University of Pennsylvania Health System

Clinical Briefings™: Clinical Reports from Penn Medicine

Friday, December 5, 2014

Paired Kidney Exchange for Kidney Transplantation

The Penn Transplant Institute is a leading center for paired kidney exchange for kidney transplantation, a practice that depends largely upon the benevolence of anonymous, altruistic donors.


Principles and Principals of Paired Kidney Exchange
A common perception of paired kidney exchange is that the process involves single, two-way exchanges between recipients and altruistic donors within their circle of acquaintance or relation. In fact, this is rarely the case.

Almost always, despite friends and family members who were evaluated as live kidney donors, the recipient has failed to find an appropriate match. Incompatibility between donor/recipient pairs can come about not only because of blood type, but because the recipient has been sensitized by previous blood transfusions, previous organ transplants or previous pregnancies.

More often, paired kidney exchanges occur as chains initiated between a “non-directed,” anonymous, altruistic donor and a matched recipient and continued when a friend or relative of this recipient repeats the process by donating to a second matched anonymous recipient. If this person, too, is linked to an unmatched donor, that donor may be enlisted to continue the chain as a donor to another anonymous recipient. Donors in the chain who do not immediately find a matched recipient may choose to begin a separate chain as “bridge” donors from the original chain (see Figure 1).

At Penn, recipients and donors who are willing to participate in paired kidney exchange must undergo a comprehensive medical evaluation. During this stage, the kidney transplant and living donor transplant teams complete a series of evaluations to determine if the procedures are safe and appropriate for the respective recipients and living donors. Only when the team feels it is safe to proceed are the donor and recipient surgeries scheduled.

The benefit of paired kidney exchange is that it offers kidney recipient and donor pairs who aren’t blood and/or tissue-type compatible an alternative to deceased donor transplantation, thus increasing the number of kidney donors while diminishing competition for deceased donor kidneys.

Paired kidney exchanges also play a critical role in expediting transplants and thereby improving outcomes. According to the United States Department of Health and Human Services, the median waiting time among patients aged 18 to 65 in the US for a deceased-donor kidney in 2014 was 4.5 years, versus 185 days for patients participating in paired kidney exchange. The estimated six-month graft survival rate for patients having paired kidney exchange was 98.8%, compared to 95.1% for deceased donor kidney transplants. [1]

Case Study

Upon learning that 32-year-old Mr. B had end-stage kidney disease, his uncle, Mr. C, volunteered to donate a kidney to him. However, tests at the Penn Transplant Institute showed that Mr. C and Mr. B were not a compatible match. Subsequently, Mr. B entered the home dialysis program at Penn and was placed on the waiting list for a deceased kidney.

Several months later, a transplant coordinator at Penn contacted Mr. C and Mr. B to ask if they would be interested in participating in a paired kidney exchange. She explained that an anonymous altruistic donor, Mr. A, had been found compatible with Mr. B and had agreed to donate a kidney to him. The coordinator asked if Mr. C would consider becoming a kidney donor for an anonymous recipient for whom he was compatible.

Mr. C agreed to become a donor, and at Penn, was paired with Mrs. D. The chain would thus involve Mr. A donating a kidney to Mr. B, and Mr. C donating a kidney to Mrs. D. All four participants in the resulting exchange were found to be physically and psychologically prepared for transplant surgery. The four surgeries were scheduled to take place at Penn Medicine on the same day in separate operating rooms.

On the morning of the kidney exchange, Mr. A had surgery first, and his kidney was transplanted into Mr. B. Later that day, a similar exchange took place. This time, Mr. C’s kidney was transplanted into Mrs. D.

All four patients recovered without incident. In the days after surgery, Mr. C and Mr. B decided to meet the pair with whom they had been matched. All donors currently have functioning transplants, due in large part to the initial intervention of Mr. A, the initiating altruistic donor.

Adding to the success of this exchange, Mr. E, the husband of Mrs. D, initiated a second chain of paired exchange kidney transplants two months later by donating a kidney to Mr. F, thus becoming an altruistic “bridge” donor to this new chain.

1. State of the OPTN/UNOS KPD Pilot Program, DHHS 2014]

Faculty Team
The Penn Transplant Institute is home to kidney, liver, lung, heart, pancreas and hand transplantation programs, and is ranked among the top 10 multi-organ transplant centers in the country.

