New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases

J Hepatol. 2011 Jul;55(1):126-32. Epub 2010 Nov 23.

 

Piana G, Trinquart L, Meskine N, Barrau V, Beers BV, Vilgrain V.

 

Source

Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, Department of Radiology, Clichy, France.

Abstract

BACKGROUND & AIMS:

To propose MRI criteria with a diffusion-weighted imaging (DWI) sequence for the diagnosis of hepatocellular carcinoma (HCC).

METHODS:
Patients, who underwent liver MRI with contrast-enhanced sequences and DWI between 2004 and 2008 and who had at least one confirmed HCC of at least 10mm, were included. Index diagnostic criteria were: (1) enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases; (2) enhancement in the arterial-dominant phase and hyperintensity on DWI; (3) enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases or hyperintensity on DWI. Two radiologists independently reviewed the corresponding sets of sequences (DWI alone; T1-weighted sequence before and after dynamic injection of gadolinium chelates; combined DWI-T1-weighted sequence). Inter-observer agreement and sensitivity were determined per nodule.

RESULTS:
Ninety-one patients were included (109 HCCs). The sensitivity of conventional MRI criteria for the diagnosis of HCC was 59.6% for both radiologists. The sensitivity of enhancement in the arterial-dominant phase and hyperintensity on DWI was 77.1% or 76.1%, depending on the radiologist. The sensitivity of enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases or hyperintensity on DWI was 84.4% or 85.3%, depending on the radiologist. The inter-observer agreement for the latter was very good (kappa coefficient 0.82). These results were consistent in HCCs smaller than 20mm.

CONCLUSIONS:
The proposed criteria, based on the characteristics of lesions after gadolinium chelate administration and hyperintensity on DWI, significantly increased the sensitivity for the diagnosis of HCC compared to conventional criteria, regardless of tumor size.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Prediction of esophageal varices in hepatic cirrhosis by noninvasive markers.

Eur J Gastroenterol Hepatol. 2011 Sep;23(9):754-8.

 

Tafarel JR, Tolentino LH, Correa LM, Bonilha DR, Piauilino P, Martins FP, Rodrigues RA, Nakao FS, Libera ED, Ferrari AP, da Silveira Röhr MR.

 

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Department of Medicine, Division of Gastroenterology and Gastrointestinal Endoscopy, Federal University of São Paulo, São Paulo, Brazil.

Abstract

OBJECTIVE:

To determine whether Model for End-stage Liver Disease (MELD) Child-Turcotte-Pugh (CTP) classification, AST to platelet ratio index (APRI), and laboratory tests could predict the presence of esophageal varices (EV) or varices which need prophylactic therapy (medium or large size EV).

METHODS:
Three hundred patients with cirrhosis (193 men; mean age 53.1 years; majority with chronic C hepatitis) were prospectively analyzed. The presence of EV (any size and medium or large EV) was correlated with patients' characteristics (MELD, CTP classification, APRI, platelets count, and liver tests).

RESULTS:
One hundred and seventy-one patients (57%) had EV, of whom 35% (105) had varices which need prophylactic therapy (VPT). The distribution of EV according to CTP classification was as follows: A, 49%; B, 75.3% and C, 80%. Independent predictors of EV were: MELD higher than 8 (P=0.02); APRI higher than 1.64 (P=0.01); platelet count lower than 93,000/mm³ (P<0.01); aspartate aminotransferase higher than 1.34 × UNL (P=0.01), and total bilirubin higher than 1 mg/dl (P=0.04). MELD higher than 8 had the highest discriminative value for presence of EV (sensitivity=80.1%; specificity=51.2%; area under receiver operating characteristics=0.68). Factors independently associated with VPT were: thrombocytopenia (<92,000/mm³; P<0.01) and aspartate aminotransferase higher than 1.47 × UNL (P=0.03). Platelet count lower than 92,000/mm³ had sensitivity of 65.7%, specificity of 57.9%, and an area under receiver operating characteristics of 0.62 for the presence of VPT.

CONCLUSION:
High values on MELD are associated with EV and thrombocytopenia, with varices which need prophylactic therapy. As a result of their low sensitivity and specificity, it is suggested to maintain the recommendation of upper gastrointestinal endoscopy for all patients with cirhosis.

