June 24, 2010

Growing New Livers

Published by Steven Novella under General Science, Science and Medicine
June 15, 2010

A team as Mass General has published the results of their preliminary research into growing new livers from hepatocyte stem cells. The work is encouraging – but to put it into perspective, it is still a long way away from growing fully functional transplantable organs.

What the team did was take rat livers and wash away all of the liver cells leaving behind just the connective tissue. They used this connective tissue as a scaffold on which to grow a new liver with hepatocytes. They then transplanted the new liver into rats. They report that the artificial livers survived for a few hours.

This is obviously a long way away from an artificial liver. First, the new livers had only hepatocytes, but not the other kinds of cells that make up a normal liver. So even if this technique worked completely, it would only create a partially functioning liver.

Another obstacle to overcome is creating a liver that has something approaching a normal infrastructure, including blood vessels and bile ducts. It’s not enough to have a mass of cells, they have to have the proper structure to function. This is not a trivial obstacle.

In fact the liver may be a deceptively difficult organ to grow in this manner. Other teams have had success using essentially the same technique with hearts – using a scaffold on which to grow new heart cells. Heart cells have the advantage of synchronizing themselves as they grow, so they beat together. The challenge is growing the internal electrical system of the heart, but this can be bypassed by using a pacemaker.

Other organs will be of varying complexity. A pancreas doesn’t seem as difficult as a lung or liver, while kidneys have a complex internal structure.

The questions is – how much potential is there in the scaffolding approach to growing organs? This seems like a stop-gap measure – a partial solution to the problem of how to grow organs. It may be useful for a couple of different kinds of organs, likes hearts, and for some other body parts – a trachea was transplanted using this method. But it seems unlikely, without further major breakthroughs, that this approach will be the ultimate solution to growing organs.

Growing new organs from scratch – from an embryonic state – may be the only way to get the full infrastructure and cellular organization. The problem here is that it takes time. An adult organ may take a decade to grow. For some organs an adult organ, or close to it, would be necessary – like heart and lungs. For others, even a several year old organ may suffice. A small liver or kidney would still provide significant function, and may continue to grow as the recipient ages.

There is also the question of what to grow the new organs in. Ideally we would grow them in vats – some completely artificial environment. But this will likely be a huge technological hurdle. There are insurmountable ethical problems to growing them in people – clones that would serve as organ banks (like in the movie, The Island). It is interesting to consider the public reaction to other human options, such as growing them in headless torsos – just a formless mass of cloned human tissue full of organs being fed intravenously.

There is also the option of genetically engineering animals to grow cloned human organs, and then sacrificing them when the organs are needed. Perhaps they can be engineered to be immunologically naked, and then matched to the recipient when it comes time to harvest the organ.

There are two significant advantages to growing organs. The first is that we have a shortage of donated organs – people die waiting for organs to be transplanted. The second is the issue of tissue rejection. Getting a transplant even from a compatible donor requires a lifetime of immunosuppressant drugs and the risk of rejection. A transplant of your own cloned tissue, however, would be 100% compatible and therefore not require drugs or risk rejection. This is a huge advantage, which would revolutionize organ transplants.


This latest study is a baby step forward in one technique which is likely to be very useful, but ultimately limited, in terms of a final solution for organ transplants. But it’s a step. We need another 50 baby steps or so before we reach our goal, but there are useful milestone along the way. I think we will see in the next decade grown hearts for transplant, and maybe even grown livers and pancreases. Skin is another organ that will likely occur sooner than later. But such predictions are inherently unreliable – there remains major obstacles to overcome and they cannot be predicted in the short term.


Higher Cancer Rates Found in Liver Transplant Recipients Receiving Cyclosporine

HOBOKEN, NJ -- June 24, 2010 -- A study published in the July issue of [Liver Transplantation shows that cyclosporine treatment is a significant risk factor for the development of de novo cancer in liver transplant recipients.

Several studies have yielded conflicting results about the incidence of de novo cancer between cyclosporine-based and tacrolimus-based regimens. Elucidating the role of different calcineurin inhibitor (CNI) regimens in the occurrence of de novo cancer after liver transplant was the goal of this study.

