A Canadian screening program for hepatitis C: Is now the time?

Provided by NATAP

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Canadian Medical Association Journal

Early release September 30, 2013. Subject to revision

\Hemant A. Shah MD MScCH HPTE, Jenny Heathcote MBBS MD, Jordan J. Feld MD MPH

Key Points

• Hepatitis C virus (HCV) infection has an enormous impact on population health in Canada and is likely underdiagnosed.
• A national strategy to screen for and treat HCV infections would substantially reduce HCV-related morbidity and mortality.
• Birth-cohort screening of people born between 1945 and 1975 coupled with a strategy for follow-up treatment and education is probably the best method to identify and provide care to affected people in Canada.
• Population-level data on the prevalence and health impact of HCV infection are needed in Canada.

Hepatitis C virus (HCV) infection causes more lost years of life and illness than any other infectious disease in Ontario, and likely in Canada.1 It is the leading indication for liver transplantation, and HCV-related morbidity and mortality is projected to rise until 2027, with staggering economic costs.2 Infected individuals often remain entirely asymptomatic until liver damage is advanced; they typically present only when symptoms from decompensated cirrhosis or liver cancer develop. However, unlike most chronic viral infections, HCV infection is curable. Successful treatment leads to viral eradication, halting the progression of liver disease and decreasing all-cause mortality.3 Thus, there is a clear rationale to identify and treat HCV infections during the asymptomatic phase. Last year, the United States changed their national policy on HCV screening and, more recently, the Canadian Liver Foundation issued a position statement advocating for birth-cohort screening in Canada.4 Here we review many of the issues involved in developing and implementing a national screening program for HCV infection in Canada.

What is the rate of HCV infection in Canada?

In the US, the prevalence of HCV infection is 1.6%; however, it is 3.6% among the "baby boomer" cohort (born 1945-1965), who account for 75% of national cases.5,6 The US data are derived from the National Health and Nutrition Examination Survey, which prospectively tests sentinel populations for HCV, providing robust population-level data. Based on these data and their own cost-effectiveness analysis, the Centers for Disease Control and Prevention (CDC) recommends routine screening of all baby boomers for HCV, in addition to screening based on risk factors.7 In Canada, less is known about the prevalence of HCV infection. The Public Health Agency of Canada (PHAC) estimates that about 250 000 Canadians, or 0.8% of the population, are infected with HCV. This estimate is based on mathematical modelling of the prevalence in at risk populations coupled with the estimated number of people in each group.2 British Columbia has collected the most comprehensive Canadian data and estimates that 1.5% of Canadians are infected with HCV.8 These data raise the question of whether the modeling approach used by PHAC has led to an underestimation of the prevalence for 2 reasons. First, the prevalence estimated by PHAC for BC was only 1.2%. Second, and more importantly, the prevalence in the rest of the country would have to be less than half that in BC, or about 0.7%, which seems unlikely.8 Studies including samples from the Canadian population as a whole are limited in both size and design, but these studies have estimated the prevalence to be between 0.5% and 2.8%.9,10 Clearly, more robust population-based data at the national level are needed to guide Canadian policy decisions.

Are Canadian data accurate?

Even more important than the prevalence of HCV infection is the prevalence of undiagnosed infections. Using the number of positive test results (192 225) and the estimated number of Canadians with HCV infection (242 521), PHAC reported in 2007 that 50 296 (21%) individuals with HCV remain undiagnosed.2 This estimate is markedly lower than in countries with active surveillance programs for HCV, and, if correct, would place Canada among the top countries in the world at diagnosing HCV infections despite not having a national screening program. The CDC estimates that 63% of Americans with HCV are unaware of their infection,7 and under diagnosis is highly prevalent even among people with insurance and access to care.11 Data from Europe show a similar pattern. Before introducing an intensive national program, 75% of infected individuals in France were unaware of their infection; after introduction of this program, the rate decreased to 44%.12 Given that it took a major national effort in France to get the diagnosis rate to 56%, it seems unlikely that Canada's estimate that 79% of infected individuals are aware of their diagnosis is correct. The Canadian data may be inaccurate for 2 major reasons. First, diagnosed cases may have been inadvertently counted more than once. Second, and more importantly, the overall prevalence may be considerably higher than estimated, particularly because groups at high risk of HCV infection are often undersampled. With the same number of positive test results, a higher prevalence would lead to a lower diagnosis rate. If Canadian data are similar to those in countries with comparable health care systems (e.g., France), the rate of underdiagnosis is likely much higher than 21%, and strategies to decrease this rate are needed.

What are the benefits and risks of screening?

Hepatitis C virus meets the criteria for a condition for which screening specific populations is potentially useful. There are many benefits: HCV is a major cause of morbidity and mortality; the prevalence of HCV is increased among baby boomers; many individuals are unaware that they are infected; and HCV infection is curable, with early intervention leading to improved overall health outcomes. Patients whose infection has been eradicated before cirrhosis develops have a life expectancy similar to that of un -infected people.13 If cirrhosis develops before treatment, viral eradication eliminates the risk of liver failure and markedly reduces the risk of hepatocellular cancer.3,13

There are potential risks associated with screening, including individuals feeling stigmatized by being "targeted," false positive results and a lack of capacity to treat the volume of newly diagnosed cases. The potential psychological harms of screening can be mitigated with pretest counselling and by developing systems to manage newly diagnosed cases. The CDC argues that even for patients who cannot access treatment, identification of HCV infection has potential adjunct health benefits, including receiving alcohol counselling and vaccinations.14 In considering their recommendations, the CDC used the widely accepted GRADE (Grading of Recommendations, Assessment, Development and Evaluations; www.gradeworkinggroup.org) criteria to weigh the benefits and risks of a screening intervention; the CDC found that the benefits significantly outweigh the potential harms.14

Who should be screened?