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Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: A meta-analysis

Journal of Hepatology
Volume 55, Issue 6 , Pages 1187-1194, December 2011

Pierre Deltenre, Alexandre Louvet, Maud Lemoine, Abbas Mourad, Laetitia Fartoux, Christophe Moreno, Jean Henrion, Philippe Mathurin, Lawrence Serfaty

Received 28 December 2010; received in revised form 16 February 2011; accepted 3 March 2011. published online 13 April 2011.

Abstract

Background & Aims
Recent studies suggested that SVR rates might be lower in HCV patients with insulin resistance (IR) than in patients without IR, but the extent of the impact of IR on treatment response has not been established. We aimed to confirm the role of IR assessed by the homoeostasis model assessment (HOMA-IR) on SVR and to determine its magnitude.

Methods
We performed meta-analysis of studies evaluating the impact of IR in HCV patients treated with pegylated interferon and ribavirin.

Results
Fourteen studies involving 2732 patients were included. SVR was less frequent in patients with IR than in patients without IR (mean difference: −19.6%, 95% CI: −29.9% to −9.4%, p<0.001). In sensitivity analyses according to HCV-1 patients, patients with IR also less frequently attained a SVR than patients without IR (mean difference: −13.0%, 95% CI: −22.6% to −3.4%, p=0.008). In addition, the baseline HOMA-IR index was lower in responders than in non-responders (mean difference: −0.92, 95% CI: −1.53 to −0.32, p<0.001). In sensitivity analyses restricted to HCV-1 patients, the baseline HOMA-IR index remained lower in responders than in non-responders (mean difference: −0.63, 95% CI: −1.13 to −0.14, p<0.001).

Conclusions
HCV patients with IR have a 20% lower SVR than patients without IR. The baseline HOMA-IR index is a major determinant of SVR.

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Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C

Journal of Hepatology
Volume 55, Issue 6 , Pages 1195-1200, December 2011

Hans L. Tillmann, Keyur Patel, Andrew J. Muir, Cynthia D. Guy, Josephine H. Li, Xiang Qian Lao, Alexander Thompson, Paul J. Clark, Stephen D. Gardner, John G. McHutchison, Jeanette J. McCarthy

Received 3 December 2010; received in revised form 1 March 2011; accepted 16 March 2011. published online 15 April 2011

Abstract

Background & Aims

IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC.

Methods
Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT.

Results
CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort.

Conclusions
IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

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VICTRELIS™ Now Available for Eligible Patients in Ontario

Canada NewsWire

MONTREAL, Nov. 22, 2011

Ontario first province to reimburse new chronic hepatitis C treatment

MONTREAL, Nov. 22, 2011 /CNW/ - Ontarians living with chronic hepatitis C now have publicly funded access to a new treatment option, as Ontario becomes the first province to reimburse VICTRELIS™ (boceprevir). The treatment qualified for a pre-approval rapid review under the Ontario Drug Benefit Act (ODBA), as it successfully met a pre-determined set of criteria, including offering substantial improvements of significant outcomes for the treatment of a serious disease.¹

Boceprevir is a first-in-class oral hepatitis C virus (HCV) protease inhibitor for the treatment of chronic hepatitis C genotype 1 infection. It is to be used in combination with peginterferon alpha and ribavirin (peg/riba) in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.² When added to peg/riba, boceprevir can significantly increase a patient's chance of clearing the virus from the body.^3,4 The treatment was authorized for use in Canada in July of this year.

"The Canadian Liver Foundation is pleased that Ontario's public drug program has agreed to reimburse boceprevir for the treatment of chronic hepatitis C," says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation. "Boceprevir represents a major advance in our ability to cure this disease, and as a result, fewer patients will have to struggle with the consequences of end-stage liver disease, liver transplants and liver cancer. We applaud the research efforts that led to this breakthrough and hope other provinces will follow Ontario's lead and rapidly reimburse this important treatment."

Eligibility criteria for boceprevir can be accessed through the following link:
http://www.health.gov.on.ca/english/providers/program/drugs/pdf/frequently_requested_drugs.pdf

Hepatitis C in Canada

An estimated 250,000 individuals in Canada are infected with HCV and there are 3,200 to 5,000 newly infected individuals each year.⁵ HCV damages the liver and may lead to serious complications, including death, when left untreated.⁶ It is the leading cause of liver transplants in Canada.⁷

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit www.merck.ca.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships.

Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

^TM Trademark of Schering Corporation, a subsidiary of Merck & Co., Inc. Used under license.

---

1	Guidelines for Rapid Review Submissions.  http://www.health.gov.on.ca/english/providers/pub/ drugs/dsguide/docs/rapid.pdf. Accessed November 15, 2011, p. 1.
2	VICTRELIS™, Product Monograph, July 27, 2011, p. 3.
3	Poordad, F., et al., for the SPRINT-2 Investigators.  Boceprevir for Untreated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1195-1206, page 1195.
4	Bacon, B.R., et al., for the HCV RESPOND-2 Investigators. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1207-1217, p. 1207.
5	Canadian Institutes of Health Research. About the Hep C Research Initiative. http://www.cihr-irsc.gc.ca/e/38855.html. Accessed November 2, 2011.
6	Public Health Agency of Canada. http://www.phac-aspc.gc.ca/hepc/pubs/multiling-hepc/index-eng.php. Accessed November 2, 2011.
7	Canadian Liver Foundation. http://www.liver.ca/Liver_Disease/. Accessed November 2, 2011.

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University launches iphone app for hepatitis treatment

Public release date: 22-Nov-2011

Contact: Sarah Stamper
sarah.stamper@liv.ac.uk
01-517-943-044
University of Liverpool

The University of Liverpool has launched an iphone app, HEP i-chart, that provides Hepatitis C (HCV) patients with quick and easy access to the latest information about drug interactions.

Hepatitis C was first discovered in the 1980s when it became apparent that there was a new virus (not the already known hepatitis A or B) causing liver damage. Hepatitis C causes inflammation and swelling of the liver. It is estimated that over 170million individuals – representing 3% of the world's population – are chronically infected with the Hepatitis C virus (HCV). Statistically, as many people are infected with HCV as are with HIV.

Since its identification, drug treatment to eradicate the virus has advanced greatly, especially in the last few years. Two new drugs have recently been licensed for treatment of HCV, and there are more drugs in development.

HEP i-chart is based on the website (http://www.hep-druginteractions.org/) developed at the University by Professor David Back and Professor Saye Khoo which provides a comprehensive online guide to the interactions between anti-hepatitis drugs and other drugs. It is a tool that provides

Hepatitis C patients and healthcare professionals with immediate access to up-to-date information on potential drug interactions between HCV drugs, and other drugs that the patient may be prescribed as well as over-the-counter, recreational or herbal medications.

Existing HCV drugs, newly licensed drugs and drugs in development can have interactions with each other and with other drugs which can impact on their effectiveness – sometimes with serious consequences. For this reason, some drug combinations must not be used, whilst others must be given with caution, possibly requiring adjustment or monitoring.

Professor of Pharmacology, David Back, said: "We are delighted to launch with our partners – KnowledgePoint360, MSD and Janssen- this new i-phone application that provides Hepatitis C patients and healthcare professionals with instant and easy access to information about HCV drug interactions which is relevant and reliable and up-to-date. This resource is especially important as new HCV drug treatments are approved and come into use."

Professor Graham Foster, President of the British Association for the Study of the Liver (BASL) said: "This new app, HEP i-chart, is a timely and much-needed resource for HCV patients as the number of new drugs which are available to treat Hepatitis C increases."

Source

Organ Transplants and Cancer Risk

November 21, 2011

Organ transplant recipients have a high risk of developing 32 different types of cancer, according to a new study. Future research to understand why may lead to better strategies for preventing cancer among transplant recipients.

In 2010, over 28,000 organ transplantations were performed in the U.S., including 16,899 kidney, 6,291 liver, 2,333 heart and 1,770 lung transplants. Transplant recipients are known to be at a higher risk for developing cancer than the general population. But past studies of cancer risk in transplant recipients focused mainly on those who received kidney transplants. Other studies were too small to accurately estimate risk for all but the most common cancer types.

For a more comprehensive look, a research team led by Dr. Eric A. Engels of NIH's National Cancer Institute (NCI) evaluated medical data from more than 175,000 transplant recipients—about 40% of all organ transplant recipients in the country. Their report appeared in the November 2, 2011, issue of the Journal of the American Medical Association.

