Natural compound from a deep-water marine sponge found to reduce pancreatic tumor size

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Sea sponges are an ancient group of animals that appeared more than 600 million years ago that have many of the same genes as humans. These scientists are taking advantage of this similarity in human and sponge genomes to isolate marine natural compounds from these organisms to develop medicines useful in the treatment of human diseases such as cancer. Credit: Florida Atlantic University, Harbor Branch Oceanographic Institute

Scientists at Florida Atlantic University’s Harbor Branch Oceanographic Institute found that a deep-water marine sponge collected off of Fort Lauderdale’s coast contains leiodermatolide, a natural product that has the ability to inhibit the growth of cancer cells as well as block cancer cells from dividing using extremely low concentrations of the compound. This work resulted in the award of a patent from the U.S. Patent and Trademark Office protecting the use of the compound against various forms of cancer.

Sea sponges are an ancient group of animals that appeared more than 600 million years ago that have many of the same genes as humans. These scientists are taking advantage of this similarity in human and sponge genomes to isolate marine natural compounds from these organisms to develop medicines useful in the treatment of human diseases such as cancer. The researchers are expanding on their original findings, recently showing that leiodermatolide can reduce pancreatic tumor size in vivo, publishing the results of this study in the International Journal of Cancer (IJC).

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer patients have less than a seven percent survival rate within five years of diagnosis, and 74 percent of patients die within the first year of diagnosis. In recent years, pancreatic cancer has received considerable attention because many well-known individuals have died from the disease. September marks seven years since the passing of actor Patrick Swayze, and October will be five years since the death of Apple Inc. co-founder Steve Jobs. The great tenor Luciano Pavarotti also died from this disease almost a decade ago.

In the article in IJC titled, “Leiodermatolide, a Novel Marine Natural Product, Has Potent Cytotoxic and Antimitotic Activity Against Cancer Cells, Appears to Affect Microtubule Dynamics, and Exhibits Antitumor Activity,” the researchers more fully define how this marine compound kills the cancer cells, and show that its effects occur not only against cells but that it also has the ability to reduce pancreatic cancer tumor weight.

Lead author Esther Guzmán, Ph.D., associate research professor at FAU Harbor Branch, along with colleagues and co-authors Amy Wright, Ph.D., research professor; Tara Pitts, biological scientist; and Priscilla Winder, Ph.D., research associate; as well as collaborators from Eisai Pharmaceuticals and the University of Central Florida, have been able to show that leiodermatolide induces programmed cell death in pancreatic cancer cells, and inhibits the growth of other cancer cells such as metastatic melanoma, colon cancer, lymphoma, and glioblastoma, a rare and deadly form of brain cancer.

Taxol™, a commonly used anti-cancer drug, works by interacting with tubulin and causing its polymerization. Leiodermatolide also interacts with tubulin but appears to affect microtubule dynamics through a unique mechanism of action compared to other microtubule interacting agents. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine — the standard of care drug for pancreatic cancer — and controls.

“Given the uniqueness of its mechanism of action, its potency, its selectivity for cancer cells, and its in vivo efficacy, leiodermatolide is an extremely interesting compound that merits further studies to determine its therapeutic potential for addressing some of the most devastating forms of cancer,” said Guzmán.Natural products, or secondary metabolites, are small, organic molecules produced by organisms. Unlike primary metabolites such as sugars, fats or proteins, these molecules are not essential to sustain life; however, the compounds are thought to confer an evolutionary advantage to the producing organism. For example, if a sponge makes a compound that is toxic to predators or tastes bad, that sponge may be protected from being eaten, and will have an advantage over one that does not produce the compound. In addition to blocking predation, natural products can have many different functions within the producing organism.

