Cocaine overdose 'antidote' in the future?

By Loren Grush Published April 18, 2012 FoxNews.com

The potential effects of a cocaine overdose can be devastating – including stroke, seizure, kidney failure and even death.

But now, a cocaine “antidote” could soon be available for emergency scenarios.

Scientists at The Scripps Research Institute in La Jolla, Cali., have come up with an injectable solution that has been shown to reverse the effects of cocaine overdose in mice. After success with their experiments thus far, the researchers are eager to move on to human clinical trials – and potentially develop a viable treatment.

“Cocaine is a stimulant – so a huge amount affects the cardiovascular system,” said Kim Janda, a professor in the Department of Chemistry and Immunology at Scripps and senior author of the study. “We’re trying to remove the cocaine from these major centers like the bloodstream and the brain, so that they won’t have any effect.”
Janda and his team have been working on developing vaccines for various other drugs such as heroin, nicotine and Rohypnol, the “date rape” drug. However, most of the vaccines they’ve come up with have been “active” vaccines – drugs that provoke a long-term antibody response. While these can be helpful in treating addiction and relapse, they can take weeks to take effect.

The antidote Janda’s laboratory has developed is a “passive” cocaine vaccine – a solution of drug-specific human antibodies that can quickly bind to the cocaine in the body and render them ineffective.

“It’s like a sponge, you spill something and you go soak it up,” Janda said. “[When cocaine] is in the body, the antibodies bind to it and remove it either through the kidney or the liver - or it’s just degraded. The antidote either sequesters [cocaine] in the blood or pull them out of the brain. The antibodies can’t go into the brain themselves, but they act as a vacuum cleaner to remove it from the brain.”

Not only did the human antibodies trigger an immediate response, they also lingered in the body for some weeks after administration, continually reducing the effect of cocaine in the body – a trait could potentially keep cocaine addicts from relapsing after overdose.

In order to create their antidote, Janda and his research associate Jennifer Treweek used a genetically engineered mouse that produced human antibodies to target the cocaine. The antibodies they found to be most effective were GNCgzk and F(ab’)2-gzk, a stripped-down version of GNCgzk.

In an attempt to mimic a real life scenario, mice were given a lethal cocaine overdose and were then administered the antibodies three minutes later. About half of the untreated mice died while the GNCgzk antibodies reduced the mortality rate to 20 percent. The stripped-down GNCgzk was even more successful – reducing the mortality rate to zero.

Not only were the researchers successful in preventing death from cocaine overdose, they were equally effective in reducing pre-morbid behaviors in the mice such as seizures, twitching and erratic movements – mannerisms that could indicate brain damage.

“That was just as important as reducing lethality,” said Treweek. “You don’t want to bring someone back from death just to have them be a vegetable.”

According to the Centers for Disease Control and Prevention, over 400,000 emergency room visits each year are cocaine-related in the United States, while over 5,100 people die from overdose. With a such a promising life-saving antidote on the horizon, the researchers are now trying to determine a way to produce a large amount of their vaccine inexpensively and efficiently – so they can make the case to move on to human trials.

Janda said that their vaccine could either come in the form of a solution or a powder – an option that could make it stored much more easily. Also, in order for the antidote to be effective, only a small amount would need to be administered.

“When we tried to develop this in the past, if you give a lethal dose of cocaine to a human, you’d need a huge amount of antibodies to combat it – tens of grams,” Janda said. “It would not be feasible to give them that much. With this antidote, we can use a 100-fold less – it’s in a realm that you can give to a person.”

From helping to reduce the immediate effects of overdose to preventing relapse in addicts, Janda and his team feel their antidote could be a practical life-saver for the future.

“Is there a need for it? Yes,” said Janda. “It could be something simple that a paramedic could have onboard [an ambulance] and just inject it. It’s easy.”

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Blood test looks promising in diagnosing depression

A preliminary study finds certain biological markers in the blood of teens with depression that are absent in healthy counterparts. It could lead to the first diagnostic testing for depression.

A new study takes a significant step in that direction by demonstrating that a simple blood test can distinguish between people who are depressed and those who are not. (Hannah Johnston / Getty Images / April 17, 2012)

By Melissa Healy, Los Angeles Times

April 17, 2012, 6:39 p.m.

Even among psychiatric disorders, depression is a difficult disease to diagnose. Its causes remain a mystery, its symptoms can't be defined with precision, and treatments are spotty at best.

But that may soon change. Scientists are looking for ways to identify patients with depression as reliably as they diagnose cardiovascular disease, diabetes and cancer. A new study takes a significant, though preliminary, step in that direction by demonstrating that a simple blood test can distinguish between people who are depressed and those who are not.

The test examined a panel of 28 biological markers that circulate in the bloodstream and found that 11 of them could predict the presence of depression at accuracy levels that ranged from medium to large. And if that were not remarkable enough, researchers pulled off this feat in a group of teenagers, whose angst often defies all efforts at classification.

The study, published online Tuesday in the journal Translational Psychiatry, offers hope that doctors can do a better job of helping adolescents whose mood difficulties go beyond those of typical teens, and whose lifelong prospects could be greatly improved by early treatment. What's more, by using objective data to diagnose mental pain, researchers hope to remove the stigma that often prevents patients from reaching out to doctors.

"Once you have a measurable index of an illness, it's very difficult to say, 'Just pull yourself together,' or 'Get over it,' " said study leader Eva Redei, a professor of psychiatry and behavioral sciences at Northwestern University's Feinberg School of Medicine in Chicago. A federal report released last year estimated that as many as two-thirds of the nation's 2 million depressed teens are too embarrassed or ashamed to get help.

The study drew responses of praise and caution from other researchers seeking better ways to diagnose and treat major depressive disorder.

"This is definitely an encouraging study," said Dr. Andrew Leuchter, a UCLA psychiatrist who is researching ways to improve treatment with genetic testing and was not involved in the new work. Finding a way to intervene with teens would be particularly valuable since a bout of depression early in life makes repeat episodes more likely, and therefore more urgent to treat, he said.

The current study focused on teens and "early onset" depression, but the researchers said they hoped to include adults in future testing.

Redei's study takes a middle-of-the-road approach to the search for a "biomarker" of depression. Her team did not look for genetic variations that might predispose an individual to depression, nor did it use advanced MRI scans to home in on peculiarities in the way the depressed brain works. Instead, the team focused on the messenger molecules that carry out genetic instructions for producing or inhibiting proteins.

The researchers started out with rats, breeding some for their vulnerability to depression and raising others to serve as healthy control subjects. In an effort to tease out the long-term molecular consequences of childhood stress, some rats from both groups spent hours restrained and alone in their cages. After several generations, the researchers identified 11 distinct molecules that were often found in the blood and brains of depressed rats but were largely absent in the healthy animals.

