University of Pennsylvania Health System

Clinical Briefings™: Clinical Reports from Penn Medicine

Thursday, April 17, 2014

Enrolling Clinical Trials: Biomarker Identification in Orthopaedic and Oral Maxillofacial Surgery Subjects to Identify Risks of Bisphosphonate Use

Department of Orthopaedics • Trauma and Fracture Service • Department of Oral & Maxillofacial Surgery

Surgeons and researchers with the Penn Orthopaedic Trauma and Fracture Service and Oral and Maxillofacial Surgery have initiated a clinical study to identify the factors that cause some individuals to experience severe adverse events as a result of prolonged bisphosphonate therapy.

Bisphosphonates block the activity of cells that resorb bone, and are commonly prescribed for the treatment of osteoporosis and other conditions that deplete or compromise bone.

Most patients taking bisphosphonates experience few ill effects during the course of treatment. However, a minority of patients taking the drugs experience severe adverse effects, including atypical femur fractures in the context of low-energy trauma, changes in cortical thickening of bone, and osteonecrosis of the jaws. 
The pathophysiology of bisphosphonate-related events in this population is thought to involve suppressed bone turnover leading to accumulating microdamage and increased susceptibility to fractures. The fractured bones are characterized by a thickened and brittle cortex, delayed healing and altered bone metabolism.

Although the link between prolonged bisphosphonate therapy and subtrochanteric femur fractures and osteonecrosis of the jaw is well known, no adequate retrospective or meta-analysis of the affected patient population exists. Precise determination of risk factors for drug-related adverse events has been complicated by the number of bisphosphonate drugs, varying dose regimens, inter-individual genetics, comorbidities, treatment compliance and other factors.

To address these issues, surgeons and researchers at Penn Medicine are conducting a study that will attempt to identify genomic and RNA biomarkers that may play a role in differential metabolism of bisphosphonates or indicate tendency toward the severe adverse events associated with these drugs.


Biomarker Identification in Orthopaedic and Oral Maxillofacial Subjects
Methods: This is a nested case-control study with matched and counter-matched controls and a reference group of healthy volunteers, with age and sex matching, if possible. The study population will include individuals with a current or past history of bisphosphonate use with bisphosphonate-related osteonecrosis of the jaw (BRONJ) or atypical fracture of the femur, and a control population comprised of non-bisphosphonate using orthopaedic patients with typical fractures and oral-maxillofacial patients without osteonecrosis of the jaw. Patients will provide blood samples for profiling of DNA and miRNA biomarkers.

Objectives: This study will consolidate the many confounding variables associated with bisphosphonate exposure to evaluate local and/or systemic biomarkers of bone health and bisphosphonate treatment in healthy individuals or in those experiencing clinical events (i.e., atypical fractures or BRONJ, as appropriate).

Primary outcome variable(s): absorption, distribution, metabolism, excretion (ADME) profiling of DNA from all sample types and of miRNA biomarkers in circulating blood.

Secondary outcome variable(s): RNA (miRNA and mRNA) biomarkers as assessed by microarray profiling and/or Taqman assays; protein biomarkers from all sample types; histomorphometric or basic histologic differences within or between bone samples from each group; results of metagenomic testing of skin, wound, oral cavity or surgical site; Incidence of osteonecrosis of the jaw or other diagnosis requiring treatment intervention; incidence of fractures or progression to arthroscopy; demographic and medical history of bisphosphonate exposure and/or adverse events in the study population.

For more information, visit clinicaltrials.gov #NCT01875458.

Faculty Team

An integrated team of surgeons, nurses, social workers, therapists, interventional radiologists, rehabilitation specialists and researchers, the Penn Orthopaedic Trauma and Fracture Service provides comprehensive orthopaedic care to patients with traumatic injuries or fractures. The Service is committed to pre-eminent orthopaedic surgery and clinical research and excellence in the education of orthopaedic trauma surgeons.

The Penn Department of Oral and Maxillofacial Surgery is composed of dental/medical specialists whose expertise encompasses non-surgical and surgical treatment of oral and maxillofacial disorders, traumatic injuries, congenital defects, oral lesions and temporomandibular joint dysfunction.

Study Team Surgeons

Samir Mehta, MD
Chief, Orthopaedic Trauma and Fracture Service
Assistant Professor of Orthopaedic Surgery

Jaimo Ahn, MD, PhD
Assistant Professor of Orthopaedic Surgery

Derek Donegan, MD
Assistant Professor of Orthopaedic Surgery

John L. Esterhai, Jr., MD
Professor of Orthopaedic Surgery

David C. Stanton, MD, DMD
Associate Professor, Oral & Maxillofacial Surgery

Clinical Research Team

Kelly McGinnis, MPA, CRA
Program Manager
Kellymm@upenn.edu

Annamarie D. Horan, MPA, PhD
Director of Clinical Research
horana@uphs.upenn.edu

Access

Penn Orthopaedics
Hospital of the University of Pennsylvania
2 Silverstein
3400 Spruce Street
Philadelphia, PA 19104

Penn Oral & Maxillofacial Surgery
Hospital of the University of Pennsylvania
5th Floor, White Building
3400 Spruce Street
Philadelphia, PA 19104

https://docs.google.com/file/d/0B0vaPQ5yI4B3U0RDVDVmQndjcWM/edit






Tuesday, April 15, 2014

Enrolling Clinical Trials: Liver Cancer Treatment and Research at Penn Medicine

From the Spring 2014 Newsletter of the Penn Medicine Division of Gastroenterology

Edgar Ben-Josef, MD, Maarouf Hoteit, MD, David Kaplan, MD, Kim Olthoff, MD, Michael C Soulen, MD

Penn Medicine is a leading medical center in the nation in providing advanced clinical care and innovative investigational treatments to patients with liver cancer at every stage of the disease.

The liver cancer treatment program at Penn Medicine involves the integration of five national leading centers of treatment and research: The Abramson Cancer Center, the Penn Transplant Institute, the Roberts Proton Center, the Penn Center for Viral Hepatitis and the Division of Gastroenterology and Hepatology.

Every patient with liver cancer at Penn benefits from the expertise of specialists in each section of the program. Cancer treatment is a collaborative process, as each decision is complicated by the need to consider different aspects of the disease. What the Penn liver cancer program does—and does well—is function as a team whose various medical and surgical disciplines are focused on state of the art care for patients with liver cancer.

The anchor of the Penn liver cancer treatment program is the weekly Liver Tumor Conference. Here, clinicians with expertise in hepatology, hepatobiliary and transplant surgery, interventional radiology medical oncology, radiation-oncology, diagnostic radiology, and pathology contribute to the deliberative decisions necessary for the treatment of each patient with liver cancer. Each case is reviewed on the basis of the type and extent of cancer, health status, prior treatments and physical condition. Options are then considered and recommendations made.

 Treatment

The standard curative therapies for HCC at Penn include surgical resection, radiofrequency ablation and liver transplantation. All curative treatments depend on confirmation that the cancer is contained within the liver, has not invaded the major liver vessels and that the number and size of the tumors are within the parameters for cure.

Surgical resection is typically performed in patients with intact liver function. Patients with impaired liver function are candidates for transplantation. Patients with small tumors who are not healthy enough for surgery are candidates for radiofrequency ablation.
The treatments at Penn for advanced HCC include chemoembolization, radioembolization or external radiation for cancers contained to the liver in patients with good liver function.

Patients also have access to systemic therapy in the form of sorafenib or a variety of investigational treatments in the setting of clinical trials, including biological therapies, targeted immunotherapies, and proton therapy.

Clinical Research

Penn Medicine prides itself in being a national leader in advancing the science of cancer medicine and in the development of innovative cancer treatments in the setting of clinical trials. There are a number of clinical trial options available to patients with Liver Cancer at Penn.

A Phase II study of proton beam irradiation of unresectable primary liver tumors [ClinicalTrials.gov Identifier: NCT00976898] 

Penn Medicine is part of a multi-center study to evaluate the efficacy and safety of proton therapy in patients with unresectable liver cancer. A recent addition to the armamentarium for HCC at Penn, proton therapy is available at the Roberts Proton Therapy Center - one of only five proton centers on the East coast.