FAU Harbor Branch’s drug discovery program, spearheaded by Wright, looks for treatments for pancreatic cancer and infectious diseases, and their scientists also have collaborations with other scientists working on other forms of cancer, malaria, tuberculosis, neurodegenerative disease and inflammation. “The primary goal of our marine biomedical and biotechnology program is to discover marine natural products with utility as medicines or as tools to better allow us to understand disease processes,” said Wright.

The research in this publication was funded by the National Institutes of Health (NIH RO1 CA093455), the State of Florida Center of Excellence in Biomedical & Marine Biotechnology (COE-HRE07), the National Oceanic and Atmospheric Administration (NOAA CIOERT NA09OAR4320073) and the Health Resources & Services Administration Center for Sustainable Use of Marine Resources (4C76HF00231-01-04).

Guzmán et al. Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity. Cancer Therapy and Prevention. 2016;DOI: 10.1002/ijc.30253 [Abstract]

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Study finds how diabetes drug metformin inhibits progression of pancreatic cancer

Metformin-induced suppression of metastasis-promoting tumor microenvironment may be most prevalent in overweight, obese patients

Massachusetts General Hospital (MGH) investigators may have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer. In their report that has been published in the open access journal PLOS One, the research team describes finding that metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer. Their findings in cellular and animal models and in patient tumor samples also indicate that this beneficial effect may be most prevalent in overweight and obese patients.

We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix and by reprogramming immune cells to reduce inflammation,” says Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, the study’s co-senior author. “We also found these effects only evident in tumors from overweight or obese individuals, who appear to have tumors with increased fibrosis.”

The study focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, which accounts for almost 40,000 cancer death in the U.S. ever year. Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 percent have type 2 diabetes or are insulin resistant. Diabetic patients taking metformin – a commonly used generic medication for type 2 diabetes – are known to have a reduced risk of developing pancreatic cancer; and among patients who develop the tumor, those taking the drug may have a reduced risk of death. But prior to the current study the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.

The researchers first found that levels of hyaluronan, a component of the extracellular matrix, were 30 percent lower in tumor samples from overweight or obese patients who were taking metformin to treat diabetes than in those who did not take the drug. In an obese animal model of pancreatic cancer, those that received metformin had reduced expression of both hyaluronan and collagen-1 and fewer activated pancreatic stellate cells (PSCs). Studies in cultured cells identified the signaling pathway by which metformin reduces the production of hyaluronan and collagen-1 by PSCs and also prevents the recruitment of tumor-associated macrophages, which increase the inflammatory environment.

In obese mouse models, the researchers found that metformin treatment reduced levels of tumor-associated macrophages by 60 percent and reduced expression of genes involved in remodeling the extracellular matrix of tumor tissue. The tumors of animals treated with metformin also had reductions in a metastasis-associated change in cellular characteristics called epithelial to mesenchymal transition (EMT) and in the overall level of metastasis. These tumor-related effects of metformin appear to be independent of the drug’s effects on metabolic pathways involved in glucose metabolism and body weight.

Nearly 200 clinical trials are currently underway investigating the effect of metformin on tumors in both diabetic and non-diabetic patients,” say co-senior author Rakesh K. Jain, PhD, director of the Steele Laboratory. “Understanding the mechanism behind metformin’s effects on pancreatic and other cancers may help us identify biomarkers – such as patient body weight and increased tumor fibrosis – that can identify the patients for whom metformin treatment would be most beneficial.” Fukumura is an associate professor of Radiation Oncology, and Jain is the Cook Professor of Tumor Biology at Harvard Medical School. Later this year Jain will be among nine recipients of the 2016 National Medal of Science.

Incio et al. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. PLOS one. 2015;DOI: 10.1371/journal.pone.0141392 [Article]

Pancreas cancer spreads from multiple types of wayward cells

Penn animal study has implications for better drug design, ‘unprecedented window’ into tumor evolution.
Tumor cells associated with pancreatic cancer often behave like communities by working with each other to increase tumor spread and growth to different organs. Groups of these cancer cells are better than single cancer cells in driving tumor spread, according to new research from the Perelman School of Medicine at the University of Pennsylvania published in Cancer Discovery online in advance of the print issue.