The tests also turned up 15 molecules that distinguished rats who suffered from a combination of depression and severe anxiety from those whose depression resulted in listless, helpless behavior.

Then the researchers tested the predictive value of the same biomarkers in a group of 14 depressed teens between the ages of 15 and 19 and a group of 14 healthy control subjects. Sure enough, the teens with depression had significantly higher concentrations of the 11 targeted molecules in their blood. In addition, there were 18 biomarkers that could distinguish between adolescents who suffered from depression alone and those who had depression and anxiety.

Dr. Sidney Kennedy, a psychiatrist at the University of Toronto who is leading a project called the Canadian Depression Biomarker Network, said Redei's study was the first to use messenger molecules as biological signposts for depression. As other efforts to find biomarkers mature — including costly brain scans and genetic analyses — those could refine and strengthen a blood test to screen large populations, he said.

"There is merit in this work," Kennedy added.

In the meantime, he praised the study for making a first attempt at one of the field's most ambitious goals: to explain, describe and distinguish among depression's many and varied forms.

Redei said her team hoped to perfect the blood panel by testing it in larger and more varied groups of subjects — including those with other psychiatric illnesses, including bipolar disorder, that are sometimes mistakenly diagnosed as major depression.

But before any such blood test could go into broad use, she cautioned, scientists would have to show that it could reliably detect the presence of illness without generating too many false positives.

"The probability that we will be able to put together a panel that's usable is rather high," she said. "This data at the moment truly proves that it can be done."

melissa.healy@latimes.com

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California to test HIV-prevention pill

Truvada, used to treat patients who are infected, will given to high-risk people who don't have the virus. At $26 a day, the pill only makes economic sense for those at greatest risk, a study found.

By Anna Gorman, Los Angeles Times

April 18, 2012

California will test an HIV-prevention pill in an attempt to slow the spread of the disease in the state, researchers announced Tuesday.

The pill, which is already used to treat HIV patients, will be prescribed to 700 gay and bisexual men and transgender women in Los Angeles, San Diego and Long Beach who are high-risk but not infected.

"With this new prevention pill, we have another intervention to put in the arsenal to try and impact this epidemic," said George Lemp, director of the California HIV/AIDS Research Program with the UC president's office.

The program awarded $11.8 million in state grants for the prevention pill studies and efforts to get about 3,000 HIV-infected people in Southern California into treatment and keep them there. The grants will go to a group of UC schools, local governments and AIDS organizations.

There are an estimated 140,000 people living with HIV or AIDS in California, including about 30,000 who don't know they are infected, Lemp said.

The pill, under the brand name of Truvada, is already approved by the Food and Drug Administration for treating HIV but not for prophylactic use. In 2010, a study published in the New England Journal of Medicine said that it reduced the risk of contracting HIV by 44% to 73%, depending on how often participants took their medication.

The two-drug pill, produced by Gilead Sciences in the Bay Area, has side effects that include nausea and vomiting, and possible kidney problems when used with other anti-HIV drugs.

A recent Stanford University study showed that the pill, which costs about $26 a day, only makes sense economically if prescribed to people at high risk, such as those with multiple partners.

The prevention pill and counseling have "enormous possibilities" for high-risk people, said Phil Curtis, director of government affairs for AIDS Project Los Angeles, which will be recruiting participants. But more research is needed to measure the effects in the real world, when patients may not be followed as closely, he said.

"It is unrealistic to expect that a patient without HIV is going to see a doctor every month," he said.

The director of San Diego's study, Dr. Richard Haubrich of UC San Diego School of Medicine, said that when taken as prescribed, the pill can prevent HIV infection. But he said the biggest impediment is people taking their medicine.

In San Diego, researchers plan to use text messages to remind people to take their pill. In Los Angeles, researchers plan to regularly measure the level of the drugs in participants' blood. Those who receive the pill will also participate in counseling and regular screening for HIV and other sexually transmitted diseases.

Critics say there is not enough evidence of the pill's effectiveness to support its use. In addition, they say the pill could lead to more men not using condoms and result in more new infections.

"Men — gay, straight, bisexual — don't want to use condoms," said Michael Weinstein, president of the AIDS Healthcare Foundation. "That's universal. If they are given another reason, then they won't."

anna.gorman@latimes.com

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First Ever National Hispanic Hepatitis Awareness Day 2012 Official Website Launch

PRESS RELEASE

April 18, 2012, 12:29 p.m. EDT

NEW YORK, Apr 18, 2012 (BUSINESS WIRE) -- National Hispanic Hepatitis Awareness Day has officially launched the unveiling of its website, www.hispanichepatitisday.org . The website holds a wealth of resources ranging from information on Hispanics/Latinos and viral hepatitis to tools on how to engage Hispanic/Latino communities on a range of events, including hepatitis C testing. The Hispanic Hepatitis Day campaign works annually at building capacity for non-profit organizations, service providers and health departments in order to reach Hispanic/Latino communities, promote screening and testing, provide viral hepatitis education, and connect people to care.

The Hispanic Hepatitis Day will take place annually on May 15, during National Hepatitis Awareness Month. This year's theme -- Let's Talk about Hepatitis! -- speaks to the critical role of raising awareness around viral hepatitis, especially screening and testing, due to the late testing realities faced by Hispanic/Latino communities. Data shows that Hispanics/Latinos progress to cirrhosis faster and have higher cirrhosis mortality rates than non-Hispanic Blacks and Whites. Research also shows that Latinos have a 40% increased chance of being infected with hepatitis C as compared to the general population. You can obtain more information about hepatitis testing or find a testing location near you by calling the CDC hotline at 1-800-232-4636 or by visiting www.hispanichepatitisday.org .

For more information on National Hispanic Hepatitis Awareness Day, please visit www.hispanichepatitisday.org  or contact Bethsy Morales-Reid, Director at bmorales@hispanichepatitisday.org  or 212-675-3288.

ABOUT THE LATINO COMMISSION ON AIDS

The Latino Commission on AIDS (Commission) is a nonprofit membership organization founded in 1990 dedicated to addressing the health challenges and addressing the impact of HIV/AIDS. The Commission is the leading national Latino AIDS organization coordinating National Hispanic Hepatitis Awareness Day, National Latino AIDS Awareness Day and other prevention, research, capacity building and advocacy programs across the United States and its territories.

