory work into novel therapies and practice-changing discoveries. The scope of Penn’s hematology and medical oncology clinical research enterprise is very broad, spanning all phases of clinical research, including pre-clinical work and discovery, phase 1 and 2 studies and leadership of national phase 3 trials intended to change the standard of care.

Penn clinical investigators regularly publish high profile and important findings in diverse fields, ranging from the most fundamental cellular investigations, to leading edge translational and clinical research.

Conducting Clinical Studies in Adoptive Immunotherapy for Chemotherapy Resistant or Refractory CD-19+ Leukemia and Lymphoma at Penn Medicine

Principal Investigators

Noelle Frey, MD
Assistant Professor of Medicine

David L. Porter, MD
Professor of Medicine

Team Members

Adam Bagg, MD
Professor of Pathology and Laboratory Medicine

Elizabeth O. Hexner, MD
Assistant Professor of Medicine

Carl June, MD
Richard W. Vague Professor in Immunotherapy

Alison Loren, MD, MSCE
Assistant Professor of Medicine

Selina M. Luger, MD
Professor of Medicine

Michael C. Milone, MD, PhD
Assistant Professor of Pathology and Laboratory Medicine

Sunita Nasta, MD
Assistant Professor of Clinical Medicine

Alexander E. Perl, MD
Assistant Professor of Medicine

Stephen J. Schuster, MD
Robert and Margarita Louis-Dreyfus Associate Professor in
Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research

Edward A. Stadtmauer, MD
Professor of Medicine

Jakub Svoboda, MD
Assistant Professor of Medicine

Donald Tsai, MD, PhD
Associate Professor of Medicine

Daniel Vogl, MD
Assistant Professor of Medicine 

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Hospital of the University of Pennsylvania
Perelman Center for Advanced Medicine
2 West Pavilion
3400 Civic Center Boulevard
Philadelphia, PA 19104

Cancer Clinical Trials at Penn Medicine
For information regarding cancer clinical trials at Penn Medicine, please visit the Oncolink Clinical Trial Matching and Referral Service at:

www.oncolink.org/treatment/trials.html.

A list of currently recruiting adoptive immunotherapy trials in various cancers and in HIV can be found at: www.uphs.upenn.edu/abramson/clinicalTrials.html. 

Download a pdf of this Clinical Briefing.

Microsurgical Vascularized Fibular Grafts for Avascular Necrosis of the Hip

Penn orthopaedic surgeons are performing free vascularized fibular grafts (FVFG) to treat patients with avascular necrosis of the hip. An elective microsurgical procedure, free vascularized fibular grafting is an option for hip joint preservation.

Avascular necrosis (AVN) involves progressive necrosis of the hip provoked by vascular compromise of circulation to bone. The resulting bone death contributes to femoral head collapse and secondary osteoarthritis and is believed to be irreversible.

The majority of patients with avascular necrosis are young, with an average age of 38. Conditions and events known to contribute to AVN in bone include sickle cell disease, rheumatoid arthritis and other disease states, as well as trauma, alcohol abuse and prolonged corticosteroid use.

Treatment options for mild-to-moderate AVN include core decompression and bone grafting. For patients with late stage AVN, the standard treatment is total hip arthroplasty.

However, microsurgical free vascularized fibular grafting (FVFG) is an alternative approach. Now offered at Penn, the procedure has several advantages by comparison to total hip surgeries. FVFG introduces healthy bone at the site of necrosis, eliminating the progression of osteonecrosis, and does not preclude later surgeries, if needed.

At Penn Medicine, FVFG surgery is available as an alternative to total hip replacement for younger patients suffering from AVN. The procedure replaces dead bone at the hip with viable, structurally sound, vascularized bone from the fibula. Blood vessels from the living bone are then attached using the operating microscope to vessels at the native hip to provide an immediate blood supply to the fibula that sustains the bone.

The procedure is performed at Penn by surgeons trained in orthopaedics and microsurgery. The unique skill set required to perform the surgery limits the number of hospitals that can offer the procedure. Success rates of 80% at five years (defined as a significant improvement in Harris hip scores and no conversion to THA) have been reported; rehabilitation from FVFG requires a period of limited weight bearing for up to six months.