This is a multi-colored metastasis in the peritoneal lining of the abdomen comprised of red and yellow fluorescent cells demonstrating that pancreatic cancer spreads through interactions between different groups of cells. CREDIT Ravi Maddipati , MD, Perelman School of Medicine, University of Pennsylvania

Ben Stanger, MD, PhD, a professor in the division of Gastroenterology, and first author Ravi Maddipati , MD, an instructor in the division of Gastroenterology, say that these results may prove useful in designing better targeted therapies to stop tumor progression and provide an improved non-invasive method for detecting early disease states in this highly lethal cancer. Stanger is also a professor in the department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute.
From other earlier studies, the Penn team also knew that cells from a primary tumor do better replicating and surviving in a group rather than if they are grown on their own. From this, the researchers asked if the spread of cancer is primarily derived from one cell or a cell cluster derived from the interactions between different cancer cell types. Stanger and Maddipati tested the hunch that clusters of cells of different genetic makeup were better at establishing secondary tumors and found that a significant fraction of metastases involve seeding by more than one type of tumor cell during the natural course of pancreatic tumor progression.

To understand this spread, the Penn researchers developed a mouse model that uses multiple fluorescent proteins to tag and track different pancreatic cancer cells as they enter the bloodstream and spread to distant organs. In this mouse model, mutations in Kras and p53 genes resulted in the formation of individual tumor cell populations that were labeled with different colors. Similar to humans, the mice developed tumors at secondary sites including the liver, lung, peritoneum, and diaphragm. They observed that these metastases were often made of cells from at least two different colors of tumor cell populations. To understand how these multi-colored lesions originated they examined blood from these mice and found that tumor cells in circulation frequently occurred as clusters comprised of different colored cancer cells.

What’s more, they also found that once these multi-colored clusters arrived at the secondary sites, the exact characteristics of subsequent growth was heavily dependent on the organ in which they now resided. During cell expansion in the peritoneum and diaphragm the lesions remained multi-colored, whereas in the lung and liver only a single color population was able to grow out. This suggested that specific factors in each organ may also influence the evolution of metastases.

These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that interactions between subpopulations of tumor cell types contribute to metastatic progression from initial tumors,” Stanger said. “The finding that metastases are frequently polyclonal and that subsequent cellular behavior is site-dependent also gives us insight into the origins and evolution of clonal diversity in metastatic disease.

If cells do cooperate during metastasis, what is the molecular basis for their communication, and can we hit that?,” Stanger asked. The work also reinforces the importance of finding tumor cell clusters in the blood as a mechanism of detecting cancer metastasis earlier.

Maddipati R and Stanger BZ. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discovery. 2015; doi: 10.1158/2159-8290.CD-15-0120 [Abstract]

Wild berry extract may strengthen effectiveness of pancreatic cancer drug

Worth considering micronutrient and drug combo for hard to treat cancers, say researchers

The findings prompt the researchers to suggest that adding ‘nutraceuticals’ to chemotherapy cycles may improve the effectiveness of conventional drugs, particularly in hard to treat cancers, such as pancreatic cancer. They base their findings on the effectiveness of extract of chokeberry (Aronia melanocarpa) in killing off cancer cells—a process known as apoptosis.

Chokeberry is a wild berry that grows on the eastern side of North America in wetlands and swamp areas. The berry is high in vitamins and antioxidants, including various polyphenols—compounds that are believed to mop up the harmful by-products of normal cell activity.

The researchers chose to study the impact of the extract on pancreatic cancer, because of its persistently dismal prognosis: less than 5% of patients are alive five years after their diagnosis. They cultured a well known line of pancreatic cancer cells (AsPC-1) in the laboratory and assessed how well this grew when treated with either the chemotherapy drug gemcitabine, or different levels of commercially available chokeberry extract alone, and when treated with both.