SOURCE: The Latino Commission on AIDS

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Single-Pill Treatment Is Associated With Better Treatment Adherence In People With HIV

Provided by The Aids Beacon

By Kieryn Graham
Published: Apr 18, 2012 10:23 am

Results from a recent study suggest that people with HIV whose antiretroviral regimen is taken as a single pill per day have better treatment adherence and a lower risk of hospitalization compared with people whose regimens consist of three or more pills per day.

“This study found that patients who receive [antiretroviral therapy] as a single pill per day are significantly more likely to be highly adherent to therapy. Furthermore, receiving a single pill per day was associated with a lower risk of hospitalization when compared with receiving multiple pills per day,” wrote the study authors.

“Although this study could not assess causality, it did show that receiving [antiretroviral therapy] as a single pill per day was associated with potential clinical and economic benefits,” they added.

According to the study investigators, high, sustained treatment adherence is necessary throughout a patient’s lifetime for optimal treatment outcomes. Studies in patients receiving older antiretroviral regimens suggest that an adherence rate of at least 95 percent is necessary to reduce risk of treatment failure, hospitalization, and death in people with HIV.

Older combination antiretroviral therapy regimens involve several pills and multiple doses per day. However, more recent regimens with fixed-dose combinations have allowed for simpler dosage schedules, often one pill per day.

Previous studies have suggested that single-pill treatments improve adherence, with adherence levels of up to 98 percent. For example, in a study among homeless people, those receiving an antiretroviral regimen consisting of a single pill per day had lower amounts of HIV virus in their blood and a 26 percent increase in adherence compared with participants who received multi-pill per day regimens.

In this study, researchers sought to confirm whether fewer antiretroviral pills taken per day improve the adherence of people with HIV. They also evaluated how adherence and number of pills per day related to the likelihood of being hospitalized.

The researchers examined medical records from 7,073 adults with HIV who took antiretroviral drugs between mid-2006 and late 2008. The researchers grouped participants according to how many pills they took per day: one pill per day (33 percent of participants), two pills per day (6 percent), or three or more pills per day (61 percent). All study participants remained on antiretroviral therapy for at least 60 days.

The average participant age was 45 years old, and about 80 percent were male.

About 42 percent of participants in the single pill per day group were previously untreated (treatment naïve), compared to 25 percent of participants in the two pills per day group and 20 percent of participants in the three or more pills per day group.

Results showed that 47 percent of single pill per day participants achieved 95 percent adherence or greater, compared with 41 percent of participants in the two pills per day group and 34 percent of participants in the three or more pills per day group.

Treatment-naïve patients and patients who received treatment in 2008 versus 2006 were more likely to achieve 95 percent adherence. Participants with alcohol or drug abuse problems and female participants were less likely to reach 95 percent adherence.

Results also showed that participants were over 40 percent less likely to be hospitalized if they were adherent to therapy.

Among patients who received a single pill per day, 6.6 percent of those who achieved 95 percent adherence were hospitalized at least once, versus 11.4 percent of participants who were not as adherent.

For participants in the two pills per day and three or more pills per day groups, 6.6 percent and 7.8 percent of patients, respectively, who achieved 95 percent adherence were hospitalized at least once, compared with 15.2 percent and 12.1 percent of patients in each group, respectively, who did not achieve 95 percent adherence.

Overall, participants who received a single pill per day were 24 percent less likely to be hospitalized than participants who received three or more pills per day.

In addition, study participants with mental disorders, drug or alcohol abuse problems, and female participants were more likely to be hospitalized, as were those covered by Medicare or who were self-insured versus those covered by private health insurance.

For more information, please see the study in PLoS One.

Photo by Hoggheff aka Hank Ashby aka Mr. Freshtags

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Wonky Policies and the Chocolate Factory: The Milton Hershey School Is Wrong on HIV

James Peron

President, Moorfield Storey Institute

Posted: 04/18/2012 12:49 pm

Right from the start the Milton Hershey School had questionable policies. Twice it changed those policies: once to remove their whites-only requirement (1970), and once to allow the enrollment of female students (1976). Now they actively discriminate against students who are HIV-positive. The school is run by a trust that actually owns controlling interests in the Hershey Company, which produces all that chocolate.

The Milton Hershey School houses 1,800 students from preschool through high school, although new students are admitted only up to age 15. The majority of students are in grade school, with 48 percent in high school. If the high school population is evenly distributed across the various grades, then approximately 76 percent of the school's students are below the age of consent in Pennsylvania.

Recently, the school refused admission to a student who appeared qualified in all ways. They chose to refuse him solely because he is HIV-positive. They said he poses a threat to all other students, saying, "We take full accountability for our students." And they point out, "Our students are children." They have to protect these children from dangerous people -- like other children who are HIV-positive.

They claimed the HIV-positive boy posed "a direct threat to the health and safety of others that cannot be avoided by reasonable modifications of the School's policies and procedures." They reject the idea of casual transmission but fear that "some of our students will engage in sexual activity with one another. Given our residential setting, when they do, they will be doing so on our watch." They said, "If we knowingly admitted a student with HIV, and that student ultimately had sexual relations with another student that led to the transmissions of HIV, we believe we would have failed in meeting our obligation."

However, this "failure" is limited to this one student. In their health policy section they write, "At times, sensitive issues arise which a student may feel unable to discuss with his/her family. These might include issues of sexuality, birth control, pregnancy, and/or sexually-transmitted diseases. In such situations, and in order to provide timely information and treatment, the student's request for confidentiality will be respected."

The school would "fail" in the unlikely situation of a 14-year-old infecting another student with HIV, yet it would not fail when children under their care become pregnant or spread sexually transmitted infections to one another. In the case of the 14-year-old, they refused his admission; in the case of pregnant students or students with STIs, the Milton Hershey School actively cooperates to hide the information from parents or guardians. Because most Hershey students are under the age of consent, this confidentiality policy, whatever you may think of it, actually violates state law in most cases.

Early in their statement they justify discrimination against an HIV-positive child because "our students are children" but elsewhere discuss how their "children" are spreading STIs and getting pregnant and why the school will hide this information from guardians and parents. They respect the rights of the students when convenient, and then invoke the safety of the "children" when convenient. The policy seems a tad inconsistent, flexible to the point of justifying any policy they want, no matter how irrational.

They say they try to educate the children, but that "some ... will engage in sexual activity with one another" and that "they will be doing so on our watch." So, on their watch, they know children are having sex. They know these children apparently are spreading STIs and becoming pregnant. Doesn't this indicate, by their own logic, that they are failing their children and that they simply don't have reasonable policies in place to prevent pregnancy and STIs? Why is HIV status their one big concern?