Case Study

Mr. A, a 26-year-old man with advanced ideopathic bilateral avascular necrosis (AVN) of the hip, presented to Penn Orthopaedics seeking alternatives to bilateral hip replacement surgery. After a consultation with the microsurgical team at Penn Orthopaedics, Mr. A chose to have free vascularized fibular graft surgery.

Following general anesthesia and an epidural block, a pneumatic tourniquet was placed at Mr. A’s thigh to facilitate fibular graft harvest. A longitudinal incision was made immediately distal to the fibular head to a point proximal to the lateral malleolus. The underlying fascia was then incised and the peroneal muscles were reflected from the fibula until the segment of fibula to be removed was clearly visualized.

Subsequently, the anterior musculature was reflected off the fibula and the interosseous membrane divided along the length of the planned fibular graft. The graft, with a portion of the peroneal artery and  adjoining veins, was then harvested and prepared for transfer and the leg incision closed.

At the femur, an incision was made over the greater trochanter and the recipient vessels identified and prepared for grafting. A guide pin was placed at the center of the necrotic bone of the femoral head and positioned to permit subchondral bone to remain in the femoral head. The femoral head was then reamed to the diameter of the harvested graft under fluoroscopic guidance.

Cancellous bone was collected from the region of the greater trochanter and placed into the cavity and impacted to fill any subchondral voids in the femoral head. Following placement of the graft in the femoral cavity, the donor and recipient vessels were microsurgically anastomosed. Blood flow was then restored to the fibula and the surgical site was closed.

Within a month of surgery, Mr. A was on crutches and reporting only mild levels of discomfort. He began weight-bearing at six weeks post-surgery and is expected to make a full recovery by six months. A second FVFG procedure for his other hip is scheduled to take place shortly thereafter.

Faculty Team

The country’s first department of orthopaedic surgery and a national leader in National Institutes of Health (NIH) funding, Penn Orthopaedics offers advanced, personally-tailored care and the latest treatment options for a variety of injuries and disorders within ten orthopaedic subspecialties. In addition to orthopaedic procedures, the collective skills of Penn’s orthopaedic specialists include microsurgery, nerve and tendon transfer and reconstructive transplantation.

Performing Microsurgical Free Vascularized Fibular Graft Surgery at Penn Medicine

L. Scott Levin, MD, FACS

Chair, Department of Orthopaedic Surgery

Paul B. Magnuson Professor of Bone and Joint Surgery

Professor of Surgery, Division of Plastic Surgery

Gwo-Chin Lee, MD

Assistant Professor of Orthopaedic Surgery

Samir Mehta, MD

Chief, Division of Orthopaedic Trauma

Assistant Professor of Orthopaedic Surgery

Charles Nelson, MD

Chief, Joint Replacement Service

Associate Professor of Orthopaedic Surgery

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Penn Orthopaedics

Hospital of the University of Pennsylvania

2 Silverstein

3400 Spruce Street

Philadelphia, PA 19104

Penn Orthopaedics

Pennsylvania Hospital

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800 Spruce Street

Philadelphia, PA 19107

Download a pdf of this Clinical Briefing.

EMT and Dissemination Precede Pancreatic Tumor Formation

To examine the early events leading to pancreatic tumor formation, a team of researchers at Penn Medicine led by Ben Z. Stanger, MD, and Andrew Rhim, MD, developed a sensitive lineage-labeling system to tag (detect and isolate) cells of pancreatic epithelial origin during stochastic tumor progression in a mouse model. An advantage of the labeling system was that it allowed the team to determine the kinetics of the epithelial-to-mesenchymal transition (EMT) and hematogenous dissemination during the natural evolution of pancreatic ductal adenocarcinoma (PDAC). It has been
proposed that carcinoma cells undergo EMT, losing epithelial characteristics and acquiring invasive properties and stem-like features in the process.

Currently, two major paradigms have been proposed to explain the metastatic process. The first, or classical model, sees metastasis as the final step in a progressive sequence in which tumors acquire mutations that promote invasive behavior and dissemination late in tumor evolution. The alternative model envisions metastasis as an inherent feature of a tumor very early in its natural history. This model is consistent with recent investigations in the field of breast cancer that suggest that cellular dissemination leading to metastasis (or metastatic seeding) may occur prior to the formation of an identifiable primary tumor among cells that would not meet a standard definition of cancer.

