Articles about new Liver Cancer drugs, treatment methods, research etc.

Cycles Of Cell Death, Proliferation Key To Liver Cancer

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26 Jun 2006

Research at the University of California, San Diego (UCSD) School of Medicine shows that Liver Cancer is likely caused by cycles of liver cell death and renewal.

The research, appearing online in June in advance of publication in the journal Proceedings of the National Academy of Sciences, underscores the importance of JNK1-mediated cell death and compensatory proliferation. The findings by Michael Karin, Ph.D., professor pharmacology in UCSDi:s Laboratory of Gene Regulation and Signal Transduction, and colleagues strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver cancer in mouse models.

One link between inflammation and cancer is known to involve the NF-kB pathway, which regulates gene expression. In research published in the journal Cell in 2005, Karin and his colleagues at UCSD implicated the pathway's activator, IKK , in chemically induced liver cancer. However, the surprising outcome of those studies was the finding that while NF-fUB activation in hepatocytes (liver cells) prevents liver cancer, its activation in inflammatory cells, such as tissue macrophages, promotes tumor development.

In their latest work, the research team studied what precedes inflammation ?V the injury of hepatocytes caused by toxic chemicals, which sets in motion the inflammation process.

Their research showed that the absence of IKKfO in hepatocytes led to increased c-Jun N-terminal kinase (JNK) activation after exposure to a chemical carcinogen used to elicit liver cancer in mice. Importantly, deletion of the gene that codes for the major isoform of JNK in liver cells, JNK1, prevented the development of liver cancer and reversed the tumor-enhancing effect caused by ablation of IKKfO.

"We found that long-term JNK activation leads to cell death; if activated briefly, it stimulates proliferation of pre-malignant and cancerous tumor cells," said Karin. Blocking JNK prevents liver injury but also inhibits liver regeneration, so the timing and context of activation are very important, he added.

"In this research, we set out to identify what causes inflammation in response to liver injury, as well as what stimulates the proliferation of surviving hepatocytes," said Karin. "Since we previously knew that JNK activity is required for normal liver cell proliferation, we wondered if the same activity is required for production of liver cancer in carcinogen-exposed mice. The results were clear JNK1 is critical for tumor development."

The scientists genetically removed JNK1 to test if its increased activation, caused by the absence of IKKfO, was responsible for accelerated tumor development. When JNK1 was removed, the number and size of cancerous liver tumors decreased, and the tumors grew more slowly. Increased JNK1 activation was found in diseased liver and tumors when compared to normal tissue.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the third leading cause of cancer deaths worldwide. Its major risk factors are persistent infection with hepatitis B and C viruses, and exposure to toxic chemicals, including alcohol iV all of which cause chronic liver injury and inflammation. Although not common in the United States., the incidence of HCC is on an upward trajectory, with little hope for treatment or cure through chemotherapy, radiation or other traditional cancer treatments.

"We now understand development of liver cancer in mice. Since inflammation drives both damage and regeneration in liver tissue, it is the repeating cycle of damage, inflammation and regeneration that leads to liver cancer," said Karin. "However, this knowledge is not satisfactory until we find out if it applies to humans."
http://www.medilexicon.com/medicalnews.php?newsid=45814∞

Omega-3 Fatty Acids Inhibit Growth Of Liver Cancer Cells

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07 Apr 2006

Two new studies by a University of Pittsburgh research team suggest that omega-3 fatty acids--substances that are found in high concentrations in fish oils and certain seeds and nuts--significantly inhibit the growth of liver cancer cells. The studies, presented today at the annual meeting of the American Association for Cancer Research (AACR), at the Washington Convention Center in Washington, D.C., suggest that omega-3 fatty acids may be an effective therapy for both the treatment and prevention of human liver cancers.

The first study, Abstract number 2679, looked at the effect and mechanism of omega-3 and omega-6 polyunsaturated fatty acids in human hepatocellular carcinoma cells. Hepatocellular carcinoma accounts for 80 to 90 percent of all liver cancers and is usually fatal within three to six months of diagnosis.