To maximize the information obtained by screening, populations with a potentially high burden of disease and a low current rate of diagnosis should be targeted. Using such rationale, the CDC identified people born between 1945 and 1965 as an ideal population for routine screening. Based on PHAC modelling, the prevalence of HCV infection in this age group is estimated to be 1.3%, accounting for 58% of all HCV infections.2 If people born up to 1970 are included, up to 69% of infections would be captured, and extending the age group to include those born up to 1975 would capture 77% of infected individuals; this is the basis for the Canadian Liver Foundation's recommendation to screen people born between 1945 and 1975.2,4

To date, Canada has advocated for the risk factor-based screening of 2 groups: people who engage in risk behaviours or have potential exposures to HCV; and those with clinical signs or symptoms that suggest HCV infection.15 There are no data on the effectiveness of this strategy in Canada. Unfortunately, data from other jurisdictions suggest that risk-factor-based screening is largely unsuccessful for many reasons.16 Primary care providers may be unaware of the risk factors for HCV infection, or they do not have time or knowledge to provide counselling,17,18 and patients may underreport risk behaviours. Hepatitis C virus is still found in screened blood from Canadian blood donors, despite donors being asked about risk factors before donation.19

Targeting immigrants from endemic countries for screening is likely effective, but this idea has met with resistance because of concerns about stigmatization and possible effects on immigration decisions.20

Many patients with HCV infection have no identifiable risk factors. Any strategy to broaden screening should not replace risk-factor-based screening, but should augment it because incident infections commonly occur among people with recognized risk factors such as injection drug use.

At the population level, birth-cohort screening (1945-1975) is likely the best strategy in Canada. A recent survey by the Canadian Liver Foundation reported that, despite this group having the highest prevalence of HCV infection, people born between 1945 and 1965 are the least likely to have been tested for HCV.21 Birth-cohort screening would thus capture a large proportion of undiagnosed cases, is easy to implement via clinical decision-support modules within electronic medical records, and aligns with existing age-based screening programs.

Birth-cohort screening is also cost-effective. Two detailed economic analyses of birth-cohort screening compared with risk-based screening in the US found that birth-cohort screening was cost-effective, with incremental cost-effectiveness ratios of US$35 700 and $37 700 per quality-adjusted life-year gained; these estimates are similar to those for mammography screening for breast cancer among women over age 50 (incremental cost-effectiveness ratio US$35 500).7,22,23 It would certainly be helpful to apply Canadian cost data to formally evaluate birth-cohort screening for HCV, but given the lower treatment costs and universal access to care for those with end-stage liver disease, it is likely to be even more cost-effective.

Which screening test should be performed?

In current clinical practice, screening is performed by use of a third-generation enzyme linked immunosorbent assay for antibodies to HCV. This test has high sensitivity (97.2%-100%) and specificity (> 99%);24,25 however, a positive result indicates only exposure to the virus. Up to 30% of people spontaneously clear HCV within 6 months of infection.26 To document active infection, patients must have evidence of HCV viremia. Thus, reflex confirmatory testing to document viremia for all first-time positive antibody tests should be considered. Although this would add cost and require coordination in the laboratory, the potential benefits include fewer referrals to specialists and reduced anxiety for those with spontaneously resolved infection.

Screening for HCV RNA as an initial test would be too costly, and using alanine aminotransferase alone would miss 35%-50% of cases.27 Other tests that document active infection, such as HCV core antigen testing, could be explored, but reduced sensitivity may render them inadequate.28

How will we care for all the individuals identified by HCV screening?

Before adopting wide-scale screening, we must have a plan in place to care for infected individuals. This plan should include an effort to improve education about the condition across health professions and to provide universal access to emerging treatments.

Current HCV therapy is not universally effective and is usually prescribed only by specialists. Treatment is costly (Can$65 000 per complete course), cures about 65%-70% of cases, involves weekly injections, and is resource-intensive and difficult to tolerate.29 However, HCV treatment is rapidly evolving. The first direct-acting antiviral agents for HCV, boceprevir and telaprevir, are approved in Canada, and many other agents are in late-phase testing. It is probable that within 3-5 years, well-tolerated oral treatments with cure rates above 90% will be available.30

Although treatment today requires specialized oversight, treatment in the future may not. Thus, any screening program should be coupled with education and support to enable primary care providers to treat HCV infection. Beginning now is sensible, so that we will be ready to expand access to care as soon as new treatments are available. It will be critical that new agents are approved and the costs are reimbursed in a timely manner so that the increased rates of diagnosis translate to improved health outcomes.

Can we afford population screening?

Screening populations is expensive. A properly executed birth-cohort screening program will be more expensive than risk-based screening in the short term, but it will reduce morbidity and mortality in the long-term, thereby saving future HCV-related costs. In the US, it is estimated that over 15 000 liver transplants and nearly 121 000 deaths will be prevented by birth-cohort screening.14 Although treatment for HCV infection is expensive, the cost of not screening and instead managing end-stage liver disease and liver cancer with transplantation and other treatments is likely to be even higher. The CDC's analysis found that HCV screening was cost-effective based on standard "willingness to pay" thresholds for the cost per life-year saved.7 Overall, it is probable that birth-cohort screening will be more cost-effective in Canada than in the US; however, we must also perform budget-impact analysis to determine whether our health care system can afford to adopt such a policy.