Performing Kidney Transplantation at Penn Medicine

Transplant Surgeons

Ali Naji, MD, PhD
Surgical Director, Kidney and Pancreas Transplant Program
Professor of Surgery

Peter L. Abt, MD
Associate Professor of Surgery

Matthew H. Levine, MD, PhD
Assistant Professor of Surgery

Paige Porrett, MD, PhD
Assistant Professor of Surgery

Transplant Nephrologists

Roy D. Bloom, MD
Medical Director, Kidney and Pancreas Transplant Program
Professor of Medicine

Melissa B. Bleicher, MD
Assistant Professor of Clinical Medicine

Simin Goral, MD
Professor of Medicine

Robert A. Grossman, MD
Professor of Medicine

Mary Ann Lim, MD
Assistant Professor of Clinical Medicine

Peter P. Reese, MD, MSCE*
Assistant Professor of Medicine and Epidemiology

Deirdre L. Sawinski, MD
Assistant Professor of Medicine

Karen Warburton, MD*
Associate Professor of Clinical Medicine

Other Renal Physicians
Meera N. Harhay, MD, MSCE

Attending Physician
Jonathan S. Maltzman, MD, PhD
Assistant Professor of Medicine

Renal Nurse Practitioners
Christina Braun, MSN, CRNP
Carolyn Mylowe, MSN, CRNP
Gail Eastman, MSN, CRNP, CCTC
Jenna Angerstein, MSN, CRNP, CCTN

Transplant Surgery Nurse Practitioners
 Alva Moy-Daley, MSN, CRNP
 Julie Spaulding, MSN, CRNP

*Living Donor Team Nephrologists

Paired Kidney Exchange at Penn Medicine
Penn performed the first successful kidney transplant in 1966, and the Penn Transplant Institute is now a leader in the effort to increase paired kidney exchanges for kidney transplantation.
In partnership with the National Kidney Registry (NKR), a consortium of 72 transplant centers nationwide, the Penn Transplant Institute recently took part in the largest kidney exchange to be concluded in under 40 days and the second largest in history (ultimately involving 28 donors and 28 recipients).

In 2012, the US Department of Health and Human Services awarded the Penn Transplant Institute’s Kidney Transplant program a Silver Level Award. Penn is the only transplant center in the region and one of a select group of programs in the nation to receive this distinction.

In addition to its partnership with the NKR, the largest and most successful kidney transplant matching program in the US, the Penn Transplant Institute is a member of the United Network for Organ Sharing (UNOS). Outside of its participation with these organizations, the Transplant Institute has a large enough waiting list to initiate donor chains within its own programs.

Access

Penn Transplant Institute Kidney Transplant Program

The Perelman Center for Advanced Medicine
2 West Pavilion
3400 Civic Center Boulevard
Philadelphia, PA 19104

Renal Electrolyte and Hypertension
Perelman Center for Advanced Medicine
South Pavilion, 1st Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Patients also evaluated at:

Penn Medicine Radnor*
250 King of Prussia Road
Radnor, PA 19087
* A facility of the Hospital of the University of Pennsylvania

Penn Medicine Bucks County
777 Township Line Road
Yardley, PA 19067

Penn Medicine—1400 East Route 70
1400 East Route 70
 Cherry Hill, NJ 08034

Penn Medicine Woodbury Heights
1006 Mantua Pike
Woodbury Heights, NJ 08097

The contact number for recipients and donors is 215.662.6200.


Thursday, November 20, 2014

Periacetabular Osteotomy for Complex Structural Hip Deformity

Department of Orthopaedic Surgery  •  Center for Hip Preservation

Orthopaedic surgeons at Penn Medicine are performing periacetabular osteotomy (PAO) surgeries for native hip preservation in adolescents, young adults and adults (generally up to 45 years of age) with dysplasia and other structural hip deformities.

Structural hip deformities affect a large proportion of younger adults who present with symptomatic hip pain in the United States. These conditions are often of congenital, developmental, or traumatic origin, and typically involve morphologic abnormalities of the acetabulum or femur leading to instability and/or impingement, a pathological conflict between the two bones during movement.

The mechanical aberrations identified with structural hip deformity commonly involve dysplasia and femoroacetabular impingement (FAI) and their associated pathologies. Hip pathology can also involve malalignment or rotational deformities of the femur (e.g., issues with femoral torsion), among other anomalies.

Impingement occurs when the proximal femur contacts the acetabulum during range of motion, such as flexion and internal rotation. Impingement is often caused by asphericity of the femoral head (cam type) or over-coverage of the acetabulum (pincer type). With dysplasia, insufficient coverage of the femoral head by the acetabulum can lead to symptomatic instability and early labral and cartilage degeneration. This continuum—from impingement to instability—is an important concept in evaluating younger patients with hip pain.

The tantamount consideration in younger patients with dysplasia and/or FAI is to preserve the native hip by addressing underlying structural abnormalities. Accordingly, orthopaedic surgeons at Penn Medicine employ a spectrum of corrective hip preservation surgeries for this population, including both arthroscopic and open techniques such as re-orientation of the acetabulum.