The researchers found a twofold overall increased risk of cancer among transplant recipients. They noted elevated risk for 32 different types of cancer, some known to be related to infectious agents (such as anal cancer and Kaposi sarcoma) and others unrelated to infections (such as melanoma and thyroid cancer). The most common cancers among transplant recipients were non-Hodgkin lymphoma (14% of all cancers in transplant recipients), lung cancer (13%), liver cancer (9%) and kidney cancer (7%).

The risk of cancer was affected by the type of transplant. Lung cancer risk, for example, was highest in lung recipients. Smoking-related disease is often the reason for a lung transplant, and lung cancer typically arises in the remaining diseased lung rather than the transplanted one. The risk of liver cancer was elevated only among liver recipients. That might be partly explained by hepatitis B or C infection in the transplanted liver or by the fact that diabetes is common among transplant recipients. The risk of kidney cancer, in contrast, increased for all recipients.

“While transplantation is a life-saving therapy for patients with end-stage organ disease, it also puts recipients at an increased risk for developing cancer, in part because of medications administered to suppress the immune system and prevent rejection of the organ,” Engels says. “The cancer risk among transplant recipients resembles that of people with HIV infection, whose risk is elevated for infection-related cancers due to immunosuppression.”

The researchers now plan to focus on the cancers that occur at higher rates among transplant recipients. They aim to discover how medical conditions and immunosuppressive medications contribute to cancer risk. “In addition, we hope our findings will stimulate other research into the carcinogenic mechanisms associated with organ transplantation,” Engels says.

Source

Liver Cancer Treatment Turns Up the Heat on Chemotherapy

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

Published: November 21, 2011

As Mark Vetter lay on the operating table, doctors isolated his liver and began bathing it in a heated, highly toxic poison sent through the organ's blood vessels.

Over the course of an hour, cancer cells in the liver started to die and continued doing so for days.

The operating room at Froedtert Hospital in the Milwaukee area was filled with onlookers who wanted to get a glimpse because the treatment was one that few doctors have witnessed.

"If everything is successful it will kill the remaining cancer cells and it is a healthy liver," a hopeful Vetter said a couple weeks after recovering from the surgery.

For someone like Vetter, who hopes to live for years, there is enough science to offer a glimmer of hope, but also the dark reality that the treatment may only offer another year or so.

The therapy he chose to undergo may have its physiological underpinnings in a theory that has come to be known as the "Lance Armstrong Effect."

The legendary cyclist bounced back from testicular cancer that had metastasized to his lungs and brain, and he went on to win several Tour de France races.

The Armstrong Effect

Why did Armstrong and nearly 70% of other testicular cancer patients survive, even when the disease had metastasized to other parts of the body?

The answer, according to proponents of this theory, lies in anatomy -- the testicles normally are a few degrees cooler than the rest of the body, and when testicular cancer cells spread to other, warmer environments inside the body, they are confronted by a heat wave.

In that stressed state, the theory goes, the cancer cells become more susceptible to treatments such as chemotherapy and radiation.

The combination of heat and chemo may be a promising approach to treating intractable cancers, said Robert Getzenberg, MD, the Johns Hopkins University School of Medicine researcher who coined the term "Lance Armstrong Effect" five years ago in a commentary in the Journal of the American Medical Association.

"We have not had much success with cancer," Getzenberg said. "There are few things that really work. Every drug we come up with, cancer develops a resistance to," Getzenberg said.

Old Idea Finds New Believers

For decades, doctors have known that heat can kill cancer cells. Dating back to the 1960s, small trials of combining heat and chemotherapy were conducted, but the treatment never caught on mainly because of its complexity and a lack of data showing a clear survival benefit, said H. Richard Alexander, MD, associate chairman of clinical research at the University of Maryland Medical Center.

But in the 1990s, Alexander and other researchers began finding benefit in difficult-to-treat cancers that had spread to the liver.

"If (liver perfusion) were just a pill, the FDA would approve it immediately because it is as good as anything else we have tried," he said. "In some patients you see very dramatic results. In some cases, you can make tumors disappear from x-rays."

But tumors can come back. So far, the gold standard of research -- a large, randomized clinical trial -- has yet to be done. So data on the survival benefit remain lacking.

To date, most of the observational research suggests that average survival is extended about a year.