Conclusion

Hepatitis C virus is a major public health problem. Fortunately, treatment is improving. Unfortunately, the lack of robust Canadian data about the prevalence of HCV infection limits our ability to draw strong conclusions about the best screening policy; however, it is likely that the currently reported prevalence and diagnosis rates are underestimates. If we assume that the true Canadian data mirror those in countries with similar health care systems, birth-cohort screening would be a good policy. Canada should follow the lead of the US and begin birth-cohort screening for HCV infection, even if only to collect the data that we need to determine whether we should be screening at all.

Source

Is really full right full left split liver transplantation a valuable tool to increase organ availability?

Hepatobiliary Surgery and Nutrition Vol 2, No 4 (August 2013)

Editorial

Matteo Cescon, Giorgio Ercolani, Alessandro Cucchetti, Matteo Ravaioli, Antonio Daniele Pinna

Department of Medical and Surgical Sciences, University of Bologna, Italy

Corresponding to: Matteo Cescon, MD, PhD. Unità Operativa di Chirurgia Generale e Trapianti, Padiglione 25, Policlinico Sant’Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy. Email: matteo.cescon@unibo.it.

Submitted Apr 16, 2013. Accepted for publication May 14, 2013.

doi: 10.3978/j.issn.2304-3881.2013.05.03

The gap between available liver grafts and the number of patients in need for liver transplantation represents an unsolved issue worldwide. To overcome this persistent disparity, which is of particular relevance for adult recipients, split liver transplantation (SLT) is one of the main resources utilized by liver transplant centers.

While this strategy is commonly accepted when one pediatric and one adult patient are transplanted by a conventional splitting technique, adult-to-adult split liver transplantation (AASLT) has not yet gained the same consensus within the transplant community due to variable results (1-3). In fact, more than one experienced Center and even multicenter series have shown inferior outcomes when compared to those achieved with whole liver grafts transplanted into adults (3,4).

With the spread of a Model for End stage Liver Disease (MELD)-based organ allocation system also outside the U.S.A. in Europe and Asia, the application of SLT has become more difficult, because at least one of the two generated partial grafts should be transplanted into a (very) sick patient (5,6).

Since AASLT is a demanding technique, it should be performed by Centers with great experience in both liver transplantation and resection, but, unless the procedure is performed by a single team for its own pair of recipients, there is another crucial requisite, that is, the perfect coordination by two Institutions involved. For this purpose, the best way to systematically apply a policy of splitting shared at a multicenter level is to establish a priori donor, recipient and logistic criteria able to minimize the risk of failure of SLT.

The paper by Aseni et al. (7) reports on the 12-year activity of AASLT of the North Italy Transplant (NIT) organization, which includes most of the liver transplant Centers in the North of Italy. Surgeons and physicians working within this organization greatly contributed to expand and innovate SLT (8-11) and, importantly, they designed a model of cooperation able to detect, once a donor with adequate characteristics for splitting had been identified, the best pair of recipients among those listed at every participating Center.

This well-constructed program represents the ideal platform to share partial grafts under strict criteria of allocation, respecting the choice of the assigned Center to perform or not SLT, and favoring the interaction between different teams, with the consequent possibility of less experienced ones of improving results. A similar commitment among Centers has never been replicated elsewhere, and its principal value resides in the attempt to systematize a practice commonly considered extemporaneous.

Considering this background, one would expect that outcomes generated by this policy are optimal and/or progressively improving over time. In fact, although the NIT criteria for splitting seemed to be eventually fulfilled, with very favorable donor characteristics, median graft-to-recipient weight (GRWR) ratio far above 1, and largely acceptable ischemia time (6 hours), the Authors report 64% grade III and IV complications, and 5-year patient and graft survival rates significantly lower than that of whole liver transplants (WLTs) performed in the same period (63% vs. 83%, and 58% vs. 80%, respectively). These data are very similar to those shown by preliminary reports of the activity of Centers acting within the same organization (3,4), meaning that there was no real improvement of results over time. The Authors conclude that AASLT should be considered a surgical option only in experimental clinical studies in experienced centers.

This latter statement sounds a little contradictory, because NIT itself is composed of Institutions performing SLT since late nineties, thus with one of the most relevant expertise in Europe. Nevertheless, the Authors could mean that not all Centers had the same skills, and this is probably related to the unequal “attitude” to perform SLT within the same cooperative group.

On the other hand, the Authors of another previous study from the same NIT experience of full-right/full-left SLT commented these results as not dismal, since they were better than those of living-donor liver transplants (LDLTs) reported in the European Liver Transplant Registry (11). We would prefer to support this latter and more optimistic point of view, considering the unfavorable logistic conditions inherent to SLT and virtually absent in LDLT. Given that, we do not believe that 63% 5-year survival is an unsatisfactory figure.

More importantly, the results reported by Aseni and Colleagues prove that, even in front of the best available policy design, AASLT remains a practice subjected to a multitude of drawbacks, most of which are uncontrollable or unpredictable. If LDLT is still considered a challenging procedure, requiring a thorough investigation of donor and recipient, then AASLT should be considered a sort half-blinded LDLT, where the average graft quality is inferior, graft anatomic and volumetric features become understandable only during or after the procedure, and the ischemia time is longer. The disarming effect is that probably even experienced Centers will continue to produce worse results as compared with WLT or LDLT, unless the workup of deceased donors chosen for splitting could approach that of LDLT. Despite the impossibility of obtaining a radiological volumetric assessment for logistic reasons, it has been shown that by the routine use of intraoperative cholangiography and ultrasound, together with surgeons skills and correct criteria of donor selection, the results could be similar to those of LDLT, even in recipients with high MELD score (6).