Herold Metselaar, MD, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands, and colleagues performed retrospective analyses in 385 liver transplant recipients who underwent surgery between 1986 and 2007.

They analysed data included age of recipient at time of transplantation, gender of recipient, primary liver transplant indication, type of primary immunosuppressive therapy, de novo malignancy post transplantation, interval from liver transplant to diagnosis of malignancy, interval from liver transplant or diagnosis of cancer to death, and interval from liver transplant to diagnosis of the first acute rejection.

All patients were followed until December 2008. The primary endpoint was de novo malignancy, which was defined as the development of cancer other than recurrent primary liver cancer. Of the 385 study participants, 50 (13.0%) patients developed at least 1 de novo cancer.

The researchers observed that cyclosporine, in comparison with tacrolimus, is the most important risk factor for de novo malignancy after liver transplant.

This higher cancer risk was not, however, found in all cyclosporine treated patients, but cyclosporine specifically enhanced development of de novo cancer in patients transplanted in more recent years (2005-2007), and in younger patients (age, <50 y). In addition, cyclosporine treatment particularly resulted in more aggressive types of cancer compared with tacrolimus, with a 1-year survival rate of <30%.

The reason for the increased cancer rates among cyclosporine recipients is believed to be the fact that from January 2005, cyclosporine dosing based on the conventional C0 level monitoring was replaced by dosing based on C2 level monitoring in all liver transplant recipients. As this was the only major change in the cyclosporine treatment in the recent study period, the team concluded that the C2 monitoring strategy was the reason for the increased early de novo cancer risk.

"Strikingly, cyclosporine treated patients transplanted from 2005 on showed a 9.9-fold higher de novo cancer risk in the early phase after liver transplant compared with patients treated with tacrolimus, said Dr. Metselaar. "These data indicate that only the specific cyclosporine treatment used in recent years was associated with a higher risk for early development of de novo cancer."

"We also observed that, compared with tacrolimus-treated patients, cyclosporine-treated patients had a 2.5-times higher risk to develop more aggressive cancer types that do not belong to the non-melanoma skin cancer and post-transplant lymphoproliferative disorder categories, indicating that cyclosporine is not only associated with a higher early de novo cancer risk, but also with cancer types having a worse prognosis," he added.


Dr. Melissa Palmer: Which Doctors Treat Liver Disease?

There are many different kinds of doctors who evaluate and treat people with liver disorders. First, there is the family physician or internist. These doctors are also referred to as primary care physicians (PCPs). They are often the first ones to discover that something is wrong with the liver. From there, the patient is customarily referred to a specialist—either a gastroenterologist, hepatologist, or infectious disease specialist—for further evaluation and treatment. This specialist may be in a practice located at an academic institution or in a private practice located in a community setting. The difference between the various types of doctors a patient with liver disease encounters may sometimes be confusing. Hopefully, this section will clarify these differences in order to eliminate any future confusion.

Vitals.com can help you find a doctor in your area. You can search for doctors by name, city, zip code and medical condition.

The Medical Doctor (MD)

Medical Doctors (MDs) are physicians who have successfully completed four years of medical school training. After graduating from medical school, these doctors must complete a minimum of one additional year of training in a hospital in what is known as an internship. They must then pass a state-licensing exam in order to practice medicine in that state. After obtaining their license, they have the right to practice medicine in that state. However, many doctors choose to continue their training in a hospital by undergoing a residency—typically an additional two years.

After completing their residency, these doctors must take an exam in order to become board certified in a specialty, such as family medicine or internal medicine. Doctors may practice medicine whether or not they pass this exam. Doctors who become family doctors or internists have general knowledge in all areas of medicine including the heart, lungs, kidneys, stomach, intestines, and liver. At this time, a doctor may decide to undergo additional specialty training, known as a fellowship, in a specific area of internal medicine, such as gastroenterology, hepatology, or infectious diseases, in order to become an expert in these areas.