Recently, this alternative model has evoked the concept that pancreatic cancer cells precede the formation of tumors. Among the mysteries of pancreatic adenocarcinoma is that while it is often discovered after the cancer has matured and metastasized, it is rarely found in its nascent stages.

 Results

The Penn team discovered that tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT).

Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.

This study was published in Cell.

Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, ReichertM, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT anddissemination precede pancreatic tumor formation. Cell. 2012 Jan 20;148(1-2):349-61.

Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

Recently, a team of researchers at Penn Medicine identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as an important regulator of inflammation and immune suppression in  pancreatic ductal adenocarcinoma (PDA). The tumor microenvironment of PDA is defined by active suppression of the immune response concomitant to inflammatory cell-associated tumor development and progression.
 
The team, comprised of specialists from the Abramson Cancer Center, the Divisions of Hematology-Oncology and Gastroenterology, and the Departments of Medicine and Pathology and Laboratory Medicine, was led by Robert H. Vonderheide, MD, DPhil, with contributions from Ben Z. Stanger MD, PhD.

The GM-CSF finding was the result of a wider investigation into the role of the antigens Gr-1 and CD11b in PDA. Both antigens are expressed as markers on myeloid-derived suppressor cells (MDSCs), which contribute to immunosuppression in PDA. Numerous in vitro studies have reported the expansion of Gr-1+ CD11b+ cells in implantable tumor models. However, the in vivo relevance of the T cell suppressive qualities remains controversial.

The Penn researchers focused on the KPC mouse model of spontaneous PDA to evaluate a mechanism of tumor-induced immune modulation critical to maintaining the local immune suppressive network characteristic of the disease. KPC mice develop primary PDA lesions that faithfully recapitulate features of the human disease, including progression from preinvasive pancreatic intraepithelial neoplasia (PanIN) to invasive cancer to metastatic disease.

The researchers found that the dense desmoplasia and leukocytic infiltration classically observed in the tumor stroma of patients with PDA is reproduced in tumors of KPC mice. In addition, Gr-1+ CD11b+ cells were shown to accumulate in the spleen as well as the tumor in this model, where these cells maintained a close proximity to tumor cells and were prominently associated with metastatic lesions.

The authors noted that Gr-1+ CD11b+ cells derived from tumor-bearing KPC mice suppressed the proliferation of splenic T cells from normal mice and that the cells exhibited high levels of arginase activity and nitrite, suggesting expression of inducible nitric oxide synthase (iNOS); both arginase and iNOS have been previously linked to immunosuppression by Gr-1+ CD11b+ cells in tumor bearing mice.

Splenic cells proved to be the link to the potential origin of Gr-1+ CD11b+ cells in PDA. In the KPC murine model, splenocytes from tumor-bearing KPC mice exhibited a c-kit+ population similar in percentage to that of c-kit+ precursors found in bone marrow and higher than that found in splenocytes from normal mice. C-kit is a cell surface marker used to identify some types of hematopoietic progenitors in bone marrow.

When the researchers isolated c-kit+ Gr-1+ CD11b+ lineage cells from the spleens of tumor-bearing KPC mice and incubated them with conditioned media obtained from previously isolated cultured PDA tumor cells, c-kit+ cells expressed high levels of Gr-1 and CD11b, exhibited arginase and iNOS activity, and potently suppressed T cell proliferation in the OT-1 T cell suppression assay.

The Penn researchers hypothesized that a tumor-derived factor might drive the generation of Gr-1+ CD11b+ cells from c-kit+ cells in the spleen. To identify this factor, a set of secreted proteins from a panel of PDA tumor cell lines was measured in conditioned media and the results compared to those for conditioned media from benign pancreatic ductal cells from normal control mice. Conditioned media from every PDA line supported proliferation of c-kit+ cells into Gr-1+ CD11b+ cells, whereas media from none of the normal pancreatic ductal cells supported c-kit+ cell proliferation.