Proton therapy is expected to have advantages in liver cancer because the liver is particularly  sensitive to the effects of radiation. Proton dose distributions can be designed to conform closely to the tumor volume with a marked reduction in radiation exposure to the non involved liver, allowing delivery of higher doses to tumors within the liver with minimal effects on the surrounding liver.

The objective of this trial is to demonstrate local control (an important endpoint in abdominal cancers) in greater than 80% of patients at two years with proton beam irradiation for unresectable hepatocellular cancer.

Secondary objectives include a determination of the safety and tolerance of the treatment program, an evaluation of tumor response, patterns of failure and five-year overall survival, among other goals.

Patients will receive proton beam irradiation in 15 fractions over 3 weeks. Acute toxicity evaluations will occur weekly during study treatment, and at 3 month follow up. Thereafter, evaluation for tumor response will be conducted using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and for acute and late toxicity per Common Terminology Criteria for Adverse Events (CTCAE ) v. 3.0.

THIS TRIAL IS CURRENTLY RECRUITING.

The primary investigator at Penn is Edgar Ben-Josef, MD. Please contact Kristi Varillo
at 215.615.3273 for more information.

A Phase II randomized multi-center placebo-controlled blinded study of sorafenib adjuvant therapy in high risk orthotopic liver transplant (OLT) recipients with hepatocellular carcinoma (HCC)

Patients with evidence of a high risk liver cancer following liver transplantation form a group for whom limited options exist to reduce the risk of cancer recurrence.

These patients are currently the subject of a randomized, blinded, placebo-controlled clinical trial at Penn Medicine to investigate the efficacy and safety of the protein kinase inhibitor sorafenib in the adjuvant setting after liver transplant. This study is under the direction of Kim Olthoff, MD, of Penn Transplant Surgery, Maarouf Hoteit, MD, of Penn Gastroenterology and Nevena Damjanov, MD, of Penn Oncology.

The primary endpoint of the trial will be two-year recurrence-free survival. Other study endpoints include one-year recurrence free survival; overall survival; safety; impact of drug-drug interactions (i.e. immunosuppression agents); impact of biomarkers (alpha-fetoprotein [AFP], protein-induced by vitamin K absence or antagonist II [PIVKA II]); the effects of therapy on wound healing; and the impact on hepatitis C viral recurrence.

The trial will include patients who had hepatocellular carcinoma (HCC) with one of the following at the time of the pathological analysis of the transplant: microvascular/macrovascular invasion, tumor outside of Milan criteria, or poor tumor differentiation.

Patients with elevated surrogate markers (AFP greater than 500 or PIVKA greater than 400) pre transplant and with biopsy proven HCC prior to liver transplantation or at the time of transplant will also be included.

Patients will be randomized to one of two treatment arms: ARM I patients will receive sorafenib tosylate orally (PO) twice daily (BID). ARM II patients will receive placebo PO BID. Treatment will continue in both arms for 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients will be followed up every six months for two years.

THIS STUDY IS CURRENTLY RECRUITING.

The contact for referrals and participants is Mary Shaw, at 215.614.0528.


https://docs.google.com/file/d/0B0vaPQ5yI4B3Z3FKQlpkV0RJVUE/edit

Complex Revision Total Hip Arthroplasty for Periprosthetic Acetabulum Fractures

Department of Orthopaedics

Orthopaedic surgeons at Penn Medicine are taking a multidisciplinary approach to the treatment of periprosthetic acetabulum fractures associated with total hip arthroplasty (THA).

Periprosthetic acetabulum fractures present a rare complication distinguished by their challenges for both surgeons and the patient population. These fractures, which involve the socket of the hipbone, can occur intraoperatively or in the post-operative period and are associated with a number of complications, including hip osteonecrosis, non-union and implant loosening.

Reduction and fixation of periprosthetic acetabulum fractures is a complex undertaking because pre-existing implants can obstruct reduction and proper placement of fixation devices. Pelvic discontinuity in particular can be challenging to manage. More often seen in women and patients with inflammatory arthritis, pelvic discontinuity occurs in the setting of both THA and hemiarthroplasty. Vertical migration of the femoral component is common. Discontinuities can occur intra-operatively or post-operatively.

Expertise in both fracture management and joint reconstruction is often necessary to provide the best care and outcomes for patients requiring THA revision in the setting of periprosthetic acetabulum fractures.

At Penn Medicine, these surgeries are routinely performed as a team approach utilizing the skill sets of a fellowship trained orthopaedic traumatologist and a fellowship trained adult reconstructive surgeon. Because managing THA-associated periprosthetic acetabulum fractures requires expertise in both fracture management and joint reconstruction, this combined effort allows for the best possible outcomes.

The treatment of intra-operative periprosthetic acetabulum fractures at Penn consists of leaving the cup in place if it is stable, revising it to a multi-hole cup, bone grafting behind the cup, and/or posterior column plating if the cup is unstable. Fractures that occur after THA are typically due to component migration secondary to osteolysis, loss of cup fixation and fracture. Treatment of these late causes at Penn involves revision to a jumbo cup, posterior column plating, the use of modular augments or use of a custom tri-flange component.

Case Study


At age 53, Mrs. L came to Penn Orthopaedics with a long-standing history of Lupus and steroid use and a right-sided THA of approximately 10 years duration. Following a slip and fall injury, she was diagnosed with a right periprosthetic acetabulum fracture (Figure 1) at an outside hospital ER and transferred to Penn Orthopaedics for definitive management. A combined approach was planned to address the complexity of her injury.


Surgery to Mrs. L’s hip was approached through the previously placed THA incision extending more posteriorly towards the posterior superior iliac spine to perform a formal Kocker-Langenbeck procedure. Once the exposure was complete, the hip was dislocated and the acetabulum exposed. The acetabular component was removed, and the acetabular fracture fully exposed and debrided. The posterior column fracture was then reduced and transfixed with an independent 3.5mm lag screw and an 8-hole 3.5mm reconstruction plate.


With the posterior column fixed, the THA revision was initiated. The acetabulum was revised using a large trabecular metal cup with a posterior column trabecular metal augment secured into the ilium and cemented to the cup for unitization. Both the cup and augment were secured with multiple screws. At completion of the acetabulum, the femoral component was evaluated and deemed stable with appropriate anteversion. The hip was then reduced with trial components and excellent stability achieved. The final components were placed and the wound was irrigated thoroughly and closed in typical layered fashion (Figure 2).

Post-operatively, Mrs. L was given posterior hip precautions and permitted touchdown weight bearing for a total of six weeks, at which point she was progressed to 50% weight bearing. At three months, weight bearing as tolerated was permitted. Mrs. L is currently six months out from surgery and is full weight bearing with minimal pain in her right hip. Recent x-rays demonstrate that the acetabular fracture is both well-fixed and healed (Figure 3).

Faculty Team

The nation’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. Penn Orthopaedics is committed to pre-eminent orthopaedic surgery, clinical research and excellence in the education of orthopaedic surgeons.

Performing THA Revision Surgery for Periprosthetic Acetabulum Fractures at Penn Medicine

Derek Donegan, MD
Assistant Professor of Orthopaedic Surgery

Neil P. Sheth, MD
Assistant Professor of Orthopaedic Surgery

Access

Penn Orthopaedics
Hospital of the University of Pennsylvania
2 Silverstein
3400 Spruce Street
Philadelphia, PA 19104

Pennsylvania Hospital
1 Cathcart
800 Spruce Street
Philadelphia, PA 19107

Penn Presbyterian Medical Center
1 Cupp Pavilion
51 N 39th Street
Philadelphia, PA 19104




Friday, April 11, 2014

Fecal Microbiota Transplantation for the Treatment of Recurrent Clostridium Difficile Infection


Department of Medicine • Infectious Disease Division


Infectious disease specialists at Penn Medicine are performing fecal microbiota transplantation procedures to treat patients with resistant and recurrent Clostridium difficile infections.

Clostridium difficile (or C diff) is the most common cause of nosocomial diarrhea in the United States, and is identified with life–threatening pseudomembranous colitis and toxic megacolon. An endospore-producing Gram-positive bacteria, C diff is characterized by an extraordinary facility for survival (difficile means difficult or obstinate).