"It has been known for some time that omega-3 fatty acids can inhibit certain cancer cells. So, we were interested in determining whether these substances could inhibit liver cancer cells. If so, we also wanted to know by what mechanism this inhibition occurs," said Tong Wu, M.D., Ph.D., a member of the division of transplantation pathology, University of Pittsburgh School of Medicine, in whose laboratory the research was conducted.

The investigators treated the hepatocellular carcinoma cells with either the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or the omega-6 fatty acid arachidonic acid (AA), for 12 to 48 hours. DHA and EPA treatment resulted in a dose-dependent inhibition of cell growth, whereas AA treatment exhibited no significant effect.

According to the investigators, the effect of omega-3 fatty acids on cancer cells likely is due to the induction of apoptosis, or programmed cell death. Indeed, the investigators found that DHA treatment induced the splitting up, or cleavage, of an enzyme in the cell nucleus known as poly (ADP-Ribose) polymerase, or PARP, which is involved in repairing DNA damage, mediating apoptosis and regulating immune response. The cleavage of this enzyme is considered a tell-tale indicator of apoptosis. Furthermore, DHA and EPA treatment indirectly decreased the levels of another protein known as beta-catenin, an overabundance of which has been linked to the development of various tumors.

"Beta-catenin is known to promote cell growth and also is implicated in tumor cell promotion. Therefore, our finding that omega-3 fatty acids can decrease levels of beta-catenin is further evidence that these compounds have the ability to interact on several points of pathways involved in tumor progression," explained Dr. Wu.

In the second study, Abstract number 2680, the investigators treated cholangiocarcinoma tumor cells with omega-3 and omega-6 fatty acids for 12 to 48 hours. Cholangiocarcinoma is a particularly aggressive form of liver cancer that arises in the ducts that carry bile from the liver and has an extremely high mortality rate. Again, the omega-3 fatty acids DHA and EPA treatments resulted in a dose-dependent inhibition of cancer cell growth, while the omega-6 fatty acid AA treatment had no significant effect. Likewise, DHA treatment induced a cleavage form of PARP in cholangiocarcinoma cells, and DHA and EPA treatment significantly decreased the level of beta-catenin protein in the cells.

According to Dr. Wu, these findings suggest that omega-3 fatty acids not only may be an effective therapy for the treatment of human liver cancers but may also be a means of protecting the liver from steatohepatitis, a chronic liver disease characterized by the buildup of fat in the liver and believed to be a precursor of hepatocellular carcinoma. The next step in the process, he said, is to test the effects of omega-3 fatty acids in mice harboring human liver tumors.
http://www.medilexicon.com/medicalnews.php?newsid=40939∞

FDA Clears Valleylab's Cool-tip(TM) RF Ablation System For Use In Ablating Non-Resectable Liver Tumors

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10 May 2006

Valleylab today announced the United States Food and Drug Administration's (FDA) marketing clearance issuance for the Cool-tip(TM) RF ablation system. The Cool-tip(TM) RF ablation system is the first and only device cleared for marketing to physicians for use in ablating non-resectable liver tumors. This minimally invasive alternative for patients with hepatic cancer, who are not ideal surgical candidates or are otherwise unable to be successfully treated with other methods, solidifies the company's commitment to the oncology market.

"The recent FDA clearance for radiofrequency ablation of liver 'tumors' and not just 'tissue/liver lesions' allows for ablation of unresectable liver tumors of various histologies," said Robert Martin, MD, assistant professor, Division of Surgical Oncology at the University of Louisville School of Medicine. "It is important to help educate physicians skeptical of this technique in regard to radiofrequency ablation efficacy and safety."

"Interventional oncologists have been ablating liver tumors since the mid- 90s with the Cool-tip(TM) RF ablation system," said Damian Dupuy, MD, professor of diagnostic imaging at Brown Medical School and director of tumor ablation at Rhode Island Hospital. "The continued acceptance of this procedure is a testament to the technology and the hard work that interventional oncologists have done over the last decade."

