Clinical Briefings™: Clinical Reports from Penn Medicine

Translational Research in Pancreatic Cancer

noreply@blogger.com (M Baker) — Tue, 21 May 2013 04:15:00 PDT

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

noreply@blogger.com (M Baker) — Tue, 21 May 2013 04:12:00 PDT

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

noreply@blogger.com (M Baker) — Tue, 21 May 2013 04:07:00 PDT

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

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

noreply@blogger.com (M Baker) — Thu, 16 May 2013 10:27:00 PDT

• 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

noreply@blogger.com (M Baker) — Tue, 14 May 2013 10:25:00 PDT

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/mesotheliomatrials pennmedicine.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 Presbyterian Medical Center

   Penn Mesothelioma and Pleural Program
   W246 Wright-Saunders
   51 North 38th Street
   Philadelphia, PA 19104

   Philadelphia Heart Institute Building
   1st Floor
   38th & Market Streets
   Philadelphia, PA 19104

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

noreply@blogger.com (M Baker) — Thu, 02 May 2013 11:25:00 PDT

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

noreply@blogger.com (M Baker) — Fri, 19 Apr 2013 10:41:00 PDT

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

1 Cathcart

800 Spruce Street

Philadelphia, PA 19107

Download a pdf of this Clinical Briefing.

EMT and Dissemination Precede Pancreatic Tumor Formation

noreply@blogger.com (M Baker) — Fri, 22 Mar 2013 09:46:00 PDT

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

noreply@blogger.com (M Baker) — Fri, 22 Mar 2013 09:34:00 PDT

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

noreply@blogger.com (M Baker) — Thu, 21 Mar 2013 11:45:00 PDT

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

Download a pdf of this Clinical Briefing.

Multimodal Treatment of Kidney Stone Disease

noreply@blogger.com (M Baker) — Thu, 21 Mar 2013 10:55:00 PDT

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

noreply@blogger.com (M Baker) — Thu, 21 Feb 2013 12:00:00 PST

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

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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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Comprehensive Surgical Options for Trigeminal Neuralgia

noreply@blogger.com (M Baker) — Fri, 25 Jan 2013 08:53:00 PST

Neurosurgeons at Penn Medicine continue to pioneer and advance a comprehensive treatment program to address trigeminal neuralgia. The Penn Trigeminal Neuralgia program encompasses the spectrum of current and innovative treatment options, including endoscopic microvascular decompression surgery, Gamma Knife® radiosurgery and neuromodulation.

Vascular compression of the fifth cranial nerve as it enters the brainstem is among the most common causes of trigeminal neuralgia. Compression of the nerve results in intense unilateral facial pain affecting the forehead, cheek, jaw and teeth.

A leading surgical option, microvascular decompression (MVD) addresses the source of the neuralgia directly by inserting a barrier between the nerve and blood vessel. The barrier (a Teflon sponge) isolates the nerve from the dilation and pressure of the blood vessel, thereby relieving the symptoms of neuralgia.

MVD is performed through a small suboccipital opening on the affected side of the skull, and has the advantage of providing long-term relief of pain and preservation of facial sensation. Recently, the endoscope has been used during surgery to provide improved visualization of the offending pathology. This has resulted in greater surgical confidence and patient success.

Gamma Knife radiosurgery is an effective, minimally invasive approach to trigeminal neuralgia, and is used in patients for whom more invasive approaches are unsuitable. Gamma Knife concentrates approximately 200 individual beams of radiation on a single point to create a focused, surgical lesion within the nerve to block the transmission of pain signals. The procedure results in minimal damage to normal tissues.

Neuromodulation is an ideal approach for patients with atypical facial pain. Electrodes are placed through small (less than 1 cm) incisions in the skin to tunnel electrodes over the supraorbital (V1) and infraorbital (V2) branches of the trigeminal nerve. The procedure is first performed as a trial. If the stimulation provides pain relief, the electrodes are attached to a pulse generator placed subcutaneously in the infraclavicular space. Studies suggest that neuromodulation offers substantial relief for the majority of patients.

Case 1
Mrs. T, a 40-year-old woman, visited a neurologist for treatment of trigeminal neuralgia radiating into the right side of her face. Over a period of several years she was prescribed Tegretol (carbamazepine), Neurontin (gabapentin) and baclofen. These drugs helped initially. Over time, however, Mrs. T experienced breakthrough pain. She was then referred to Penn Neurosurgery, where she estimated her pain to be 10/10 during breakthrough episodes. After a discussion of her options, Mrs. T
agreed to microvascular decompression procedure.

The procedure: Following general anesthesia, a one-inch incision was made behind Mrs. T’s right ear and a 1 cm keyhole incision made in the dura mater (see “Minimally Invasive Endoscopic MVD Surgery,” back page). Endoscopic microsurgical exploration revealed that the superior cerebellar artery was compressing the nerve at the dorsal root of the right trigeminal nerve (Fig. 1). The artery was dissected away from the nerve and a Teflon sponge placed between the vessel and nerve to act as a barrier. The endoscope and instruments were then retracted and the small wound closed.

Results: Mrs. T went home on the second postoperative day. She was able to discontinue her medications within two weeks of surgery, and at her six-month follow-up reported a significant reduction in discomfort.

Case 2
Mr. Z, an 80-year-old man with a history of left-sided V2 trigeminal neuralgia, came to Penn Neurosurgery to explore options for treatment following an increasing intolerance to the side effects of medication, which included carbamazepine, neurontin, and trileptal. Because of his age, it was recommended that Mr. Z have Gamma Knife radiosurgery rather than an open procedure.

The procedure: Mr. Z was fitted with a frame to stabilize his head during the procedure. A series of imaging scans was then performed to accurately pinpoint the root of the trigeminal nerve and develop dose planning (Fig. 2). During the procedure, approximately 200 beams converged at the target to deliver a single dose of gamma knife radiation (80 Gy). Mr. Z. was discharged home the same day.

Results: Mr. Z’s pain improved over the course of several weeks, during which time he noticed a gradual diminishment in the number and severity of triggers for his neuralgia. At his six-month follow-up visit, he reported that he was able to satisfactorily control his pain with occasional NSAID use.

Gamma Knife® is a registered trademark of Elekta AB (publ) or it’s subsidiaries.

Case 3
Mrs. L, a 55-year-old woman, had a twelve-month history of burning pain radiating from her forehead. This pain was precipitated by a chickenpox outbreak. The skin vesicles had disappeared, but the pain had increased over time in both intensity and duration, and was constant when she was referred to Penn by an outside neurologist. Her treatments for pain included the antiepileptic drugs carbamazepine and gabapentin, both of which had provided transient relief, but to which her pain was now refractory.

The procedure: After a discussion of her options, Mrs. L chose to have a neuromodulation procedure. During her surgery, an electrode was implanted above her eyebrow and under the skin (Fig. 3).

Results: Mrs. L trialed the effects of the stimulation for several days before concluding that the “tingling” sensation was very soothing. She went on to permanent implantation with an implanted battery and was discharged on the same day as her surgical implant. At one year followup, she continued to have approximately 70% relief of the pain with use of the stimulator and was pleased with the results.

Faculty Team
Penn Neurosurgery is comprised of a skilled team of neurosurgeons, each of whom has a particular subspecialty focus. This permits the department to encompass the spectrum of surgically treated disorders of the nervous system. Given the enormous volume and intensity of exposure, patients benefit from that experience as well as the multidisciplinary approach to achieving the best possible outcomes.

Treating Trigeminal Neuralgia at Penn Medicine

John Y.K. Lee, MD
Director, Cranial Nerve Disorder Center
Medical Director, Penn Gamma Knife Center
Assistant Professor of Neurosurgery

Eric L. Zager, MD
Professor of Neurosurgery

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Penn Neurosurgery
Pennsylvania Hospital
Washington Square West Building
235 South 8th Street
Philadelphia, PA 19106

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

Download a pdf of this Clinical Briefing.

Cardiofocus HeartLight® Endovascular Ablation System for the Treatment of Paroxysmal Atrial Fibrillation

noreply@blogger.com (M Baker) — Mon, 10 Dec 2012 08:16:00 PST

Cardiac electrophysiologists at Penn Medicine are participating in a clinical trial of the HeartLight® endoscopic ablation system (Cardiofocus, Inc. Marlborough, MA) in patients with paroxysmal atrial fibrillation (PAF). The primary objective of the trial is to demonstrate the safety and efficacy of the system to achieve elimination of AF compared to current ablation systems.

PAF is initiated by rapidly firing foci in the proximal pulmonary veins and is defined by intermittent, self-limiting episodes that often progress over time despite medical intervention.

Catheter-based electrical isolation of the pulmonary veins is currently the standard of care for patients with drug-resistant PAF. However, the difficulty of creating contiguous lesions while manipulating ablation catheters around the pulmonary veins is well known, and often limits long-term procedural success.