At the University of Pittsburgh Medical Center, about 25 liver perfusion cases are done a year, said cancer surgeon David Bartlett, MD.

Average survival is about two years, he said. About 5% of patients live five years. One man still is alive 12 years after undergoing the treatment, Bartlett said.

Not Too Hot, Not Too Cold

At Froedtert, the doctors use a basic, highly invasive approach:

• Wheel the patient to the operating room
• Make a long incision in the abdomen
• Isolate the liver with clips, catheters, and cannulas, and perfuse it with the drug melphalan
• The drug is heated to about 102 degrees and mixed at concentration 20 times stronger than a standard chemotherapy dose

Others are in the early stages of testing more sophisticated methods for using heat and chemo, including the use of iron oxide and gold nanoparticles that have been chemically bonded with antibodies designed that seek out specific cancer cells. With the tiny metallic particles inside, the tumors, but not healthy tissue, then are heated using friction caused by radiofrequency or alternating magnetic field devices.

"We can heat them so much that we can burn them up," Getzenberg said.

The ideal approach, though, which now is being tested with prostate cancer in lab and animal models, involves heating the tumors to 107 degrees, which makes them much more vulnerable to chemotherapy agents, he said. Such nanoparticle and heat cancer therapies remain unproven and likely are a few years down the road

The "If" Factor

From his perspective as a patient undergoing a newly discovered "old" therapeutic approach, the treatment is just one more "if" for Vetter.

If he had not gone in for a routine eye exam two years ago, doctors would not have found the tumor in his left eye and he might be dead -- he's one of about five in one million people a year who develop ocular melanoma, a disease that often metastasizes to the liver.

If he had preferred, he could have traveled hundreds of miles to one of a couple centers in the country that specialize in the unconventional treatment. Instead, he chose to be one of the first such patients to undergo that unconventional treatment at a center in his hometown.

Of course, there is the biggest if: if this treatment works, how long will he live?

At 66, Vetter, a Milwaukee area private labor attorney, is no Lance Armstrong.

He looks trim and fit, hardly like someone who had been battling an often fatal disease for more than two years.

The Process

The treatment Vetter underwent lasted about an hour, "the most tolerable duration," according to T. Clark Gamblin, MD, one of the Froedtert/Medical College of Wisconsin cancer surgeon who operated on Vetter.

The trick is to get the right mix of chemo, heat, and time so to be lethal to cancer cells without causing too much harm to healthy liver cells. While some normal liver cells may die, that's acceptable because the liver has the ability to regenerate tissue.

"You are putting the liver on bypass," said Kiran Turaga, MD, a Froedtert/Medical College cancer surgeon. "It's like the liver is out of the body."

Vetter's surgery was the second such case at the hospital and the latest in a long line of treatments he has tried.

As a veteran of the cancer war, he knows he will be undergoing continual monitoring in the months to come.

He also says he understands there is no way to know how much the treatment will help.

"I have not changed much of anything about the way I live my life," he said in a recent interview from his Milwaukee area home. "My goal is to be sitting in this room in 20 years."

Source

New treatments of chronic hepatitis C

Presse Med. 2011 Nov 4. [Epub ahead of print]

Fontaine H, Sogni P, Pol S.

Source

Hôpital Cochin et Inserm U1016, Assistance publique-Hôpitaux de Paris, université Paris-Descartes, unité d'hépatologie, 75014 Paris, France.

Abstract

The current treatment of chronic hepatitis C since several years, the association of pegylated interferon and ribavirine, allows to obtain a virological eradication in 55% of patients, all genotypes and 45% of those infected with the genotype 1, the most prevalent. The cure, defined by an undetectable viremia 24 weeks after the discontinuation of treatment is associated to a improvement of the prognosis of the patients with a decrease of mortality and morbidity. The development of news antiviral C molecules, efficient against the genotype 1, two protease inhibitors, boceprevir or telaprevir (which approval has been recently obtained), in association with pegylated interferon and ribavirine, allows to obtain a viral eradication in 70 to 75% of cases, with a reduction of treatment duration to 24 weeks in half of patients. This evolution will modify the therapeutic indications, the therapeutic schemas, the virologic follow-up, the risk factors of sustained virological reponse, the tolerance with the appearance of new adverse effects.

Copyright © 2011. Published by Elsevier Masson SAS.

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