I understand why liberals and libertarians are shocked by a policy singling out a boy with HIV and labeling him a "threat." It's enough to make me stop eating Hershey's chocolates. But shouldn't conservatives be upset and boycott Hershey, as well? After all, the owners of Hershey run a school where they admit that children under their care are sexually active, and they will deal with the pregnancies, birth control, and STIs entirely in secret if the student requests it. Has Hershey actually managed to craft a policy guaranteed to offend everyone?

On the other hand, they claim that their students "live as families in homes with 10 to 12 other students, where our houseparents care for them 24 hours a day, 7 days a week, throughout the calendar year." They have classroom sizes of 15 students per teacher and have surveillance systems throughout the campus. It makes you wonder why they assume that this one boy would be spreading HIV with willing partners with that much adult supervision. On the other hand, the school admits to problems with STIs and teen pregnancy, calling into question how observant all this adult supervision may be.

If they have decent adult supervision, then why can't they admit this one boy? If they don't have decent adult supervision, then they have bigger concerns than this boy.

The school may do some good. It may do a lot of good. However, the way they defend their policy in regard to this child raises awkward questions detrimental to the school itself.

Individuals wishing to complain about the policy may email the school at mhs-communications@mhs-pa.org.

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The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011

Liver International

Early View (Online Version of Record published before inclusion in an issue)

Review Article

Peipei Song¹, Ruoyan G. Tobe², Yoshinori Inagaki¹, Norihiro Kokudo¹, Kiyoshi Hasegawa¹, Yasuhiko Sugawara¹, Wei Tang^1,*

Article first published online: 20 MAR 2012

DOI: 10.1111/j.1478-3231.2012.02792.x

© 2012 John Wiley & Sons A/S

Abstract

In the past 10 years, many guidelines for hepatocellular carcinoma (HCC) have been published worldwide. To promote standard care for HCC, we systematically evaluated 17 current guidelines for HCC around the world, including 5 guidelines from the USA, 7 from Asia and 5 from Europe, according to the selection criteria of credibility influence and multi-faceted. After a systematic evaluation, we found that these guidelines have both similarities and differences in terms of what organizations or bodies drafted the guidelines and the approach, applicability, content and recent updates of the guidelines as well as in terms of diagnostic and treatment algorithms. The differences could be attributed to various aetiological factors, high-risk patients, health systems, health resources, medical technology, treatment choices and income levels in different countries. Besides, although the full implementation of guidelines could benefit clinicians, patients and authorities, there is still a gap between projected goals and implementation. The factors potentially influencing implementation are what organizations or bodies are drafting guidelines, content and emphasis, modification and consistency of guidelines. Comparative analysis suggested that countries pay close attention to targeted audiences, a basis in evidence, a basis in available resources, applicable patients and systematic evaluation when establishing and implementing domestic guidelines for HCC.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 80–90% of all cases of liver cancer [1]. It is the fifth most common cancer and the third leading cause of cancer-related deaths around the world, and more than 600 000 deaths are reported globally each year [2, 3]. Many studies worldwide have examined the management of HCC over the past 10 years [4, 5, 6]. Following a management model, guidelines were defined as ‘systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances’ [7]. The full implementation of guidelines could achieve the following goals: (i) serving as a guide for appropriate clinical decision-making by clinicians; (ii) improving the quality of healthcare and outcomes for patients and (iii) supporting and influencing regional or national authorities that allocate resources [8]. A systematic review of clinicians’ attitudes regarding guidelines (30 sources from 1990 to 2000 were analysed) found that 70–75% of clinicians agreed that guidelines were a useful source of advice, a good educational tool, and could help to improve the quality of healthcare [9]. An observational study evaluated the outcomes of guideline-adherent therapy and guideline-nonadherent therapy in 1,778 patients with early onset breast cancer, and the study found that guideline-adherent treatment for early onset breast cancer patients significantly improved their recurrence-free survival and overall survival [10].

Evaluation of current guidelines for hepatocellular carcinoma

In the past 10 years, many guidelines for HCC have been published worldwide since the European Association for the Study of the Liver published their guidelines for HCC (EASL Guideline) in 2001 [11]. In this article, we did an English language literature search on the topic of the guidelines or consensus for HCC published in PubMed database during the period 2001–2011. References that satisfied all of the following three criteria were included: (i) Credibility, as measured by whether the guidelines were widely cited by subsequent guidelines or other publications regarding the management of HCC after the original guidelines were published; (ii) Influence, an indication that the guidelines were created with the support of government or academic/medical societies and that the guidelines attract nationwide attention regarding their implementation and the standard care for HCC and (iii) Multi-faceted, meaning that the guidelines included content on the diagnosis and treatment of HCC at a minimum. After screening, 46 articles were adopted to form 17 current guidelines for HCC around the world, including 5 guidelines from the USA, 7 from Asia, and 5 from Europe (Table 1). The 17 current guidelines were comparatively analysed to systematically evaluate these guidelines for HCC in this article.

Table 1. Current characteristic guidelines for the management of HCC around the world

Publishing time	No.	Drafted by (Guidelines)	Abbreviations
2001	1	European Association for the Study of the Liver (Clinical management of hepatocellular carcinoma. Conclusions of Barcelona-2000 European Association for the Study of the Liver Conference)	EASL Guideline
2003	1	British Society of Gastroenterology (Guidelines for the diagnosis and treatment of hepatocellular carcinoma in adults)	BSG Guideline
	2	Korean Liver Cancer Study Group and National Cancer Center (Practice guideline for diagnosis and treatment of hepatocellular carcinoma)	Korean Guideline
2004	1	Belgian Association for the Study of the Liver (BASL guidelines for the surveillance, diagnosis and treatment of hepatocellular carcinoma)	BASL Guideline
2005	1	National Comprehensive Cancer Network (NCCN clinical practice guidelines in oncology - Hepatocellular carcinoma)	NCCN Guideline
	2	American Association for the Study of Liver Disease (Management of hepatocellular carcinoma)	AASLD Guideline
	3	Japanese Ministry of Health, Labor and Welfare (Clinical practice guidelines for hepatocellular carcinoma)	J-HCC Guideline
2006	1	Saudi Gastroenterology Association (Saudi Gastroenterology Association guidelines for the diagnosis and management of hepatocellular carcinoma: Summary of recommendations)	SGA Guideline
2007	1	American College of Surgeons (Consensus and controversy in the management of hepatocellular carcinoma)	ACS Guideline
	2	Japan Society of Hepatology (Expert panel of Japan Society of Hepatology: Clinical practice manual for hepatocellular carcinoma)	JSH Guideline
2008	1	European Society for Medical Oncology (Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up)	ESMO Guideline
	2	Italian Southern Oncological Group (Highlights of regional meeting of Italian Southern Oncological Group (GOIM): focus on hepatocellular carcinoma: biological and clinical background, therapeutic guidelines and perspectives)	GOIM Guideline
	3	Asian Pacific Association for the Study of the Liver (Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma)	APASL Guideline
2009	1	Chinese Society of Liver Cancer	Chinese Guideline
		Chinese Society of Clinical Oncology
		Chinese Society of Hepatology Liver Cancer Study Group (The expert consensus on the treatment standards for hepatocellular carcinoma)
	2	Asian Oncology Summit 2009 organized by Elsevier under the auspices of the Lancet Oncology and Singapore Society of Oncology (Management of hepatocellular carcinoma in Asia: Consensus statement from the Asian Oncology Summit 2009)	AOS Guideline
	3	World Gastroenterology Organisation (Hepatocellular carcinoma: A global perspective)	WGO Guideline
2010	1	United States National Cancer Institute (Hepatocellular carcinoma: Consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting)	NCI (USA) Guideline