Recurrence of atrial fibrillation following ablation is thought to be caused by recovery of the electrical connection between the pulmonary veins and the left atrium, resulting from either undetected gaps in the series of lesions produced during an ablation or the failure to create complete transmural lesions.

The CardioFocus Endoscopic Ablation System with Adaptive Contact (HeartLight) study seeks to examine the potential of this new device to improve the efficacy and durability of first-time ablation procedures.

Under the direction of cardiac electrophysiologists at Penn, the study has the purpose of demonstrating the safety and effectiveness of the System in the treatment of atrial fibrillation (AF) by creating electrical isolation of the pulmonary veins.

The HeartLight endoscopic ablation system is the first catheter ablation system to incorporate an endoscope to permit direct, real-time visualization of a beating heart. The system also employs a compliant, dynamically adjustable balloon catheter for improved contact with the PV ostium and laser energy for more efficient, durable and precise ablation treatment.

It is hoped that these improvements will produce more reliable and consistent outcomes for PAF patients having ablation therapy.

Case Study

Mr. U, a 54-year-old man, was referred to the elecrophysiology program at Penn Medicine after several years of atrial fibrillation of progressively increasing frequency despite antiarrhythmic medications, including flecainide, propafenone, and sotalol. He was also hypertensive, for which he took several medications, as well as warfarin to thin his blood. He had no other medical conditions of note. After discussing his options for therapy, Mr. U agreed to participate in the HeartLight EAS trial.

During his procedure, Mr. U had intravenous lines placed in the thigh veins that allowed access to his heart. Under intracardiac ultrasound and fluoroscopy, a small needle was used to puncture the membrane separating his right and left atrium. The HeartLight laser balloon was advanced into the left atrium and then sequentially into each of the four pulmonary veins (Figure 1), where lesions were placed in a circumferential manner.

This produced electrical isolation of the pulmonary veins from the heart (documented with a circular mapping catheter), preventing the triggering impulses for atrial fibrillation from escaping from the veins and starting the arrhythmia. Four hours after the procedure, Mr. U was ambulating; he was discharged the following day without incident.

At home, Mr. U’s rhythm was carefully monitored via a transtelephonic device. No arrhythmia recurrence was found at his initial four week follow-up visit. His AF-related medications have been discontinued.

Faculty Team
Penn Medicine has the largest electrophysiology program on the East Coast and one of the largest hospital-based programs in the US. Comprised of full-time, board-certified electrophysiologists and specialized nurse practitioners and physician assistants, the EP team is dedicated exclusively to treating and eliminating serious and potentially life-threatening heart rhythm disturbances. The team’s leadership in ablative and arrhythmia device therapy is evident in their collective contribution to more than 600 articles to scientific journals in the last 10 years.

Principal Investigator for the Cardiofocus EAS HeartLight® Clinical Trial at Penn

Mathew D. Hutchinson, MD
Assistant Professor of Medicine
Telephone: 215.615.5220

Co-Investigator
Fermin C. Garcia, MD
Assistant Professor of Clinical Medicine

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Inpatient Electrophysiology
Location:
Hospital of the University of Pennsylvania
9 Founders Building
3400 Spruce Street
Philadelphia, PA 19104

Outpatient Electrophysiology Locations:
Penn Heart & Vascular Care
Perelman Center for Advanced Medicine
East Pavilion, 2nd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Penn Cardiac Care
250 King of Prussia Road
2nd Floor
Radnor, PA 19087

Download a pdf of this Clinical Briefing.

Diagnosis of Pulmonary Hypertension and other Pulmonary Vascular Diseases

noreply@blogger.com (M Baker) — Mon, 10 Dec 2012 07:28:00 PST

Specialists at Penn Medicine have developed a comprehensive approach to the diagnosis and treatment of pulmonary vascular diseases. Cardiovascular and pulmonary physicians collaborate at the core of this multidisciplinary regional referral program that also draws upon experienced experts in cardiothoracic surgery, thoracic imaging and lung pathology.

Pulmonary hypertension (PH) is a chronic condition defined by abnormally high blood pressure in the lungs and has many potential etiologies. These range from common forms of heart and lung disease (congestive heart failure, emphysema/COPD) to rare and serious diseases that only effect the blood vessels of the lungs (i.e., pulmonary arterial hypertension, or PAH).

Accurate diagnosis of PH is critical, and misdiagnosis leading to inappropriate or ineffective treatment of the condition is common. Thus, the initial focus of the Penn program is a meticulous clinical evaluation with careful attention to the symptoms, physical exam findings and echocardiographic findings of PH in the individual patient.

For most patients, the initial non-invasive diagnostic assessment can quickly and accurately pinpoint the underlying cause of PH. For patients requiring more extensive testing, the PH team at Penn Medicine offers a range of specialized diagnostic tests that requires disease-specific knowledge and expertise, including right heart catheterization, exercise catheterization and additional exercise testing (metabolic exercise testing).

The Penn program offers diagnosis and management of other pulmonary vascular diseases, as well, including hereditary hemorrhagic telangiectasia, occult hemoptysis, unexplained hypoxemia, congenital abnormalities of the pulmonary vascular bed and pulmonary vascular tumors.

Genetic testing, advanced imaging techniques, interventional angiography and surgery are called into play when appropriate for the definitive diagnosis and management of these uncommon conditions.

Medical therapy for PH is complex, and requires expertise in selecting the optimal medication (monotherapy vs. combination therapies), dosing, timing of initiation, and monitoring of potential adverse effects. Treatments include oral, inhaled and intravenous (pump-infused) medications.

Under the leadership of Steven Kawut, MD, patients also have the opportunity to participate in the latest NIH- and industry-sponsored clinical trials of potential new therapeutic agents.

Surgical therapy includes thromboendarterectomy for patients whose pulmonary hypertension is caused by small blood clots within the pulmonary arteries, as well as heart and/or lung transplantation for eligible patients. Continued follow-up care is required for all patients with PH, and is especially important for patients with PAH.

In these patients, it is critically important to determine how the function of the right ventricle responds to medical therapy over time. The PH program at Penn Medicine is also at the forefront of non-invasive assessment of right heart function, which greatly assists in our ability to frequently reassess our patients, and ensure that they reach specific and critical goals with respect to improved right heart function. We believe this approach truly affords an advantage to our patients, optimizing patient care and outcomes.

Case Study
Ms. B presented at age 58 with severe dyspnea and near-fainting with daily activities. Her physical examination revealed right heart failure. Her walk distance in 6 minutes was moderate to severely reduced at 344 meters. Initially, she had been placed on two oral medications, with modest improvement. Her initial echocardiogram at Penn revealed
moderate right heart enlargement and moderate right heart dysfunction (Figure 1A).

Ms. B was enrolled in the Freedom C2 TDE-PH-308 trial, [1] involving an oral form of treprostinil diethanolamine, a highly potent investigational PH medication, which had previously only been available via intravenous 24-hour/day portable pump infusion. One year later, her symptoms have improved dramatically, with minimal shortness of breath with any activity. She is now attending exercise classes and has lost more than 20 lbs as a result. Her walk distance has increased to nearly 500 meters. Her most recent echocardiogram revealed only mild right heart enlargement and normal right heart function (Figure 1B).

Reference
1. A 16-Week, international, multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of oral UT-15C sustained release tablets in subjects with pulmonary arterial hypertension (FREEDOM-C2). ClinicalTrials.gov Identifier: NCT00887978.

Faculty Team
For patients with suspected or confirmed pulmonary vascular disease, including pulmonary hypertension, Penn offers a multidisciplinary collaboration of pulmonologists, cardiologists and advanced practice nurses that is unique within the mid-Atlantic region. Members of the team are available to see patients in two convenient locations.

The Pulmonary Hypertension Program at the Perelman Center for Advanced Medicine

K. Akaya Smith, MD
Assistant Professor of Medicine
Pulmonary, Allergy and Critical Care Division

Prashanth Vallabhajosyula, MD
Assistant Professor of Surgery,
Division of Cardiovascular Surgery

Frances Rogers, CRNP
Nurse Practitioner
Coordinator, Pulmonary Hypertension Program

Sarah Matthews RN,
Registered Nurse

Maria Alpizar
Administrative Assistant, Pulmonary Hypertension Program
Cardiovascular Division

The Pulmonary Vascular Disease Program at
Penn Presbyterian Medical Center

Harold I. Palevsky, MD
Director, Pulmonary Vascular Disease Program
Professor of Medicine

Jason S. Fritz, MD
Assistant Professor of Clinical Medicine

Steven Kawut, MD
Associate Professor of Medicine

Darren B. Taichman, MD, PhD
Adjunct Associate Professor of Medicine

Chris Archer-Chicko, MSN, CRNP
Nurse Practitioner

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

Penn Lung Center
Penn Presbyterian Medical Center
Philadelphia Heart Institute
1st Floor, Rear
51 N 39th Street
Philadelphia, PA 19104

Download a pdf of this Clinical Briefing.