Among 11 proteins examined, only granulocyte-macrophage colony-stimulating factor was expressed at high levels by every PDA line but by none of the normal pancreatic ductal lines, suggesting that tumor-derived GM-CSF might be linked to Gr-1+ CD11b+ cell generation.

When recombinant GM-CSF was tested in in vitro assays, the researchers found that GM-CSF drove proliferation and differentiation of c-kit+ Gr-1+ CD11b+ splenocytes isolated from tumor-bearing mice into functional myeloid-derived suppressor cells. Further investigation concluded that GM-CSF is both necessary and sufficient for in vitro generation of functional, immunosuppressive Gr-1+ CD11b+cells, and that in vivo GM-CSF secreted by transformed pancreatic epithelial cells is critically involved in the regulation of inflammation associated with PDA.

When tumor-derived GM-CSF was abrogated in vivo, tumors failed to grow, rejected by an T cell response. Importantly, the investigators showed that GM-CSF is expressed by more than 95% of pancreatic tumors from patients, providing further rationale for novel strategies to inhibit GM-CSF in clinical trials.

This study was published in Cancer Cell.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, VonderheideRH. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating FactorRegulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer.Cancer Cell. 2012 Jun 12;21(6):822-35.

Distal Anterior Interosseous Nerve Transfer to the Deep Motor Branch of the Ulnar Nerve for Restoration of Hand Function in High Ulnar Nerve injury

Surgeons at Penn Medicine are performing nerve transfer surgery to restore function to the hands of patients with high ulnar injuries. Nerve transfer surgeries at Penn are performed by surgeons in the Division of Plastic Surgery and the Departments of Neurosurgery and Orthopaedic Surgery.

Injury to the proximal ulnar nerve can result in a spectrum of sequelae resulting in severe functional deficit of the intrinsic hand muscles. These effects include progressive weakness of the hand as a result of denervation and the phenomenon of ulnar clawing (or claw hand), a condition in which the metacarpals of the ring finger and little finger (innervated by the ulnar nerve) are drawn back toward the wrist while their respective interphalangeals are curled into the palm.

Direct repair of high ulnar nerve injuries is complicated by the distance between the site of injury and the hand muscles’ target motor endplates. During the months required for axon regeneration, the denervated muscles are subject to atrophy and fibrosis. Anterior interosseous nerve (AIN) transfer to the deep motor branch of the ulnar nerve has been shown to abbreviate the healing process by securing a regenerative nerve source closer to the target muscles.

A branch of the median nerve of the arm, the AIN runs parallel to the ulnar nerve for much of its course. Nerve transfer between the distal AIN and the deep ulnar nerve can restore motor control to the denervated hand and, when performed as a complement to other treatments, may improve fine motor control or address lingering weakness or lack of abduction/adduction in the digits innervated by the ulnar nerve.

At Penn Medicine, hand reconstruction surgery involves a consideration of all of the appropriate treatment options, including rehabilitative therapy, nerve repair and nerve grafting, in addition to nerve transfer surgery. Each case is approached on an individual basis and involves the input of hand surgeons, neurosurgeons and rehabilitation specialists.

Case Study

Mrs. K, a 52-year-old woman, was referred to Penn Plastic Surgery three months after an automobile accident in which she sustained significant right ulnar nerve damage. At presentation, she was found to have some strength in the flexor carpi ulnaris and flexor digitorum profundus tendons of the two ulnar fingers and some recovery of sensation to her dorsal ulnar hand and proximal ulnar fingers. However, she had persistent lack of intrinsic hand function, including clawing of the ring and small fingers (Figure 1), lack of index finger abduction/adduction and positive Froment and Wartenberg signs indicative of ulnar neuropathy.

An electromyogram was consistent with left ulnar neuropathy including nerve conduction to the small finger and absence of motor unit potentials in the first dorsal interosseous muscle. In the absence of clinical signs of recovery of ulnar-innervated intrinsic hand function (particularly to the intrinsic hand muscles over the three month period) and the limited timeframe to attempt to reinnervate the intrinsic hand muscles before motor endplate atrophy and muscle fibrosis, Mrs. K agreed to have a distal nerve transfer to reinnervate her intrinsic hand muscles.
During her surgery at Penn, surgeons first exposed the ulnar nerve on the ulnar side of the distal forearm, then identified the deep motor branch, and separated it from the adjacent ulnar artery and the sensory branches. A limited internal neurolysis was used to separate the motor nerve fascicles from the sensory fascicles.