Classification of guidelines for hepatocellular carcinoma

The 17 current guidelines were categorized according to the following criteria (Table 2): (i) Organizations or bodies drafting the guideline. Guidelines were classified into ‘Government-financed guidelines’ (1 guideline) and ‘Guidelines drafted by academic/medical societies’ (16 guidelines). Usually, guidelines were drafted by an expert panel that consisted mainly of hepatologists. In particular, the guideline drafted with the support of the Japanese Ministry of Health, Labor and Welfare (J-HCC Guideline) and the guideline drafted with the support of the Asian Pacific Association for the Study of the Liver (APASL Guideline) specified an expert panel consisting of radiologists, statisticians and other experts besides hepatologists. (ii) Approach. Guidelines were devised by ‘Literature Analysis’ (providing data-supported recommendations) (5 guidelines) or an ‘Expert panel’ (providing experience-supported recommendations) (12 guidelines). Guidelines drafted by an expert panel were classified as those that were ‘conclusions of a society conference’ (4 guidelines) and those drafted by an ‘expert panel commissioned by an academic/medical society’ (8 guidelines). (iii) Applicability. Fifteen of the 17 guidelines applied to HCC. The British Society of Gastroenterology Guideline (BSG Guideline) [14] applied to adult HCC and the National Comprehensive Cancer Network Guideline (NCCN Guideline) [15] applied to hepatobiliary cancers although the management of HCC was part of the NCCN Guideline. (iv) Content. All 17 guidelines dealt with diagnosis and treatment. Ten guidelines mentioned epidemiology, 8 mentioned prevention, 11 mentioned surveillance and 1 mentioned follow-ups. None of the 17 guidelines were published in a version for patients or the public, so the content was primarily technical and appropriate for use by clinicians with professional knowledge. v) Evaluation measures. The 17 guidelines featured three major types of evaluation measures: 8 guidelines had evidence categories and recommendation grades, 3 had dissemination evaluation and 2 had resource-based recommendations. (vi) Recent updates. Six of the 17 guidelines have been revised after publication. The other 11 guidelines may not have been revised because the guidelines were only recently published or a system for updates had not been established.

Table 2. Classification of current guidelines according to various criteria

Areas	Guidelines	Approach	Content	Evaluation measures	Recent updates
Note: D&T, diagnosis and treatment; E, epidemiology; P, prevention; S, surveillance; F, follow-up. a government-financed guidelines; the others are guidelines drafted by academic/medical societies. b Conclusions of a society conference. c Expert panel commissioned by an academic/medical society. d Applies to HCC in adults. e Applies to hepatobiliary cancers; the other guidelines apply to HCC.
America	NCCN Guidelinee	expert panelc	D&T + E + S	consensus categories	2010
	AASLD Guideline	literature analysis	D&T + S	evidence categories and recommendation grades; dissemination evaluation	2010
	ACS Guideline	expert panelc	D&T	—	—
	WGO Guideline	expert panelc	D&T + E + P + S	resource-based recommendations	—
	NCI (USA) Guideline	expert panelb	D&T + E	—	—
Asia	Korean Guideline	literature analysis	D&T	evidence categories and recommendation grades	2009
	J-HCC Guidelinea	literature analysis	D&T + P + S	evidence categories and recommendation grades; dissemination evaluation draft; evaluation prior to publication	2009
	SGA Guideline	literature analysis	D&T + E + P	evidence categories and recommendation grades	—
	JSH Guideline	expert panelc	D&T + S	question and answer analyser system	2009
	APASL Guideline	expert panelc	D&T + E + P + S	evidence categories and consensus grade	—
	Chinese Guideline	expert panelc	D&T	—	—
	AOS Guideline	expert panelb	D&T + P + S	evidence categories and recommendation grades; resource-based recommendations	—
Europe	EASL Guideline	expert panelb	D&T + E + P + S	—	—
	BSG Guidelined	literature analysis	D&T + E + S	evidence categories and recommendation grades	—
	BASL Guideline	expert panelc	D&T + E + P + S	—	—
	ESMO Guideline	expert panelc	D&T + E + P + S + F	dissemination evaluation	2010
	GOIM Guideline	expert panelb	D&T + E	—	—

Summary of diagnostic algorithms in current guidelines for hepatocellular carcinoma

Early diagnosis of HCC remains a key goal in improving the prognosis of patients [16]. Characteristic diagnostic algorithms in the 17 guidelines are described herein (Fig. 1) and these algorithms have been assessed from different viewpoints according to current studies.

Figure 1. The diagnostic algorithm in current guidelines for HCC.

There are three types of diagnostic algorithms in the 17 guidelines: (i) Size-based diagnostic algorithms. When a nodule is detected, definitive diagnosis will be achieved with a nodule diameter of <1 cm, 1–2 cm and >2 cm, was recommended by 8 of the 17 guidelines. Definitive diagnostic approaches include imaging [ultrasonography (US)/computed tomography (CT)/magnetic resonance imaging (MRI)], a combined approach [US/CT/MRI + biopsy or α-fetoprotein (AFP)], and a histological approach (biopsy). (ii) Non size-based diagnostic algorithms. HCC can be diagnosed with characteristic features on dynamic CT or dynamic MRI (i.e. a nodule is hypervascular in the arterial phase with washout in the portal venous or delayed phase) regardless of tumour size, as recommended by 4 of the 17 guidelines. (iii) Diagnostic algorithms with no criteria. These algorithms only provide a diagnostic tool and do not describe a detailed diagnostic algorithm, which was true for 5 of the 17 guidelines.