Barrett’s Esophagus and Esophageal Adenocarcinoma: Diagnosis, Treatment and Ongoing Research at Penn Medicine

noreply@blogger.com (M Baker) — Thu, 11 Oct 2012 07:30:00 PDT

Penn Medicine is a national center of excellence in gastrointestinal and liver disorders and is the leading regional resource for the diagnosis and treatment of esophageal adenocarcinoma and its precursor, Barrett’s esophagus.

The Barrett’s esophagus and esophageal adenocarcinoma treatment program at Penn is comprised of a multidisciplinary team of specialists in the fields of gastroenterology, oncology, pathology and surgery supported by the latest and best available technologies for the diagnosis and treatment of the conditions.

According to Gregory G. Ginsberg, MD, Penn Gastroenterology has the largest published series of endoscopic eradication for high grade dysplasia and intramucosal adenocarcinoma in the greater Atlantic region. A past president of the American Society of Gastrointestinal Endoscopy (ASGE), Dr. Ginsberg is director of endoscopic services at Penn Gastroenterology and a professor of medicine.

In addition to dedicated specialists and expertise, adds Gary Falk, MD, MS, the management approach at Penn involves state of the art technology and access to NIH-funded clinical trials of developing and innovative therapies for both esophageal adenocarcinoma and Barrett’s esophagus.

Dr. Falk is a professor of medicine and co-director of the GI Esophagology and Physiology Laboratory at the Hospital of the University of Pennsylvania. Like Dr. Ginsberg, he is a past president of the ASGE.

Pathophysiology of Esophageal Adenocarcinoma and Barrett’s Esophagus

Esophageal adenocarcinoma is among the deadliest of cancers, with a survival rate of just 17% at five years post-diagnosis. A pre-cancerous precursor to esophageal adenocarcinoma, Barrett’s esophagus is the leading risk factor for the disease. The condition is defined by the replacement of normal squamous esophageal mucosa with intestinal columnar epithelium in response to chronic acid exposure.

Over time, this abnormal tissue can progress to dysplasia and ultimately to adenocarcinoma.
In the United States, the incidence of both esophageal adenocarcinoma and Barrett’s esophagus has risen dramatically since the 1970s. The cause for this increase remains at issue, but obesity is generally regarded to be a major risk factor.

Despite an alarming rise in incidence, esophageal adenocarcinoma remains a relatively rare cancer in the United States (~12,000 cases/year according to SEER data). Barrett’s esophagus is by contrast relatively common, affecting about three million adults older than age 40, the vast majority of whom will never develop esophageal adenocarcinoma.

Diagnosis of Barrett’s Esophagus and Esophageal Adenocarcinoma

Endoscopy is the gold standard for the diagnosis of premalignant and malignant lesions in both Barrett’s esophagus and esophageal adenocarcinoma. Gregory Ginsberg, MD, leads the endoscopy program at Penn Gastroenterology.

“Early detection and prevention are the cornerstones of the Barrett’s esophagus and esophageal cancer management program at Penn Medicine,” Dr. Ginsberg says. “Survival increases dramatically if the disease is caught early, at or before the transformation from dysplasia to cancer.”

Recently, Penn has introduced a new generation of endoscopic technology, including routine high-definition white light endoscopy (Figure 1) and electronically enhanced narrow band imaging (Figure 2), that offer improvements in tissue inspection and degree of detection to better discern metaplastic and dysplastic tissue.

“It’s important to note that advanced endoscopic technologies are only meaningful adjuncts in the hand and eyes of endoscopists—-like those at Penn-—who have dedicated themselves to image assessment and correlation,” Dr. Ginsberg says, adding that Penn’s breadth of resources, including advanced endoscopic imaging, therapeutic endoscopy, endoscopic ultrasound and strong pathology and esophageal surgery programs have made it a regional leader for the evaluation and management of dysplasia and early esophageal cancer.

Confocal laser endomicroscopy and endocytoscopy are also being used at Penn as research tools to assess the capacity of these technologies to improve dysplasia detection and discrimination.

Treatment Strategies

At Penn, the treatment of Barrett’s esophagus and esophageal adenocarcinoma is dependent upon the stage and nature of the disease and the patient’s physical status and comorbidities.

For patients with no dysplasia, treatment involves proton pump inhibitors (PPIs) for reflux control and meticulous endoscopic surveillance with high-definition white light endoscopy in conjunction with narrow band imaging and a rigorous biopsy protocol.

The treatment of low-grade dysplasia is complicated by its poorly understood natural history, among other factors.

“The diagnosis of low-grade Barrett’s esophagus demands the sort of expert pathology review available only at centers like Penn Medicine,” Dr. Falk says. “The transition from Barrett’s esophagus to dysplasia is subtle and guidelines clearly recommend expert GI pathology review in such cases.”

Once low-grade dysplasia is pathologically confirmed, Dr. Falk adds, a repeat endoscopy with four quadrant biopsies at 1 cm intervals is carried out to reaffirm the diagnosis and exclude higher-level lesions. Selected patients with confirmed multifocal low-grade dysplasia may then be candidates for radiofrequency ablation (RFA).

At Penn, RFA is one of several modalities for patients with high-grade dysplasia and intramucosal carcinoma; others include endoscopic mucosal resection (Figure 3) or multimodal endoluminal therapy; surgery is reserved for failures of endoscopic therapy.

“Endoscopic therapy has replaced operative esophagectomy for high-grade dysplasia and mucosal cancers in Barrett’s esophagus,” Dr. Ginsberg says. “The concern for patients with high-grade dysplasia or early esophageal adenocarcinoma is that they be managed at a Center of Excellence. These patients require concentrated expertise in endoscopy, pathology, surgery and oncology.”

The goal of multimodal endoluminal therapy is complete eradication of Barrett’s esophagus. The therapy is safe and effective
in selected patients and compares favorably
with operative and observational therapies.

Penn Celiac Disease Treatment Program

noreply@blogger.com (M Baker) — Thu, 11 Oct 2012 06:45:00 PDT

Under the direction of Octavia Pickett-Blakely, MD, MHS, the multidisciplinary celiac disease (CD) treatment program at Penn Medicine involves clinician specialists, nurses and nutritional counselors dedicated to the management of celiac disease (celiac sprue).

CD is an immune-mediated enteropathy caused by sensitivity to gliadin, a family of glycoproteins linked to gluten formation and found in foods and products containing wheat, rye, barley and their by-products. Individuals with gluten sensitivity produce anti-gliadin antibodies to several of the gliadin subtypes.

These antibodies, in turn, provoke an abnormal T cell-mediated immune response characterized by mucosal inflammation, abnormal villous architecture and ultimately, small bowel malabsorption.

Untreated CD causes a slight increase in the risk of small bowel adenocarcinoma and T-cell lymphoma. With a prevalence of 1 in 133 in the general population, as many as three million people in the United States have CD.

Diagnosis

Celiac disease has a classic presentation that includes gastrointestinal symptoms, weight loss, a characteristic rash (dermatitis herpetiformis) and in children, failure to thrive.

“An overlap in the gastrointestinal symptoms of celiac disease with those of other bowel diseases merits a high level of suspicion,” says Dr. Pickett-Blakely.

The link between symptoms and disease are not always readily apparent, however.

“Celiac disease is a multi-system disorder, so it can present as a variety of non-autoimmune diseases such as iron-deficiency anemia or osteoporosis,” Dr. Pickett-Blakely explains. “Symptoms can manifest as biochemical abnormalities, anemia, hepatomegaly, dermatological conditions, infertility and neuropsychological conditions.”

The screening algorithm for CD at Penn Medicine combines serology, genetic testing and the gold standard for diagnosis, upper endoscopy with duodenal biopsy.

“We use serology in high risk patients as a non-invasive screening test,” Dr. Pickett-Blakely says. At Penn, the serological tests for CD include anti-tissue transglutaminase antibody (tTG), anti-endomysial (EM) IgA or IgG antibodies, or anti-gliadin antibody. Antiendomysial and tissue transglutaminase antibodies and a quantitative IgA are usually tested simultaneously during initial screening.

To provide an accurate rendering of a patient’s serology, these tests are performed while the patient is on a gluten-containing diet. About 95% of people with CD have HLA-DQ2, a human leukocyte antigen (HLA) marker, on chromosome 6; 5% will also have a second marker, HLA-DQ8. These markers have a high negative predictive value in asymptomatic individuals with a family history of celiac disease and other autoimmune disorders; at Penn, patients in this population are tested for both HLA-DQ2 and HLA-DQ8.

