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eDigest Summer 2013


3D Printing in Liver Transplantation

What if surgeons were provided with a three-dimensional (3-D), exact model of a liver before surgery—one so accurate they could practice on it before making a single cut in the operating room and improve outcomes?

This is a reality at Cleveland Clinic, one of only a few centers using this game-changing technology for organs. The Digestive Disease Institute is now “printing” 3-D livers, which gives surgeons a clinical edge.

“Imagine you are a surgeon going to perform a resection of half of a liver for a transplant and you are actually provided with a 3-D model of that liver you will encounter the next day,” says Nizar Zein, MD, Chief of Hepatology and Medical Director of Liver Transplantation at Cleveland Clinic. “You can look at the 3-D ‘print-out’ and plan your surgery.”

The technology has long been used in the engineering field for printing models, but not until recently has the concept become practical for medical purposes. Dr. Zein leads a team that include, in addition to liver physicians and surgeons, biomedical engineers and imaging specialists to develop the technology at Cleveland Clinic, where more than 15 livers from individual patients have been printed since 2012. What’s more, Dr. Zein says in at least two cases at Cleveland Clinic, surgery plan was slightly altered after reviewing a 3-D model of the liver to be operated on.

“We can replicate the human organ with nearly 100 percent accuracy,” Dr. Zein affirms, relating the surgical and training benefits of this technology. “This is a slam-dunk for education, and beyond that, there are many other potential applications.”

Better Planning = Better Outcomes

Not only can this technology benefit transplant recipients, it can be used for donors as well. Cleveland Clinic developed a protocol and successfully 3-D printed a synthetic liver that replicated the liver of donors undergoing Living Donor Liver Transplantation (LDLT) by giving a portion of their healthy liver to loved ones. 3-D models provided similar or more accurate measurements of the liver volume than the standard CT scan. The conclusion: pre-operative 3-D printing could potentially result in better surgical planning and improved outcomes.

Surgeons could possibly define whether vascular grafts are necessary. They could determine exact cutting points. “They could review the models before surgery and take those models into the operating rooms, as well,” Dr. Zein says.

How 3-D Printing Works

A 3-D printer works like a copy machine, except rather than inserting paper and getting a two-dimensional image, you feed the machine with material that produces—essentially builds up—a 3-D model. The machine lays down thin, successive layers of material to form a 3-D object. In this way, a copy of a liver can be created by using a CT scan as the “original.”

Cleveland Clinic is still fine tuning the process including materials, efficiency and the use of color dyes. “We are trying to come up with the perfect clinical model in terms of consistency, color, type of resin, all that,” Dr. Zein says.

He anticipates finalizing the best formula for this novel technology within a year.

In that time, Dr. Zein hopes to complete models for 20 livers total, which will help to validate the technology clinically in terms of how it may decrease complications and determine how it may be used for training purposes.

For more information, please contact Dr. Zein at 216.444.6126 or at zeinn@ccf.org.


Pig Whipworm and Crohn's

A pivotal trial testing whether the microscopic eggs of pig whipworm (trichuris suis ova or CNDO-201) may help those with severe-to-moderate Crohn’s disease is now nearing completion.

The research is based on what’s known as the “hygiene hypothesis” of Crohn’s disease, and multiple animal and human studies.

“We don’t really know why people get Crohn’s, but one theory is based on an epidemiological observation that the disease is principally seen in developed countries such as the United States and Europe while it is hardly ever seen in underdeveloped countries that have endemic infection of parasitic worms in the gastrointestinal tract,” explains Bret Lashner, MD, site primary investigator at Cleveland Clinic for the TRUST-I trial. “This has led researchers to hypothesize that this type of infection has a protective effect in the gut.”

TRUST-I, a multicenter phase 2 clinical trial sponsored by Coronado Biosciences, recently finished enrollment in 250 Crohn’s disease patients. The trial enrolled and randomized patients with moderate-to-severe Crohn’s disease to receive either 7,500 ova or placebo once every two weeks, for 12 weeks.