Periacetabular osteotomy (PAO), for example, addresses the underlying structural deficiencies of a shallow or poorly oriented acetabulum. In PAO, a series of osteotomy cuts encompass the acetabulum, preserving the hip abductors and the posterior, weight-bearing column of the pelvis. The socket is then freed from the pelvis and reoriented in a position of better coverage of the femoral head. This offers the opportunity to restore more normal hip joint mechanics and ideal loading of the articular cartilage. The goal is long-term durability of the native joint in adolescent and young adult patients with dysplasia.

PAO is not a “standard” surgery, and patient selection is important. The procedure is demanding, in that osteotomy and precise reorientation are required, and each step requires a certain level of experience and training. However, the potential advantages of PAO, which include greater long-term joint stability and durability of the cartilage, may help younger patients to avoid or delay joint-replacement surgery, such as total hip arthroplasty.

Case Study

Mr. J, a 25-year-old man, was referred to the Center for Hip Preservation at Penn Medicine with structural deformity of the right hip, the result of a segmental fracture of the proximal femur at age four. His hip and leg were placed in a cast, and his fracture healed in a malaligned position.

As a young adult, Mr. J had chronic, progressive and disabling pain (especially in the setting of his high-demand work as a manual laborer) that he managed with daily opioid medications. In the months prior to evaluation at Penn, he had extensive physical therapy and an intra-articular injection for pain control. He was unemployed for much of this time.

At Penn, Mr. J was deemed a candidate for hip preservation. Imaging determined that he had severe acetabular dysplasia, a tear of his acetabular labrum, a torsional deformity of the femur (45 degrees of retrotorsion) and FAI due to a cam lesion of the femoral head-neck junction (Fig. 1).

Despite these abnormalities, however, there was no evidence of overt osteoarthritis at his hip. After discussion of the risks, benefits and treatment alternatives, Mr. J elected to have corrective surgery. Pre-procedural imaging and modeling were completed to ensure proper intra-operative alignment targets of the reoriented hip and femur.

At PAO was performed to correct the acetabular dysplasia. Nerve monitoring and fluoroscopic imaging were used to ensure safe and accurate surgery. Bone grafting was completed at the acetabular osteotomy sites, with autograft harvested from the pelvic osteotomy mobile fragment. A surgical hip dislocation was also performed, with careful preservation of the critical blood supply to the femoral head. A labral repair and femoral head-neck osteochondroplasty were completed to address the intra-articular sequelae of FAI.


Although Mr. J’s intra-articular causes of FAI were optimized, the extra-articular rotational deformity of the femur did not allow for adequate impingement-free range of motion. Therefore, a subtrochanteric derotational osteotomy with internal fixation was performed to bring the femur into normal rotational alignment. Bone autograft harvested from the greater trochanteric bed was used to supplement the osteotomy fixation (Fig. 2).

Mr. J was on crutches the day after his procedure and was in the hospital for three days, where he received physical therapy, as well as a continuous passive motion machine. Partial weight-bearing was permitted on discharge. He was weaned from all pain medications by several months post-operatively. At six months, he was walking with no gait aids, and by seven months he had found full-time work.

Faculty Team

The Penn Medicine Center for Hip Preservation is comprised of a multi-disciplinary team dedicated to the diagnosis and treatment of hip pain in adolescent, young adult and adult patients. Patients evaluated for hip pain at Penn also have access to the region’s first integrated Musculoskeletal Center, which includes state-of-the-art motion analysis, neuromuscular testing, and advanced metabolic measurements through the Center for Human Performance.

The exceptional procedures offered at the Penn Center for Hip Preservation include hip arthroscopy with labral repair, arthroscopic and open treatment of focal cartilage injury, management of avascular necrosis of the femoral head with stem-cell therapy, treatment of sequelae of childhood disease like Perthes disease and slipped capital femoral epiphysis (SCFE), complex femoral osteotomy and limb deformity correction, repair of abductor and hamstring tendon injury, microsurgery and vascularized fibular grafting, surgical hip dislocation, and periacetabular (Ganz/ Bernese) osteotomy, among other advanced treatments.