The toxicity of chokeberry extract on other normal lining cells was tested and found to have no effects up to the highest levels used (50 ug/ml), suggesting that it may not be able to prevent the formation of new blood vessels (anti-angiogenic properties), a process that is important in cancer cell growth. But the analysis indicated that 48 hours of chokeberry extract treatment of pancreatic cancer cells did induce some cell death (1 ug/ml).

And low doses of the extract greatly boosted the effectiveness of gemcitabine, when the two were combined, added to which lower doses of the conventional drug were needed. This suggests either that the compounds work together synergistically, or that the extract exerts a “supra-additive” effect, say the researchers.

They go on to say that the potential of naturally occurring micronutrients in plants, such as those found in chokeberry, has not been adequately explored, at least in clinical trials. And they point to similar experimental studies, indicating that chokeberry extract seems to induce cell death and curb invasiveness in brain cancer, as well as other research, highlighting the potential therapeutic effects of particular polyphenols found in green tea, soya beans, grapes, mulberries, peanuts and turmeric.

This work, first adds reinforcement to the concept that therapy for intractable cancers might usefully be augmented by the inclusion of micronutrient supplementation into regimens,” the researchers write.

More specifically, it suggests that elements in chokeberry extract, while not intrinsically toxic, can have supra-additive effects in combination with at least one other conventional cytotoxic drug,” they conclude.

Abdullah Thani et al., (2014). Cytotoxicity of gemcitabine enhanced by polyphenolics from Aronia melanocarpa in pancreatic cancer cell line AsPC-1. J Clin Pathol.,  doi: 10.1136/jclinpath-2013-202075. EPub Ahead of Print [Abstract]

Pancreatic survival rates at standstill for 4 decades

Long-term survival from pancreatic cancer has failed to improve in 40 years – with the outlook remaining the lowest of the 21 most common cancers, according to new figures published by Cancer Research UK. Today just over three per cent of pancreatic cancer patients survive for at least five years, only a fraction more than the two per cent who survived that long in the early 1970s.

Across all cancers, half of patients now survive at least twice that long. But most cases of pancreatic cancer go undetected until it is too late for surgery. And with the lack of effective tests and treatments for the disease, the majority of patients still die within a year.

But Cancer Research UK is planning to more than double its £6 million annual research spend on pancreas cancer within five years, making inroads into an area of research that until now has been globally neglected. The disease is now under the spotlight across the charity’s five institutes nationwide.

Professor Andrew Biankin is among the three quarters of scientists at Cancer Research UK’s Beatson Institute at the University of Glasgow who are contributing to pancreatic cancer research.

He said: “Pancreatic cancer has very few symptoms at first and I see far too many patients who, out of the blue, are told they may have just months or even weeks to live. We’ve been waiting too long for new drugs to treat the disease and there are very few options available for people with advanced forms of the disease. It’s a situation that simply has to change and we can only do that by funding more high quality research and trials, to get treatments out of the lab and into patients as soon as possible.”

Working with Professor Sean Grimmond, Professor Biankin is leading a team of researchers studying the unique pattern of faults in tumour samples from 400 pancreatic cancer patients and comparing this to their treatment and outcomes to create a map that will help guide the treatment of future patients.

They’re also trying to identify molecules that could be used as early warning signs for the disease, to help diagnose patients before their cancer becomes too advanced.

Yasmin, 41, from London, lost her father Shaukat to pancreatic cancer in 2008. She said: “I lost my dad just 18 months after he was diagnosed with pancreatic cancer. I don’t want other families to go through what we did. The more research we do, the more chances we have to find cures. Progress is being made but it’s hard to cope with the fact that it couldn’t help dad. By the time pancreatic cancer is diagnosed, it’s often too late for treatment to work. I miss my dad every day. Life changes around you, things go on, but I’m always aware there’s somebody missing.”