C diff spores are resistant to most oral and parenteral broad-spectrum antibiotics (including the penicillins, quinolones,cephalosporins and lincosamides) as well as chemotherapeutic agents, gastric acid, alcohol and disinfectants. Spores can emerge in the gut after seemingly effective antibiotic treatment and can survive for years on outside surfaces to present an ever-present threat to susceptible hosts. A more virulent and resistant strain of C diff appeared in the US hospitals in 2002.

Once mature C diff appears in the unchallenged environment of the gut following antibiotic treatment, the bacteria spread rapidly, exuding cytotoxins as a component of propagation. These toxins bind to and penetrate the gut epithelium and mucosa, destroying cell structure, cleaving the water-tight junctions between cells and contributing to profound colonic mucosal injury and inflammation. The normal balance in the gut then shifts from absorption of fluids and electrolytes to excretion, leading to diarrhea.

Treatment

The first line treatment for C diff is metronidazole if the infection is not severe. However, the recurrence rate following an initial infection is 15-30% and there is a 50% chance of a subsequent recurrence if disease reappears once. Metronidazole is not used for recurrent infections. Second and later infections are treated with vancomycin. Both drugs are effective against C diff, but because both alter the gut microbiome to favor their ubiquitous target, some patients will have recurrences despite therapy. Patients who have three or more recurrences may have chronic C diff infection, a course characterized by repeated episodes of treatment followed by disease relapse in which each relapse increases the likelihood of subsequent infections. 

At Penn Medicine, infectious disease specialists are successfully treating recurrent C diff infection with an investigational biological alternative to antibiotic therapy. Known as fecal microbiota transplantation (FMT), the therapy involves restoring the normal gut microbiome in patients following repeated recurrences of C diff with antibiotic therapy. In a recent comparative clinical trial, FMT effectively cured 94% of patients in patients with recurrent C diff vs. 31% of patients receiving vancomycin 500 mg 4x daily for five days. [1]

Donors for FMT therapy at Penn Medicine are closely screened to avoid exposing recipients to pathogens, transmissible diseases and inflammatory disorders. The Food and Drug Administration currently considers FMA investigational, and its use is restricted to patients with recurrent C diff infection (R-CDI) not responsive to standard therapies.

Reference
1. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-415.

Case Study

Mr. W, a 63-year-old man, was referred to the Penn Medicine Division of Infectious Disease for recurrent antibiotic-associated C diff infection. His recent medical history included severe diarrhea with expulsion of blood and mucus following three days of lincomycin Hcl therapy for a severe urinary tract infection. Ultimately, the UTI was successfully resolved with a course of quinolone antibiotics.

Several weeks afterward, a second, prolonged bout of diarrhea at his vacation home brought Mr. W back to his physician. A fecal sample at this visit tested positive for C diff toxins. Mr. W was then referred to a local gastroenterologist, who prescribed metronidazole.

Mr. W was counseled at this time about the need for strict hygiene and cleanliness in his personal environment. At the conclusion of therapy, he had no evidence of C diff infection. After a weekend trip to his vacation home, however, Mr. W’s symptoms returned. He was cautioned again about hygiene, and prescribed an extended course of vancomycin. This time, Mr. W was exceedingly cautious and took great care to avoid infection. Three weeks into his therapy, however, he had another recurrence of diarrhea.

At this point, Mr. W discovered references to FMT therapy at Penn Medicine in an online forum, and was referred to the Division of Infectious Diseases for a consultation, which involved a thorough review of the investigational nature of the therapy and its risks. At the conclusion of this discussion, he provided his informed consent for treatment.

On the day of his treatment, Mr. W stopped taking vancomycin. He received a single infusion of fecal microbiota in saline into his small bowel via a nasoduodenal tube and returned home. His diarrhea resolved the next day and within three days, normal bowel activity had resumed. At his six month follow-up, Mr. W reported no further episodes of diarrhea. Samples taken at this visit demonstrated a robust gut microbiome.

Faculty Team

Specialists in the Division of Infectious Diseases at Penn Medicine offer consultation regarding infectious disease problems, such as viral infections, diarrhea, tuberculosis, osteomyelitis, parasitology, and HIV. In particular, treatment is available for patients with problems associated with immunosuppression and international travel. Primary care is also available for HIV, hepatitis B, and hepatitis C patients.

Performing FMT at Penn Medicine

Stephen J. Gluckman, MD
Medical Director, Penn Global Medicine
Professor of Medicine

David L. Holtzman, MD, MSc
Infectious Disease Fellow

Brendan J. Kelly, MD
Attending Physician,
Division of Infectious Diseases

Ebbing Lautenbach, MD, MPH, MSCE
Chief, Division of Infectious Diseases;
Robert Austrian Professor

Pablo Tebas, MD
Professor of Medicine

Access

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

Penn Presbyterian Medical Center
Infectious Diseases Division
Medical Arts Building, Suite 102
51 N 39th Street
Philadelphia, PA 19104

Pennsylvania Hospital
1 Pine West
800 Spruce Street
Philadelphia, PA 19107


https://docs.google.com/file/d/0B0vaPQ5yI4B3TG00LTBwdmlMbmM/edit


Advances in Hepatitis Therapy

From the Spring 2014 Newsletter of the Division of Gastroenterology at Penn Medicine

K. Rajender Reddy, MD

With the introduction of the direct acting antivirals, the treatment of the hepatitis C virus has entered a transformative era in which simpler, safer and more efficacious regimens for a broader range of hepatitis genotypes and patient populations may be possible.

Hepatitis C (HCV) provokes an immune-mediated inflammatory response in the liver that either clears the virus (~15% of cases) or leads to a chronic infection that is the precursor for cirrhosis, end-stage liver disease and hepatocellular carcinoma.

For all of these reasons, HCV is the leading cause of liver transplantation in the United States, where cirrhosis is now the 8th leading cause of death and liver cancer has doubled in incidence in the last two decades. [US Burden of Disease Collaborators. JAMA 2010;310:591-608.]

Identified in 1989, the HCV genome consists of a linear single-stranded RNA molecule containing untranslated regions flanking a polyprotein processed into structural (C, E1, E2 and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) subunits by host and viral protease. [Chisari FV. Nature 2005;436, 930-932.] The latter have become important targets for antiviral therapy.

Of the six HCV genotypes now known, genotypes 1 and 2 account for the vast majority of chronic infections in the United States (~70% and 20%, respectively).

The characteristic persistence of HCV infection can be attributed to the capacity of the virus to evade innate antiviral defenses and antagonize the host immune response. Soon after inoculation, a robust type 1 (IFN) reaction occurs in the liver. IFNs are the primary cytokines involved in the induction of the antiviral state in cells and the activation and regulation of innate immunity.

In about 30% of infected persons, the initial IFN response is sufficient to clear the virus.

In individuals in whom the IFN response is inadequate, however, the virus uses its NS3/4A and NS5A proteases, among others, to block molecular signaling within the IFN pathway, antagonizing the host response. Moreover, HCV can generate genetically distinct viral variants, each with its own capacity to evade and control the host response. The end result of these processes is a life-long, highly communicable infection.

Treatment of HCV

Until very recently, the standard of care for most patients with HCV involved dual therapy with pegylated interferon (pegIFN) and ribavirin (RBV) for 24 to 48 weeks. Pegylated interferon is a chemically modified form of alpha interferon; ribavirin is a guanosine analog used to halt viral RNA synthesis.

Neither drug is particularly effective as monotherapy for HCV (<5% sustained virologic response, or SVR) but in patients with genotype 1, HCV will have a significant sustained virologic response SVR at 12 months. As a measure of efficacy, SVR is clearly associated with durable response; decreased progression to cirrhosis; decreased liver decompensation; decreased post-transplant recurrence and improvement in survival.

Both pegIFN and RBV are associated with treatment-related adverse reactions of a severity sufficient to cause dosing modification in 35% to 42% of patients (with potential consequent effects on SVR) and discontinuation in ~20%. These factors, and the need for shorter duration treatments with greater efficacy, prompted a vigorous search for alternatives to pegIFN+RBV.

Direct Acting Antivirals

A rapidly evolving treatment landscape for HCV evolved with a greater understanding of the viral life cycle. The latest addition to HCV treatment are the direct acting antivirals (DAAs), so-called because they interfere directly at different stages with the replication cycle of HCV. These agents fall into four major classes: the NS3 protease inhibitors (PIs); the NS5A inhibitors; the NS5B nucleoside inhibitors and the NS5B non-nucleoside inhibitors.