Performing Periacetabular Osteotomy for Hip Preservation at Penn Medicine

Atul F. Kamath, MD
Director, Center for Hip Preservation
Assistant Professor of Orthopaedic Surgery
Consultants to the Penn Center for Hip Preservation

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

Charles L. Nelson, MD
Chief, Adult Reconstruction Section
Associate Professor of Orthopaedic Surgery

John D. Kelly, IV, MD
Associate Professor of Clinical Orthopaedic Surgery

J. Bruce Kneeland, MD
Section Chief, Musculoskeletal Imaging Division
Professor of Radiology


ReachMD
To hear Dr. Kamath discuss hip preservation for younger patients, visit the ReachMD(TM) series Medical Breakthroughs from Penn Medicine.

https://docs.google.com/file/d/0B0vaPQ5yI4B3cUdVc0E3akVSQUk/edit






Tuesday, October 14, 2014

Sialendoscopic Management of Salivary Stones and other Salivary Duct Pathologies

Surgeons with Penn Otorhinolaryngology-Head and Neck Surgery are performing novel high-tech diagnostic and interventional sialendoscopy procedures to treat patients with diseases of the parotid and submandibular salivary glands.

At Penn, the primary objective for patients with sialolithiasis (stone disease) and inflammation of the salivary gland (sialadenitis) is to make a diagnosis, clear the duct and preserve the native salivary gland, if possible, and to achieve these ends using the safest, least invasive and most appropriate therapy.

In many cases, diagnosis is aided by radiography, usually after the onset of classic symptoms. Sialoliths of small to moderate size may be treated by sialendoscopy, a relatively recent innovation that is used at Penn Medicine for both diagnosis and treatment.

About Sialendoscopy
Sialendoscopy is a minimally invasive technique that has the potential to avoid nerve injury and the facial and oral scarring associated with traditional open surgery. The sialendoscope combines a delicate, semi-rigid (1.3 mm) fiber-optic endoscope, an irrigation port and a working channel in a single instrument. The endoscope broadcasts high definition images to a monitor. (See Fig 1).
Irrigation is used to dilate the ducts, permitting exploration of the branches of the salivary duct system. The working channel is the conduit for the instruments used to remove obstructions such as salivary duct stones, including custom-designed baskets, micro-burrs and guidewires.

The approach to larger salivary stones during sialoendoscopy sometimes employs hybrid treatments such as laser fragmentation. In these cases, otorhinolaryngologists at Penn collaborate with urologists, who use similar techniques to treat kidney stones. If accessible, larger stones can thus be broken up into smaller fragments, permitting them to be eliminated by irrigation or basket retrieval.
Multiple or deeply placed stones may require a combined approach or a more limited open approach where the sialendoscope is used to transilluminate the duct.

In addition to sialolithiasis, the indications for sialendoscopy at Penn Medicine include ductal injuries, duct stenoses, radioactive-iodine induced sialadenitis and autoimmune sialadenitis, including Sjogren’s Syndrome.

Case Study
JG, a 23-year-old male, came to Penn Medicine for suspected parotitis after experiencing repeated episodes of post-prandial facial swelling over a three month period. A CT scan at Penn found a 3mm density in JG’s left parotid duct deemed highly suspicious for a salivary stone (see Fig. 2).
After a consultation to review his treatment options, JG opted for sialendoscopy.

At the start of the procedure, the left parotid duct papilla was dilated to permit irrigation of the duct. A 1.3 mm scope was then advanced and navigated within the duct to the obstruction, a compact sialolith, lodged at a bifurcation distal to the parotid gland.

With further irrigation to dilate the duct, a six-wire basket was placed over a guide wire and extended until it grasped the stone. At this point, the stone was gently drawn beyond the bifurcation, but floated into the opposite duct. A micro-sialendoscopic burr was then introduced, freeing the stone, which was grasped by a 3-wire basket and extracted by rotating past the muscle to the papilla. JG’s recovery from surgery was unremarkable, and he was discharged the same day. At his one-year follow-up visit, there was no evidence of evolving sialoliths in the cleared duct or elsewhere.


Faculty Team
The faculty of Penn Otorhinolaryngology-Head and Neck Surgery are leaders in the field in patient care, surgical innovation and clinical and laboratory research. The Department logs more than 86,000 patient visits each year—the highest volume in the nation of any center or program performing otorhinolaryngology-head and neck surgery—and offers comprehensive and multidisciplinary programs to manage every disease or disorder affecting the organs and tissues of the nose, ears, throat, face and skull base.

