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Glycoprotein Biomarkers for Malignancy in Pancreatic Cysts

We speak of pancreatic cancer as if it is one thing, but there are many kinds of pancreatic cancer; one classification had this number at 17.  A frequent anatomic / physiologic action of the pancreas is that it tends to produce cysts (and sometimes even “pseudocysts” – pockets of fluid often seen as a result of pancreatitis).  Many of these cysts are benign, but some percentage are or become malignant. It is often difficult to differentiate between the innocent cystic structures, and ones that may become serious current or future problems.

Unexpected findings have become an increasingly frequent issue, as our ever advancing radiographic tools have progressed to a point where they often identify troubling elements in the pancreas (or elsewhere) which were not the target of the initial procedure – but now which we are must deal with in terms of their clinical significance – for the long-term good of the patient, and their peace of mind.  The clever term has arisen for these unexpected findings: radiological “incidentalomas.” Pancreatic cysts then are often incidentalomas – requiring an element of diagnosis and explanation.

Also until now, carcinoembryonic antigen levels (CEA) – including the knowledge of its limitations – was often considered the general marker of choice for this task; a high level tending to point toward malignancy. We should also here begin to discuss individual “mucins” that are glycoproteins related to a series of a “family” of about twenty MUC genes. These mucins tend to line the surface of epithelial cells found in human lung, GI tract, eye, and other organs. Several of the MUC proteins have found to be overexpressed in colon, breast, ovarian, lung and pancreatic cancers.

Now comes a clever study by Jabbar and colleagues from University of Gothenburg, Sweden who published their results in the February 2014 issue of the Journal of the National Cancer Institute, outlining their work in utilizing mucin proteomics as a biomarker process to differentiate benign pancreatic cysts from those that may become precursors of pancreatic cancer.

Over about a five-year period of time (2007-2012) the authors evaluated 102 patients with what appeared to be pancreatic cysts, ultimately including 91 patients in their study who met their established inclusion criteria. The researchers then used endoscopic ultrasound to aspirate contents of the cysts, examining the extract for cytological (cell) changes, CEA levels, and individual MUC (mucin) levels including a panel of mucins. They found that MUC1, MUC2, and MUC5AC particularly appeared to identify cysts with potential for pancreatic cancer malignancy.

The results of this study were that mucin proteomic profiling (97.5%) was a more accurate method of identifying malignancy potential than either CEA levels (78.0%), or cytology (71.4%).  The authors suggest that proteomic biomarkers involving a panel of mucin glycoproteins appear to be a promising manner of differentiating benign cycts from those with malignant potential for pancreatic cancer. This is a highly persuasive study that requires confirmation.


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Dale O’Brien, MD

The Relationship Between Diabetes and Pancreatic Cancer

“It’s complicated.”  But why should pancreatic cancer (ductal adenocarcinoma of the pancreas) be any less convoluted than other aspects of the pancreas?  The origin of the embryologic pancreas develops from TWO buds off of the foregut – that EACH “typically” moves and develops, eventually merging to form what we know as the pancreas.  This somewhat individualistic merging process alone produces many anatomic anomalies, as any experienced pancreatic cancer surgeon will tell you.  Also, separately, the function of the pancreas is complicated, divided roughly into exocrine (digestive juice producing) and endocrine (the hormone producing “islet”) areas.

Pancreatic cancer can arise literally from virtually any type of cell in the pancreas. The most common kind, that which has such a rough prognosis arises in the duct lining cells that line the pathways that carry digestive juice downstream (left to right) eventually usually combining with bile juice (at the bile duct junction) to deposit the combined product, so useful for ordinary digestion, into the first (duodenal) portion of the small bowel. This type of tumor then is called pancreatic ductal adenocarcinoma.

And what are we to make of the general observation of this relationship between this form of pancreatic cancer and what seems empirically to be an increased association of the onset of diabetes?  After all, they are from completely different functional areas of the pancreas. Is this association real, or a form of recollection bias?  If so, is diabetes mellitus a cause of ductal pancreatic cancer – or a result of it?