Upper endoscopy with duodenal biopsy has been demonstrated to be effective for the early diagnosis of CD. Typically, biopsy will demonstrate intraepithelial lymphocytosis, crypt hyperplasia and villous hyperplasia that improve with a gluten-free diet.

Treatment

Patients with CD require treatment because over time, untreated persons with gluten-sensitive enteropathy have a higher prevalence of small bowel cancer, malabsorption and other serious complications.

Strict avoidance of gluten is the first line therapy for the management of uncomplicated celiac disease. According to Jung Kim, RD, a clinical dietitian specialist who works closely with Dr. Pickett-Blakely at Penn to advise and treat patients with CD, gluten appears in many unexpected places.

“It’s used as a binder and filler in processed foods, toothpastes, cosmetics and many other products,” Kim says. “So I spend a lot of time teaching recently diagnosed patients about hidden sources of gluten.”

The process of giving up known sources of gluten—let alone hidden ones—can be overwhelming at first, but in time, patients learn the essentials of a diet comprised of fresh fish, meats, milk, cheese, fruits, vegetables and other gluten-free foods. Symptomatic patients generally improve within two to four weeks of starting a gluten-free diet.

Celiac disease program patient follow-up is coordinated by Kimberly Carter, MS, PA-C and Dr. Pickett-Blakely. “Patients with newly diagnosed celiac disease usually have follow-up blood tests twice in the first year,” Carter says. “This is to ensure that the patient’s antibody levels are stabilizing and that no micronutrient deficiencies develop.”

Patients whose levels remain high or fail to respond to a gluten-free diet may not be avoiding hidden sources of gluten and require further counseling.

Patients and physicians wishing to contact the celiac disease program
at Penn may call 215.649.8222 or 800.789.PENN (7366).

The Future: Advances in Clinical Research in Barrett’s Esophagus and Esophageal Adenocarcinoma

noreply@blogger.com (M Baker) — Wed, 10 Oct 2012 09:57:00 PDT

Penn Gastroenterology is currently engaged in a series of NIH-supported clinical and translational studies that have the scientific and clinical aims of discovering effective chemopreventative agents for Barrett’s esophagus, finding better ways to determine who progresses from non-dysplastic Barrett’s to cancer, and determining who best responds to specific therapies.

Chemoprevention of Barrett’s Esophagus

Combination Esomeprazole and Aspirin

With the NCI funded Cancer Prevention Network, researchers at Penn Gastroenterology were involved in a multicenter randomized clinical trial to evaluate esomeprazole and aspirin
compared with esomeprazole and placebo for the prevention of esophageal cancer in patients with Barrett’s esophagus.

Combined with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, was found to signifi cantly reduce tissue concentrations of prostaglandin E2 in Barrett’s esophagus patients with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients, and were published in the journal Gastroenterology, with Dr. Falk as lead author.

Metformin for Barrett’s Esophagus

Penn researchers are also involved in a randomized, doubleblind, controlled phase II trial investigating the use of metformin for chemoprevention in Barrett’s esophagus. An oral drug used to treat diabetes, metformin is thought to prevent esophageal cancer from forming. The primary objective of the trial is to evaluate the effect of metformin on the signaling molecule pS6K1, a phosphoprotein.

pS6K1 is part of a recently identified inflammation-associated signaling pathway activated in Barrett’s esophagus cell lines and esophageal cancer cells that may enhance cell proliferation in Barrett’s esophagus.

The trial is being performed under the aegis of the Cancer Prevention Network (CPN). Dr. Falk is the Principal Investigator at Penn.

The Barrett’s Esophagus Translational Research Network (BETRNet)

Penn Gastroenterology was selected in 2011 to be part of a collaborative effort to better define the pathology of esophageal adenocarcinoma and Barrett’s esophagus. Established through a National Cancer Institute (NCI) grant, the Barrett’s Esophagus Translational Research Network (BETRNet) brings together the researchers and facilities of Penn Gastroenterology, Columbia University and the Mayo Clinic to provide new insights into how Barrett’s esophagus develops and to translate these findings into new avenues in chemoprevention, diagnosis and therapy.

The common understanding of the pathogenesis of Barrett’s esophagus and esophageal adenocarcinoma has lagged behind that of many cancers, says John Lynch, MD, PhD, a physician scientist with Penn Medicine’s Division of Gastroenterology, because to date, physiologically relevant laboratory models and an integrated research network to study these diseases have not been developed.

The BETRNet was initiated to address this disparity. A disease-specific, investigator-driven translational research network, BETRnet has three primary goals:

• Identify the role of Notch signaling proteins in animal models of Barrett’s esophagus to determine the effects of Notch inhibition or Notch activation on progression to cancer.

• Characterize the stem/progenitor cell of origin in Barrett’s esophagus in mouse models. A pilot clinical trial using an antagonist of a G-protein coupled receptor expressed on stem/ progenitor cells up-regulated in the disease will be conducted to determine if regression of Barrett’s esophagus occurs.

• Identify novel biomarkers and gene signatures in Barrett’s esophagus, correlating data sets from animal and human models to clarify which cells play the most important role in
disease progression. A cohort of patients undergoing RFA for Barrett’s esophagus will be assembled to identify biomarkers of response to therapy and to study the development of the
disease.

At Penn, the co-principal investigators include Drs. Lynch, Falk and Ginsberg, with Antonia Sepulveda, MD, PhD, professor of Pathology and Laboratory Medicine, and Anil K. Rustgi, MD, T. Grier Miller professor of Medicine and Chief of the Division of Gastroenterology.

According to Dr. Rustgi, Penn will bring to the network both a large patient population and expertise in Barrett’s esophagus inflammatory animal models.

Proton Radiotherapy for the Treatment of Upper Gastrointestinal and Biliary Malignancies

noreply@blogger.com (M Baker) — Wed, 26 Sep 2012 06:58:00 PDT

Radiation oncologists at Penn Medicine are investigating the use of proton radiotherapy to treat upper gastrointestinal malignancies, including cancers of the pancreas, stomach, duodenum and bile ducts (extrahepatic cholangiocarcinoma).

Definitive treatment of these tumors usually includes some combination of surgical resection, radiotherapy and chemotherapy. After surgery, upper GI malignancies (including cholangiocarcinoma) are often treated with combined chemoradiation with continuous infusion 5-FU, which acts as a radiation sensitizer and to address systemic micrometastases.

Chemoradiation is a standard of care for unresected pancreatic cancer and is used as a preoperative treatment for locally advanced disease in some patients. In these settings, the combination of radiation to the stomach and bowel results in significant acute gastrointestinal toxicity, often made more severe by concurrent 5-FU and chemotherapy itself. The acute toxicity of treatment makes it difficult to deliver radiation to the abdomen, and patients often require treatment breaks or discontinuation of therapy.

These factors can compromise the efficacy of treatment. In the current study at Penn [ClinicalTrials.gov Identifier: NCT01449864], proton therapy with concurrent continuous infusion 5-FU or oral capecitabine chemotherapy will be administered for the treatment of upper gastrointestinal and biliary malignancies in the neo-adjuvant and adjuvant setting.

There are dosimetric data and Phase I clinical data to suggest that proton radiotherapy for pancreatic cancer is feasible and tolerable and may help reduce normal tissue toxicity. Based on these findings, it is expected that proton radiotherapy will lead to reduced normal tissue toxicity when given with concurrent chemotherapy, which will ultimately make chemoradiation more tolerable and potentially enable radiation dose escalation or the addition of other chemotherapeutic agents to 5-FU or oral capecitabine.

Clinical Study

Proton Radiotherapy for Upper Gastrointestinal Malignancies

Objectives: This is a study of concomitant proton radiotherapy and chemotherapy for patients with upper gastrointestinal and extra-hepatic biliary malignancies. The primary objectives of this study are feasibility and acute toxicity. The study will be deemed infeasible if >10% of patients:

• Cannot be given treatment because anatomy is such that a dosimetrically satisfactory treatment plan cannot be devised (i.e., 95% of target volume covered by 95% of the dose)

• Are unable to tolerate more than 25% of treatments using proton radiotherapy. (This can be for any reason, including the inability to set the patient up within acceptable limits of tolerance, or the patient is unable to tolerate treatment position or immobilization for the duration of treatment. Any treatments that cannot be delivered with protons will be delivered using photons, so that the patient receives the prescribed tumor dose. Up to 25% of treatments can be delivered using photons). Toxicity will be deemed unacceptable if greater than 60% of patients experience Grade 3 or higher acute non-hematologic toxicity from proton beam therapy and continuous infusion 5-FU or oral capecitabine chemotherapy in patients with upper GI/biliary malignancies.