The Doctor of Osteopathy (DO)

Doctors of osteopathy (DOs) are commonly referred to as osteopaths. These are doctors who graduated from a four-year osteopathic school. They must also complete a one-year internship in a hospital in order to be eligible to obtain a license to practice medicine. Osteopaths can also choose to undergo an additional two-year residency, and may thereafter undergo specialty training in a specific area of medicine.

Osteopaths tend to focus on treating “the body as a whole,” particularly on the body’s ability to heal itself. Osteopaths typically center their treatment on the musculoskeletal system, the muscles and bones, often using techniques such as bone manipulation and a form of massage.

The Family Physician

A family physician is a doctor—either an MD or a DO—who has been trained to prevent, diagnose, and treat medical conditions in people of all ages. The family physician takes care of the general health of the patient and his entire family. Their training is not limited to internal medicine, but includes some training in psychiatry, obstetrics, gynecology, and surgery. These are the “Marcus Welby” doctors, seemingly able to handle almost any general problem.

There is a separate board certification examination specifically for family practitioners. This is known as the family practice boards. Specializing in family practice medicine requires an additional three years’ training beyond medical school. The amount of exposure to, and degree of expertise in liver disease varies among family practitioners. However, family physicians have not undergone additional specialized training in liver disease.

The Internist

An internist is a doctor—an MD or a DO—who is trained to prevent, diagnose, and treat medical conditions in adolescents and adults, including the elderly. Internists have received some basic training in subspecialty areas of internal medicine, including gastroenterology, hepatology, and infectious diseases. Internists are trained to treat both straightforward and complex problems of the internal organs. They are also trained in emergency medicine and critical care medicine. There is a separate board certification examination specifically for internists. It is known as the internal medicine boards. Specializing in internal medicine requires an additional three years’ training beyond medical school.

The amount of exposure to, and degree of expertise in liver disease varies among internists. Internists have the option of continuing their training in a subspecialty of internal medicine. This requires applying for, and being accepted into, a fellowship in the subspecialty of their choice. gastroenterology, hepatology, and infectious diseases are among the many subspecialties of internal medicine.

The Gastroenterologist

A gastroenterologist is an internist who has completed specialty training in the treatment of digestive disorders. Digestive disorders include disorders of the esophagus, stomach, small and large intestines, pancreas, gallbladder, and liver. In order to become board certified in gastroenterology, the doctor must first become board certified in internal medicine. In order to become eligible to even take the examination for board certification in gastroenterology, a gastrointestinal (GI) fellowship lasting an additional two to three years beyond an internal medicine residency must be completed.

During the course of their two to three years of training in gastroenterology, some gastroenterologists have little exposure to patients with liver disease. On the other hand, some gastroenterologists have a great deal of exposure to patients with liver disease during the course of their gastroenterology specialty training. Thus, the level of experience and expertise among gastroenterologists in diagnosing and treating liver disease varies greatly. It is important for the patient to determine the gastroenterologist’s level of expertise in liver disease prior to establishing a long-term medical relationship with this type of doctor.

The Hepatologist

A hepatologist is the most experienced and qualified type of doctor to treat people with liver disease. Since there is currently no separate board certification examination in the field of hepatology, there is no official definition of a hepatologist. However, there are specialized training programs for doctors who are focused solely on liver disease. These are known as hepatology fellowships and typically last from one to two years. Over the course of a hepatology fellowship, a doctor receives comprehensive training in the diagnosis and treatment of liver disease. This specialty training typically includes extensive exposure to all liver diseases, including those that are rare and infrequently seen. This intense training in liver disease is rarely matched in a gastroenterology fellowship.

A physician who successfully completes a hepatology fellowship is considered a hepatologist. Most hepatologists, although not all, are also gastroenterologists. These doctors have successfully completed both a hepatology and a gastroenterology fellowship. Occasionally, gastroenterologists who have not completed a fellowship in hepatology nonetheless focus their medical practice primarily on the diagnosis and treatment of people with liver disease. While these physicians do not have a separate diploma in the field of liver disease, they may also be considered hepatologists.