Awareness and use of radiofrequency ablation is increasing, as made evident by the growth in Cool-tip(TM) RF ablation system sales. The Cool- tip(TM) RF system works by combining a radiofrequency generator with a 17- gauge internally cooled needle electrode to deliver therapeutic energy directly to the tumor. The electrode is inserted through the tissue and is guided to the tumor using imaging technology such as CT or ultrasound. Radio waves create energy at the needle tip to heat and destroy the tumor from the inside out. During the ablation, water internally circulates through the electrode cooling adjacent tissue. This maximizes the amount of energy that can be delivered and creates the largest ablation possible in a minimal amount of time. Because ablation with the Cool-tip(TM) ablation system is minimally- invasive, the procedure can be repeated until the entire liver tumor is ablated.

"We are proud to be the first radiofrequency ablation company to receive FDA clearance for the ablation of non-resectable liver tumors," said Kevin Seifert, president of Valleylab. "It is very important for us as a company to be able to provide physicians with a comprehensive offering of safe and effective Valleylab products for their patients with inoperable liver tumors."
http://www.medilexicon.com/medicalnews.php?newsid=42982∞

Liver Tumours - Hepatocarcinoma - Controlled By Yttrium-90

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13 Jul 2006

The University Hospital at the University of Navarra is the only centre throughout the entire Spanish state for the treatment of liver tumours by means of radioembolisation and the one with the greatest accumulated experiences in the treatment throughout Europe. The technique consists of injecting spheres marked with Yttrium-90 - of very few microns in size - into the hepatic artery, from where they preferentially make for the tumorous zone. Here they remain lodged and emit radiation, which damages the tumour cells.

The treatment is complex and requires the close collaboration of the Departments of Nuclear Medicine, Conventional and Interventionist Radiology, Hepatology and Oncology.

In the primary tumours of the liver, also called hepatocarcinomas, the results show that the treatment is very efficacious in preventing treated lesions from growing: it achieves control - not eradication - of the disease in over 90% of the cases, at times over quite prolonged periods. Nevertheless, it does not avoid the appearance of new lesions in the liver and other organs.

Advantages and suitability

The treatment of hepatic tumours through radioembolisation has the advantage that it is not an exclusive procedure given that it can be administered in combination with quimiotherapy in those tumours that are responsive to this treatment. Moreover, its tolerance is quite high, it does not require long hospital stays, (normally patients stay just one day), and has a low risk of complications.

The technique incorporated at the University Hospital is particularly suitable for treating primary tumours of the liver (hepatocarcinomas) as well as secondary ones, above all, metastasis of cancer of the colon and endocrine tumours. Radioembolisation is an efficient alternative in those cases where the liver is host to several tumours and cannot be extirpated. The technique does not substitute surgery, rather provides the possibility of treatment in situations where there have been no therapeutic options to date.

However, when there is a risk that the spheres access the digestive tract, there are side-effects to the treatment. Moreover, neither is it recommended for patients who, in prior assessments, have been observed to capture very few spheres and, thus, in these cases, it is predicted that the treatment is not going to be efficacious.

Procedure

This therapeutic procedure is characterised by radiating the tumours directly and respecting the healthy liver. The microspheres are injected through a catheter in the hepatic artery, the only blood vessel that irrigates the tumorous zones of the liver, thus guaranteeing that the radiation preferentially targets the tumorous zone. The microspheres are marked with Yttrium-90 and transmit radiation when they arrive at the tumorous zone. Their effects can be evaluated after two months.

Once the suitability of the microspheres is established, specialists in Nuclear Medicine are responsible for deciding the suitability of the treatment and of calculating the dose appropriate for each patient. The principal aim of these treatments is to ensure that the radioactive spheres exclusively target the zone affected. However, there are situations where, given circulation problems or those involving connections between blood vessels, the spheres may travel to the lungs or other organs, such as the stomach or the intestinal tract and, thereby, cause considerable damage through side effects.

This is why, one week prior to treatment, and in cooperation with the Radiodiagnostic Service, a treatment simulation is carried out. In the first place, a hepatic arteriograph is carried out in order to view the arterial anatomy of the liver and, thereby, the vessels feeding the tumour. The hepatic artery has many anatomical variants and so there are branches thereof that feed other zones such as the duodenum and the bile duct. This is why hepatic vascularisation has to be restricted with the treatment preferentially targeting the liver.