The secondary objectives of the study include:
• An assessment of the late complications from proton beam therapy and continuous infusion 5-FU or oral capecitabine in patients with upper GI and biliary malignancies;

• A comparison of the dose distribution to tumor and surrounding normal structures using Dose Volume Histograms (DVHs) generated from the proton plan used to treat the patient and the photon plan generated for comparison purposes; and

• A determination of the rates of local control and overall and progression-free survival among patients treated with proton therapy and continuous infusion 5-FU or oral capecitabine for upper GI and biliary malignancies.

Methods: Patients will be stratified by treatment site into two major strata: 1) pancreatic-like tumors (including pancreatic, biliary, and duodenal adenocarcinomas) and 2) gastric-like tumors (including gastric and GE junction adenocarcinomas), based upon the different acute toxicity profiles. This study will be conducted in two phases. In the first phase, feasibility will be established using the primary objectives (above). The second phase (open registration) will begin no earlier than 90 days after the last patient in each stratum of the initial phase has started radiation treatment, and once feasibility has been verified. The secondary objectives will serve as the objectives for the second phase of the study.

Principle Investigator: John Plastaras, MD, PhD
Contact: 215.662.2812, or admin@ctsrmc.org.

Faculty Team

Among the largest and most respected programs in the world, Penn Radiation Oncology offers a variety of innovative treatment options to patients with cancer. In addition, as a national leader in basic science, translational research and clinical trials, Penn Radiation Oncology offers patients access to the latest treatment options––including proton therapy––before they are widely available elsewhere in the region.

Performing Clinical Research in Gastrointestinal Proton Therapy at Penn Medicine

Edgar Ben-Josef, MD
Vice Chair of Translational Research
Professor of Radiation Oncology

Stefan Both, PhD
Assistant Professor of Radiation Oncology,
Director of Translational Physics Research

Bruce Giantonio, MD
Professor of Medicine

Stephen M.Hahn, MD
Henry K. Pancoast Professor of Radiation Oncology

James M. Metz, MD
Clinical Director
Professor of Radiation Oncology

Peter O’Dwyer, MD
Professor of Medicine

John P. Plastaras MD, PhD
Clinical Research Director
Assistant Professor of Radiation Oncology

Ursina Teitelbaum, MD
Clinical Assistant Professor of Medicine

Zelig A. Tochner MD
Professor of Radiation Oncology

Paul S. Wissel, MD

Access

Penn Radiation Oncology
Perelman Center for Advanced Medicine
Concourse Level
3400 Civic Center Boulevard
Philadelphia, PA 19104

Roberts Proton Therapy Center
Perelman Center for Advanced Medicine
Concourse Level
3400 Civic Center Boulevard
Philadelphia, PA 19104

Consultations also available at:
Abramson Cancer Center
Penn Presbyterian Medical Center
Medical Arts Building, Suite 103A
Philadelphia, PA 19104

Clinical Research at the Roberts Proton Therapy Center

The Roberts Proton Therapy Center has the advantage of being part of a world class academic medical center, Penn Medicine, and an NCI-designated Comprehensive Cancer Center, Penn’s Abramson Cancer Center. In addition to its primary mission of improving the treatment of cancer,
however, the Roberts Proton Therapy Center at Penn Medicine has the purpose of expanding, defining and clarifying the therapeutic uses for proton therapy through clinical research.

Recent clinical protocols have sought to increase and enhance the effectiveness of proton therapy and to determine which cancers should be treated with proton versus conventional radiation. In addition to abdominal cancers, the conditions currently being investigated at the Roberts Proton Therapy Center include cancers of the prostate, breast and lung. For more information, visit:
http://www.pennmedicine.org/Roberts-Proton.

Download a pdf of this Clinical Briefing.

Proton Radiotherapy for Soft Tissue Sarcomas of the Extremities

noreply@blogger.com (M Baker) — Fri, 07 Sep 2012 11:52:00 PDT

Radiation-oncologists at Penn Medicine are investigating proton therapy for the treatment of patients with soft tissue sarcomas (STS) of the extremities.

Soft tissue sarcomas offer a particularly challenging profile. STS are rare and diverse (the array of lesions includes more than 50 histologic types and subtypes) and develop in connective tissue throughout the body, with the majority occurring in the extremities. The etiology of STS remains obscure, but known risk factors include prior radiation therapy for cancers (less than five percent of STS) and certain genetic syndromes.

Treatment of STS is dependent upon the type and stage of the lesion, with the objectives of reducing recurrence, maximizing function and promoting optimal survival. Resection is the standard of care for STS, often with adjuvant radiation therapy and less commonly with chemotherapy, which has limited efficacy for most sarcoma types. Complete resection with negative margins can achieve 80% control of lesions, a rate that rises to 95% with adjuvant radiation therapy. With conventional photon treatment, improvements in local tumor control may come at the risk of acute and late side effects such as lymphedema, joint stiffness, soft tissue fibrosis and compromised wound healing.

Proton radiotherapy (PRT) has been shown to spare normal tissues adjacent to the target lesion because of its absence of exit dose, and for this reason may particularly benefit STS patients by limiting radiation exposure. This is especially true for patients with tumors near critical organs and sensitive structures.

Preliminary results from an ongoing clinical trial of proton re-irradiation [1] (ClinicalTrials.gov Identifier: NCT01126476) at the Department of Radiation Oncology at Penn Medicine suggest that proton therapy may also benefit patients with locally recurrent soft tissue sarcomas and is associated with good early outcomes and only moderate toxicity. Further follow up on these patients is needed to assess the long-term utility of PRT re-irradiation in STS.

1. Milby AB, MD; Deville C, Both S, Tochner Z, Metz J, Varillo K, Lackman RD, Plastaras JP.
Prospective study of proton reirradiation for soft tissue sarcoma: early outcomes and
morbidity. Presented at PTCOG Scientific Meeting, (May 17-19, 2012), Seoul, Korea.

Clinical Study

Proton Radiotherapy for Extremity Soft Tissue Sarcomas [ClinicalTrials.gov identifier: NCT01561495].

This study is open to patients with a histologic diagnosis of soft tissue sarcoma of the extremities; all patients must be considered operable/resectable and candidates for pre- or post-operative radiotherapy.

The study population will be divided into pre- and post-surgical groups. Each group will be treated in two phases. The primary objective of the first phase will be to determine whether treatment with proton therapy is feasible (i.e., safe and deliverable on a regular basis).

The study will be deemed infeasible if >10% of patients are:

• unable to receive treatment because anatomy is such that a dosimetrically satisfactory
treatment plan cannot be devised (95% of planning target volume covered by 95%
of the dose);
• unable to tolerate more than 25% of treatments using proton radiotherapy;
• unable to complete all treatments within 10 days of the estimated date of treatment
completion (or require a treatment break greater than 5 days).

The study will also be deemed infeasible if >33% of all patients experience a significant treatment toxicity.

In the second phase of Proton Radiotherapy for Extremity Soft Tissue Sarcomas, the investigators will determine if proton therapy has less long-term side effects compared to conventional photon radiation in both pre-operative patients and post-operative patients with STS of the lower extremity.

The primary objective of Phase II in the pre-operative group will be to evaluate the wound complication rate of pre-operative proton radiotherapy. In the post-operative group, the primary objective of Phase II will be to evaluate the functional outcome (e.g., fibrosis, joint stiffness, edema) at two years after post-operative proton radiotherapy.

Principal Investigator: Curtiland Deville, MD
Contact: admin@ctsrmc.org

Faculty Team

Among the largest and most respected programs in the world, Penn Radiation Oncology offers a variety of innovative treatment options to patients with cancer. In addition, as a national leader in basic science, translational research and clinical trials, Penn Radiation Oncology offers patients access to the latest treatment options––including proton therapy––before they are widely available elsewhere in the region.

Performing Clinical Research in Proton Therapy for Soft Tissue Sarcoma at Penn Medicine

Curtiland Deville, MD
Assistant Professor of Radiation Oncology

Stephen M. Hahn, MD
Henry K. Pancoast Professor of Radiation Oncology

William Levin, MD
Clinical Assistant Professor of Radiation Oncology

James M. Metz, MD
Clinical Director
Professor of Radiation Oncology

John P. Plastaras, MD, PhD
Clinical Research Director
Assistant Professor of Radiation Oncology

Zelig A. Tochner MD
Professor of Radiation Oncology

Access
Penn Radiation Oncology
Perelman Center for Advanced Medicine
Concourse Level
3400 Civic Center Boulevard
Philadelphia, PA 19104

Abramson Cancer Center
Penn Presbyterian Medical Center
Medical Arts Building, Suite 103A51
North 39th Street
Philadelphia, PA 19104

Download a pdf of this Clinical Briefing.