For many reasons, it is to the patient’s advantage to choose a hepatologist to treat his liver disease. The patient can be virtually assured that the hepatologist will have substantial experience in the diagnosis and treatment of the full range of liver diseases. Furthermore, hepatologists are likely to be the first to learn about the most up-to-date therapies—both FDA-approved and experimental—and to incorporate them into their practices. However, whether someone chooses to see a gastroenterologist or a hepatologist, it is important to find a doctor who is willing to work with him as an equal partner in the healing process.

Infectious Disease Specialists

An infectious disease specialist is an internist who has completed a specialty fellowship in infectious diseases of all types. Many infectious disease specialists treat people with liver disease caused by infectious – such as hepatitis B and C (both of which are caused by viruses). During the course of their two years of training in infectious diseases, some infectious disease specialists have little exposure to patients with viral hepatitis. On the other hand, some infectious disease specialists receive a great deal of exposure to patients with viral hepatitis during the course of their specialty training. Thus, the level of expertise among infectious disease specialists in diagnosing and treating viral hepatitis varies greatly. It is important for the patient to determine the infectious disease specialist’s level of expertise in treating hepatitis B or C prior to establishing a long-term medical relationship with this type of doctor. It should be stressed that infectious disease doctors have no special expertise treating liver diseases that are not caused by infections – such as alcoholic liver disease or autoimmune hepatitis.

All contents of this article are Copyright © Melissa Palmer, MD

Dr. Palmer is an internationally renowned hepatologist who has been practicing medicine since 1985. She maintains the largest private medical practice devoted to liver disease in the United States. Dr. Palmer was trained in hepatology (as well as medical school) at the Mount Sinai School of Medicine in New York City. She lectures frequently on liver disease-related topics to her medical peers and to the general public. She has appeared on television many times and is often quoted in magazines and newspapers. Dr. Palmer is a board member of the New York chapter of the American Liver Foundation, and she sits on the nutrition subcommittee of the national chapter of the American Liver Foundation, the advisory board of the Latino Organization for Liver Awareness (LOLA) and the Primary Biliary Cirrhosis Organization (PBCers).

Bayer’s Liver Cancer Drug to Be Tested Against Sirtex

June 24, 2010, 2:21 AM EDT
By Simeon Bennett

June 24 (Bloomberg) -- Bayer AG’s Nexavar treatment for advanced liver cancer will be tested against a radiotherapy made by Sirtex Medical Ltd. in a final-stage study of patients in the Asia-Pacific region.

A total of 360 patients with inoperable liver cancer in 13 countries will receive either Nexavar or Sydney-based Sirtex’s SIR-Spheres, Singapore’s National Cancer Centre, the trial organizer, said in an e-mailed statement today.

“We hope to conclude which therapy is more beneficial to patients in terms of better survival, tumor shrinkage and quality of life,” Pierce Chow, who will lead the study, said in the statement. “This therapy will then serve as first line and the other as second-line treatment.”

About 80 percent of liver cancer cases occur in the Asia- Pacific region, and most people are diagnosed too late for surgery, according to the World Health Organization. The cancer kills about 610,000 people worldwide each year, making it the fourth most-deadly tumor, the United Nations agency said.

A previous trial that combined the two treatments extended patients’ lives by almost a year, a result that was better than either product on its own, according to the statement. The results were first presented at the American Society of Clinical Oncology’s conference in Chicago last month.

Liver cancer is caused mainly by the hepatitis B and C viruses, which are transmitted through blood or sexual contact and attack the organ, according to the U.S. National Cancer Institute. Left untreated, patients with advanced liver cancer have a median survival of about three months, the Singapore Cancer Centre said in the statement.

Microscopic Beads

SIR-Spheres are injectable microscopic polymer beads designed to shrink tumors by carrying a radiotherapy drug directly to them, avoiding the damage to healthy tissue that’s caused by conventional radiotherapy.

Bayer, of Leverkusen, Germany, co-markets Nexavar with New York-based Onyx Pharmaceuticals Inc.

Sirtex fell 4.3 percent to A$5.08 in Australian trading. The stock has lost 33 percent this year after surging more than fourfold in 2009.