FDA approval for the protease inhibitors telaprevir and boceprevir came in 2011.

The NS5B nucleoside inhibitor sofosbuvir and a third protease inhibitor, simeprevir, were approved in late 2013. Two additional DAAs, the protease inhibitor faldaprevir and the NS5A complex inhibitor declatavir are expected to be approved in 2014. At least six more DAAs are anticipated in the next five years, including ledispasvir, an HCV NS5A inhibitor and the NS3 protease inhibitor asunaprevir.

Comparisons of the DAAs are made on the basis of overall efficacy; pangenotypic efficacy; resistance profile; adverse events profile; and drug-drug interactions. By these criteria, the NS5B nucleoside inhibitors excel in every category. The second generation PIs and NS5A inhibitors are, by comparison, similar to the NS5B nucleosides in having superior efficacy and adverse event profiles, but are average otherwise.

The protease inhibitors are potent, but because the amino acid sequences of the protease domains they affect differ across genotypes, they exhibit varying pangenotypic efficacy. Resistance is also an issue with the PIs. The first generation PIs telaprevir and boceprevir offer a significant advantage in SVR when combined with pegIFN and RBV as triple therapy.

Their use in the majority of patients, however, is tempered by a number of concerns, including dosing regimen complexity (decisions to continue, stop or combine agents are made at specific time-points during therapy depending upon viral response), added pill burden, drug-drug interactions, poor pangenotypic efficacy, resistance and significant adverse effects.

By contrast, sofosbuvir and simeprevir appear to have brought the goal of an ideal HCV regimen closer to hand.

The efficacy of Sofosbuvir 400 mg/daily has been established in HCV genotypes 1-4 (including patients with liver cancer awaiting liver transplantation) in combination with pegIFN+RBV and RBV alone. Study populations have included treatment naïve, treatment experienced, pegIFN refractory or intolerant, cirrhotic, non-cirrhotic and null-responder populations, as well as patients with HCV/HIV-1 infection.

Dose modification is generally not necessary for sofosbuvir, but may be a concern when the drug is combined with IFN or RBV. Sofosbuvir has a mild adverse event profile and few drug-drug interactions; resistance is not a significant issue.

SVRs established during clinical trials are shown in the table below. _________________________________________________________________________________

__________________________________________________________________________________

It should be noted that cost is a significant issue with sofosbuvir ($1000/pill), and that the demographics and disease burden of the participants in the described clinical trials may not accurately reflect those of the HCV population as a whole.

Simeprevir is a second generation PI. In combination with pegIFN+RBV, simeprevir has established efficacy against HCV genotype 1 in patients with compensated liver disease, including cirrhosis. The drug has been studied in genotype 1 null responders, relapsed patients, partial responders, and treatment naïve patients.

The treatment duration for treatment naïve and prior relapsers is 12 weeks of imeprevir/pegIFN+RBV with an additional 12 weeks of pegIFN+RBV. Partial and null responders receive simeprevir/ pegIFN+RBV for 12 weeks and pegIFN+RBV for an additional 36 weeks. In studies of treatment naïve HCV genotype 1 patients, simeprevir/ pegIFN+RBV achieved significant SVRs at 12 weeks in 80% of patients when compared to placebo (P < 0.001). Among relapsed patients, 83% receiving simeprevir/pegIFN+RBV demonstrated SVR at 12 weeks versus 37% in the placebo arm. SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group.

Simeprevir has a significant issue in that patients with genotype 1a Q80K polymorphism are resistant to the drug. Resistance testing in this subset of patients is thus recommended for the drug.

Simeprevir has not been studied in patients previously treated with protease inhibiters or in patients with moderate-to-severe liver damage, in whom the drug exhibits higher exposures. Simeprevir does react with drugs that are strong inhibitors or inducers of cytochrome CYP3A.

Current Recommendations for Treatment

Genotype 1 patients with cirrhosis for whom there is evidence of SVR and no contraindications should be treated immediately. If IFN-eligible, these patients should receive triple therapy with sofosbuvir/pegIFN+RBV for 24 weeks. If IFN-ineligible, patients should receive sofosbuvir+RBV for 24 weeks. Motivated patients with lesser fibrosis (with possible SVR and no contraindications) and those with extra-hepatic manifestations should also be treated immediately.

Patients with genotypes 2 should receive sofosbuvir+RBV for 12 weeks if eligible; patients with advanced genotype 3 disease should receive sofosbuvir+RBV for 24 weeks; genotype 4 patients with advanced disease should receive sofosbuvir/pegIFN+RBV for 24 weeks. More data is needed before recommendations can be made for genotypes 5 and 6.

Penn Center for Viral Hepatitis

Established in 2010 under the direction of K. Rajender Reddy, MD, and associate director Kyong-Mi Chang, MD, the Penn Center for Viral Hepatitis is a regional nucleus for viral hepatitis care, research and education. Since its initiation, the Center has played an essential role in bringing to market simpler, safer and more effective drug therapies for hepatitis C.

Among other recent achievements, the Center participated in the Phase III studies to investigate the safety, tolerability, and antiviral efficacy of a fixed-dose combination (FDC) of sofosbuvir and ledispasvir for the treatment of genotype 1 HCV infection in adults. The drug, the first of its kind to combine two DAAs in a single pill for use without IFN and possibly without ribavirin, is expected to be approved sometime in the next year.

The Center has also participated in other cutting edge oral regimens in Phase II and III programs. Through these programs several of the patients benefited immensely through successful outcomes.

The education of medical students, residents, fellows, pharmacy students, and physician extenders occurs throughout the Center’s programs. Training involves the virology, immunology, epidemiology, and clinical management of viral hepatitis and HIV/viral hepatitis co-infection.

The center also seeks to enhance public awareness, patient education and patient advocacy of viral hepatitis infections and HIV/viral hepatitis co-infection.



https://docs.google.com/file/d/0B0vaPQ5yI4B3Z3FKQlpkV0RJVUE/edit



Thursday, April 3, 2014

Diagnosis and Treatment of Chronic Non-Tuberculous Mycobacterium Infection


Pulmonologists and infectious disease specialists at Penn Medicine are testing treatment regimens for patients with nontuberculous mycobacterial infections.

Mycobacteria are a widespread family of aerobic, rod-shaped bacilli associated with chronic infections, including tuberculosis (Mycobacterium tuberculosis). Many nontuberculous mycobacteria (NTM) also cause chronic infections of the lungs and other body sites. Myobacterium avium complex (MAC), is responsible for more than 80% of pulmonary NTM infections in the United States. Mycobacterium abscessus lung infections are increasingly common as well. Nonpulmonary sites of infection include skin and soft tissue, bones or joints or tendons, and lymph nodes.

The number of infections caused by NTM has risen sharply in the US during a time when the incidence of tuberculosis has stabilized or decreased (Figure 1). For unknown reasons, this increase is happening primarily in immunocompetent persons, particularly women 65 years of age and older. These infections appear to be particularly common in the Philadelphia area.

The diagnosis of NTM infection is complicated by the universality of mycobacteria in the environment and the non-specific character of the symptoms identified with infection. Infected persons typically have a chronic productive cough. Hemoptysis, low-grade fever and weight loss occur variably in patients with advanced disease. In immunocompetent patients, NTM infection is often suspected on the basis of abnormal findings on CT imaging of the chest.

At Penn Medicine, pulmonologists and infectious disease specialists in close collaboration with pathologists and radiologists have developed an algorithm for the diagnosis and treatment of NTM infections. The leading considerations for the diagnosis of NTM at Penn involve the characteristics of mycobacteria and the symptoms identified with infection, as well as the implications of treatment.

NTM infections cannot be diagnosed on the basis of nonspecific symptoms or by the presence of mycobacteria alone, which are often found incidentally in lung samples. Moreover, because the antibiotics used to control NTM infections are associated with severe persistent potential adverse effects (including irreversible impairment of hearing, vision, and kidney function), treatment of NTM infection cannot be initiated in the absence of confirmation.