At the proximal border of the pronator quadratus, the distal anterior interosseous nerve was identified and separated from the underlying anterior interosseous vessels. The anterior interosseous nerve was then divided from the pronator quadratus muscle and brought
towards the ulnar nerve.

A neurorrhaphy was performed of the proximal end of the distal anterior interosseous nerve to the distal end of the nerve fascicles going to the deep motor branch of the ulnar nerve (Figure 2). The surgical incision was closed, and the patient was splinted for three weeks. This was followed by months of occupational therapy with a certified hand therapist.


Within a year of her surgery, Mrs. K had full active flexion and extension of her fingers. She could adduct her small finger with effort, and there was no evidence of clawing of her ring and small  fingers (Figure 3). She still has some intrinsic motor and sensory deficits, but has returned to her full-time job. She continues to see improvement with a home exercise program as recovery is expected to continue for up to 18 months after surgery.

Faculty Team

Penn Plastic Surgery performs more than 1,800 surgeries each year and our surgeons meet with thousands of other patients seeking consultations. Penn plastic surgeons use the latest technology and surgical techniques for both cosmetic and reconstructive surgery. This includes microsurgery, a technology using high-powered microscopes that permit surgeons to visualize and reattach severed blood vessels and nerves to re-establish sensory and motor function to the face, hands and limbs.

Hand reconstructive procedures at Penn Medicine are often a multidisciplinary effort involving the collaboration of plastic surgeons, neurosurgeons, orthopaedic surgeons and other committed specialists.

Performing Distal Anterior Interosseous Nerve Transfer at Penn Medicine

Ines C. Lin, MD
Assistant Professor of Plastic Surgery

Eric L. Zager, MD
Professor of Neurosurgery

L. Scott Levin, MD, FACS
Chair, Department of Orthopaedic Surgery
Paul B. Magnuson Professor of Bone and Joint Surgery
Professor of Surgery, Division of Plastic Surgery

David J. Bozentka, MD
Chief, Hand Surgery; Chief, Orthopaedic Surgery at Penn
Presbyterian Medical Center
Associate Professor of Orthopaedic Surgery

David R. Steinberg, MD
Director, Hand & Upper Extremity Fellowship
Associate Professor of Orthopaedic Surgery

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Perelman Center for Advanced Medicine
East Pavilion, 1st Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Hospital of the University of Pennsylvania
3 Silverstein
3400 Spruce Street
Philadelphia, PA 19104


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Multimodal Treatment of Kidney Stone Disease

Urologists at Penn Medicine are managing kidney stones with a range of interventions that reflects the variable characteristics and effects of stone disease, and an approach to diagnosis that encompasses accuracy of stone identification and patient safety.

Kidney stones (renal calculi) form as solid concretions or crystals; about 80% are composed of calcium, with the remainder comprised of ammonium magnesium phosphate (struvite), uric acid and cystine. The incidence and prevalence of kidney stone disease has been rising for more than two decades in the United States. Men are predominantly affected, but stone disease is no longer uncommon in women, peaking in both sexes between the ages of 40 and 60.

CT scans are an invaluable guide for stone disease treatment planning, providing information relevant to stone location, size and composition. At Penn, low-dose non-contrast helical CT (providing less than 50 percent of the radiation dose of a standard CT scan) is the standard of diagnosis for kidney stone disease. This approach limits radiation exposure for patients who may require repeated serial scans while providing most of the information necessary for treatment planning.

At Penn, treatment of kidney stone disease emphasizes noninvasive therapies and minimally invasive surgery and is determined by stone size, location in the urinary tract and intensity on CT (an artifact linked to stone composition). Stones small enough to pass out of the body (less than 5mm) require no more treatment than pain management and careful monitoring.

Larger calculi may be amenable to noninvasive shock wave lithotripsy, a treatment that uses ultrasound energy to break stones into small fragments. Stones that are refractory to lithotripsy or too large to split may be treated by minimally invasive ureteroscopy, a procedure that permits direct visualization and retrieval of the stone.