Breast Reconstruction Surgery following Mastectomy for Breast Cancer

noreply@blogger.com (M Baker) — Fri, 29 Jun 2012 08:31:00 PDT

Surgeons in the Division of Plastic Surgery at Penn Medicine offer the most advanced treatment options for patients in need of cosmetic and reconstructive surgery, as well as a comprehensive skin care program.

At Penn, breast reconstruction has evolved to encompass three approaches: implants with or without tissue expansion, autologous tissue reconstruction, and a combination of implants and autologous tissue. Penn Plastic Surgery offers saline and silicone based implants, including the recently introduced stable cohesive silicone gel (or “gummy bear”) implants. The latter are available investigationally, a result of Penn Plastic Surgery’s commitment to clinical research to advance breast reconstruction techniques and implants.

The stable cohesive implants are composed of a denser, more form-stable silicone gel, and are available in a variety of molded shapes and sizes to accommodate a wide range of patient anatomies and preferences. Implants composed of the new gel are expected to be more durable and to have fewer issues with leakage than standard silicone implants.

Currently, Penn Plastic Surgery performs 400 autologous breast reconstructions a year. These procedures use the patient’s own tissue, and by comparison to implants, are generally considered to provide a more natural appearance. Patients at Penn have the option of free transverse rectus abdominus myocutaneous (TRAM) flap, deep inferior epigastric perforator (DIEP) flap and superficial inferior epigastric artery (SIEA) flap breast reconstruction.

All of these procedures are performed microsurgically and avoid the “muscle tunnel” approach necessary for some reconstruction surgeries. Microsurgery permits the major veins and arteries to be severed at the donor site and reattached at the chest and armpit adjacent to the site of reconstruction with very low complication rates.

Reconstruction of the nipple-areolar complex is an important component to complete breast reconstruction and has been shown to have a major psychological benefit to the patient. Penn Plastic Surgery offers nipple reconstruction as a two-step office procedure that includes the establishment of a nipple projection followed by tattooing by a micropigmentation specialist to restore the natural
appearance of the nipple and areola.

Case Study 1

Mrs. L, a 54-year-old woman, came to the Center for Human Appearance at Penn for an autologous breast reconstruction two years after a radical right breast mastectomy. A free deep inferior epigastric artery perforator (DIEP) flap procedure was planned. Prior to surgery, a duplex ultrasound identified the most suitable perforator vessels at the abdominal harvest site to ensure adequate flap perfusion.

During the procedure, the appropriate perforators and the deep inferior epigastric vessel were incised microsurgically and transferred with skin, fat and blood vessels to the mastectomy site. The donor site was then closed. Following placement of the flap and the assurance of good perfusion, Mrs. L’s left breast was lifted to ensure symmetry. Total operative time was 5.5 hours. Mrs. L remained in the hospital for four days and was sent home to recover.

Seven months later, she returned to Penn for nipple reconstruction and tattooing. At her one-year follow-up, she expressed satisfaction with the shape and contour of her breast
reconstruction (Figure 1).

Case Study 2

Ms. M, a 38-year-old woman, presented to the Center for Human Appearance for a total, bilateral nipple-sparing mastectomy for the treatment of ductal carcinoma in situ (DCIS) followed immediately by breast reconstruction surgery. After a consultation to discuss her options she chose to have implant reconstruction with investigational stable cohesive silicone gel implants.

During the mastectomy procedure, Ms. M received a tissue expander beneath the skin and muscles of her chest wall containing a small amount of saline. She was discharged from the hospital on postoperative day two. Three weeks later, she returned for the first of a series of bi-weekly saline injections via the valve in the tissue expander to stretch the muscle and skin to accommodate the implants.

At four months post-surgery, Ms. M returned for the second stage of her breast reconstruction. During this procedure, the tissue expanders were removed through the original incision and the cohesive silicone gel implants placed. Ms. M went home the same day to recover. At her one-year follow-up, virtually no evidence of the bilateral total mastectomy was apparent (Figure 2).

Faculty Team

The experienced surgeons in the Division of Plastic Surgery at Penn Medicine offer the most advanced treatment options for patients in need of cosmetic and reconstructive surgery, as well as a comprehensive skin care program. In addition to breast reconstruction, specialty areas include craniofacial reconstruction, congenital anomalies, reconstruction following tumor and trauma, microsurgical techniques, cleft lip and palate surgery, and cosmetic facial and body surgery.

Performing Breast Reconstruction Surgery at Penn

Suhail K. Kanchwala, MD
Assistant Professor of Surgery

Stephen J. Kovach III, MD
Assistant Professor of Surgery

David W. Low, MD
Professor of Surgery

Joseph M. Serletti, MD
Henry Royster–William Maul Measey Professor of Surgery

Liza C. Wu, MD
Assistant Professor of Surgery

Medical Aesthetician/Micropigmentation

Mandy Sauler

Micropigmentation at Penn Medicine

Micropigmentation is a cosmetic procedure used to restore the natural appearance of the nipple and areola following breast reconstruction.

Performed by a specialist at Penn, micropigmentation involves a preliminary consultation to ensure that the color, shade and size of the tattoo are both appropriate for the patient’s skin tone and account for scar tissue, if present.

For women who have had a single mastectomy, the micropigmentation specialist will match the pigment to ensure a complementary appearance.

The objectives of micropigmentation may involve more than one session to permit
the skin to fully absorb the pigment.

Aftercare instruction is included to
ensure best outcomes.

Access

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

Download a pdf of this Clinical Briefing.

Clinical Research in Fertility Care: The PANDORA Trial

noreply@blogger.com (M Baker) — Fri, 29 Jun 2012 06:23:00 PDT

Researchers at Penn Fertility Care and Penn Ob/Gyn Care are conducting the Periconception and Antepartum Nutrition, Developmental Outcomes and Reproductive Ability (PANDORA) trial, a clinical study that examines maternal nutritional and environmental factors to determine their potential as precipitants for offspring health and fertility risks in adulthood.

Fetal growth is driven in large part by the environment in utero and by adaptations of the fetus to maternal conditions. While significant attention has been focused on drastic maternal deprivation during mid to late gestation as a basis for altered fetal growth, subtle environmental perturbations throughout gestation may also impact fetal organ development in the absence of overall growth restriction. Dietary and environmental exposures in and around the time of conception appear to be critical for conditioning fetal growth patterns.

There is good evidence, as well, that the risk of obesity, hypertension and diabetes in adulthood may be promoted by fetal responses to maternal conditions and exposures during pregnancy. Such altered responses include changes in metabolism and hormone production, as well as changes in tissue sensitivity to hormones that may affect the development of various organs and lead to persistent alterations in physiology.

In addition, a growing body of literature suggests a link between maternal environment, fetal growth restriction and poor odds of reproduction in adulthood. The PANDORA Trial was initiated at Penn Fertility Care to examine these concerns.

About PANDORA

Objectives: The primary aim of PANDORA is to investigate the association between maternal levels of folate, vitamin B12, Vitamin D, and Bisphenol-A and neonatal markers of growth and ovarian sufficiency. The secondary aim of the study is to test the association between these same maternal exposures and time to pregnancy and risk of miscarriage.

Methods: In this prospective study, maternal exposures will be measured both prior to conception and during pregnancy. Samples of maternal urine and serum will be collected at specific intervals preconception and if pregnancy is achieved, at 18-20 weeks gestation. The principal clinical outcome
Clinical Research in Fertility Care: The PANDORA Trial Center for Research on Reproduction and Women’s Health of interest is birth weight.Additional outcomes (collected from umbilical cord blood at delivery) include biomarkers associated with neonatal growth, infant growth potential, and ovarian development.

Participants will be healthy women between 28 and 45 years of age either attempting pregnancy spontaneously or seeking infertility care with in vitro fertilization. A brief questionnaire will be administered at study enrollment that addresses diet and vitamin/supplement intake. At delivery, umbilical cord blood will be collected to measure the following metabolic and reproductive biomarkers: IGF-1, IGF-2, IGFBP3, insulin, leptin and Anti-Mullerian Hormone (AMH, which will be measured in female neonates only).

During the study, participants are provided with ovulation predictor kits and home pregnancy tests at no cost; study related transportation costs are also covered. Enrolled study participants are also eligible to receive an early first trimester pregnancy ultrasound at no cost.

Discussion: In conducting the PANDORA study, the researchers wish to understand how preconception, early gestational, and subtle nutritional/environmental perturbations disrupt the balance of fetal development in utero, and whether fetal responses to specific maternal exposures at unique intervals impact markers of fetal growth and development. Ultimately, these responses could promote offspring risks of obesity, metabolic disease, cardiovascular disease and and ovarian dysfunction in adulthood.