Once suspected, NTM infection is confirmed at Penn through a combination of individualized tests, including lab work, CT scans and bronchoscopy. Long-term treatment is structured from a perspective that permits physicians to alter regimens when necessary to ensure the continuity and efficacy of therapy, avoid persistent adverse events and preclude the risk of antibiotic resistance. When necessary, doctors at Penn use two drugs not generally available elsewhere, clofazimine and bedaquiline to control problematic infections.

Case Study

Mrs. E, a 57-year-old woman, was referred to the Penn Lung Center by her primary care provider with a three-month history of chronic productive cough and fatigue. Following the onset of cough, she had self-medicated with amoxicillin for two weeks to no effect. With the exception of hypertension and hypothyroidism, for which she took daily medications, her medical history was unremarkable. She did not smoke and had no contact with known pulmonary irritants in her daily life.


A CT scan at Penn revealed bronchiectasis, partial volume loss in the lower right lobe, and scattered lower lobe nodules in both lungs (Figure 2). A bronchoalveolar lavage was then performed. Cultures of fluid were positive for Mycobacterium avium-intracellulare (MAI) complex, a common co-infection. Mrs. E began a daily three-drug regimen consisting of clarithromycin, rifamycin and ethambutal and continued her therapy for 15 months, during which time her dosage was adjusted twice to address side effects. At the conclusion of 12 consecutive months of culture negativity, she discontinued therapy. To date, she remains free of NTM infection.

Faculty Team

The Penn Lung Center offers patient-focused, compassionate care and a comprehensive approach to the diagnosis and treatment of lung disease. The multidisciplinary team of expert clinicians and researchers at Penn have pioneered technological and treatment advances that allow the Penn Lung Center to provide patients with more leading-edge treatment options than any other lung program in the region. Pulmonologists at the Penn Lung Center often collaborate with infectious disease specialists at Penn Medicine regarding infectious disease problems, including bacterial and viral infection, osteomyelitis, parasitology and HIV.

Treating Non-tuberculous Mycobacterial Infections at Penn Medicine


Penn Lung Center

John H. Hansen-Flaschen, MD
Chief, Pulmonary, Allergy and Critical Care Medicine Division
Paul F. Harron, Jr. Family Professor

Daniel Dorgan, MD
Assistant Professor of Clinical Medicine

Infectious Diseases

Keith W. Hamilton, MD
Assistant Professor of Clinical Medicine

Pablo Tebas, MD
Professor of Medicine

Access


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

Infectious Diseases

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


To speak with a Penn specialist about NTM infection, please call 215.662.6932 (ext. 7).


https://docs.google.com/file/d/0B0vaPQ5yI4B3UUJWaEhocFdkSzA/edit




Tuesday, December 24, 2013

Autologous Vascularized Lymph Node Transfer for the Management of Secondary Lymphedema

 Penn Plastic Sugery | Center for Human Appearance

Surgeons at the Center for Human Appearance at Penn Medicine are performing microsurgical vascularized lymph node transfer surgery (VLNTx) procedures for patients with lymphedema following cancer surgery.

Lymphedema manifests as the accumulation of protein-rich fluid in the interstitial spaces at the cellular level, particularly in the extremities, and is a common side effect of surgery and radiation therapy for cancer. In its advanced stages, the condition is characterized by chronic edema, cellulitis, inflammation, fibrosis, pain and disfigurement.

The Lymphedema Treatment Program of the Center for Human Appearance at Penn is designed to manage lymphedema at every stage. The Program team comprises lymphedema therapists, physical medicine and rehabilitation specialists, radiologists, medical and surgical oncologists and plastic surgeons.  The Program offers compression garments, massage therapy and lymphedema pumps to patients with mild-to-moderate lymphedema to provide symptomatic relief and inhibit the progress of the disease.

Autologous vascularized lymph node transfer surgery (VLNTx) is available at Penn for patients with more advanced lymphedema. VLNTx relieves the symptoms of lymphedema by transferring healthy lymphatic tissue from a donor site in the patient’s body to a recipient site at the affected extremity to augment the drainage of lymph. Because the tissue is the patient’s own, immunosuppressants are unnecessary.

During the surgery, scarred and fibrotic tissue is first removed from the recipient site. Healthy vascularized lymphatic tissue is then obtained from a supraclavicular flap, transferred to the recipient location and microsurgically anastomosed there to an artery and vein. Over time, the transposed tissue stimulates reconnections between the obstructed and healthy lymphatic systems, promoting lymph flow and reducing inflammation and infection in the limb. Typically, a substantial reduction in limb diameter occurs within two to three weeks.


Case Study
Mrs. M, a 54-year-old woman, came to Penn Plastic Surgery for evaluation of severe, advanced lymphedema in her right leg three years after a right-sided mastectomy for breast cancer followed by radiation therapy.

When her lymphedima became apparent in the weeks after surgery, Mrs. M began a course of therapy that included massage, compression sleeves and the use of a lymphedema pump. While these treatments were efficacious in the short term, Mrs. M’s lymphedema became resistant to therapy over time and was exacerbated by repeated episodes of cellulitis. Distressed by the progressive disfigurement of her leg, Mrs. M contacted her oncologist and was referred to Penn Medicine.

On physical examination at Penn, Mrs. M’s right leg circumference exceeded that of her left by almost 40%. After a thorough review of the available options for treatment, Mrs. M opted for a VLNTx procedure.

During her surgery, scarred and fibrotic tissue was first removed from Mrs. M’s groin until what remained was healthy tissue. An estimation from the incision site was then made to determine the dimensions of the tissue to be transferred. A flap comprised of superficial lymph nodes and their vasculature was then harvested from the base of her neck, transferred to the recipient site and microsurgically anastomosed to an artery and vein.

Mrs. M went home two days after surgery. Her recovery was unremarkable. At her first follow-up visit three weeks after surgery, her edema and swelling was substantially diminished (Figure 1) and she reported that she had returned to a moderate exercise regimen. She continues to use compression garments, and visits Penn Medicine’s Lymphedema Services for regular monitoring and assessment.

Faculty Team


Penn Plastic Surgery performs more than 1,800 cosmetic and reconstructive procedures each year, and is the hub for the largest volume of breast reconstruction surgeries (including latissimua and DIEP flaps) in the region. 

As a result of its expertise in breast reconstruction, plastic surgeons at Penn are actively involved in the management of the adverse cosmetic effects related to cancer treatment, including lymphedema. Treatments embrace both non-surgical and surgical techniques, including microsurgery, a technology that permit surgeons to perform anastomoses on minute blood vessels, nerves and other tissues.

Performing Autologous Vascularized Lymph Node Transfer Surgery at Penn Medicine

Suhail K. Kanchwala, MD
Assistant Professor of Surgery

Joy C. Cohn, PT, CLT-LANA
Team Leader, Lymphedema Services

Access

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

https://docs.google.com/file/d/0B0vaPQ5yI4B3QXdiY285bUx2UDA/edit


Friday, December 20, 2013

Enrolling Clinical Trials: Ex Vivo Lung Perfusion for Improved Donor Evaluation and Safe Organ Transplantation

 Penn Heart and Vascular | Penn Lung Center | Penn Transplant Institute

Transplant surgeons at Penn Medicine are investigating an approach known as ex vivo lung perfusion (EVLP) to enhance donor lung evaluation for transplantation in suboptimal organs not ordinarily used for transplantation. Penn Medicine is the first in the region to incorporate this new technique into lung transplantation surgeries.

Lung transplantation is often the only treatment option available for patients with end-stage lung disease. However, only 15% to 20% of donor lungs are currently deemed viable for transplantation. Reasons for this shortage include the lung’s susceptibility to injuries from excess fluid accumulation, bacteria, or damage from intensive care unit-related complications, any of which can render the organ medically unsuitable for transplantation.

Ex vivo lung perfusion is a process by which suboptimal donor lungs are pre-conditioned to improve their potential for transplantation. The technique involves connecting the lung to a ventilator, pump and filters inside a sterile plastic dome. An acellular perfusate (Steen solution) containing nutrients, proteins and a gas mixture (oxygen, carbon dioxide and nitrogen) is then circulated through the lung.  A leukocyte depletion filter removes inflammatory cells from the circulated perfusate, including cytokines and tumor necrosis factor. Circulation is controlled by a centrifugal pump and normal body temperature is maintained by a heater/cooler.