This is the vineyard in which Nikfarjam and his surgical colleagues at the University of Melbourne in Australia have been working in regard to their recent study published on March 9, 2014 in the Annals of Surgical Oncology.  The researchers tried to better quantify the strength of the association between diabetes and pancreatic cancer over time, and to better qualify the relationship.  After reviewing forty years of published medical articles as found in electronic databases (1973 through 2013), the authors identified eighty-eight studies that met their criteria. These included fifty cohort studies and thirty-three case-study studies involving the onset of diabetes and the risk of pancreatic cancer.

They found that the relative risk overall between the onset of newly diagnosed diabetes mellitus was statistically significant but at a reasonably modest 1.77.  Though through a consideration of time as a factor, the authors conclusions demonstrated a more complex picture. They found that the closer in time to the diagnosis of diabetes: the more likely the discovery of pancreatic cancer.  So, for example, the researchers calculated the relative risk at less than one year at 6.69 (the pancreatic cancer occurred nearly seven times more frequently than what one might expect), but that this factor dropped such that at ten years the relative risk was only 1.36.

This is a lovely study that further quantifies the elusive relationship between diabetes and ductal pancreatic cancer. There are still many questions, and it leaves the chicken versus egg question unsolved.  But increasingly the evidence mounts that during the year or two or more after the onset of diabetes mellitus, a pancreatic cancer diagnosis is much more likely.  That this is a high risk period that demands heightened clinical scrutiny.

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Dale O’Brien, MD


Hedgehog Pathway Inhibition Slows Pancreatic Cancer Cell Growth

You may wonder what this has to do with pancreatic cancer (ductal adenocarcinoma of the pancreas), but please know that those of us who are old enough to remember once shivered and screamed in horror at the 1958 move, The Fly, whereby the protagonist ended up half human, half housefly (musca domestica).  This fear may not be too far from the truth, as the evolution of human DNA may include remnants of our flying antagonists.

In 1995, three biologists (Lewis, Nüsslein-Volhard and Wieschaus) shared the Noble Prize in Medicine for their work beginning in the late 1970s in studying genetic mutations related to body segmentation in the development of the fruit fly (Drosophila), including the identification of the three “hedgehog” genes related to this process. The name “hedgehog” was given as a result of the stubby and especially disordered and hairy look of the mutated drosophila denticles on the mutated larvae.

Not only are hedgehog genes active in flies, but their actions are integral to normal development in human embryos.  Also, the complex hedgehog signaling pathway appears to have key but not fully understood mechanisms in human adults, including the production of adult stem cells. Disruption of this signalling pathway can cause severe birth defects, miscarriage, and death. And the adult activation of the hedgehog pathway (overexpression of its components) appears to be related to the development of a number of especially difficult cancers, including pancreatic cancer. It is thought that undue activation of the hedgehog signaling pathway may transform the adult stem cells (generally: good) into specific cancer stem cells (generally: bad, as they may cause, protect and/or abet the rapid growth of the tumor).

Professor Tony Magee and researchers from the Imperial College London (along with a Danish colleague) and based on a grant from the UK’s Pancreatic Cancer Research Fund, on March 7, 2014 published the results of their pre-clinical work in the journal PLoS.  The researchers inhibited the effect of “hedgehog acyltransferase” in pancreatic cancer cells, an enzyme that appears to be critical in the signaling pathway.  As suspected, the result was that the growth and spread of the pancreatic cancer tumor cells were severely curtailed.

The authors’ conclusions were that hedgehog acyltransferase is in fact a key component of the hedgehog pathway, and that its amelioration may help impede pancreatic cancer growth and spread.

This careful and thoughtful work is early stage, but may prompt an important angle of attack by way of future pancreatic cancer research leading to clinical trials.


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Dale O’Brien, MD

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