During the planning stage, instead of introducing Yttrium-90 spheres, macroaggregates of albumin marked with Tecnecium were used. "This involves a radiotracer by which a gammagraph can be carried out in order to quantify the distribution by the organism of the radiotracer so that possible leaks of the spheres during treatment can be monitored. It should be taken into account that such a leak of Yttrium-90-marked microspheres can be damaging to the organs. Thanks to prior gammagrapy, the safety of the treatment is guaranteed and the dosage suitable for each patient calculated.

Once the suitability for treatment is established, the Yttrium administration kit is prepared - individualised for each patient, and the Yttrium administered by specialists from the Radiodiagnostic Service. This process requires the supervision of radiophysicians whose work is that of radiological protection and in the calculation of the dosage. "Before administering radiometabolic treatment, an estimate of the dosage the patient is to receive should be calculated, given that the amount of Yttrium-90 the organ will absorb has to be individualised for each patient. In the calculations, the body surface of-the patient has to be taken into account. With all these figures, we can determine the optimum dosage to irrad?ate the tumour to the maximum and the healthy liver to the minimum.
http://www.medilexicon.com/medicalnews.php?newsid=46981∞

Tissue Microenvironment Implicated In Susceptibility To Liver Cancer Metastases

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17 Aug 2006

A new research study reports that, in addition to the metastatic potential of tumor cells, a permissive target environment plays a critical role in promoting progression and metastases of liver cancer. The findings, which appear in the August issue of Cancer Cell, published by Cell Press, may lead to strategies for identifying and possibly treating patients that are highly likely to develop metastases.

Hepatocellular carcinoma (HCC) is a liver cancer with an extremely poor prognosis because of its propensity to spread and invade surrounding tissues. Dr. Xin Wei Wang from the National Cancer Institute, Bethesda, Maryland, Dr. Zhao-You Tang from Fudan University, Shanghai, China, and colleagues recently identified a gene expression signature for primary HCC tumor cell specimens that could predict the metastatic potential of HCC in patients with 78% accuracy. To better understand the mechanisms underlying HCC metastases, the researchers went on to examine whether the metastatic propensity of HCC might also be influenced by the microenvironment of the local tissue.

A thorough examination of noncancerous hepatic tissues from two groups of HCC patients, those with and those without detectable metastases, revealed profound differences in gene expression profiles. Specifically, a unique 17 gene expression signature involving genes associated with inflammation and the immune system was identified in patients with the metastatic phenotype. These patients exhibited a global decrease in gene products associated with inflammation and an increase in anti-inflammatory gene products. Importantly, the genetic signature described in this study provided greater than 92% accuracy in predicting metastases, a result that far exceeds the accuracy of the previously described profile based on primary HCC cells.

The researchers also found that the colony-stimulating factor 1 (CSF1) is playing a prominent role in metastasis of liver cancer cells. "The CSF1 may be reprogramming the immune cells to switch from secreting cytokines that create a pro-inflammatory microenvironment to one that is anti-inflammatory--a condition that supports the growth and metastases of liver tumor cells," explains Dr. Wang.

The findings suggest that, in addition to the metastatic potential of the tumor cells themselves, the inflammatory status of the tissues surrounding the tumor cells may play a key role in tumor metastases and progression. "The genetic signature identified in this study is a superior predictive tool to determine HCC metastases and relapse and may have possible utility in clinical settings to identify HCC patients who might benefit from certain postsurgical treatment to prevent metastases and/or recurrence," said Dr. Wang.
http://www.medilexicon.com/medicalnews.php?newsid=49666∞

Innovative Cancer Treatment: Destroying Tumors With Heat

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11 Mar 2007

"In radio frequency ablation, the heat is generated by a multi-pronged probe placed into the tumor tissue in a procedure monitored by ultrasound or computer tomography. You could say the tumor is 'boiled away' on the spot," explained Professor Riccardo Lencioni from the Radiology Department at the University of Pisa, Italy, at the kick-off press conference for the European Congress of Radiology (ECR) 2007, held at Austria Center Vienna from March 9 to 13 and attended by some 16,000 participants from 92 countries. "The advantage of RFA is the small diameter of the probes of about 1.2 millimeters and the attainable lesion size of several centimeters without shifting the probes. At the same time, bleeding is effectively stopped along the insertion path through the obliteration of potential sources of blood. This method prevents puncture channel metastases caused by the dispersion of cancer cells."