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Humar A, Ramcharan T, Sielaff TD, et al. Split liver transplantation for two adult recipients: an initial experience. Am J Transplant 2001;1:366-72. [PubMed]
2. Broering DC, Wilms C, Lenk C, et al. Technical refinements and results in full-right full-left splitting of the deceased donor liver. Ann Surg 2005;242:802-12, discussion 812-3. [PubMed]
3. Giacomoni A, Lauterio A, Donadon M, et al. Should we still offer split-liver transplantation for two adult recipients? A retrospective study of our experience. Liver Transpl 2008;14:999-1006. [PubMed]
4. Cardillo M, De Fazio N, Pedotti P, et al. Split and whole liver transplantation outcomes: a comparative cohort study. Liver Transpl 2006;12:402-10. [PubMed]
5. Cescon M, Grazi GL, Ravaioli M, et al. Conventional split liver transplantation for two adult recipients: a recent experience in a single European center. Transplantation 2009;88:1117-22. [PubMed]
6. Lee WC, Chan KM, Chou HS, et al. Feasibility of split liver transplantation for 2 adults in the Model of End-Stage Liver Disease era. Ann Surg 2013;258:306-11. [PubMed]
7. Aseni P, De Feo TM, De Carlis L, et al. A prospective policy development to increase split-liver transplantation for 2 adult recipients: results of a 12-year multicenter collaborative study. Ann Surg 2013. [Epub ahead of print]. [PubMed]
8. Colledan M, Andorno E, Valente U, et al. A new splitting technique for liver grafts. Lancet 1999;353:1763. [PubMed]
9. Gridelli B, Spada M, Petz W, et al. Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease. Transplantation 2003;75:1197-203. [PubMed]
10. Cescon M, Spada M, Colledan M, et al. Feasibility and limits of split liver transplantation from pediatric donors: an Italian multicenter experience. Ann Surg 2006;244:805-14. [PubMed]
11. Zambelli M, Andorno E, De Carlis L, et al. Full right full left split liver transplantation: the retrospective analysis of an early multicenter experience including graft sharing. Am J Transplant 2012;12:2198-210. [PubMed]

Source

Intravenous interferon administered during liver transplantation is not effective in preventing hepatitis C reinfection

Dig Dis Sci. 2013 Oct;58(10):3010-6. doi: 10.1007/s10620-013-2749-z. Epub 2013 Jun 29.

Russo MW, Narang T, Eskind L, Hayes D, Casingal V, Purdum PP, Hanson JS, Ahrens W, Norton J, Bonkovsky H.

Transplant Center, Department of Medicine, Carolinas Medical Center, 1000 Blythe Blvd, 3rd Floor Annex Building, Charlotte, NC, 28203, USA, Mark.Russo@carolinashealthcare.org.

Abstract

BACKGROUND: Post-transplant hepatitis C is a major challenge after liver transplantation (LT). Antiviral therapy is associated with lower efficacy in the post-transplant setting.

AIMS: The purpose of this study was to determine the safety and effect of intravenous interferon (IFN) during the anhepatic phase of LT on hepatitis C viral load.

METHODS: Fifteen consecutive subjects undergoing liver transplant for hepatitis C cirrhosis were enrolled in the study, ten of which received study drug and five subjects served as controls. Cases received weight-based ribavirin and subcutaneous IFN at time of incision followed by intravenous IFN at the start of the anhepatic phase. Adverse events and viral levels were recorded. Repeated measures ANOVA was employed to test for differences over time, between the groups, and time by group interaction.

RESULTS: All subjects had genotype 1 virus. Hepatitis C viral load was lower at week 4 in cases compared to controls (769,004 ± 924,082 IU/ml and 2,329,896 ± 3,731,749 IU/ml, respectively), but did not reach statistical significance (p = 0.50). Three subjects developed adverse events related to IFN including pulmonary edema, rejection, and neutropenia.

CONCLUSIONS: Intravenous IFN administered during the anhepatic phase of liver transplant did not prevent graft reinfection and was associated with manageable adverse events. This regimen could be further studied if direct acting antiviral agents alone are insufficient for treating post-transplant hepatitis C.

PMID: 23812862 [PubMed - in process]

Source

Diabetes Mellitus and Advanced Liver Fibrosis Are Risk Factors for Severe Anemia During Telaprevir-based Triple Therapy

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

DOI: 10.1111/liv.12342

This article is protected by copyright. All rights reserved.

James F. Crismale1, Valérie Martel-Laferrière1, Kian Bichoupan1, Emily Schonfeld1, Alexis Pappas1, Christina Wyatt2, Joseph A. Odin1, Lawrence U. Liu1, Thomas D. Schiano1, Ponni V. Perumalswami1, Meena Bansal1, Douglas T. Dieterich1, Andrea D. Branch1,*

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12342

Publication History
Accepted manuscript online: 1 OCT 2013 12:35AM EST
Manuscript Accepted: 22 SEP 2013
Manuscript Revised: 14 SEP 2013
Manuscript Received: 20 MAY 2013

Keywords: hepatitis C virus; telaprevir; pegylated-interferon; ribavirin; triple therapy; anemia; diabetes mellitus

Abstract

Background

Adding telaprevir to pegylated-interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment.