“The pig whipworm, which is not pathogenic for humans, may potentially stimulate the innate immune system enough to help certain patients with Crohn’s disease,” Dr. Lashner says. Preliminary data from a phase 1 clinical study of TSO in patients with Crohn’s disease were positive and top-line data from the TRUST-I phase 2 trial are expected in fourth quarter of 2013.

For more information, please contact Dr. Lashner at 216.444.6524 or at lashneb@ccf.org.


Surgeons Call Outcomes Database a “Goldmine”

Data mined from the nation’s largest colorectal outcomes database support clinical decisions and research studies.

Cleveland Clinic colorectal surgeons are confident their treatment decisions are evidence-based, thanks to a robust outcomes database containing hundreds of data points on 30,000 operations going back as far as 1978.

“We collect outcomes for all surgical cases and link the outcomes to patient-reported quality of life. This is increasingly important in today’s healthcare environment, and more importantly, we feel this is the appropriate way clinical success should be evaluated,” says Luca Stocchi, MD, Director of Research in the Department of Colorectal Surgery.

Although data on colorectal patients had been gathered for 35 years, they were maintained in separate, disease- and procedure-specific databases. When Cleveland Clinic adapted an electronic medical records system, Department of Colorectal Surgery chair Feza Remzi, MD, foresaw the value of integrating these databases into a single database, whose variables could be populated directly and automatically from patients’ medical records.

Over the last three years, information on all surgical procedures performed in the department requiring a hospital stay of one night or more has been added to the database. In addition to patient-reported quality of life, age, diagnosis, type of surgery, length of surgery, type of instruments used, comorbidities and complications are among the fields recorded. Complexity is noted using department-developed categories.

Disease- and procedure-specific parameters are also included. For cancer patients, this includes type of cancer, stage and size of tumor; for ileal pouch patients, the type of pouch created, how it was constructed and whether it was a secondary reconstruction of a dysfunctional primary pouch are included.

The result is a goldmine of data on short- and long-term outcomes for each surgical treatment that are used to prospectively assess the choice of procedure offered to each patient. “Our assessment has implications for the way we do an operation, as well as for the dissemination of technical knowledge that can affect the delivery of surgical care,” says Dr. Stocchi.

In the case of ileoanal anastomosis, long-term data is generally unavailable, records of every patient who has undergone the procedure at Cleveland Clinic provides unprecedented information on how bowel function evolves and whether benefits remain consistent over time. “We want to know how good these operations are, not only now, but into the future,” says Dr. Stocchi.

In addition to supporting clinical treatment decisions, the database is mined for an impressive number of research projects conducted on an ongoing basis.

“More than 90 percent of our publications use data stored in our outcomes database,” says staff scientist and researcher Elena Manilich, PhD.

Findings from these studies are disseminated publicly every year through podium and poster presentations at national meetings of the American Colon and Rectal Surgery Society and American College of Surgeons and through papers published in leading journals. This has helped Cleveland Clinic colorectal surgeons set many standards of care across the country and around the world.

“We are one of the few institutions that consistently publish our data for everyone to see. It can have tremendous impact,” he says. “In the case of ileoanal pouch for ulcerative colitis, for example, we showed that one surgical procedure viewed with suspicion when it was first proposed was actually beneficial. Today, its value is no longer questioned,” says Dr. Stocchi.

Now the nation’s largest and most comprehensive colorectal surgery database, the Cleveland Clinic’s data repository maintains its relevance by changing with the times. In addition to the expected, familiar data points, genetic and genomic data are collected. The information is beginning to give colorectal surgeons a better understanding of why certain patients have specific illnesses.

“Without these outcomes, genomic studies would not exist,” says Dr. Manilich.

For more information, please contact Dr. Stocchi at 216.445.7882 or at stocch1@ccf.org.


Open Clinical Trials

Featured Clinical Trials

Highlights of our featured clinical trials in both Cleveland and Florida:

IRB 13-467 Massarat Zutshi, MD

Anal Fissure

A Phase 3B, Randomized, Double-Blind, Placebo-controlled, Parallel-Treatment Group, Multicenter Efficacy and Safety Study of Topical Diltiazem Hydrochloride 2% Cream in subjects with Anal Fissure

Summary: For patients who have been diagnosed with an anal fissure (small tear in the skin that lines the anus). The purpose of this study is to investigate the effectiveness and safety of an experimental drug to help with treatment of pain associated with anal fissure. Patients will apply the study drug (cream) or placebo three times a day for 28 days. There are 4 study visits and a phone call over a 5 week period.