Performing Sialendoscopic Procedures at Penn Medicine

Christopher H. Rassekh, MD, FACS
Associate Professor of Otorhinolaryngology-Head and Neck Surgery
Director, Penn Medicine Sialendoscopy Program

Erica R. Thaler, MD
Professor of Otorhinolaryngology-Head and Neck Surgery

Assisting with Laser Lithotripsy
Keith N. Van Arsdalen, MD
Director, Lithortriptor Center
Professor of Urology in Surgery

Key Team Members
Joshua H. Atkins, MD, PhD
Assistant Professor of Anesthesiology and Critical Care

Laurie A. Loevner, MD
Professor of Radiology

Rita Glenn-West, BSN, RN, CNOR
Coordinator, Operating Room Sialendoscopy Procedures

Tashara Nicholson
Clinical Administrative Assistant
Assistant to Dr. Rassekh in Sialendoscopy Clinic

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

Sialendoscopy Clinical Briefing



Tuesday, July 22, 2014

Living Donor Liver Transplantation at Penn Medicine

Penn Transplant Institute



Transplant surgeons and hepatologists at Penn Medicine are performing living donor liver transplantation for patients with end-stage liver disease.

In the United States, the number of patients currently on the waiting list for liver transplantation is approximately three times that of available donor livers. Living donor liver transplantation (LDLT) allows for increased access to a lifesaving transplant and has become a very successful and accepted standard of care for many patients with end-stage liver disease. Post-transplant outcomes with LDLT are comparable to, or better than, deceased donor transplants.

Adult-to-adult LDLT involves removing 40% to
60% of the liver from a healthy donor (typically a family member or friend of the recipient) and transplanting it into a patient who has been deemed appropriate for liver transplantation. While LDLT is major surgery, donors return to normal activity soon after the procedure. Because the liver has the remarkable capacity to regenerate, the donor’s liver is restored to nearly normal size within a few months after donation.

One of the greatest benefits of living donation is that it can be made available to patients with a lower Model for End Stage Liver Disease (MELD) score, eliminating the long wait for a deceased donor, and reducing the risk of a patient dying while waiting for a transplant.

The Penn Transplant Institute performs LDLT in patients with mean MELD scores of 15±5, depending upon blood type (Figure 1), which is a great benefit in our region, where the mean MELD at transplant for deceased donors since 2008 has been in the range of 27±7.

Transplanting at a lower MELD score means patients don’t have to wait until they are critically ill to obtain a liver. The Penn Transplant Institute has been performing pediatric living donor transplantation since 1996, and adult living donor transplants since 1999, with an established track record of superb patient and graft survival. Since 2002, our adult 1- and 3-year patient survival rates are 98% and 91%, respectively, compared to national rates of 90% and 82% at 1 and 3 years
(Figure 2).

Case Study

JD, a 28 year-woman with cirrhosis secondary to biliary atresia, has been followed by the hepatology program at Penn Medicine since the age of 18.  In 2013, following the development of bleeding esophageal varices, hepatic encephalopathy, and ascites, her case was referred to the Penn Liver Transplant team.

After considering the internal waitlist criteria and reviewing JD’s MELD score of 18 and other factors, the Committee concluded that her symptoms and medical status were appropriate to place her on the United Network for Organ Sharing (UNOS) liver transplant wait list.  However, because she was blood type A, her standing on the list was unlikely to result in any offers of deceased donors.

Despite optimal medical management, JD’s condition continued to deteriorate, with multiple hospitalizations for complications of her liver disease, included repeated bouts of encephalopathy, ascites and spontaneous bacterial peritonitis. Even with her worsening condition, however, her MELD score never rose above 23. This meant that she was below the threshold needed to be at the top of the list for an optimal organ given her blood type and the regional organ scarcity.

As a result of her declining condition, JD stopped working and married her boyfriend in a rapidly planned wedding, because she wasn’t sure she would live long enough to plan a formal wedding. After speaking with the liver transplant team about the possibility of a living donor transplant, JD consulted with her family and close friends.

Several weeks later, a longtime friend, AJ, decided that he wished to be evaluated as a living donor. At age 24, AJ was within the donor age parameters, his physical condition was excellent, and he had no history of past or current serious disease.

Following a very thorough medical and surgical evaluation, extensive imaging, and laboratory testing, as well as private meetings with a social worker, psychiatrist, and independent donor advocate, AJ was found to be a suitable living donor candidate.

Having determined that AJ arrived at the decision of his own volition, he was cleared to complete his evaluation, and donate a portion of his liver to his friend.

Two weeks later, AJ donated the right lobe of his liver to JD, with both donor and recipient back at home a little over a week later.  Six months after the surgery, JD and AJ are even closer friends than before.  JD is back to working full time, and enjoying life as a newlywed.  AJ returned to work after three months, and now is a full-time grad student, and  while returning to his previous level of physical activity, has been coaching a high school crew team.

___________________________________________________________________________________

The National Institutes of Health Adult-to-Adult Living Donor Liver Transplant study (A2ALL)

The Penn Transplant Institute is among a consortium of nine centers of excellence participating in the multicenter National Institutes of Health-sponsored Adult-to-Adult Living Donor Liver Transplant study (A2ALL), which explores both long-term outcomes in donors and recipients.

