Pancreatic+Cancer+and+Early+Onset+Diabetes

toc Pancreatic ductal adenocarcinoma, the most common Pancreatic Cancer at 95%, is a cancer predominately caused by environmental factors. 90% of pancreatic cancer occurs sporadically, which means that the genetic mutation that gave rise to the cancer was acquired sometime during the patient's lifetime. For the remaining 10%, those whose cancer is inherited, the cancer can arise from many different factors, including faulty proto-oncogenes that over-express cell proliferation.
 * by Quincy Mehta and Michael Creswell**

The link between the onset of diabetes and pancreatic cancer is becoming closer and more significant than previously thought. Because of the connection between diabetes and pancreatic cancer, diabetes could be used as a tool for the early detection of pancreatic cancer. In addition, by understanding diabetes as a biomarker, new and promising treatments can be catered toward early pancreatic cancer. Early detection of pancreatic cancer can lead to its early eradication, increasing the patient's chances for survival.

Type 2 diabetes is often found in patients with pancreatic adenocarcinoma. As of now, type 2 diabetes is either a risk factor for pancreatic cancer or a metabolic consequence of pancreatic cancer. Strong evidence suggests type 2 diabetes is a metabolic consequence; this is supported both by experimental and clinical data. In addition, in vivo and in vitro experiments show pancreatic cancer cells alter muscular and liver glucose metabolism as well as cause peripheral insulin resistance--this makes natural insulin less powerful against reducing blood glucose levels.

=Early Detection Techniques of Pancreatic Cancer =
 * [|what is diabetes]**

Early detection techniques are invasive and unnecessary for normal patients who do not have an elevated risk for developing pancreatic cancer. Cutting edge procedures such as endoscopic ultrasonography and endoscopic retrograde cholangiopancreatigraphy are both very effective and have revolutionized detection of pancreatic cancer, but are only for those at an elevated risk for developing the disease. Endoscopic ultrasonography uses a probe with a sonograph to detect early cancerous growth. The sonograph uses high-frequency sound waves to produce a graphic representation of the area of interest. This gives doctors a clear image of a possible tumor and the knowledge needed to diagnose it appropriately. 1. Endoscopic retrograde cholangiopancreatography is a technique where the patient is injected with dyes directly into the pancreas. Later, a doctor watches how the dyes travel, the pattern that the dye follows allows the doctor to identify abnormal cell growth. 2

A more primitive and direct technique for detecting pancreatic cancer is a direct biopsy of the pancreas. During this procedure, a long needle is inserted into the patient's abdomen and guided to the pancreas; a small tissue sample from the pancreas is removed and screened. 3. An alternative to a direct biopsy is a procedure called a laparoscopy. During this procedure, doctors make an incision in the patient's abdomen and insert a laparoscope (a small tube with a light). The laparoscope allows the doctor to visualize the patient's organs and make the appropriate diagnosis. 22.

Another method for detecting pancreatic cancer, used when endoscopic retrograde cholangiopancreatography cannot be performed, is a procedure called a percutaneous transhepatic cholangiography (PTC). A dye is injected into the liver or bile duct. After the dye has been administered, an x-ray is taken to identify blockages. Specific blockages suggest pancreatic cancer. 22.

In addition to the previously mentioned methods, physical exams, patient history, chest x-rays, CT scans, MRIs, and PET scans are also used to detect pancreatic cancer. These techniques are more general to any type of cancer. 22.

While these techniques for pancreatic cancer detection are effective, they are too invasive for an average patient who is not at risk for pancreatic cancer. To screen for potential pancreatic cancer patients who may benefit from these detection techniques, new onset diabetes could be used as a potential biomarker to hint toward cancer. = = = Treatment of Pancreatic Cancer =

There are a variety of ways to treat pancreatic cancer. The type of treatment used depends on what stage the pancreatic cancer is in. Currently, there are four methods for treating pancreatic cancer: radiation, chemotherapy, targeted therapies, and surgery. Surgical removal is the most common method for treatment of pancreatic cancer. Surgery is often followed by post-operative chemotherapy and radiation therapy. 21