Pancreatic cancer is the tenth most common cancer in the UK. Every year, around 8,800 people are diagnosed with the disease and around 8,300 die from it.

Harpal Kumar, Cancer Research UK’s chief executive, said: “It’s shocking that so many patients are still losing their lives to pancreatic cancer, which is why we’ve made it a priority to ignite a new wave of research that will see the disease detected earlier and much needed treatments getting to patients sooner.

Overall, more than half of all cancer patients now survive at least a decade, which is testament to the power of research to transform people’s lives. But disappointingly, we are nowhere near that level with pancreas cancer, and we won’t stop until we can bring those kinds of results to all patients, regardless of their cancer type.”

Unique study focuses on combined treatment approach for locally advanced pancreatic cancer

The study and accompanying clinical trial aim to identify tumor biomarkers and provide clues into individual treatment response

Investigators at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute are developing a novel, multistep investigational treatment for one of the most complex and difficult-to-treat forms of the disease, locally advanced pancreatic cancer.

Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative five-year survival rate of only 4 percent for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.

To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer,” said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Samuel Oschin Comprehensive Cancer Institute. “Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how, and why, some patients respond better than others.”

Tuli was the first author of a pre-clinical study recently published in the journal Translational Oncology. Using animal models, the study evaluated a novel treatment for pancreatic cancer that combines radiation, chemotherapy and treatment with a specific drug that can inhibit the repair of cancer cells damaged by chemotherapy and radiation. Successful research findings led to a clinical trial now enrolling eligible patients.

Many standard cancer treatments for pancreatic cancer, including chemotherapy and radiation therapy, kill tumors by damaging their DNA. When such DNA damage occurs, proteins known as PARPs move to the site of damage and begin to mend these broken strands of DNA, allowing cancerous cells and tumors to recover, grow and proliferate, thereby escaping the effects of treatment.

With this knowledge, researchers combined radiation with a drug to prevent PARP from repairing cancerous cells. When the treatment was given to laboratory mice, the combination resulted in prolonged survival.

Based on this research, we are now conducting a first-in-human study combining the PARP inhibitor with radiation and chemotherapy in patients with locally advanced pancreatic cancer, with an ultimate goal of improving survival rates and treatment outcomes,” said Tuli.

The investigational treatment regimen also could prove beneficial to patients with other forms of cancer. Recent research findings suggest PARP could be beneficial for patients who carry either or both the BRCA1 or BRCA2 mutations. “Normal” BRCA genes help suppress tumor formation and repair damaged DNA; the mutated genes’ protective mechanisms are compromised, leading to genetic defects that result in cancer. But the “defective” repair capability is a process that may be exploited by treatments, such as PARP inhibition, which further impairs the ability of tumors to repair their own DNA after insult with radiation.

In addition to adding a novel PARP inhibitor to the regimen, investigators are seeking to identify other markers related to DNA damage that could provide a molecular signature, or biomarker, to forecast how a patients’ tumor would respond to treatment and help guide personalized treatment options in the near future.

Identifying individual biomarkers to better understand how a patient may respond to treatment is an essential step toward personalizing medicine for every individual,” said Steven Piantadosi, MD, PhD, director of the Samuel Oschin Comprehensive Cancer Institute and Phase One Foundation Chair. “It is the goal of our cancer institute to combine the most advanced patient-centered clinical care with innovative research that expands treatment options and improves outcomes. This is especially true in pancreatic cancer, which has been long known as a challenging disease to fight.”

Tuli et al., (2014). Radiosensitization of Pancreatic Cancer Cells In Vitro and In Vivo through Poly (ADP-ribose) Polymerase Inhibition with ABT-888. Transl Oncol., EPub Ahead of Print [Abstract]

Personalized medicine may be best way to treat cancer

If a driver is travelling to New York City, I-95 might be their route of choice. But they could also take I-78, I-87 or any number of alternate routes. Most cancers begin similarly, with many possible routes to the same disease. A new study found evidence that assessing the route to cancer on a case-by-case basis might make more sense than basing a patient’s cancer treatment on commonly disrupted genes and pathways.