In general, the tests used to diagnose HCC around the world include imaging diagnosis, serological diagnosis and histological diagnosis. Imaging diagnosis tools in wide use are US, CT and MRI, with a respective sensitivity of 60% (95% CI 44–76%), 68% (95% CI 55–80%) and 81% (95% CI 70–91%) and a respective specificity of 97% (95% CI 95–98%), 93% (95% CI 89–96%) and 85% (95%CI 77–93%) [17]. The sensitivity and specificity of AFP, which has been widely used in serological diagnosis, vary widely and total AFP is not always specific for HCC [17, 18]. A biopsy (also known as fine needle aspiration cytology, FNAC) has overall sensitivity and specificity of 95.2% and 100% [19], but biopsy tests should be avoided if curative surgery is planned because the chance of needle track tumour seeding following a biopsy is 2.7% unless such a biopsy might change management of the patient or the major diagnostic doubt persists that cannot be resolved with imaging techniques or AFP [20].

Assessment of the 17 guidelines indicated that they had similar diagnostic approaches and agreed with current studies, but the 17 guidelines did differ in terms of detailed diagnostic algorithms: (i) Imaging diagnosis. HCC can be diagnosed by two instances of characteristic features on US/CT/MRI with a nodule of 1–2 cm according to the NCCN/European Society for Medical Oncology (ESMO) Guideline [15, 21] or with a nodule >2 cm according to the EASL/BSG/Belgian Association for the Study of the Liver (BASL)/Saudi Gastroenterology Association (SGA) Guideline [11, 14, 22, 23]. In contrast, the American Association for the Study of Liver Disease (AASLD)/Korean Guideline recommended that HCC be diagnosed by an instance of characteristic features on dynamic CT/MRI with a nodule >2 cm [24, 25]; the J-HCC/Japan Society of Hepatology (JSH)/APASL/Asian Oncology Summit (AOS) Guideline recommended that HCC be diagnosed by an instance of characteristic features on dynamic CT or dynamic MRI regardless of tumour size [12, 13, 26, 27]. The AASLD/Korean/APASL Guideline recommended that US be used as a screening test and not as a test for confirmation because US may reveal a nodule but US cannot characterize nodules and has little ability to detect the microflow in nodules [13, 24, 25]. (ii) Serological diagnosis. AFP was considered to be a useful and feasible screening tool in China, but it serves as an adjunctive diagnostic tool in the EASL/BSG/Korean/BASL/SGA/ESMO Guideline [11, 14, 21, 22, 23, 25] and AFP alone is not recommended. The combined testing of des-γ-carboxyprothrombin (DCP) and AFP or lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) could help to increase the sensitivity of HCC diagnosis [28, 29] but is used in only a few countries. Testing of DCP (also known as prothrombin induced by vitamin K absence-II, PIVKA-II), for example, is currently approved in Japan, South Korea and Indonesia [30, 31]. (iii) Histological diagnosis. A biopsy is recommended by all 17 guidelines if imaging diagnosis or serological diagnosis does not reveal characteristic features of HCC, but the EASL Guideline [11] recommends that a biopsy, rather than imaging techniques or AFP, be performed for definitive diagnosis when the nodular diameter is 1–2 cm since imaging techniques do not have sufficient accuracy to distinguish HCC from other benign or malignant conditions and AFP will usually remain at normal levels or be slightly elevated.

Summary of treatment algorithms in current guidelines for hepatocellular carcinoma

The choice of treatment approaches for HCC depends greatly on the extent of disease [32]. The treatment algorithms for HCC in the 17 guidelines were comparatively assessed in line with current studies on treatment approaches, with an emphasis on treatment criteria and new advances in treatment.

In general, a liver resection should be the first approach for non-cirrhotic patients with local lesions, a liver transplant should be the first approach for patients with decompensated cirrhosis (Child–Pugh C), and advances in the utilization of nonsurgical invasive therapies, such as PEI, RFA and TACE, should also be incorporated in the management of HCC [33, 34, 35]. These points were cited by all 17 guidelines and agree with current studies. The 17 guidelines do differ regarding appropriate candidates for surgery. For example, according to the EASL/NCCN/World Gastroenterology Organisation (WGO) Guideline, appropriate candidates for a liver resection are patients with a single tumour ≤5 cm and up to three tumours ≤3 cm each with good liver functional reserve [11, 15, 36]. In contrast, the J-HCC/JSH Guideline recommends that a liver resection be performed for patients with Child–Pugh A/B and 3 tumours or less regardless of tumour size [37, 38]. A liver resection has been found to be most beneficial for solitary tumours in patients without cirrhosis, with post-resection 5-year survival rates of 41–74% [39, 40, 41]. For cirrhosis patients with local lesions and good liver function (Child–Pugh A), the choice of a resection or transplant is a subject of discussion. European guidelines such as the EASL Guideline [11] recommend a liver transplant as the first approach because resections are performed a second time more often than transplants. A resection may have to be performed again in 50% of cases at 3 years and 70% at 5 years [42, 43]; a transplant may have to be performed again for patients meeting the Milan criteria (a solitary tumour ≤5 cm or up to three tumours ≤3 cm each) in approximately 10% of cases and the 5-year survival rate for such patients is 70–80% [44, 45]. In contrast, the J-HCC/JSH Guideline recommends a liver resection as the first approach in these cases. Local ablation therapy is another choice for patients with a single tumour or up to three tumours ≤3 cm each and good liver function (Child–Pugh A/B) whereas a liver transplant is recommended for patients age 65 years or younger with Child–Pugh C and a single tumour ≤5 cm or up to three tumours ≤3 cm [37, 38]. Besides, AOS Guideline recommends antiviral therapy with a nucleoside or nucleotide analogue for patients with hepatitis B virus (HBV) and combination peginterferon alfa 2a plus ribavirin for patients with hepatitis C virus (HCV) could delay progression of liver cirrhosis and reduce HCC occurrence [27].

In recent years, research on biotherapy and molecular targeted therapy has attracted a great deal of attention [46, 47, 48]. Sorafenib has been approved for the treatment of patients with unresectable HCC by the European Medicines Evaluation Agency and the U.S. Food and Drug Administration in 2007 and by the State Food and Drug Administration of China in 2008 [49]. The efficacy of sorafenib in advanced HCC has resulted in an overall decrease in mortality of 31%, with a median survival of 10.7 months for patients taking sorafenib versus 7.9 months for those taking a placebo [50, 51]. Sorafenib was recommended for the treatment of advanced patients by 11 guidelines, but the WGO Guideline [36] noted that sorafenib may be unavailable in poorer regions and moderately equipped regions because it is too expensive for patients in these regions.