Aims

We identified variables associated with severe anemia during telaprevir-based triple therapy.

Methods

An observational study was performed on 142 HCV-infected patients between June 2011 and March 2012. All subjects completed 12 weeks of telaprevir-based triple therapy or discontinued early due to anemia. Severe anemia was defined by a hemoglobin ≤8.9 g/dL; advanced fibrosis was determined by Fib-4 ≥3.25.

Results

The 47 (33%) patients who developed severe anemia were similar to those who did not in sex, race, and prior response to dual therapy, but they were more likely to have diabetes (23.4% vs. 6.3%, p<0.01), advanced fibrosis (46.8% vs. 29.5%, p=0.04), and a history of anemia during previous dual therapy (29.7% vs. 11.4%, p=0.02). Patients developing severe anemia were older (59 vs. 56 years, p=0.02), had lower baseline platelet counts (134 vs. 163 x10⁹/L, p=0.04), hemoglobin (14.0 vs. 15.0 g/dL, p<0.01), estimated glomerular filtration rate (79 vs. 90 mL/min/1.73m², p=0.03), and a higher median ribavirin/weight ratio (14.9 vs. 13.2 mg/kg, p<0.01). In multivariable logistic regression, presence of diabetes (OR=5.61, 95%CI: 1.59-19.72), Fib-4 ≥3.25 (OR=3.09, 95%CI: 1.28-7.46), higher ribavirin/weight ratio (OR=1.31 per mg/kg, 95%CI: 1.13-1.52), and lower baseline hemoglobin (OR=0.57 per g/dL, 95%CI, 0.41-0.80) were independently associated with developing severe anemia.

Conclusions

Severe anemia occurred in one-third of patients receiving telaprevir-based triple therapy. Risk was greater in patients with diabetes, advanced liver fibrosis, higher ribavirin/weight ratio and lower baseline hemoglobin.

Source

Researchers identify liver cancer progenitor cells before tumors become visible

Provided by MedicalXpress

October 10, 2013

This is a stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks). Credit: University of California - San Diego

For the first time, researchers at the University of California, San Diego School of Medicine have isolated and characterized the progenitor cells that eventually give rise to malignant hepatocellular carcinoma (HCC) tumors – the most common form of liver cancer. The researchers found ways to identify and isolate the HCC progenitor cells (HcPC) long before actual tumors were apparent.

Writing in the October 10, 2013 issue of the journal Cell, principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology, and colleagues report that HcPC take form within dysplastic or abnormal lesions often found in damaged or cirrhotic livers. The liver damage can be due to viral infections like hepatitis or from chronic alcohol abuse.

"It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually pre-malignant lesions that harbor tumor progenitor cells," said study co-author Debanjan Dhar, PhD, a postdoctoral researcher in Karin's lab. "Here we show that HcPC are likely derived from dysplastic lesions, can progress to malignant tumors and further demonstrate that the malignant progression of HcPC to full-blown liver cancer depends upon the microenvironment that surrounds them."

The researchers were able to characterize HcPC based on several biomarkers that distinguish them from normal cells. They also identified cellular signaling pathways activated in HcPC that are critical "to their malignant potential," said Dhar.

The findings may have profound implications for treating HCC which, while relatively rare in the United States compared to other types of cancer, is difficult to diagnose and treat, with poor prognoses for patients. HCC is usually fatal within three to six months of diagnosis, according to National Institutes of Health data. An estimated 30,000 new cases of liver cancer are diagnosed annually in the U.S., predominantly among men. More than 21,600 Americans die from liver cancer each year, a rate that has been rising slowly for several decades. In other parts of the world, HCC is a major cause of cancer-related deaths.

Most cancers are best detected and treated at the earliest possible stage. HCC is problematic because it develops slowly and frequently displays no symptoms. By the time it is detected, said Dhar, it is usually at an advanced stage with no effective therapy.

"Our findings can be translated into both early detection and therapeutic intervention," he said. "Better understanding of HcPC cellular networks will provide us with new and effective therapeutic targets."

For example, the researchers were able to detect "potential" malignant lesions in needle biopsies of a subset of patients infected with the hepatitis C virus, but who hadn't yet developed HCC. Hepatitis C is a major risk factor for HCC development.

Dhar said identifying premalignant lesions in high-risk patients based on HcPC markers would allow for earlier detection and therapeutic interventions. "Furthermore, in future, therapies can be developed to specifically eliminate the HcPC even before a tumor has developed."

Explore further: New evidence for genetic bases of liver cancer reported

Journal reference: Cell

Provided by University of California - San Diego

Source

Novel stem cell technique may transform liver and pancreatic transplant therapies

By Loren Grush Published October 10, 2013 FoxNews.com

Foregut stem cells (green) differentiated into pancreatic cells expressing insulin. (Dr. Nicholas Hannan)

Researchers from the University of Cambridge have developed a new technique for creating stem cells of the human liver and pancreas – a breakthrough that could significantly transform the future of transplant therapies.

The novel method involves altering the signal pathways of cells specific to the human foregut – the upper portion of the gastrointestinal (GI) tract.  Through this manipulation, researchers were able to stop the cells from developing fully and push them into a state of constant self-renewal.

As a result, these “foregut stem cells” can then be further amplified by physicians, who can then form them into liver or pancreatic cells.  These cells could potentially be used to treat damaged organs or tissue, in addition to conditions such as type 1 diabetes or metabolic liver disease.