The study found little or no overlap in the most prominent genetic malfunction associated with each individual patient’s disease compared to malfunctions shared among the group of cancer patients as a whole.

This paper argues for the importance of personalized medicine, where we treat each person by looking for the etiology of the disease in patients individually,” said John McDonald, a professor in the School of Biology at the Georgia Institute of Technology in Atlanta. “The findings have ramifications on how we might best optimize cancer treatments as we enter the era of targeted gene therapy.

The research was published February 11 online in the journal PANCREAS and was funded by the Georgia Tech Foundation and the St. Joseph’s Mercy Foundation.

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Venn diagrams show the unique, annotated genes identified as significantly differentially expressed in the group analysis and in the personalized analysis(es) of at least 1 patient (P1: Patient 1, P2: Patient 2, P3: Patient 3, P4: Patient 4). Credit: Lili, et al., 2014

In the study, researchers collected cancer and normal tissue samples from four patients with pancreatic cancer and also analyzed data from eight other pancreatic cancer patients that had been previously reported in the scientific literature by a separate research group.

McDonald’s team compiled a list of the most aberrantly expressed genes in the cancer tissues isolated from these patients relative to adjacent normal pancreatic tissue.

The study found that collectively 287 genes displayed significant differences in expression in the cancers vs normal tissues. Twenty-two cellular pathways were enriched in cancer samples, with more than half related to the body’s immune response. The researchers ran statistical analyses to determine if the genes most significantly abnormally expressed on an individual patient basis were the same as those identified as most abnormally expressed across the entire group of patients.The researchers found that the molecular profile of each individual cancer patient was unique in terms of the most significantly disrupted genes and pathways.

If you’re dealing with a disease like cancer that can be arrived at by multiple pathways, it makes sense that you’re not going to find that each patient has taken the same path,” McDonald said.

Although the researchers found that some genes that were commonly disrupted in all or most of the patients examined, these genes were not among the most significantly disrupted in any individual patient.

By and large, there appears to be a lot of individuality in terms of the molecular basis of pancreatic cancer,” said McDonald, who also serves as the director of the Integrated Cancer Research Center and as the chief scientific officer of the Ovarian Cancer Institute.

Though the study is small, it raises questions about the validity of pinpointing the most important gene or pathway underlying a disease by pooling data from multiple patients, McDonald said. He favours individual profiling as the preferred method for initiating treatment.

The cost of a molecular profiling analysis to transcribe the DNA sequences of exons — the parts of the genome that carry instructions for proteins — is about $2,000 (exons account for about two percent of a cell’s total DNA). That’s about half the cost of this analysis five years ago, McDonald said, and a $1,000 molecular profiling analysis might not be far off.

As costs continue to come down, personalized molecular profiling will be carried out on more cancer patients,” McDonald said.

Yet cost isn’t the only limiting factor, McDonald said. Scientists and doctors have to shift their paradigm on how they use molecular profiling to treat cancer.

Are you going to believe what you see for one patient or are you going to say, ‘I can’t interpret that data until I group it together with 100 other patients and find what’s in common among them,'” McDonald said. “For any given individual patient there may be mutant genes or aberrant expression patterns that are vitally important for that person’s cancer that aren’t present in other patients’ cancers.

Future work in McDonald’s lab will see if this pattern of individuality is repeated in larger studies and in patients with different cancers. The group is currently working on a genomic profiling analysis of patients with ovarian and lung cancers.

“If there are multiple paths, then maybe individual patients are getting cancer from alternative routes,” McDonald said. “If that’s the case, we should do personalized profiling on each patient before we make judgements on the treatment for that patient.”

Lili et al., (2014). Evidence for the importance of personalized molecular profiling in pancreatic cancer. Pancreas43:198-211 [Abstract]