Together, these procedures have been shown in clinical trials to reduce post-transplantation rejection of suboptimal donor lungs [1] and to provide patient survival rates similar to those of  standard donor lungs. [2]

The Penn Lung Transplant Ex Vivo Lung Perfusion Program is one of six sites in the United States participating in the ongoing FDA investigational multicenter clinical research trial designed to compare outcomes from lung transplants using the ex vivo technique with those using the traditional method [ClinicalTrials.gov Identifier: NCT01365429].

The goal of the Program is to expand the pool of donor lungs available and extend this life–saving therapy to more patients awaiting transplant.

For more information about ex vivo lung perfusion at Penn, please visit: http://bit.ly/YqbYSk, or contact Jaya Tiwari, CCRP, clinical research project manager, at 215.614.0387.

References
1. Fildes JE, et al. Improved clinical outcome of patients transplanted with reconditioned donor lungs via EVLP compared to standard lung transplantation. Transpl Int. 2011; 24: 77.
2. Cypel M, et al. One year survival and functional status of patients from the Human Ex vivo Lung Perfusion (HELP) trial. J Heart Lung Transplant. 2011; 30: S8.




Case Study

A single left donor lung was offered to Penn Medicine for EVLP evaluation with intent for possible transplant after being rejected by all other centers as unsuitable for transplantation because of pulmonary edema and questionable aspiration. EVLP was performed according to the clinical trial protocol with reconditioning followed by functional assessment. Airway pressure, lung compliance, and pulmonary vascular resistance were recorded.

During evaluation, hemodynamic (flow, pulmonary vascular resistance, pressure) parameters were stable. Lung radiographs taken 1 hour and 3 hours into EVLP showed improvement in pulmonary edema. The donor lungs improved their oxygenation capacity to a PaO2/FIO2 of 452 at the end of the EVLP.

The lungs were then deemed suitable for transplantation and a consented patient on the waiting list underwent a left single lung transplant. The lung recipient was extubated after 16 hours. The PaO2 was 103 mmHg at 3 liters of oxygen on postoperative day one.

The patient was discharged from the hospital on postoperative day 21 and has since completed a 10 month follow-up evaluation with no hospital readmissions. He has had stable lung function parameters on spirometry during the entire postoperative period, is doing well and is enjoying an excellent quality of life.

Faculty Team

Since the inception of Penn Medicine’s lung transplant program in 1991, nearly 850 successful lung transplants have been performed and many lives have been dramatically improved. In recent years, surgeons at Penn Medicine have performed more than double the number of lung transplants than any other transplant program in the Philadelphia region.

Performing Lung Transplantations at Penn

Penn Heart & Vascular

Edward Cantu III, MD
Surgical Director of Lung Transplantation
Assistant Professor of Surgery

Wilson Szeto, MD
Associate Professor of Surgery
Prashanth Vallabhajosyula, MD
Assistant Professor of Surgery

Penn Lung Center

Vivek Ahya, MD
Medical Director, Lung Transplantation Program
Associate Professor of Medicine

Jason Christie, MD, MS
Director of the Center for Translational Lung Biology Perelman School of Medicine
Associate Professor of Medicine

Joshua Diamond, MD, MSCE
Instructor of Medicine

Denis Hadjiliadis, MD
Paul F Harron Jr. Associate Professor of Medicine

Robert M. Kotloff, MD
Chief, Section of Advanced Lung Disease
and Lung Transplantation

The Craig and Elaine Dobbin/Nancy P. Blumenthal
Professor for Advanced Lung Disease

James C. Lee, MD
Assistant Professor of Medicine

Rupal Shah, MD
Instructor of Medicine

Penn Transplant Institute

Nancy Blumenthal, MSN, CRNP, CCTC
Director of Clinical Practice, Senior Nurse Practitioner

Kevin Carney, MSN, CRNP, CCTC

J. Eric Hobson, MSN, CRNP

Belinda Turner, MSN, CRNP

James Mendez, MSN, CRNP

Social Worker
Christopher Erickson, MSW, LCSW

Dietitian
Katie Stratton, RD

Transplant Pharmacist
Tamara Claridge, PharmD

Pulmonary Rehabilitation
Rodney Simcox, RRT

Transplant Outreach
Denny DuPont

Manager, Transplant Outreach and Communication

Access

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

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

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



https://docs.google.com/file/d/0B0vaPQ5yI4B3NXhqWEdHTXhXMUU/edit

Thursday, December 5, 2013

Enrolling Clinical Trials: Stereotactic Body Radiotherapy (SBRT) and Proton Therapy for Hepatocellular Carcinoma (HCC) and Cholangiocarcinoma

Department of Radiation Oncology • Abramson Cancer Center

At the Abramson Cancer Center and Penn Medicine, a team of specialists is exploring the use of radiotherapy for liver cancer. A leading cause of cancer deaths worldwide, hepatocellular carcinoma (HCC) is expected to increase in prevalence in the United States secondary to the aging cohort of patients with chronic hepatitis C infection and the rising incidence of cirrhosis from nonalcoholic steatohepatitis related to obesity.

Cholangiocarcinoma, a tumor originating in bile ducts, is also increasing in incidence. The latest SEER database analysis reports that ~16% of patients with primary liver cancer–most of which is HCC–survive five years. The majority of patients with cholangiocarcinoma die within 6 – 12 months of diagnosis.





  

Proton Therapy for HCC and Intrahepatic Cholangiocarcinoma

Liver transplantation offers a potentially curative treatment for many patients with HCC, but is not an option for patients with multiple, large or metastatic hepatic lesions or intrahepatic cholangiocarcinoma. The efficacy of standard cancer treatments for HCC, including chemotherapy and radiation, is poor. Studies now suggest that proton therapy may offer improved local control and survival rates for these patients.

Proton dose distributions can be designed that conform more closely to the tumor volume with a marked reduction in radiation exposure to the non involved liver. This allowes delivery of higher doses to tumors within the liver, an organ extremely sensitive to the effects of radiation.

The Abramson Cancer Center and Penn Medicine are participating in a multi-center phase II clinical study investigating the use of proton therapy in patients with unresectable primary hepatoma (hepatocellular carcinoma) or intrahepatic cholangiocarcinoma.

Phase II study of proton beam irradiation of unresectable primary liver tumors [ClinicalTrials.gov Identifier: NCT00976898]

Objectives: The primary objective of this study is to demonstrate 2 yr LC of >80% with proton beam irradiation for unresectable hepatocellular cancer. This will be benchmarked against 2yr LC of 55%. Secondary objectives include a determination of the safety and tolerance of this treatment program, an evaluation of tumor response, patterns of failure and five-year overall survival, among other goals.

Methods: Patients will receive proton beam irradiation in 15 fractions over 3 weeks. Acute toxicity evaluations will occur weekly during study treatment, and at 3 month follow up. Thereafter, evaluation for tumor response will be conducted using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and for acute and late toxicity per Common Terminology Criteria for Adverse Events (CTCAE ) v. 3.0.

The primary investigator for this trial at Penn is Edgar Ben-Josef. Please contact Kristi Varillo at 215.615.3273 for more information.

Proton/IMRT Case Study

RG, a 46 y.o. man, presented in 2009 with a large hepatic mass involving the entire left lobe as well as portions of segment 8. There was an additional 1.3 cm right hepatic tumor in segment 6, most likely multifocal HCC. He had an FNA and core needle biopsy confirming HCC. At that time his AFP was 70,000.

RG had excellent responses to multiple chemoembolizations (6 total) and one radio embolization with Y-90 TheraSpheres®. In 4/12, however, an enlarged 2 cm pericardiac lymph node was noted, supplied by the right internal mammary artery. RG was treated with chemoembolization via the left hepatic artery and bland embolization via the right internal mammary artery, but his AFP continued to rise and imaging suggested progression of disease.

An MRI in 11/12 showed an enlarging right pericardiophrenic lymph node and a 6.2 x 7.1 cm tumor in the left lobe with multiple scattered foci of peripheral enhancement. RG was then referred for radiation therapy and received 55 Gy in 25 fractions, using a combination of protons and IMRT (Figures 1&2). His treatment was completed in 1/13.

RG had a very good clinical and radiographic response. An MRI in 7/13 demonstrated a decrease in size of the left lobe lesion (to 5.5 x 6.4 cm), as well as the size of the pericardiac lymph node. His AFP decreased from 375 to 1.2. He had no clinical toxicity and no change in liver enzymes.