According to the researchers, their technique improves upon existing methods for creating liver or pancreatic stem cells, which sometimes do not yield enough cells for transplantation.

“We had identified that problem going forward: There is no process to amplify a population of cells that can be used for transplant therapy,” lead author Dr. Nicholas Hannan, from the University of Cambridge Wellcome Trust MRC Stem Cell Institute, told FoxNews.com. “We thought if we could develop a technique that would allow us to capture the progenitive population of cells, this would be the perfect cell type you would want to expand and have at the ready to differentiate into liver and pancreatic cells.”

Currently, most stem cells begin as human pluripotent stem cells (hPSCs).  These types of stem cells sit at the top of the hierarchy for differentiation, as they have the potential to transform into any one of the three primary embryonic layers of human cells – the mesoderm, the ectoderm or the endoderm.  Since these kinds of stem cells are also self-renewing, they provide physicians with a potentially infinite source of viable cells for regeneration.

However, differentiating hPSCs into liver and pancreatic cells can be tricky.  To create these kinds of cells, hPSCs must be differentiated solely into the endoderm layer – the tissue primarily associated with organs of the digestive and respiratory system.   

But since hPSCs have a lot of variability in terms of how they are derived and the kinds of cells they can become, cell cultures intended to create pancreatic or liver cells are often “contaminated” with the wrong cell types, rendering the precursor population unusable for further differentiation.

To address this problem, the researchers studied the conditions under which cells differentiate specifically into the human foregut. Hannan explained that at some point during development, all cells eventually move through the foregut state – when they are just part of the endoderm layer.

“As we do develop organs, we have to naturally move through the foregut state,” Hannan said.  “Everyone develops a foregut during development, and most of the techniques that produce cells actually transition through the foregut state, but isolating it is difficult.  Our natural tendency is to move down the developmental program.”

Hannan and his team discovered that in order to restrict these cells to the foregut state, a specific set of genes in the cells needed to be expressed.  When they developed their stem cell populations under these conditions, the non-endodermal cells eventually stopped growing while the endodermal cells flourished.

“We’ve basically taken pluripotent cells and induce them into the endoderm,” Hannan explained. “So these foregut cells can’t make mesoderm or ectoderm.  They’re restricted solely to the endoderm layer.”

The result of this gene manipulation was a “purer” population of human foregut stem cells (hFSCs), able to self-renew and differentiate into any cell in the human foregut.  The researchers also found that transplanting these cells did not form any tumors, making them a safe choice for physicians and patients.

According to Hannan, these cells have the potential to aid a variety of patients – such as those suffering from type 1 diabetes, individuals with inherited metabolic problems of the liver, and even patients who require a liver or pancreas transplantation.

“What we have now is a progenitive pool of cells that can make any cell type in the foregut,” Hannan said.  “Literally, the millions and millions of cells required (for transplantation) are difficult to amplify without the culture system we’ve developed.”

The research was published in the journal Stem Cell Reports.

Source

Galectin Therapeutics' Preclinical Data Show Its Inhibitors Reverse Cirrhosis & Significantly Reduce Fibrosis and Portal Hypertension

Press Release

Oct. 10, 2013, 8:01 a.m. EDT

Galectin Therapeutics' Preclinical Data Published in PLOS ONE Show Its Galectin Inhibitors Reverse Cirrhosis and Significantly Reduce Fibrosis and Portal Hypertension

 

Findings Suggest Role for GR-MD-02 and GM-CT-01 in Treatment of Liver Fibrosis and Cirrhosis in Humans

NORCROSS, Ga., Oct 10, 2013 (GLOBE NEWSWIRE via COMTEX) -- Galectin Therapeutics /quotes/zigman/9334018/quotes/nls/galt GALT +7.73% , the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today announced that new preclinical data show its galectin inhibitors, GR-MD-02 and GM-CT-01, have significant therapeutic effects on fibrosis regression and cirrhosis reversal. Results were published in an article titled "Regression of Fibrosis and Reversal of Cirrhosis in Rats by Galectin Inhibitors in Thioacetamide-Induced Liver Disease" in PLOS ONE, an international, open-access journal with rigorous peer review.

In the preclinical study, fibrosis was induced in rats by injecting thioacetamide (TAA) into the abdominal cavity. Rats were then treated with GR-MD-02 (galactoarabino-rhamnogalaturonan) or GM-CT-01 (galactomannan). In the initial part of the study, rats that completed eight weeks of thioacetamide injections were given four weeks of treatment with GR-MD-02; results showed an almost 50 percent reduction in collagen content, a marker of chronic fibrosis. Rats were then exposed to additional thioacetamide injections and developed extensive fibrosis (cirrhosis); treatment with four once weekly doses of GR-MD-02 or GM-CT-01 while continuing treatment with the toxin TAA led to marked reduction in fibrosis and reversal of cirrhosis. Overall, the study demonstrated that GR-MD-02 or GM-CT-01 led to significantly reduced fibrosis, reversal of cirrhosis and a significant reduction in portal hypertension.

"These preclinical data suggest a potential role for GR-MD-02 and GM-CT-01 in the treatment of liver fibrosis and cirrhosis in humans," said Peter G. Traber, MD, President, Chief Executive Officer and Chief Medical Officer, Galectin Therapeutics Inc. "There are currently no approved therapies for fibrosis. Encouraging data like these published in PLOS ONE increase the body of scientific knowledge of galectin inhibitors and add momentum to Galectin Therapeutics' development program. We recently announced that GR-MD-02 received Fast Track designation from the FDA for fatty liver disease with advanced fibrosis."