Challenges and prospects

The current guidelines have both similarities as well as differences in terms of what organizations or bodies drafted the guidelines and the approach, applicability, content and recent updates of the guidelines as well as in terms of diagnostic and treatment algorithms. The differences could be attributed to various aetiological factors, high-risk patients, health systems, health resources, medical technology, treatment choices and income levels in different countries. For example, infection with HBV or HCV is the main aetiological factor for HCC development globally, HCV infection is the primary aetiological factor in Western countries but HBV infection is the primary aetiological factor in Asian countries except Japan. The optimal interval for surveillance and the targeted populations are also defined differently. The AASLD Guideline recommends the optimal interval for surveillance is 6 months and it does not need to be shortened for patients with higher risks of HCC including in the setting of cirrhosis; the targeted populations are Asian HBV carriers who are men and ≥40 years of age and carriers who are women and ≥50 years of age, as well as African HBV carriers who are ≥20 years of age and for patients with HCV or any form of cirrhosis [24, 52]. In contrast, Korean/J-HCC/JSH/AOS Guideline recommends the interval for surveillance could be shortened for patients with super-high risk. For example, the J-HCC Guideline and JSH Guideline recommend surveillance could be taken with the interval of 3–4 months for patients with cirrhosis type B or C, and 6 months for patients with HBV, HCV or cirrhosis [26, 27, 37, 53]. With regard to diagnostic algorithms, US is the most widely used modality for HCC screening and diagnosis largely because of its relatively low cost and ready accessibility [54]; CT and MRI can have a higher diagnostic accuracy than US but are more costly [13]. With the continued development of imaging techniques, dynamic CT, dynamic MRI and contrast-enhanced ultrasound (CEUS) are featured in guidelines from some high-income countries with advanced medical techniques, such as the USA, Japan and South Korea [37, 38, 52, 55]. In the AASLD Guideline (2010 update), dynamic CT and dynamic MRI are recommended to be applied for diagnosis of HCC with both the nodule diameter of 1–2 cm and larger than 2 cm; but CEUS is not recommended to be applied owing to its less discriminative ability to differentiate HCC from intra-hepatic cholangiocarcinoma as well as its less availability [52]. With regard to treatment algorithms, research on biotherapy and molecular targeted therapy has attracted a great deal of attention, but molecular targeted therapy as recommended by NCCN/AASLD/JSH/ESMO Guideline is expensive, with an average cost around US$6 000 per month [56], so it can only be performed in countries with extensive financial resources for healthcare services [15, 21, 38, 52].

Projected goals and implementation of guidelines for hepatocellular carcinoma

According to the projected goals of guidelines, the full implementation of guidelines could benefit clinicians, patients and authorities. Many guidelines for cancer have been published around the world, but few studies have been published regarding the implementation of those guidelines, and little is known about how these guidelines are influencing decision-making by clinicians or whether the guidelines are of use to individual patients and authorities [57]. Only two countries have published studies on the awareness of guidelines for HCC and how influential these guidelines are. One is from Japan [58], which surveyed 2,279 members of the Liver Cancer Study Group of Japan and 689 primary care physicians in Osaka and Hyogo prefectures. After the introduction of J-HCC, 19–21% of hepatologists or liver surgeons changed their practices and 50–52% did not change but were convinced that their choice of treatment was similar to that recommended in the guidelines; 43% of primary care physicians changed their practices to follow the recommendations in the guidelines or paid closer attention to patient preferences. The other country publishing studies on the awareness of guidelines for HCC and how influential these guidelines are, is the USA [59], which found that most gastroenterologists correctly identified common high-risk scenarios, methods and intervals for HCC screening as recommended by AASLD. Gastroenterologists who knew the HCC guidelines applied them in their own practice, but approximately one quarter did not know how to appropriately deal with a positive result, likely hampering the overall effectiveness of screening. No other supporting data were found with regard to implementation improving outcomes for patients and influencing regional or national authorities when allocating resources. Therefore, goal (i) has been achieved in a few countries, but there are still gaps in the achievement of goals (ii) and (iii).

Factors potentially influencing the implementation of guidelines for hepatocellular carcinoma

What organizations or bodies are drafting guidelines

Of 17 guidelines studied, only the J-HCC Guideline was established with governmental support, which came from the Japanese Ministry of Health, Labor and Welfare [60]. The remaining 16 guidelines were established by academic/medical societies through academic research or conclusions of an expert panel, particularly one of hepatologists. The absence of governmental support and lack of public health experts may lead to gaps in information on the management of HCC, especially with regard to appropriate prevention and surveillance measures, domestic health systems, health resources, income levels, and similar topics. This may lead to health resources not being optimally allocated. Of the 17 guidelines, only the J-HCC Guideline incorporated public comments – prior to publication, the 2005 version was evaluated by an external review board and the 2009 revision was available on the web for comments from the public [61]. Failing to include the public, and especially patients with HCC, might lead to a lack of public awareness and influence patient adherence to guidelines.

Content and emphasis of guidelines

All 17 guidelines dealt with diagnosis and treatment, but only 5 guidelines mentioned epidemiology, prevention, or surveillance and only 1 guideline mentioned follow-ups. The absence of some content, and especially that dealing with epidemiology, prevention and surveillance, may mean that patients lack adequate information about prevention and early detection and authorities may lack adequate information on the optimal distribution of health resources to efforts like measures to prevent HBV/HCV and establish nationwide screening and surveillance programmes. Unlike the ‘Guidelines for patients’ of the NCCN in the USA [62] and the National Institute for Health and Clinical Excellence in the UK [63], none of the 17 guidelines are available in a version for patients or the public. The content is primarily technical and hard for patients and the public to understand. In the course of diagnosis and treatment, patients usually receive information from clinicians, so this lack of information could influence patient awareness of and adherence to guidelines.

Modification of guidelines

The NCCN clinical practice guidelines for oncology have set the standard for cancer care in the USA. To promote standardized treatment practices around the world, NCCN committees reviewed NCCN Guidelines for seven types of cancers to identify any modifications required for those guidelines to apply to the Middle East and North Africa based on available evidence and regional experience [64]. Of the 17 guidelines, only the AOS Guideline and WGO Guideline suggested providing different recommendations for countries with minimal resources, moderate resources, or extensive resources [27, 36]. Another serious issue is how to implement guidelines in different regions of a country once domestic guidelines are established. Thus, the lack of information on the status of local resources could influence guideline implementation.