Individuals with large stones lodged in the kidney are candidates for percutaneous lithotomy. This procedure involves making a small tract into the kidney from the back to gain access and break the stones. In some cases, laparoscopic (key hole surgery) or robotic procedures may be necessary to clear all of the stones. These procedures are generally more invasive and reserved only for select patients.

Case Study

Mr. D, a 47-year-old male, was referred to Penn Urology by his primary care provider for treatment of a renal calculus. Two weeks prior to his visit, he experienced the acute onset of severe right flank and abdominal pain accompanied by hematuria and vomiting. Mr. D was treated in a Penn emergency room where he underwent a low dose CT scan. This revealed an uncomplicated semi-opaque calculi approximately 0.9 cm in diameter in the middle portion of his right kidney (Figure 1) and a 5 mm stone in the distal right ureter, which he subsequently passed.

The passed stone was sent for analysis and found to be a calcium oxalate stone. Fearing another episode of pain, Mr. D inquired about treatment options for the stone in his kidney. The size and location were appropriate for shock wave lithotripsy but other stone parameters on the CT scan predicted a lower chance of success compared to ureteroscopy.

Because it is noninvasive, and despite a lower chance of success, Mr. D decided to undergo shock wave lithotripsy. When a single session failed to fracture the stone, however, Mr. D asked to have it removed. A ureteroscopic procedure was then performed under general anesthesia to retrieve and remove the stone via basket extraction. Mr. D went home the same day. Two years after his procedure, and with a few
dietary modifications, he reports no further issues with stone disease.

Faculty Team

Penn Urology offers the latest in techniques to critically evaluate and manage all types of urologic disease, including urethral obstruction, enlarged prostate, bladder tumors, urinary stones and cancer. As leaders in minimally invasive and noninvasive procedures, Penn urologists collaborate with specialists in radiology, pathology, medical oncology and radiation oncology to offer high quality personalized care. Penn Urology is a leader, as well, in innovative approaches to therapy, including robotic surgery and endourologic techniques to visualize and treat disorders from kidney to bladder.

Treating Stone Disease at Penn Medicine

Phillip Mucksavage, MD
Assistant Professor of Clinical Urology in Surgery

Keith N. Van Arsdalen, MD
Professor of Urology in Surgery and Radiology

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Pennsylvania Hospital
299 South 8th Street
Philadelphia, PA 19106

Perelman Center for Advanced Medicine
West Pavilion, 3rd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Penn Medicine Cherry Hill
409 Route 70 East
Cherry Hill, NJ 08034

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Enrolling Clinical Trials: Stent Grafts for the Repair of Juxtarenal and Pararenal Abdominal Aortic Aneurysms

Endovascular surgeons with the Division of Vascular Surgery and Endovascular Therapy at Penn Medicine are performing clinical studies to evaluate investigational stent grafts for the treatment of juxtarenal and pararenal aortic aneurysms.

These trials are currently enrolling participants at Penn. Open surgical treatment of pararenal or juxtarenal abdominal aortic aneurysms (AAAs) is complicated by the proximity of the renal and visceral arteries. Renal failure is a leading cause of postoperative morbidity in these surgeries, particularly among patients with preoperative renal insufficiency.

Minimally invasive endovascular stent graft systems designed for the repair of sub-renal aortic aneurysms are now being investigated in the division of Vascular Surgery and Endovascular Therapy at Penn.

The division is currently enrolling for clinical trials investigating the Zenith® p-Branch™, Endologix Ventana™ fenestrated and Cordis INCRAFT™ stent grafts.

Zenith p-Branch OTS Multicenter Study

The Zenith p-Branch OTS Multicenter study will provide an early clinical experience and evaluate the safety and effectiveness of the Zenith p-Branch stent graft (Cook Medical, Bloomington, IN) as an off-the-shelf option for the treatment of pararenal or juxtarenal abdominal aortic aneurysms.

Advantages include fenestrations incorporated in the design of the graft to maintain perfusion through the renal arteries and visceral vessels (celiac artery and superior mesenteric artery) and the preclusion
of open surgery. The study device(s) are inserted through a small incision near each
hip and guided into place in the aorta.