The preclinical study was conducted predominantly at the Icahn School of Medicine at Mount Sinai in New York City. The senior author, Dr. Scott Friedman of Mount Sinai, is an international expert in the pathogenesis and treatment of liver fibrosis. The PLOS ONE article can be found online at http://dx.plos.org/10.1371/journal.pone.0075361

GM-CT-01 and GR-MD-02 are proprietary molecules, which are generated from naturally occurring carbohydrate polymers using proprietary processes, and possess the property of binding to and inhibiting galectin proteins, predominantly galectin-3. In July, the Company successfully dosed the first patient in a Phase 1 clinical trial of GR-MD-02 and enrollment is ongoing.

About Galectin Therapeutics

Galectin Therapeutics /quotes/zigman/9334018/quotes/nls/galt GALT +7.73% is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com.

Forward Looking Statements

This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. These statements include those regarding the potential role for GR-MD-02 and GM-CT-01 in the treatment of liver fibrosis and cirrhosis in humans. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others, that our plans, expectations and goals regarding any potential therapeutic uses and benefits of our drugs and any future pre-clinical or clinical studies are subject to factors beyond our control. Future clinical studies may not begin or produce positive results in a timely fashion, if at all, and could prove time consuming and costly. Plans regarding development, approval and marketing of any of our drugs are subject to change at any time based on the changing needs of our company as determined by management and regulatory agencies. Regardless of the results of current or future studies, we may be unsuccessful in developing partnerships with other companies or obtaining capital that would allow us to further develop and/or fund any studies or trials. To date, we have incurred operating losses since our inception, and our ability to successfully develop and market drugs may be impacted by our ability to manage costs and finance our continuing operations. For a discussion of additional factors impacting our business, see our Annual Report on Form 10-K for the year ended December 31, 2012, and our subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

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Also See: Galectin Inhibitors Reverse Liver Cirrhosis in Preclinical Studies

Can-Fite BioPharma to Present Its Liver Cancer Drug at the 18th World Congress on Advances in Oncology in Greece

SOURCE: Can-Fite BioPharma

October 10, 2013 07:00 ET

Phase II Trial to Commence Under FDA Orphan Drug Designation

PETACH TIKVA, ISRAEL--(Marketwired - Oct 10, 2013) - Can-Fite BioPharma Ltd. (TASE: CFBI), (OTCQB: CANFY), a biotechnology company developing a pipeline of small molecule drugs that address inflammatory and cancer diseases, announced today that the Company will be presenting its cancer drug, CF102, at the 18th World Congress on Advances in Oncology and the 16th International Symposium on Molecular Medicine, which is taking place in Crete, Greece on October 10^th through 12^th 2013. Can-Fite's CEO Dr. Pnina Fishman will be presenting on Friday, October 11 at 12:00 pm. The event is hosted by Spandidos Publications, a leading publishing group in the biomedical sciences field, and will focus on developing technologies for the treatment of cancer.

Can-Fite's CF102 is currently in Phase II clinical trials for primary liver cancer (hepatocellular carcinoma) in the U.S., Europe, and Israel. The United States Food and Drug Administration (FDA) granted CF102 Orphan Drug Designation. The Company is currently preparing for a 130 patient Phase II study in the treatment of advanced liver cancer in subjects with Child-Pugh B. According to Global Industry Analysts (GIA), the global liver cancer drug market is expected to exceed $2 billion by 2015. GIA further reports that liver cancer represents the fifth most commonly occurring cancer and the third leading cause of deaths related to cancer in the world.

"At the conference, I will share information about how CF102 targets the A3AR receptor, a highly specific target that binds with and destroys cancer cells, while leaving healthy cells unharmed. This creates potent and broad anti-cancer effects. I will also explain the drug's mechanism of action and share data from our Phase I/II clinical study," stated Can-Fite's CEO, Dr. Pnina Fishman. "Along with the rest of the presenters and participants at the 18^th World Congress on Advances in Oncology, we are working hard to advance the science of cancer treatment."

About Spandidos Publications
Spandidos Publications Ltd. was founded in 1992 and has developed into a leading publishing group in the biomedical sciences field. They currently publish eight journals: International Journal of Molecular Medicine, International Journal of Oncology, Molecular Medicine Reports, Oncology Reports, Experimental and Therapeutic Medicine, Oncology Letters, Biomedical Reports and Molecular and Clinical Oncology.

About Can-Fite Biopharma Ltd.
Can-Fite Biopharma Ltd is an Israeli public company, the ordinary shares of which are traded on the Tel Aviv Stock Exchange (the "TASE") (TASE: CFBI). Level II American Depository Receipts of the company are traded on the U.S. Over-the-Counter Markets (the "OTC Markets") (OTCQB: CANFY). Can-Fite, which commenced business activity in 2000, was founded by Pnina Fishman, Ph.D., researcher in the Rabin Medical Center, and by Ilan Cohn Ph.D., patent attorney and senior partner at Reinhold Cohn Patent Attorneys in Israel. Dr. Fishman serves as the Chief Executive Officer of Can-Fite. Dr. Fishman founded Can-Fite on the basis of her scientific findings, and Can-Fite is focused on the development of small molecule orally bioavailable drugs, in particular, ligands that bind to the A3 adenosine receptor. Such drugs mediate anti-inflammatory and anti-cancer effects and are suggested as a biological predictive marker. Can-Fite's lead drug candidate, CF101, is in clinical development for the treatment of autoimmune inflammatory diseases. Can-Fite's CF102 drug candidate is being developed for the treatment of liver diseases and its CF602 drug is being developed for the treatment of inflammation and sexual dysfunction. To date, more than 700 patients have participated in clinical trials conducted by Can-Fite. Can-Fite previously licensed its activity in the ophthalmic field to OphthaliX Inc., in which it holds a controlling interest and which is currently listed on the OTC Markets (OTCQB: OPLI).