Reports from A2ALL have shed light on the principal conditions for optimal graft survival in ALDLT recipients. Among these are the experience of the transplant center, recipient age, and cold ischemia time. A significantly lower risk of graft failure exists among centers that have performed more than 15 ALDLTs, and both older recipient age and cold ischemia >4.5 hours have been linked to higher rates of graft failure. [1]

A2ALL has also shown that there is significant benefit for living donor transplant patients with symptomatic liver disease and relatively low MELD scores as a result of decreased death on the wait list. [2] Data from the UNOS database shows that post-transplant graft and patient survival is better with living donors at three and five years than for deceased donor liver transplants. [3]

References

1. Olthoff KM, Abecassis MM, Emond JC, et al. Outcomes of adult living donor liver
    transplantation: comparison of the Adult-to-adult Living Donor Liver Transplantation Cohort
    Study and the national experience. Liver Transpl. 2011;17(7):789-797.
2. Berg CL, Merion RM, Shearon TH, Olthoff KM, et al. Liver transplant recipient survival benefit
    with living donation in the model for endstage liver disease allocation era. Hepatology. 2011;
    54(4):1313-1321.
3. Goldberg DS, Abt PL, Olthoff KM, Shaked A. Superior Survival Using Living Donors and
    Donor-Recipient Matching Using a Novel Living Donor Risk Index. Hepatology. 2014.

___________________________________________________________________________________

Faculty Team

The Penn Transplant Institute offers a comprehensive liver transplant program for patients suffering with end-stage liver disease, liver cancer, and metabolic liver disease. Physicians at Penn have performed more than 1,500 liver transplants and have extensive experience in treating patients with Hepatitis B and C, autoimmune and cholestatic liver disease, alcoholic cirrhosis, liver cancer, and
metabolic disease.

Performing Living Donor Liver Transplantation at Penn Medicine


Liver Transplant Surgeons

Kim M. Olthoff, MD
Chief, Division of Transplant Surgery
Donald Guthrie Professor in Surgery

Abraham Shaked, MD, PhD
Director, Penn Transplant Institute
Eldridge L. Eliason Professor of Surgery

Peter L. Abt, MD
Associate Professor of Surgery

Hepatology

David S. Goldberg, MD, MSCE
Medical Director, Living donor liver transplantation

George A. Makar, MD, MSCE
Medical Director of Liver Transplantation

Living Donor Coordinator

Linda Wood, BSN, RN

Access

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

Monday, June 2, 2014

Intraoperative Molecular Imaging Detects Residual Tumor Cells During Lung Cancer Surgery

Penn Lung Center • Division of Thoracic Surgery

At Penn Medicine, surgeons are using molecular imaging technology to prevent cancer recurrence by improving the detection of residual cancer cells during surgery.

Surgery is 8 to 10 fold more effective than chemotherapy or radiation therapy for almost all solid tumors, and is the most important predictor of long-term survival in cancer patients in the United States. However, the overall success of cancer surgery is diminished by local recurrence in up to a third of patients.

Recurrence is typically due to malignant cells that remain in the surgical field even when the algorithm for their eradication involves meticulous resection at the surgical margins, excision of involved lymph nodes and satellite lesions and the use of intraoperative frozen sectioning by pathologists to ensure the complete eradication of cancer during surgery. That these efforts so often fail demonstrates the challenge of identifying invasive and occult cancer cells through observation and palpation during surgery.

To improve the long-term efficacy of cancer surgery, thoracic surgeons and radiation oncologists at Penn Medicine are using investigational intraoperative imaging systems that visually enhance residual cancer cells and the abnormal tissue densities typical of malignant lesions. These systems use fluorescent contrast agents that have an organic tropism for cancer cells, and that once absorbed, glow under certain lighting conditions, permitting lesions and cancerous cells to be identified and readily removed.

Using these systems in separate applications during surgery, the team at Penn Medicine has identified nodules as deep as 1.3 cm from the surface of solid organs and as small as 0.2 cm in size, as well as nodules in organs other than that of the primary tumor. In addition, cancer cells that are invisible to optical observation have been identified at the margins of surgery in lung cancer patients.

Case Study

Mrs. M, a 64-year-old woman, was referred to Penn Thoracic Surgery for evaluation following six-months of persistent cough and bronchial irritation. Mrs. M had never smoked, and with the exception of hypertension, her medical history was unremarkable. A chest x-ray at Penn revealed a mass (>3.5 cm) in the upper lobe of her left lung in ` Figure 1: A small lesion (0.7 cm) appears under near-infrared light in the lower left lobe of a patient thought to have Stage IA pulmonary adenoma. The lesion was undetected by PET/CT scan and visual examination; this patient was subsequently re-staged to stage IIIA. close proximity to the pleura.