Consistency of patient management

A serious issue is how to implement guidelines that clinicians should follow. Although many therapies for the treatment of HCC are available and these therapies are effective for select patient groups, the therapy chosen by clinicians does not always coincide with that recommended by guidelines, and this is especially true in non-specialized centres [65]. Only two countries had studies on the awareness and influence of published guidelines, indicating that not all clinicians change their practices to follow guidelines. To promote guidelines for use by clinicians nationwide, the more appropriate approach might be to establish guidelines for the domestic health system and implement those guidelines at pilot medical institutions and then adopt those guidelines nationwide.

Factors that warrant attention when establishing and implementing guidelines

Basis in user

Owing to the specificity and depth of medical knowledge, different versions of guidelines should be created for clinicians, patients and authorities: (i) Guidelines for clinicians – emphasizing technical aspects and particularly advanced diagnostic and treatment techniques. Clinicians should include not only hepatologists but also clinicians in internal medicine, imaging, pathology and similar fields. (ii) Guidelines for patients – emphasizing basic medical knowledge about the prevention of HBV/HCV and other risk factors for HCC and encouraging patient adherence to guidelines. (iii) Guidelines for authorities – emphasizing public health policies and health resources with an eye towards aspects such as HBV vaccine programmes, HCC surveillance programmes, essential drug lists and health insurance.

Although different versions of guidelines target different populations, participants in drafting those guidelines should include clinicians, patients and authorities as well as experts in health policy, health economics, health statistics, and epidemiology.

Basis in evidence

According to levels of evidence (from level 1 to level 5, from high to low) from the Oxford Center for Evidence-Based Medicine (EBM) [66], guidelines drafted based on a literature analysis have a different level of evidence (level 1–level 3) than do guidelines drafted by an expert panel (level 5), but both are still in accordance with EBM. There are two guidelines in Japan. Published in 2005, the J-HCC Guideline is a systematic review of the medical literature on HCC in English; a total of 7192 publications were selected, with most coming from MEDLINE (1966–2002). After the second selection, 334 articles were adopted in the guidelines to form 58 pairs of research questions and recommendations [67]. Although the J-HCC Guideline have been acknowledged by many Japanese clinicians and have contributed greatly to clinical practice, 45% of the research questions are grade C recommendations and the guidelines lack the most up-to-date articles [68]. The JSH summarized HCC treatment as performed in Japan based on a consensus of opinions from many experts even though clear evidence was not available and published the JSH Guideline in 2007. The two guidelines do not contradict since they play different roles in Japan. In fact, the JSH Guideline provides additional information for the J-HCC Guideline based on the experience of experts, and this is especially helpful for up-to-date information lacking supporting data [69]. Assessment of guidelines established by Literature Analysis or Expert Panel in the current study found that both have advantages and disadvantages. Thus, the best move is to establish guidelines for HCC by combining a systematic literature review with experience from experts. In January 2012, an international consensus on liver transplantation for HCC was published based on a novel format which combines the topic identification from Organizing committee, the evidence-based reviews and discussion from Expert groups, and the recommendations revision from Jury together [70]. This may be a helpful exploration and could benefit people involved in designing new guidelines in the future.

Basis in resources

Evidence-based guidelines that outline optimal approaches to the management of HCC have been established and adopted in affluent countries, but many of the current methods of HCC control and intervention cannot be implemented in low-income and middle-income countries (LMCs) [27]. This could be owing to the failure of recommendations to consider inconsistent resource distribution in LMCs with high overall standards of living and failure to address deficits in infrastructure and resources. Recommendations also fail to consider implementation costs or provide guidance on how a suboptimal system can be incrementally improved to become an optimum system.

As noted by the WHO, guidelines defining optimal care and services have limited use in resource-constrained countries [71], so local resources in terms of health systems, medical technology, income levels and other resources must be fully considered when establishing domestic guidelines.

Applicable patients

The collection and analysis of epidemiological HCC data will play a critical role in guiding future disease prevention strategies and optimizing patient management [72]. There are many geographical variations in the prevalence of HBV-related and HCV-related HCC. The major aetiological factor is HBV infection in northeast and southeast Asia as well as HCV in Europe and in the USA [73]. There are also geographical variations in other cancerogenic factors such as aflatoxin B, which is found more frequently in developing nations where food is less well preserved [74]. From the perspective of cost-effectiveness analysis, epidemiological information, measures for domestic prevention, screening and surveillance and appropriate selection of treatment candidates should all be taken into account.

Systematic evaluation

The 17 guidelines studied feature many evaluation measures such as evidence categories and recommendation grades. In particular, the management of HCC in Japan has achieved remarkable results, which are attributed to a combination of quantitative and qualitative forms of evaluation incorporated in the guidelines [75].

Assessment of the 17 guidelines indicated that systematic evaluation must be performed when establishing and implementing guidelines. Assessment included disease progression, prognosis, and responses to treatment as well as recommendations from other studies and assessment of the implementation and adoption of guidelines. Systematic evaluation should be done before evaluation, during evaluation and after evaluation: (i) Before evaluation. A multidisciplinary team to treat malignant tumours has been found to improve patient quality of life [76]. The participation of a multidisciplinary team including hepatologists, pathologists, radiologists, surgeons and oncologists is recommended by the AASLD/SGA/WGO Guideline [23, 36, 52]. An expert panel should consist of experts from multiple departments, including clinicians as well as experts in health policy, health economics, health statistics, and epidemiology. (ii) During evaluation. When establishing guidelines, steps that should be performed include a systematic examination and analysis of the literature, soliciting the experiences and knowledge of experts, evaluating draft guidelines both internal and externally prior to publication. (iii) After evaluation. Studies should examine guideline implementation, including acknowledgement of the guideline, outcomes of adhering to the guideline, updates to the guideline every 3–4 years to incorporate new evidence.

Conclusion

In the past 10 years, many countries and areas have published guidelines for HCC. Seventeen current guidelines examined in this study have both similarities as well as differences, and differences are attributed to varying aetiological factors, high-risk patients, health systems, health resources, medical technology, treatment choices and income levels in different countries. Although the full implementation of guidelines could benefit clinicians, patients and authorities, there is still a gap in achieving projected goals. The factors potentially influencing guideline implementation are what organizations or bodies are drafting guidelines and guideline content and emphasis, modification, and consistency of patient management.

Comparative assessment of 17 guidelines indicated that different versions of guidelines should be established for target audiences of clinicians, patients and authorities. When such guidelines are established, participants should include clinicians, patients, and authorities as well as experts in health policy, health economics, health statistics and epidemiology. To promote standard care for HCC, countries should establish and implement domestic guidelines combining a basis in evidence, a basis in available resources, applicable patients and systematic evaluation.

Acknowledgements

Conflict of interest: No conflicts of interest to disclose.

Funding: This work was supported by Grants-in-Aid from Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology of Japan and supported by Japan-China Medical Association.

References

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