--Editors: Lena Lee, Suresh Seshadri.

To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net

To contact the editor responsible for this story: Jason Gale at j.gale@bloomberg.net .


Small Molecule Anti-virals with Optimized Efficacy and Fewer Side Effects Fuel Growth in the Hepatitis C Therapeutics Market in Indonesia, Finds Frost & Sullivan

Posted on : 2010-06-24

Author : Frost & Sullivan

News Category : PressRelease

SINGAPORE, June 24 /PRNewswire/ -- Regular blood screening conducted in hospitals for at-risk patients, particularly injecting drug users (IDUs), has expanded the patient base and enhanced prospects for the hepatitis C therapeutics market in Indonesia. Moreover, increasing health awareness in Indonesia has encouraged the population (mostly urban) to opt for annual physical examinations and regular blood screening that enable the detection of Hepatitis C.

New analysis from Frost & Sullivan (http://www.pharma.frost.com/), Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia, finds that the global hepatitis C treatment market earned revenues of $2.3 billion in 2007, and is expected to increase to approximately $4.5 billion by 2017 due to new drug launches occurring after 2010.

"Small molecule anti-virals with improved efficacy are poised to take the market forward," says Frost & Sullivan Vice President, Rhenu Bhuller. "Several strategies are being explored in clinical trials, including add-on therapy to the current standard of care, interferon replacement, and ribavirin replacement."

Refined versions of interferons, oral formulations of small molecule inhibitors, and the new drug class known as protease inhibitors are in the pipeline and represent the future of hepatitis C virus (HCV) treatment. Despite the initiatives undertaken, only 2 percent of those diagnosed are placed under treatment, primarily because of the lack of government reimbursement.

Treatment of hepatitis C is restrained by the high cost of medication for patients who do not have health insurance. While Indonesia offers healthcare coverage to its population, many of the poor people are unable to apply for the insurance. Those not entitled are expected to bear the cost themselves, which is approximately $1,000 per month.

The low rate of treatment and compliance is also caused by patients' fear of side effects associated with treatment. These include bone marrow depression, flu-like symptoms, neuropsychiatric disorders, and autoimmune syndromes. Besides, limited efficacy for those infected with genotype-1 strain and an inconvenient mode of administration has contributed to non-compliance.

Studies have shown that patients treated with combination therapy of the two drugs are more likely to reach sustained virological response than those treated with monotherapy. With this, more patients are likely to accept treatment, as there is a better chance for them to completely recover from Hepatitis C. In Indonesia, the standard treatment for HCV is Peg intron; Peg intron + Ribavirin; Pegasys; and Pegasys + Ribavirin.

Physicians interviewed agreed that patients respond better to combination therapy and recovery rates are higher for patients on Pegylated interferon (Peg intron or Pegasys) + Ribavirin. Additionally, most patients are HIV positive, making treatment more difficult, as the possibility of co-infection is higher among these patients.

Companies that offer treatments with improved efficacy and fewer side effects, combined with disease education can help overcome the challenges clouding the market landscape. Encouraging better compliance now will enhance the likelihood of future compliance, especially for improved treatments. Creating incentives for patients to stay on HCV treatment will improve the chances of patient compliance. In order to increase their HCV market share with newer drugs, companies must make sure that patients are aware of their disease status.

"Awareness programs are mostly centered in urban areas, with the aid of media such as television and internet as a source of information delivery," says Bhuller. "Outreach programs must target rural areas to stop the onslaught of the disease."

Creating marketing campaigns that highlight better efficacy, partnerships with governments to lower costs, but increase distribution, and broadening diagnosis efforts will increase market presence.

If you are interested in more information on this study, please send an e-mail to Nicklaus Au, Corporate Communications, at nicklaus.au@frost.com ,with your full name, company name, title, telephone number, company e-mail address, company website, city, state and country.

Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia is part of the Pharmaceuticals & Biotechnology Growth Partnership Services program, which also includes research in the following markets: Global Pharmaceuticals & Biotechnology and Global Healthcare. All research services included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants.

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Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia


SOURCE Frost & Sullivan