 * Radiation therapy-** Radiation therapy uses X-rays and high-energy photon beams to cause genomic damage to tumor cells and force cell death. Treatment is performed each day over the course of a few weeks. In resectable pancreatic cancer, radiation therapy is used to both shrink the tumors prior to surgery and prevent the pancreatic cancer from reappearing after surgery. 20


 * Chemotherapy-** Chemotherapy is often used when pancreatic cancer has metastasized. Chemotherapy is effective because works against pancreatic cancer and, more importantly, secondary tumors that the doctors have not yet discovered. The most common chemotherapy drugs for pancreatic cancer are 5-fluorouracil, Gemcitabine, and Capecitabine. 5-fluorouracil and gemcitabine are administered intravenously during visits to an Oncologist. 5-fluorouracil is an anti-metabolite that interferes with the production of thymidine, a nucleoside. Gemcitabine is a analogue nucleoside that replaces cytidine during replication. Capecitabine is administered orally and is often used in place of 5-fluorouracil, usually if the patient is concurrently undergoing radiation therapy. Gemcitabine is the most recommend drug for treating metastatic pancreatic cancer. 20 Interestingly, pancreatic cancer is quite hard to access using chemotherapy due to its poor perfusion and desmoplastic ( growth of fibrous or connective tissue) stroma. To add to confusion, the therapeutic window, the balance between toxicity and efficacy, of chemotherapies is quite small. Additionally, chemotherapies have very short half-lives and often do not reach their desired target. Researchers speculate that by increasing vasculature and preventing the accumlation of connective tissues in the stroma, chemotherapies would more easily reach and better apoptose their targets. The accumulation of connective tissues occurs due to a paracrine signal between neoplastic pancreatic cancer cells and stroma cells that activates the sonic the hedgehog pathway in the stroma cells leading to stromal desmoplasia. This effectively builds a wall of connective tissues around the new cancer cells and allows for the tumor to expand without being trimmed by chemotherapy. The drug IPI-926 inhibits the transmembrane receptor SMO (smoothened) that is responsible for activating the sonic the hedgehog pathway. The drug has a long half-life and fits in as a pivotal ingredient in a pancreatic cancer drug cocktail. When treated with IPI-926, mice had SMO inhibited. This led to an increase in tumor perfusion and a decrease of desmoplasia. The increase in tumor perfusion was so significant, that the vasculature of the pancreatic tumor matched that of regular pancreatic tissue. Researchers tested genetically modified mice that developed their own pancreatic cancer with these drug cocktails to see if IPI-926 was significant. The delivery of the chemotherapy drug doxorubicin was 60% more effective when using the chemo/IPI-926 cocktail than conventional chemotherapy. When treated with a IPI-926/gemcitabine cocktail, mice had doubled survival rates and had a decrease in tumor size. Additionally, metastasis to the liver decreased four fold. Researchers feared that while the cocktail they brewed is effective at knocking down the walls that cancer builds, increasing perfusion, and attacking it, what if cancer was building an immunity to IPI-926 as it had to other chemos? When looking at the resistance genes for gemcitabine there was no difference found between gemcitabine alone and the IPI-926 cocktail. IPI-926, in combination with early detection techniques, greatly improves the fight against pancreatic cancer. 23.


 * Targeted therapy-** Targeted drug therapies attack a specific pathway that is unique to cancer cells. A commonly used drug, Erlotinib (Tarceva), inhibits proliferative signals that cause division and cell growth. In patients with advanced pancreatic cancer, Erlotinib is often used in conjunction with chemotherapy. 21.


 * Pancreatectomies-** The ideal treatment option for pancreatic cancer is a myriad of different resections all classified as pancreatectomies. This includes the removal of the pancreas and other organs. Currently, it is the most effective treatment option for pancreatic cancer. 4. This procedure is only able to be used in 10-15% patients because only pancreatic cancer that is caught early can be successfully surgically removed. 4.