Prospective, multicenter, single arm safety and effectiveness trial of the Endologix fenestrated stent graft system for the endovascular repair of juxtarenal/pararenal (JAA/PAA) aneurysms (Ventana Study)

The Ventana Study is designed to evaluate the safety and efficacy of the Endologix Ventana fenestrated stent graft system (Endologix Inc., Irvine, CA) for the endovascular repair of juxtarenal or pararenal aortic aneurysms.

Based on the approved Endologix AFX Endovascular AAA design, the Ventana system is the first device designed as a potential off-the-shelf endovascular repair option for JAA/PAA. The design couples a bifurcated stent graft to a moveable fenestrated/scalloped proximal extension and renal stent grafts with the intent to be applicable to approximately 80-90% of patients presenting with JAA/PAA.

The trial primary endpoints will evaluate safety (major adverse events) at 30 days and effectiveness (treatment success) at one year, with continuing followup to five years.

INSPIRATION Study - A multicenter, open-label, prospective, nonrandomized study of the INCRAFT™ stent graft system in subjects with abdominal aortic aneurysms.

The INSPIRATION study is a safety and efficacy investigation of the INCRAFT AAA Stent Graft System three-piece modular system (Cordis®, Bridgewater, NJ) in subjects with abdominal aortic aneurysms. Technical success will be defined by the successful deployment of the stent-graft to the desired location in the absence of Types I, III or IV endoleaks at the conclusion of the procedure.

Safety will be defined by the absence of Types I, III or IV endoleaks and device and/or procedural  related major adverse events (death, MI, stroke and renal failure) within 1 month post-procedure.
INCRAFT™ is designed for the endovascular repair of infrarenal AAAs with complex aortic anatomies.

INCRAFT utilizes nitinol stent and polyester graft technology in an ultra-low profile delivery system, which assists the physician in deploying the device in a controlled, consistent and precise manner within the aortic neck and iliac arteries. The ultra-low profile delivery system also serves to increase patient eligibility for endovascular aortic repair and to decrease the risk for access complications.

Faculty Team
Penn Medicine has been at the forefront of clinical research in endovascular devices to treat abdominal aortic aneurysms for almost two decades. Penn is currently among the handful of research centers nationwide involved in clinical trials to expand the indications for endovascular stent grafts to include previously underserved patient populations and complex and complicated aneurysmal disease, including juxtarenal and pararenal aneurysms.

The Division of Vascular Surgery and Endovascular Therapy at Penn performs more carotid, aortic, and peripheral arterial repairs than any other medical center in the region and is involved in advanced FDA trials to investigate new ways to treat abdominal and thoracic aortic aneurysms.

For more information about eligibility for the aortic aneurysm device trials at Penn, please call a Vascular Surgery and Endovascular Therapy physician and arrange for a prompt office appointment.

Hospital of the University of Pennsylvania

Ronald M. Fairman, MD
Chief, Division of Vascular Surgery and Endovascular Therapy,
Clyde F. Barker-William Maul Measey Professor of Surgery
Office: 215-614-0243

Clyde F. Barker, MD
Donald Guthrie Professor of Surgery

Benjamin M. Jackson, MD
Assistant Professor of Surgery
Office: 215-614-0176

Edward Y. Woo, MD
Program Director and Vice Chief,
Division of Vascular Surgery and Endovascular Therapy
Associate Professor of Surgery
Office: 215-615-1698

Grace Wang, MD, FACS
Assistant Professor of Surgery
Office: 215-662-2069

Penn Presbyterian Medical Center

Michael A. Golden, MD
Associate Professor of Surgery
Office: 215-662-9660

Venkat R. Kalapatapu, MD
Assistant Professor of Surgery
Office: 215-662-9686

Access

Hospital of the University of Pennsylvania
3400 Spruce Street
4 Silverstein Pavilion
Philadelphia, PA 19104

Perelman Center for Advanced Medicine
Penn Heart and Vascular Center
East Pavilion, 2nd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Penn Presbyterian Medical Center
Department of Surgery
266 Wright Saunders Building
39th & Market Streets
Philadelphia, PA 19104


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