Heat treatment of metastases or tumors may be painful depending on their location and the organ involved. Patients are therefore sedated or given anesthesia for this procedure. "This method of local obliteration is well-suited for the early treatment of liver, kidney, lung, breast and bone tumors," noted Professor Lencioni. "Unlike radiation or chemotherapy, this procedure has the advantage that it can be repeated - if need be - because of the lack of systemic side-effects. Thermoablation monitored by appropriate imaging can be carried out during brief hospital stays of two to three days."

Option for Inoperable Lung Cancer

This method is becoming increasingly important, for example, in the treatment of lung carcinomas, especially in cases where surgery is out of the question. Many patients with lung carcinomas are poor surgical candidates because they are long-term smokers and have contracted co-existent secondary illnesses that would make surgery more riskly. For non-small-cell lung carcinomas, there is also a relatively high risk of recurrence even after tumors are removed surgically. In many cases, chemotherapy and radiation therapy do not yield satisfactory results either.

Successful in Liver Tumors - Alternative to Surgery

RF ablation has been used successfully in the treatment of early-stage liver tumors for six years. Professor Lencioni: "For tumors with a diameter of about three centimeters, sustainable tumor destruction has even been achieved with a single needle insertion. In terms of patients' response rates and survival rates, this procedure is comparable to conventional surgical procedures and offers an alternative to surgery."

For larger tumors in the liver, the success rate of RF ablation is just 50 percent, however. In about half the cases, the tumor spreads to adjoining tissue even after radio frequency treatment. The chances of a cure for large tumors of the liver increase with minimally invasive procedures undertaken directly in the blood vessels. This fact has led to a new treatment approach.

TACE: Transarterial Chemoembolization

Transarterial chemoembolization with drug-eluting microspheres ("Precision TACE") is an innovative treatment option for liver tumors. Professor Lencioni: "TACE is a well established treatment for liver cancer. It is based on the fact that up to 95 percent of the hepatocellular carcinomas are supplied by the hepatic arteries. Normal liver tissue, for its part, receives about two thirds of its blood supply through the portal vein and about one third from arterial blood. Chemoembolization causes the hepatic arteries to close up and the tumor tissue dies. Normal liver tissue is not affected."

In Precision TACE, doxorubicin-eluting particles are delivered to the tumor via the hepatic artery. Professor Lencioni: "Owing to the microspheres, the drug for inhibiting cell growth in the tumor is present in the liver tissue in a concentration a hundred times greater than in systemic intravenous chemotherapy. Side-effects such as vomiting or stomach pain are completely absent. Blockage of the arterial flow of blood also prolongs the period of action for chemotherapeutic agents."

Pilot Study with Doxorubicin

Studies on animal models have shown that the cytostatic agent doxorubicin can significantly increase the effect on liver tumors when combined with RF ablation. Tumor cells not completely destroyed by RF ablation are at least so weakened by the exposure to high heat that doxorubicin can take full effect and destroy the tumor completely. A pilot study is being done to determine whether or not these promising results are applicable to human beings.

"Twenty patients with a liver tumor larger than three centimeters in size were subjected to RF ablation followed 24 hours later by chemoembolization with doxorubicin. In 70 percent of the cases, the tumor was completely destroyed," reported Professor Lencioni. "Overall, the data from the pilot study appear to favor the combined application of RF ablation and transarterial chemoembolization to combat hepatocellular liver carcinoma. The combined method also has an excellent safety profile. The procedure has low complication rates while offering a good quality of life and shortening the hospital stay."

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