Conventional pancreatectomies is a combination of the removal of the whole pancreas, spleen, gallbladder, common bile duct, and even parts of the small intestine and stomach, this leads to many post-operative complications. 4. A version of a pancreatectomy, called the Whipple Operation, involves the removal of the head of the pancreas, part of the bile duct, the gallbladder, and the duodenum. After these structures, have been removed, the surgeon sutures the bile duct directly to the intestine, this allows gastrointestinal secretions to be directed to the gut. 5.

Here is a video of a Whipple Operation being performed in Mexico City, Mexico. The Whipple Operation is considered one of the most advanced surgeries. media type="youtube" key="znZZnhXl9oQ" height="315" width="560" align="center"

Even though pancreatectomies sound extremely dangerous, they are the best option for pancreatic cancer patients. In a study conducted by doctors at the //Mayo Clinic,// pancreatectomies improved or resolved the patient's hyperglycemia and diabetes. In this study, 41 pancreatic cancer patients who were also diabetics had pancreaticoduodenectomies and were studied postoperatively to analyze their glycemic status. Of the 41 patients, 30 had "new-onset" diabetes before surgery. Amazingly, postoperatively 57% of these patients had their diabetes resolved. By getting a pancreatectomy, patients with newly found glucose intolerance were cured, additionally, this finding presented further evidence that pancreatic cancer has a strong correlation with glucose intolerance. 6.
 * Post-Operative Complications:** Following a pancreatectomy, patients are given a combination of chemotherapy and radiation to kill any residual cancer left behind after the operation. Unfortunately, patients can lose their ability to secrete insulin and other pivotal enzymes after pancreatectomies where the majority of the pancreas is removed. 4. 41% of pancreatectomies result in post-operative problems. A common consequence is internal bleeding. This sends a patient back into surgery to discover and cauterize the rupture. Another complication, more common than internal bleeding, is delayed gastric emptying where ingested food and liquid do not leave the stomach at an average rate. To prevent gastric emptying, feeding tubes are inserted to the site of operation where nutrients are delivered directly to the patient, bypassing problemed areas.

Partial or full resection of the pancreas is one of most successful solutions to treat pancreatic cancer. This procedure has both negatives and positives. The surgery is very complicated and often yields a plethora of postoperative side effects, however, in most cases, when surgery goes as planned, the patient can leave the clinic complication, tumor, and diabetes free.

= What Type of Diabetes is Linked to pancreatic cancer? =

Patients with hyperglycemia and “new onset” type 2 diabetes are identified as high risk for developing pancreatic cancer. A potential barrier with using diabetes as a biomarker for pancreatic cancer is this biomarker is limited--many people have diabetes, yet not many have pancreatic cancer. It's true, not everyone with diabetes develops pancreatic cancer, however, the results are startling for patients with pancreatic cancer that also have diabetes. 80% of patients who have pancreatic cancer also have diabetes and hyperglycemia. Additionally, after successful treatment of pancreatic cancer (if at all possible; usually a resection of all or part of the pancreas), diabetes and hyperglycemia often get better and even remit. Doctors at the //Mayo Clinic// found patients who had both pancreatic cancer and diabetes, that diabetes usually developed two years prior to being diagnosed with pancreatic cancer. 6.

In addition to the link between type 2 diabetes and pancreatic cancer, type 1 diabetes has shown a correlation with pancreatic cancer. In 2003, Swedish researchers conducted a study using data from 1965-1999. The researchers found that type 1 diabetes does not put a person at a significant risk for pancreatic cancer. 7. Researchers speculate that type 1 diabetes does not increase a person's risk for pancreatic cancer because patients with pancreatic cancer have increased risk for type 2 diabetes due to hyperinsulinemia, a condition that type 1 diabetics do not have. Hyperinsulinemia is a condition characterized by increased circulating levels of insulin in relation to glucose in the blood. 7. Two counter studies have been performed that suggest type 1 diabetes does in fact provide an increased risk for pancreatic cancer. However, these studies used patients that were at a higher cut off age than the Swedish study previously discussed. In addition to using older patients, there are several other confounding variables that could lead researchers to misinterpret the data and believe there is an association between type 1 diabetes and pancreatic cancer. Many of these risks are attributed to the older age and obesity. 8.