IRB CC888 Prashanthi Thota, MD

Barrett’s Esophagus

Effect of Vitamin D Supplementation on 15-Prostaglandin Dehydrogenase Expression in Barretts Esophagus

Summary: For patients (over 18) who have been diagnosed with Barrett’s esophagus. The purpose of this study is to evaluate the effect of a once weekly high dose of Vitamin D supplementation on the progression of Barrett’s esophagus. Vitamin D may affect the levels of several proteins that may influence the risk of esophageal cancer. Eligible participants will have 2 upper endoscopies with biopsies and blood drawn at the 2 visits. Depending on the pathology report of current Barrett’s esophagus status, the study will last for 2 weeks or 3 months.

IRB 13-497 Federico Aucejo, MD

Liver transplant

A Phase II Randomized Multicenter Placebo-Controlled Blinded Study of Sorafenib Adjuvant Therapy in High Risk Orthotopic Liver Transplant (OLT) Recipients with Hepatocellular Carcinoma (HCC)

Summary: For patients who have received a liver transplant and are at a high risk of liver cancer recurrence. The purpose of this study is to determine if sorafenib is an effective treatment option for preventing liver cancer in high-risk patients following liver transplantation. Participation will last approximately 4 years after transplant: There is a 2 year treatment phase (15 clinic visits) and 2 year follow-up (4 visits). The tests and procedures are standard treatment for transplant care. Patients will be randomly assigned to one of two treatment groups (sorafenib or placebo) and will begin taking the study drug or placebo between 6-12 weeks after liver transplant.

IRB 13-049 Charles Miller, MD:

Liver transplant

Discovery and Validation of Proteogenomic Biomarker Panels in a Prospective Serial Blood & Urine Monitoring Study of Liver Transplant Recipients – Transplant Proteogenomics (CTOT)

Summary: For patients 18 and over who will undergo a primary living donor or deceased donor liver transplant. This study includes living donors who are donating a liver for a patient in this study. The main focus of this study is to develop blood and/or urine tests that will help to detect early signs of rejection in people who have had a liver transplant. Researchers will examine blood, urine, and tissue samples and try to identify markers for certain conditions such as rejection, response to therapy, and scarring of the liver. Additionally, researchers hope to identify biomarkers that can detect damage to the native kidneys before blood levels of creatinine rises. By studying gene expression, researchers hope to be able to diagnose these conditions earlier and improve liver survival. The study will last for 2 years after liver transplant (approximately 13 study visits). Patients will have additional visits for blood draws and urine specimens if they have a rejection.

The living donor will have one study visit. The main purpose of the study for the living donors is to request a blood sample for genetic testing. Researchers will study the genetic markers that can be found in the DNA which is present in the cells. There is a need to develop non- invasive tests that can detect changes in the liver before damages occurs.

IRB 12-111 Conrad Simpfendorfer, MD:

Fluorescent Cholangiogram

Fluorescent Cholangiogram: A comparative analysis to conventional cholangiography

Summary: All the patients undergoing Laparoscopic Cholecystectomy are being asked to participate in this study. Fluoroscopic and fluorescent (FC) cholangiographies are performed to delineate the extrahepatic biliary ducts. For the FC a single dose of 0.05 mg/kg of indocyanine green (ICG) is administered intravenously one hour prior to surgery. A Storz® xenon light source and laparoscope with a charge-coupled device that filters out light wavelengths except 830 nm with a specific 780 nm infrared light source is used during the surgery. During the procedure, alternate exposure from xenon to infrared lights is used to identify the biliary structures before and after dissection. A questionnaire to assess the surgeon’s visibility of extrahepatic bile ducts with fluorescence before and after dissection is performed. Cost, time and effectiveness of both methods are compared.

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