TACE and SBRT for Patients Awaiting Liver Transplantation

Specialists at the Abramson Cancer Center and Penn Medicine have initiated a prospective randomized trial assessing the use of a powerful new technology, stereotactic body radiation therapy (SBRT), in combination with transarterial chemoembolization (TACE) versus TACE alone as a therapeutic bridge to transplantation.

SBRT delivers highly focused radiotherapy to tumors in five or fewer fractions. Because the distribution of dose conforms so well to the target, very high doses (biologically more effective) can be delivered at any one session. SBRT also excells at limiting dose to normal tissue, and has been shown to be an effective therapy for liver metastases; with a short follow up of 2 years its efficacy rivals that of resection.

The Abramson trial will combine this technology with TACE in patients awaiting OLT. Theoretically, SBRT complements TACE by more easily targeting residual tumor cells at the periphery of a lesion and delivering higher doses to tumors partially shrunken by chemoembolization.
A pilot trial of transarterial chemoembolization with or without stereotactic body radiation therapy for hepatocellular carcinoma patients awaiting liver transplantation [ClinicalTrials.gov Identifier: NCT01918683]

Objectives: This study examines the efficacy of TACE with or without SBRT as a bridge to transplantation in patients with HCC awaiting OLT. The primary objective of the study is to determine whether adding SBRT to TACE improves local tumor control and rate of complete necrosis in patients with HCC.

Methods: Patients will be randomized into two arms: (A) TACE alone (i.e. control group) or (B) TACE combined with SBRT (i.e. experimental group). After initial TACE, patients will be followed with contrast enhanced MRI or CT scans at 1 month post-TACE and then every 3 months until OLT.
In Arm A, additional TACE of a previously treated lesion will be performed for (1) >50% viable tumor following initial TACE (i.e. less than a partial response by EASL criteria to initial TACE) (2) disease progression defined as >25% increase in amount of enhancing tissue in target lesion(s) and/or new enhancement in previously treated lesions warranting further locoregional therapy, or (3) as needed to maintain the patient within criteria for OLT. Patients with stable disease by imaging criteria otherwise will not undergo additional TACE.

In Arm B, SBRT will be performed after initial TACE. SBRT will only be performed on lesions previously treated by TACE (i.e. no HCC will receive SBRT only as a bridging therapy), and may occur as early as one month following TACE. Following SBRT, further treatment of a previously treated lesion with additional TACE will be performed for (1) disease progression or (2) to maintain patient within criteria for OLT. Patients with stable disease (SD) by imaging criteria otherwise will not undergo additional TACE of previously treated lesions.

Patients may undergo liver transplantation at anytime during the study period according to organ availability as governed by OPTN guidelines and the treating physicians in the Department of Transplant Surgery.

The primary investigator for this study at Penn is Edgar Ben-Josef, MD. Please contact Sally McNulty at 215.662.7720 for more information.

Faculty Team

The Abramson Cancer Center of the University of Pennsylvania supports eleven Research Programs that bring together investigators from 41 departments and eight University schools with a shared interest in specific types of cancer or scientific themes. Many programs span multiple research disciplines (e.g., fundamental and translational).

Clinical Research Team for Proton Therapy and TACE/SBRT Clinical Trials

Interventional Radiology

Michael Soulen, MD
Professor of Radiology

Gregory Nadolski, MD
Assistant Professor

Medical Oncology

Nevena Damjanov, MD
Associate Professor of Clinical Medicine

Pathology

Emma Furth, MD
Professor of Pathology and Laboratory Medicine

Radiology

Mark A. Rosen, MD, PhD
Associate Professor of Radiology

Radiation Oncology

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

John P. Plastaras, MD
Assistant Professor of Radiation Oncology

Transplant and Hepatobiliary Surgery

Abraham Shaked, MD, PhD
Eldridge L. Eliason Professor of Surgery

Kim Olthoff, MD
Donald Guthrie Professor in Surgery

Gastroenterology/Hepatology

Maarouf Hoteit, MD
Assistant Professor of Clinical Medicine

Center for Clinical Epidemiology and Biostatistics

Rosemarie Mick, MS

Access

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

https://drive.google.com/file/d/0B0vaPQ5yI4B3eFZRYk1hUVQ0ZzQ/edit?usp=sharing


Friday, November 8, 2013

Proton Therapy for Advanced Cancers of the Head and Neck

Radiation-oncologists at Penn Medicine have introduced proton therapy (PT) as an option for the treatment of advanced salivary gland cancers, tongue-base and tonsil cancers, skull-based malignancies and recurrent cancers of the head and neck.

The prevailing complication for standard radiation treatment of advanced head and neck cancers is the intrinsic proximity of critical organs that are highly sensitive to radiation, including the brain, brain stem, spine, salivary glands and swallowing structures. Classic radiation treatment protocols must thus consider whether the minimum exposure required to adequately treat a malignancy will prove toxic to nearby normal organ tissues.

Radiation overexposure can cause loss of sensory function, impaired salivary production and swallowing capacity, as well as neurological damage and the risk of secondary cancers. However, efforts to minimize exposure outside of the target lesion that result in the inadequate delivery of therapeutic doses may increase the risk of cancer recurrence.

It is thought that the physical properties of proton therapy may offer unique advantages for the treatment of head and neck cancers. Among the most important of these is rapid dose fall-off at the distal edge of the target (Bragg-Peak effect), a characteristic that allows for significant reductions in radiation dose to normal organs, improved dose homogeneity and the potential for dose escalation.

Dosimetric studies of head and neck cancer patients comparing intensity-modulated forms of standard radiation therapy (IMRT) to proton therapy (IMPT), have demonstrated that critical organs were optimally spared with IMPT, with lower estimated secondary cancer risks as a result of lower integral dose received by normal tissue. [1]

Through the Roberts Proton Therapy Center at Penn Medicine, patients with head and neck cancers are being treated in clinical studies to confirm whether the dosimetric advantages of proton therapy shown in previous studies will translate to gains in treatment outcome and patient-reported improvements in side effects and quality of life.

Patients with salivary gland malignancies are currently treated with double scattering proton therapy. Compared to IMRT, proton therapy can decrease dose to adjacent normal organs and limit the area of low dose radiation delivered to normal tissues (Figure 1). These dosimetric gains could potentially translate to improved long-term results such as decreasing rates of chronic xerostomia and radiation-induced secondary malignancies.

Many patients with cancers of the base of tongue and tonsils are being treated with pencil beam scanning proton therapy at the Roberts Center in collaboration with the Departments of Otorhinolaryngology-Head and Neck Surgery and Medical Oncology. Patients are treated initially with a minimally-invasive approach via TransOral Robotic Surgery (TORS). For patients who then require additional treatment, proton therapy is a promising option, one which maintains a high rate of cancer cure with potential gains in lessening the traditionally-observed side effects associated with radiation therapy.

Pencil beam scanning PT is also being used at Penn for the treatment of base of skull malignancies. Treatment of tumors at this particular site with conventional radiation has traditionally been limited by an inability to deliver adequate doses of radiation without exceeding constraints on critical structures in the brain and optic apparatus. Pencil beam scanning allows for enhanced conformal dose around critical structures through modulation of dose in depth, while retaining the rapid dose fall-off from the Bragg-Peak effect.

Re-irradiation with proton therapy for recurrent head and neck cancer is being investigated at Penn Medicine in clinical trials with the hope that improving coverage of affected areas while minimizing normal tissue toxicity can inhibit treatment-related morbidity and improve clinical outcomes in a population that otherwise has limited options. In a previous study, [2] overall survival at two years among patients re-irradiated with protons for recurrent nasopharyngeal carcinoma was approximately 50%. Two-year survival was significantly higher in those with “optimal” dose-volume histogram coverage versus those with “suboptimal” coverage (83% and 17%, respectively, P=0.006).

References

1. Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for
the treatment of head and neck tumors. Radiother Oncol 2006;80:263-7.
2. Lin R, Slater JD, Yonemoto LT, et al. Nasopharyngeal carcinoma: repeat treatment with
conformal proton therapy–dose-volume histogram analysis. Radiology 1999;213:489-494.