The principal investigator for PANDORA is Samantha Butts, MD, MSCE. For information about the study or to refer a patient, please contact Arjun Prabhu at 267-234-1727 (Arjun.Prabhu@uphs.upenn.edu) or Shanaye Jeffers at 215-268-5110 (Shanaye.Jeffers@uphs.upenn.edu).
Faculty Team

Penn Fertility Care and Penn Ob/Gyn Care patients benefit from the research efforts developed through the Center for Research on Reproduction and Women’s Health (CRRWH) and The Women’s
Health Clinical Research Center in the Department of Obstetrics and Gynecology. The Department and Centers are prominent National Institutes of Health grant recipients, and have realized an international reputation for innovations and developments in the field of women’s health research.

Infertility and Obstetric Clinical Research at Penn Medicine: The PANDORA Trial
Samantha F. Butts, MD, MSCE
Assistant Professor of Obstetrics and Gynecology

Access
Penn Fertility Care*
3701 Market Street, 8th Floor
Philadelphia, PA 19104

Penn Fertility Care
Pennsylvania Hospital
801 Spruce Street
Spruce Building, 7th Floor
Philadelphia, PA 19107

Penn Fertility Care at Penn Health for Women*
Penn Medicine Radnor
250 King of Prussia Road
Radnor, PA 19087

Maternal Fetal Medicine
Hospital of the University of Pennsylvania
2000 Courtyard Building
3400 Spruce Street
Philadelphia, PA 19104

*A facility of the Hospital of the University of Pennsylvania.

The Women’s Health Clinical Research Center

Under the direction of Kurt Barnhart, MD, MSCE, the Women’s Health Clinical Research Center (WHCRC) promotes collaboration among department faculty and across Penn Medicine to coordinate and carry out high quality clinical research in women’s health. The Center is designed to help investigators initiate and pursue useful clinical research, whatever their degree of experience.

The Center has the following resources to aid investigators:
        • Needs assessment – This process includes assistance
          in identifying research opportunities, submitting grant
          applications, budgeting projects and identifying research
          personnel.

        • Assistance with the supervision and oversight of clinical
          research conducted within the Center, including:
               • Communication with regulatory offices within the
                 University, including the Office of Regulatory Affairs and
                 the Office of Human Research;
               • IRB preparation, continuing renewals, amendments and
                 adverse event reporting;
               • Setting up a study binder and understanding the needs of
                 study monitoring.

        • Support in the conduct of a study which includes:
               • Assistance in identification of the appropriate study
           design to address a study question;
               • Biostatistical support for pilot or investigator initiated
                 projects;
           • Editorial support for grant applications, abstracts and
                 manuscripts.

Currently, the WHCRC is pursuing investigations in reproductive health,
contraception, infertility, gynecologic oncology, urogynecology and
obstetrics.

For more information about these and other clinical trials in reproductive
health and infertility at Penn Fertility Care, please call 215-662-7727, or
email: reproresearch@obgyn.upenn.edu.

Download a pdf of this Clinical Briefing.

CAD-CAM Modeling for Craniofacial Surgery

noreply@blogger.com (M Baker) — Mon, 14 May 2012 08:04:00 PDT

Surgeons at Penn Medicine are using computer-aided design and manufacturing (CAD-CAM) programs to create custom-designed cutting and placement guides for preoperative planning and bone positioning during reconstructive surgery for complex craniofacial malformations.

CAD-CAM procedures use computed tomography (CT) data to generate anatomically accurate three-dimensional (3D) models of the patient’s bone structure, permitting cephalometric assessment of traumatic and pathological defects prior to surgery. These renderings can be used to fabricate guides for both the early resection process and the later precise placement of bone for fixation during surgery and/or custom prosthetic implants.

CAD-CAM templates are precise to within 1 mm, resulting in faster surgeries and optimal aesthetic results, particularly in complex correction of facial and skull deformities. Their use, and that of CAD/CAM 3D models, has been shown to improve the predictability of outcomes in complex cranio-maxillofacial surgery and to decrease total operating time, thereby reducing the duration of intraoperative general anesthesia and wound exposure time.^1,2

Case Study

Ms. C, a 23-year-old woman, was referred to Penn Plastic Surgery for correction of orbital hypertolerism, a condition defined by excessive distance between the eyes and orbits, and vertical orbital dystopia, a condition where the eyes are not level. Three-dimensional CT scans at presentation revealed anterior and inferior displacement of the orbital bones and bilateral nonalignment (Figure 1).

Surgery to correct these defects would require the orbits to be moved in three dimensions to differential degrees. Prior to surgery, Ms. C received a cranial CT scan which was then converted into CAD format. Three dimensional cephalometric measurements were then used to determine the resection and placement/fixation parameters, and this was all “pre-planned” by the surgical team. This data was then used to manufacture the respective templates for the surgical procedure.

In the operating room, the bones of the orbits were able to be cut and repositioned precisely based on CAD/CAM pre-fabricated jigs, an improvement in accuracy and efficiency. She has recovered well, and returned to work four weeks after surgery. Post-operative photographs and 3D-CT scans (Figure 2) have demonstrated a marked improvement in her appearance, and she feels that her vision has been improved with the surgery.

Reference
1. Mehra P, Miner J, D’Innocenzo R, Nadershah M. J Maxillofac Oral Surg. 2011;10:6–13.
2. Sharaf B, Levine JP, Hirsch DL, et al. J Craniofac Surg. 2010; 21:1277-1280.

Faculty Team

Penn Medicine’s Adult Craniofacial Reconstructive Surgery Program is focused on the care of patients seeking consultation about their facial function and appearance. Penn surgeons use the latest technology for both cosmetic and reconstructive surgery, including CAD-CAM technology for cranial, facial and jaw surgery and microsurgical innovations to visualize and re-attach severed blood vessels and nerves, and optimize post-surgical feeling and function. In addition, the Center uses lasers, dermabrasion and chemical peels to treat skin conditions, and collaborates with skin care specialists to ensure that patients’ skin care needs are met.

Plastic Surgery
Jesse A. Taylor, MD
Assistant Professor of Surgery

Scott P. Bartlett, MD
Professor of Surgery

Oral and Maxillofacial Surgery
Eric J. Granquist, DMD, MD
Joli C. Chou, DMD, MD

Otorhinolaryngology-Head and Neck Surgery
Ara A. Chalian, MD
Associate Professor of Otorhinolaryngology:
Head and Neck Surgery

Neurosurgery
M. Sean Grady, MD
Charles Harrison Frazier Professor of Neurosurgery

James M. Schuster, MD, PhD
Associate Professor of Neurosurgery

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

Download a pdf of this Clinical Briefing.

Proton Therapy for Stage I, IIA, IIB and Relapsed Seminoma

noreply@blogger.com (M Baker) — Mon, 07 May 2012 08:18:00 PDT

Researchers at Penn Radiation Oncology are now treating patients with stage I, IIA, IIB and relapsed testicular seminoma with proton therapy.

Testicular cancers are the most common solid malignancies in men aged 20 to 35 years. The majority of these tumors (60%) are pure seminoma. Of patients diagnosed with seminoma, approximately 80% have stage I disease.

Almost all patients with stage I seminoma are cured. For those patients who require adjuvant radiation following radical inguinal orchietomy, conventional photon external beam radiotherapy has been directed to the lymph nodes of the para-aortic and pelvic regions. However, photon radiotherapy exposes normal tissues to radiation with well known treatment-related adverse effects, including fatigue and nausea.

Furthermore, in patients with testicular cancers, radiation-associated second malignancies (non-germ cell malignancies after 10 to 35 years) are a major concern. Second cancers are one of the causes of death among testicular cancer survivors.

To address these concerns for patients with seminoma, reductions in radiation dosing and fields and newer therapies, including carboplatin and surveillance, have emerged. Because proton therapy spares normal tissues distal to the target lesion, it also has been proposed as an alternative to conventional radiotherapy for seminoma.

Recently, researchers at Penn Radiation Oncology performed an institutional review board-approved study1 to compare photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities (below). A Phase II study of adjuvant proton therapy for the treatment of Stage I, IIA, IIB and relapsed seminoma is now open at Penn. This multi-center trial will evaluate the outcomes of proton therapy in a larger group of patients.

Predicted rates of secondary malignancies from proton versus photon radiation therapy for stage I seminoma

Methods and Material: Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors.

Results: Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p<0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22–5.01), large bowel (0.81; 95% CI, 0.39–1.01), and bladder (0.03; 95% CI, 0.01–0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, –0.01–0.06).

Conclusions: For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined (Figure 1) and warrants further study for patients with seminoma to decrease radiation-induced toxicity.

Reference
1. Simone CB 2nd, Kramer K, O’Meara WP, Bekelman JE, Belard A, McDonough J, O’Connell J. Int J Radiat Oncol Biol Phys. 2012;82:242-249. (Go to article.)