A PET/CT scan found no evidence of spread to nearby lymph nodes or metastases. A transthoracic needle aspiration biopsy of the mass revealed malignant cells, and a histological analysis identified a moderately-differentiated cancer with clear cell features consistent with a primary pulmonary adenocarcinoma. Cytogenetic analysis was negative for EGFR/Kras mutations and ALK rearrangement.

There was no evidence of metastases. Mrs. M’s cancer was classified as a surgically resectable Stage IA pulmonary adenocarcinoma. After a discussion during which Mrs. M expressed apprehensions about cancer recurrence based on personal experience, she provided her informed consent to take part in the fluorescent image-guided investigation.

Prior to surgery, Mrs. M underwent CT scanning. The scan was reviewed by a radiologist to confirm the presence of a solitary pulmonary nodule. Twenty-four hours before her surgery, an intravenous contrast agent was administered.

During her surgery, surgeons located the primary nodule using visual inspection and manual palpation. Following an inspection of the ipsilateral lung by both surgeons that found no other lesions, the operating room lights were removed, and the near-infrared spectroscopy (NIR) imaging system was sterilely draped and positioned above the chest.

The primary nodule was imaged and photo-documented by white light and fluorescence. The imaging system was then used to search for additional nodules in her lung, subsequently identifying a single small (0.7 cm) lesion in the lower lobe of her left lung (Figure 1) close to the pleural surface, and two lymph nodes near the original primary tumor. Both lesions and the lymph nodes were removed and re-imaged for confirmation in the operating room before being submitted to pathology. Mrs. M’s cancer was then re-staged to stage IIIA.

Mrs. M remained in the hospital for two days following her surgery and was discharged home. Her recovery was unremarkable. She received adjuvant chemotherapy and radiaton therapy without significant morbidity. At her six-month and one-year follow-up visits, x-rays and CT/PET scans found no evidence of recurrent cancer.

Faculty Team

The lung cancer team at Penn Medicine is leading an effort to revolutionize the early diagnosis, prevention and treatment of lung cancer. Penn is a major center for lung cancer clinical trials, allowing patients to benefit from the newest and best therapies available.

Thoracic Surgery

Joel D. Cooper, MD
Professor of Surgery


John C. Kucharczuk, MD
Associate Professor of Surgery

Taine T.V. Pechet, MD
Associate Professor of Surgery

Sunil Singhal, MD
Assistant Professor of Surgery
Thoracic Medical Oncology

Corey J. Langer, MD
Professor of Medicine

Kenneth M. Algazy, MD
Clinical Professor of Medicine

Tracey Evans, MD
Assistant Professor of Medicine

Thoracic Radiation Oncology


John Christodouleas, MD
Assistant Professor of Radiation Oncology

Keith Cengel, MD, PhD
Assistant Professor of Radiation Oncology

Thoracic Oncology Pulmonology

Andrew Haas, MD, PhD
Assistant Professor of Medicine


Morris Swartz, MD
Associate Professor of Medicine

Anil Vachani, MD
Assistant Professor of Medicine

Access

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

Abramson Cancer Center
Perelman Center for Advanced Medicine
West Pavilion, 2nd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

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

Pennsylvania Hospital
700 Spruce Street
Philadelphia, PA 19107


https://docs.google.com/file/d/0B0vaPQ5yI4B3c3lPSWpWZWJJbFU/edit

Wednesday, April 30, 2014

Personalized Diagnostics for Hematologic and Solid Tumor Cancers

Pathologists and specialists in laboratory medicine at the Penn Center for Personalized Diagnostics (CPD) are performing genomic testing—including large-scale, massively parallel DNA sequencing and chromosomal analysis for identification of large structural rearrangements—to define genomic alterations in hematologic and solid tumor cancers for cancer patients at Penn Medicine.

Massively parallel DNA sequencing (sometimes known as next-generation sequencing or NGS) can recognize abnormalities in tumor cells that are not readily apparent to pathologists at a microscopic level. When applied to the DNA of an individual’s cancer cells, the process can yield a complete profile of the tumor genome, including personal mutation signatures for distinct tumor subtypes, that is as distinct as a fingerprint.

In addition, the testing for genomic rearrangements can detect tumor susceptibility to some targeted therapies.  Together these analyses are powerful detectors of signatures that can be used to identify individualized treatment options and to gauge the extent to which a patient will respond to treatment.