Case Study

Mr. V, a 54-year-old man, was referred to an otorhinolaryngologist at Penn Medicine after presenting to his personal physician with a mass in his left neck mass. At Penn, a CT scan found a 3.3 cm lesion at the left lingual tonsil; a subsequent needle biopsy determined that the mass was an HPV-positive tonsillar cancer. Mr. V was scheduled for a TransOral Robotic Surgery (TORS) procedure to remove the lesion (T2 stage), followed by a left neck dissection, which found multiple nodes positive for stage 4A tonsillar cancer. Considered a good candidate for proton therapy, Mr. V was treated postoperatively with PT to limit morbidity associated with radiation therapy and enhance his outcome.

Mr. V’s recovery was unremarkable, and he did well throughout his PT therapy, experiencing only mild and transient changes in taste (with return to normal by 6 weeks) and no weight loss as a result of treatment. He returned to work soon afterward, and remains cancer free at one year post-surgery.

Oncology offers patients access to the latest treatment options––including proton therapy––before they are widely available elsewhere.



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 Proton Therapy for Head and Neck Cancers at Penn Medicine

Radiation Oncology

Peter H. Ahn, MD
Assistant Professor of Radiation Oncology

Michelle Alonso-Basanta, MD, PhD
Assistant Professor of Radiation Oncology

Alexander Lin, MD
Assistant Professor of Radiation Oncology

Robert Lustig, MD
Professor of Clinical Radiation Oncology

Medical Oncology

Charu Aggarwal, MD, MPH
Assistant Professor of Medicine

Kenneth M. Algazy, MD
Clinical Professor of Medicine

Roger B. Cohen, MD
Professor of Medicine

Arati Desai, MD
Assistant Professor of Medicine

Otorhinolaryngology

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

Jason Newman, MD
Assistant Professor of Otorhinolaryngology - Head and Neck Surgery

Bert W. O’Malley, Jr., MD
Gabriel Tucker Professor and Chairman of Otorhinolaryngology - Head and Neck Surgery

Christopher H. Rassekh, MD
Associate Professor of Clinical Otorhinolaryngology - Head and Neck Surgery

Gregory Weinstein, MD
Professor and Vice Chairman of Otorhinolaryngology - Head and Neck Surgery

Access

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

Otorhinolaryngology - Head and Neck Surgery
Hospital of the University of Pennsylvania
5 Silverstein
3400 Spruce Street
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 Center 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 head and neck cancers, the conditions currently being investigated at the Roberts Center include seminoma and cancers of the prostate, breast, lung and abdomen. For more information about the
Roberts Proton Therapy Center, visit: http://www.pennprotontherapy.org.


https://drive.google.com/file/d/0B0vaPQ5yI4B3SUhOT3lTUmFSRVk/edit?usp=sharing








Wednesday, November 6, 2013

Comprehensive Management of Acoustic Neuromas

Specialists at the Center for Cranial Base Surgery at Penn Medicine are treating acoustic neuromas (vestibular schwannomas) with the most advanced modalities, including: 1) sophisticated microsurgery with and without endoscope assistance and 2) precision stereotactic radiosurgery (Gamma Knife® Perfexion[TM] and CyberKnife). The Center is comprised of cranial base neurosurgeons, otorhinolaryngologists and radiation oncologists who together develop comprehensive treatment plans for these complex tumors.

Acoustic neuromas are benign tumors that generally arise inside the internal auditory canal, a bony passage shared by the seventh (facial) and eight (auditory) cranial nerves. Expanding in a confined region of the skull, these indolent tumors can cause pressure on both nerves, resulting in unilateral hearing loss, vertigo, tinnitus, headaches and balance problems.

The objectives for neuroma treatment are maintenance of quality of life, complete removal or stabilization of tumor growth, preservation of hearing and preservation of facial nerve function (a normal smile). Factors influencing the decision for desired procedure include patient age, size of tumor, health status, risk tolerance and desired outcome.

Small to medium-sized tumors (p< 2.5cm) can be treated with either surgical resection or Gamma Knife Perfexion radiosurgery with excellent results. Surgical resection has the advantage of complete removal of the tumor with little likelihood of recurrence, and remains the gold standard for benign tumors. However, surgery has higher risks of complications than Gamma Knife radiosurgery.

By contrast, Gamma Knife controls (rather than removes) brain tumors, halting their growth with close to 200 beams of targeted gamma ray energy. The benefits of Gamma Knife include a low side effect profile and high quality of life after the procedure. Unfortunately, a small percentage of tumors can continue to grow after radiosurgery. 

For larger tumors (>2.5cm), microsurgical resection is the best option. At Penn Medicine, the cranial base team uses three microsurgical approaches. The retrosigmoid approach is the most versatile, as it allows both small and large tumors to be removed and provides the ability to preserve hearing. The translabyrinthine approach does not require significant brain retraction and is also quite versatile, but is only for patients in whom hearing cannot be preserved. The middle fossa approach is used only for small tumors confined to the internal acoustic canal.

In addition to conventional surgical approaches, John Y. K. Lee, MD, of Penn Neurosurgery, has pioneered the use of the endoscope in the cerebellopontine angle to provide angled views and minimally invasive options.


Case Study 1

Mr. M, a 38-year-old man, was referred to Penn Neurosurgery with right-sided hearing loss, tinnitus and progressive gait ataxia. An MRI revealed a large acoustic neuroma measuring 3.4 cm anteroposteriorly, and 3.0 cm superoinferiorly with significant brainstem compression (Figure 1). Because of the tumor’s large size, Mr. M underwent retrosigmoid craniotomy. Both microscopy and endoscopy were used to obtain an optimal result. The tumor was completely resected; the facial nerve was anatomically preserved, and his gait improved. By his three-month visit, Mr. M had normal facial function and had returned to work without any restrictions. He has remained well at several years follow-up.


Case Study 2

Mrs. G, a 67-year-old woman, was referred to the Center for Cranial Base Surgery at Penn Medicine after her personal physician confirmed a moderate loss of hearing in her right ear. An MRI at Penn showed a tumor at the right auditory canal consistent with an acoustic neuroma (Figure 2, left) with a total volume of 3 cc. Mrs. G chose the less invasive option of Gamma Knife surgery for her therapy. Her Gamma Knife treatment involved a single outpatient session, during which she received a 12 Gy prescription to the 50% isodose line. Her recovery was unremarkable and she has since enjoyed an improved quality of life without side effects. Five years after her treatment (Figure 2, right), Mrs. G retains moderate hearing in her right ear and normal facial function.

Faculty Team

The Center for Cranial Base Surgery at Penn Medicine specializes in the evaluation and treatment of tumors of the head, neck and face. Currently, the Center treats ~100 patients/year for acoustic neuroma, employing an individualized algorithm for treatment approach.

Treating Acoustic Neuromas at Penn Medicine 
Neurosurgery

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

M. Sean Grady, MD
Charles Harrison Frazier Professor and Chairman
Department of Neurosurgery
Co-Director, Cranial Base Center
Otorhinolaryngology–Head and Neck Surgery

Bert O’Malley, Jr., MD
Co-Director of the Cranial Base Center
Gabriel Tucker Professor of Otorhinolaryngology

Douglas Bigelow, MD
Director, Division of Otology/Neurotology
Associate Professor of Otorhinolaryngology–

Head and Neck Surgery

Michael J. Ruckenstein, MD
Vice Chairman, Department of Otolaryngology
Professor of Otorhinolaryngology–Head and Neck Surgery

Radiation Oncology

Michelle Alonso-Basanta, MD, PhD
Assistant Professor of Radiation Oncology

James Kolker, MD
Clinical Assistant Professor of Radiation Oncology

Suneel Nagda, MD
Assistant Professor of Clinical Radiation Oncology

Geoffrey A. Geiger, MD
Assistant Professor of Clinical Radiation Oncology 

Access
Penn Neurosurgery
Hospital of the University of Pennsylvania
3400 Spruce Street
3rd Floor, Silverstein Building
Philadelphia, PA 19104

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

Department of Otorhinolaryngology — Head and Neck Surgery
Hospital of the University of Pennsylvania
3400 Spruce Street
5th Floor, Silverstein Building
Philadelphia, PA 19104

Pennsylvania Hospital
811 Spruce Street
Philadelphia, PA 19107


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