Faculty Team
Among the largest and most respected programs in the world, Penn Radiation Oncology offers a variety of innovative treatment options to patients with cancer. In addition, as a national leader in basic science, translational research and clinical trials, Penn Radiation Oncology offers patients access to the latest treatment options––including proton therapy––before they are widely available elsewhere.

Performing Clinical Trials in Proton Therapy for Testicular Cancer at Penn Medicine

Justin E. Bekelman, MD
Assistant Professor of Radiation Oncology

John Christodouleas, MD
Assistant Professor of Radiation Oncology

Curt Deville, MD
Assistant Professor of Radiation Oncology

Thomas Guzzo, MD
Assistant Professor of Urology in Surgery

Katherine L. Nathanson, MD
Associate Professor of Medicine

Neha Vapiwala, MD
Assistant Professor of Radiation Oncology

David J. Vaughn, MD
Professor of Medicine

Access
Penn Radiation Oncology
Perelman Center for Advanced Medicine
Concourse Level
3400 Civic Center Boulevard
Philadelphia, PA 19104

Clinical Research at the Roberts Proton Therapy Center

The Roberts Proton Therapy Center has the advantage of being part of a world class academic medical center, Penn Medicine, and an NCI-designated Comprehensive Cancer Center, Penn’s Abramson Cancer Center. In addition to its primary mission of improving the treatment of cancer, however, the Roberts Proton Therapy Center at Penn Medicine has the purpose of expanding, defining and clarifying the therapeutic uses for proton therapy through clinical research.

Recent clinical protocols have sought to increase and enhance the effectiveness of proton therapy and to determine which cancers should be treated with proton versus conventional radiation.
In addition to seminoma, the conditions currently being investigated at the Roberts Center include cancers of the abdomen, brain, breast, head and neck, lung and prostate.

For more information about the Roberts Proton Therapy Center, visit: http://www.pennmedicine.org/Roberts-Proton.

Download a pdf of this Clinical Briefing.

Multidisciplinary Management of Adult Congenital Heart Disease

noreply@blogger.com (M Baker) — Mon, 07 May 2012 06:23:00 PDT

The Philadelphia Adult Congenital Heart Center, a joint program of Penn Medicine and the Children’s Hospital of Philadelphia (CHOP), is designed to serve the unique healthcare needs of adults with congenital heart disease (ACHD).

Among less than a hundred such programs in the United States, the Center is comprised of specialists in cardiovascular surgery, anesthesiology, interventional catheterization, electrophysiology, non-invasive imaging and heart failure/ transplantation, genetics and reproductive services, collaborating to provide comprehensive inpatient and outpatient care.

In addition to surgery, the programs and services offered at the Center include the evaluation of patients for heart transplantation, the care of women requiring high-risk obstetrics and genetic research to develop better approaches to congenital heart disease.

Heart Transplantation — Between 2010 and 2011, nine patients with congenital heart disease underwent heart transplantation at the Hospital of the University of Pennsylvania, five of whom were combined heart-liver transplants for failing Fontan physiology.

High-Risk Obstetrics — The Maternal-Fetal Medicine group manages women with congenital anomalies, both repaired and unrepaired, ranging from severe aortic stenosis to tetralogy of Fallot to single ventricle physiology. The Center published the first report of successful pregnancies in two women with Hypoplastic Left Heart Syndrome in 2010.

Genetics — The Center collaborates with experts in genetics and dysmorphology at CHOP who specialize in DiGeorge Syndrome (at the “22q and You Center”), as well as channelopathies such as Long QT syndrome, and works closely with world-renowned geneticists in the field of Marfan syndrome and other connective tissue disorders at the Hospital of the University of Pennsylvania

About Adult Congenital Heart Disease

As a result of advances in cardiac surgery and medical therapies, it is estimated that there are now more than a million adults with congenital heart disease living in the United States, and that for the first time, adults with congenital heart disease outnumber children with the disorder. The spectrum of congenital heart disease varies widely from simple lesions (e.g., isolated septal defects) to complex anomalies such as functional single ventricles. Adults with congenital heart disease require ongoing sub-specialty care and lifelong surveillance to ensure continued survival and quality of life.

Case Study

At age 22, Ms. M was referred to the Philadelphia Adult Congenital Heart Center for further evaluation and management of truncus arteriosus type A1 status post-complex right ventricular outflow tract (RVOT) reconstruction.

Surgical repair of common cyanotic congenital heart defects in infancy such as truncus arteriosus (and, more commonly, tetralogy of Fallot) often results in marked anatomic distortion of the pulmonary arteries and pulmonary valve insufficiency which can lead to right ventricular failure in adulthood (Figure 1).

During the previous year, Ms. M had developed increasing exercise intolerance and fatigue and dyspnea while walking between classes on campus. She was known to have an 80 mmHg gradient across the right ventricular outflow tract with free regurgitation; the right ventricular systolic pressures were approximately three-quarters systemic.

The Philadelphia Adult Congenital Heart Center is the only program in the region to offer a percutaneous option in select patients with congenital disease of the right ventricular outflow tract that would otherwise require surgery.

Given the complex anatomy of her RVOT reconstruction, Ms. M was offered a percutaneous pulmonary valve replacement. Subsequently, she received a Melody ^® transcatheter pulmonary valve during a two-hour, minimally invasive procedure performed by interventional cardiologists at the Philadelphia Adult Congenital Heart Center. Ms. M remained in the hospital overnight and went home the next day.

Six months after the Melody valve procedure, she returned to clinic reporting increased endurance and is now able to keep up with her friends at school. She has incorporated exercise back into her routine and walks over a mile on the treadmill daily. Repeat echocardiograms demonstrate a decrease in right ventricular size and no pulmonary insufficiency.

Melody® is a registered trademark of Medtronic, Inc.,
Minneapolis, MN.

Faculty Team

The Philadelphia Adult Congenital Heart Center team includes cardiovascular surgeons, cardiac anesthesiologists, cardiac specialists in catheterization, electrophysiology, non-invasive imaging, and heart failure/transplantation as well as genetics and reproductive services working together to provide comprehensive inpatient and outpatient care.

Medical Team

Yuli Kim, MD*†

Alex Davidson, MD†

Richard Donner, MD†

Martin St. John Sutton, MBBS*

Surgical Team

Stephanie Fuller, MD*†

Thomas L. Spray, MD†

Nurse Practioner

David Drajpuch, CRNP†

Patient Coordinators

Joanna Acosta*
Markesha Peterkin†

*Penn Medicine
†Children’s Hospital of Philadelphia

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

The Children’s Hospital of Philadelphia
3400 Civic Center Boulevard
Philadelphia, PA 19104

Download a pdf of this Clinical Briefing.

Clinical Briefings™: Clinical Reports from Penn Medicine

Translational Research in Pancreatic Cancer

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

Pancreatitis Research

EMT and Dissemination Precede Pancreatic Tumor Formation

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

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

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

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

Faculty Team

Gynecologic Oncology

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

Mesothelioma Clinical Trials at Penn Medicine

Faculty Team

Thoracic Surgery

Pulmonary Medicine

Interventional Pulmonology

Endocrine and Oncologic Surgery

Hematology-Oncology

Pathology

Radiology

Radiation Oncology

Clinical Research & Operations

Patient Navigator

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

Microsurgical Vascularized Fibular Grafts for Avascular Necrosis of the Hip

EMT and Dissemination Precede Pancreatic Tumor Formation

Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

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

Multimodal Treatment of Kidney Stone Disease

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

Comprehensive Surgical Options for Trigeminal Neuralgia

Cardiofocus HeartLight® Endovascular Ablation System for the Treatment of Paroxysmal Atrial Fibrillation

Diagnosis of Pulmonary Hypertension and other Pulmonary Vascular Diseases

Barrett’s Esophagus and Esophageal Adenocarcinoma: Diagnosis, Treatment and Ongoing Research at Penn Medicine

Penn Celiac Disease Treatment Program

The Future: Advances in Clinical Research in Barrett’s Esophagus and Esophageal Adenocarcinoma

Proton Radiotherapy for the Treatment of Upper Gastrointestinal and Biliary Malignancies

Clinical Study

Faculty Team

Performing Clinical Research in Gastrointestinal Proton Therapy at Penn Medicine

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Clinical Research at the Roberts Proton Therapy Center

Proton Radiotherapy for Soft Tissue Sarcomas of the Extremities

Breast Reconstruction Surgery following Mastectomy for Breast Cancer

Clinical Research in Fertility Care: The PANDORA Trial

CAD-CAM Modeling for Craniofacial Surgery

Proton Therapy for Stage I, IIA, IIB and Relapsed Seminoma

Multidisciplinary Management of Adult Congenital Heart Disease

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

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