At the CPD, a joint initiative between the Department of Pathology and Laboratory Medicine and the Abramson Cancer Center at Penn Medicine, approximately 75% of patients tested have received genomic testing results that altered prognosis or empowered the treating oncologists to alter the patients’ treatment therapy, or both.

The Penn CPD is a CAP/CLIA certified laboratory. The equipment and instrumentation at the CPD currently include an Illumina HiSeq 2500, two Illumina MiSeq sequencers and an ION® Personal Genome Machine, all of which are capable of detecting low-level mutation loads and are instrumental in the sequencing of genomic DNA in tumor specimens.

The CPD offers two cancer gene-sequencing panels (below), a custom hematologic malignancy panel, focused primarily on AML, MDS and CLL, and a more comprehensive solid tumor panel, containing 47 genes known to be mutated in a wide range of tumor types.




Case Study
Mr. M, a 43-year-old policeman, was referred to the Abramson Cancer Center by his personal physician after a chest CT scan revealed a massive lesion in his right lung (Figure 1). The x-ray was preceded by several months of declining health attended by weight loss, severe headache, back pain and chronic low-grade fever.

A sputum analysis and fine needle aspiration biopsy at the Abramson Cancer Center confirmed the presence of stage IV non-small cell lung cancer (NSCLC). Soon thereafter, a full-body MRI found lesions at Mr. M’s spine and brain, as well. 

Mr. M was young and had never smoked, characteristics more likely to be associated with the presence of mutations in targetable genes, including the epidermal growth factor receptor (EGFR), and the tyrosine kinase mutation EML4-ALK, both potent oncogenic drivers linked to lung tumorigenesis.

EGRF mutations are identified in 15% to 20% of lung adenocarcinomas and ALK gene rearrangements are found in 3% to 5% of NSCLCs.  Both gene mutations are seen predominately in younger patients who never smoked, a unique subset of the NSCLC population, and are rarely seen in older individuals and those with a smoking history.

In recent years, very efficacious tyrosine kinase inhibitors have been developed to treat patients with EGFR and EML4-ALK mutations. However, because each agent is designed to target a specific mutation, it was critical to initiate a complete profile of Mr. M’s tumor genome.

At the Penn Center for Personalized Diagnostics, a comprehensive solid tumor panel and cytogenetic analysis was subsequently performed on tissue derived from Mr. M’s tumor. The report delivered to his oncologist two weeks later confirmed an EML4-ALK translocation (Figure 2).


 Mr. M immediately began therapy with crizotinib, an oral, small molecule tyrosine kinase inhibitor that targets ALK. Crizotinib has been shown in clinical trials to offer sustained progression-free survival in NSCLC patients with brain metastases, and is associated with much lower rates of adverse effects than many other cancer therapies.

Mr. M responded well to treatment. A CT scan taken at eight weeks post-diagnosis demonstrated an 80% reduction in the dimension of his lung tumor (Figure 3), near eradication of brain metastases and a significant reduction of spinal lesions. At one year post-diagnosis, Mr. M has returned to work and his disease is stable.

Faculty Team

A joint initiative between the Department of Pathology and Laboratory Medicine and the Abramson Cancer Center at Penn Medicine, the Center for Personalized Diagnostics (CPD) integrates molecular genetics, pathology informatics and genomic pathology to develop personalized diagnostic profiles for individuals with cancer. Using customized computational methods, including large-scale, massively parallel DNA sequencing and chromosomal analysis, the CPD identifies personal mutation signatures for distinct tumor subtypes. This information may then be used to determine whether a tumor is susceptible to targeted therapies and to elucidate potential cancer treatment options.

The Penn Center for Personalized Diagnostics

Faculty and Staff

David B. Roth, MD, PhD, FCAP
Acting Director, Center for Personalized Diagnostics

Jennifer Morrissette, PhD, FACMG
Clinical Director
215.898.5578
jennifer.morrissette@uphs.upenn.edu

David B. Lieberman, MS, CGC
Genetic Counselor
215.349.8416
david.lieberman@uphs.upenn.edu

Access

Center for Personalized Diagnostics
3020 Market Street, Suite 220A
Philadelphia, PA 19104
215.573.0675


https://docs.google.com/file/d/0B0vaPQ5yI4B3dlFGSHFWdUFZSlU/edit





Visit www.reachmd.com to hear an interview with David D. Roth, MD, of the Center for Personalized Diagnostics at Penn Medicine. Dr. Roth discusses the CPD and the ways it can help physicians and oncologists create customized treatment plans for patients with cancer. 

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


https://docs.google.com/file/d/0B0vaPQ5yI4B3dVNKVWFrWTVjWTA/edit


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.



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