Safe Harbor Statement
This press-release contains forward-looking statements, about Can-Fite's expectations, beliefs or intentions regarding, among other things, its product development efforts, business, financial condition, results of operations, strategies or prospects. In addition, from time to time, Can-Fite or its representatives have made or may make forward-looking statements, orally or in writing. Forward-looking statements can be identified by the use of forward-looking words such as "believe," "expect," "intend," "plan," "may," "should" or "anticipate" or their negatives or other variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical or current matters. These forward-looking statements may be included in, but are not limited to, various filings made by Can-Fite with the U.S. Securities and Exchange Commission (the "SEC"), press releases or oral statements made by or with the approval of one of Can-Fite's authorized executive officers. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to risks and uncertainties that could cause Can-Fite's actual results to differ materially from any future results expressed or implied by the forward-looking statements. Many factors could cause Can-Fite's actual activities or results to differ materially from the activities and results anticipated in such forward-looking statements, including, but not limited to, the factors summarized in Can-Fite's filings with the SEC and in its periodic filings with the TASE.

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Liver transplant recipients' cancer risk

Provided by MedicalXpress

October 10, 2013

Credit: Shutterstock

Liver transplant recipients are more susceptible to cancer, especially skin cancers, new Flinders University research shows.

Of the 198 people who had a liver transplant or were managed post-transplant in South Australia between 1991 and 2010, a quarter of patients developed post-transplant malignancies, with skin cancer being the most common (16 per cent) and the remaining nine per cent being solid organ malignancies, including lymphoma, lung, prostate and colorectal cancer.

The study, undertaken by Flinders Professor Bogda Koczwara, SA Liver Transplant Unit Director Dr John Chen and Perth oncologist Hilary Martin, aimed to assess overall survival rates for patients with post-transplant malignancies.

The recipients were aged between 19 and 64 years, with the majority of patients being treated for liver failure due to cirrhosis.

Dr Chen, based at Flinders Medical Centre, said the reason liver transplant recipients incurred a greater risk of cancer was because of the side-effects of immunosuppressive drugs, which prevent the patient's body from rejecting the organ.

"When you perform a transplant you have to lower the patient's immunity so they don't reject the organ but there's a price to pay, and that price is an increased risk of infections and malignancies," Dr Chen said.

"Transplant rejection used to be a major problem in the past but we've significantly improved the process of immunosuppression – the only problem is the side-effects remain an issue," he said.

"While there's been a lot of work done to fine-tune these drugs to minimise the risk of infection and malignancies, we still need to work out the right combination for different patients."

The study showed recipients diagnosed with a skin cancer that could be treated locally had an excellent prognosis, with none of the patients developing disease progression, recurrence or dying from the skin malignancies.

Patients with solid tumours had substantially worse overall survival, at 47 per cent compared with the skin cancer group of 88 per cent during the follow-up period.

Of the patients with solid tumours, those suitable for local therapy alone had satisfactory outcomes, however those with advanced malignancies requiring systemic therapy experienced significant treatment-related toxicities and had poor outcomes.

Dr Chen said because transplants were so successful these days, recipients were living longer and therefore had an even greater vulnerability to cancer, which often occurs later in life.

Until scientists find a way to minimise the adverse effects of immunosuppression, he said transplant recipients required ongoing surveillance and monitoring.

"The main thing we can do is regular check-ups for skin cancers, and for patients who are at high risk of other cancers, such as smokers, we can survey the aerodigestive tract and for older patients we can do periodic colonic surveillance to look for large bowel tumours.

"Although it's more common for liver transplant recipients to develop cancer, the good news is they can be cured with early detection and treatment."

The study was published earlier this month in the Asia-Pacific Journal of Clinical Oncology.

Explore further: Renal risk index: A clinical tool to predict the risk of end-stage renal disease

Provided by Flinders University

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Management of anaemia and other treatment complications

Dig Liver Dis. 2013 Sep 30;45S5:S337-S342. doi: 10.1016/j.dld.2013.07.010.

Hézode C.

Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France. Electronic address: christophe.hezode@hmn.aphp.fr.

Abstract

Antiviral treatment for hepatitis C virus infection has dramatically changed with the advent of triple therapy including telaprevir or boceprevir, which is associated with a new spectrum of adverse events. These may lead to dosage reduction and early discontinuation of therapy. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the telaprevir-based regimen. The first-line management of anaemia is ribavirin dose reductions. In cirrhotic patients, aggressive ribavirin dosage reductions, erythropoietin alpha and blood transfusions are effective in managing anaemia. Several deaths and cases of severe infections and hepatic decompensation were reported in cirrhotics treated in real-life setting. Patients with platelet count≤100,000/mm³ and serum albumin<35g/L should not be treated with triple therapy as it is related to a high risk of developing severe complications. The management of rashes, if well planned, does not require telaprevir discontinuation. However, approximately 5% of rashes were severe and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. Successful treatment can be enhanced by a strong patient support network including a multidisciplinary team.

Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: Anaemia, Hepatitis C, Protease inhibitor, Rash

PMID: 24091113 [PubMed - as supplied by publisher]

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