To add to the misinterpretations, type 2 diabetes constitutes 90-95% of all diabetes, yet patients with type 2 diabetes are sometimes misclassified as type 1 diabetes patients. 7 9.

= "New-Onset" Diabetes =

Finding patients to identify a possible correlation between “new onset” diabetes and pancreatic cancer is quite difficult. In fact, 1/3 of patients with type 2 diabetes are undiagnosed. Patients that do not know they have diabetes could also have pancreatic cancer. Many patients that are studied are those who were hospitalized due to diabetes or are patients at a clinic. These patient's diabetes are far too advanced to be described as "new onset" diabetes but are miscategorized because this is the first incidence of diabetes. This is because the initial onset of diabetes is unknown. Using the sudden onset of diabetes as a biomarker to place patients at a higher risk for developing pancreatic cancer must start with increased diabetes awareness--both on the part of the patient and of the medical professional. Another problem among studies that have attempted to link diabetes with pancreatic cancer is diabetes has been found as an early manifestation of pancreatic cancer. 10. The link between new onset diabetes and pancreatic cancer is quite elusive due to their confounding factors. Additionally, screening for pancreatic cancer using noninvasive CT scans and MRI may cause more harm then good. CT scans and MRI have been shown to increase the risk of osteocarcinoma. .12.

= Pancreatic cancer gives rise to Diabetes, through an Alteration in Glucose Metabolism =

A recent study found that pancreatic cancer cell lined media reduces glucose metabolism in myoblasts (muscle cells). The altered glucose metabolism results from reduced glycogen synthesis and an accumulation of ATP and NADH. When ATP and NADH are elevated, pyruvate dehydrogenase is inhibited, a key component of aerobic respiration. Myoblasts that were exposed to pancreatic cancer lined media increased lactate production and induced proteolysis, the process of breaking down proteins into smaller polypeptides or completely into amino acids. These metabolic consequences were likely caused by the pancreatic cancer lined media altering the expression of genes involved in protein biosynthesis and glucose metabolism by using paracrine signaling. 11.

Researchers believe this same data can be analogously applied to insulin secreting beta cells found in the pancreas. If this connection proves true, early-onset type 2 diabetes, is likely a direct result of pancreatic cancer. 11.

This altered glucose metabolism has also been studied in vivo. Referring to the figure, fast acting blood glucose in the normal pancreas was at 5.4 (mmol/L). Following the discovery of a tumor in 2005, blood glucose increased to 7.2 (mmol/L), indicating hyperglycemia. After the resection of the tumor, blood glucose returned a normal 5.7 (mmol/L). 6.

= Transcription Factor KLF11 =

KLF11, also known as TIEG2, is a pancreas transcription factor whose known action is to inhibit exocrine cellular growth. It has gained attention due to its newly discovered role as a glucose regulated transcription factor, specific to the insulin gene. This was found both in vitro and in vivo. Additionally, type 2 diabetes has been linked with two variants of the KLF11 gene that have been found to impair transcriptional activity of insulin. KLF11 impairs the insulin promoter and causes levels of insulin released in beta cells to be down regulated. Significant mutations to the exocrine pathway that KLF11 is a part of results in both pancreatic cancer and type 2 diabetes. 12. KLF11 also directly targets oxidative stress genes superoxide, dismutase2, and catalase1 by decreasing their activity. The figure above shows the decreased activity of superoxide, dismutase2, (represented by SOD2), and catalase1 (represented by catalase1). 12

In addition, KLF11 is down regulated in epithelial cell tumors and is involved in a number of cancers, including pancreatic cancer. When KLF11 is expressed in the pancreas, KLF11 leads to a vast reduction in the weight and size of the organ. KLF11 has been shown to lead to the inhibition of neoplastic transformation and cell growth. 12.

The link between pancreatic cancer and type 2 diabetes can be explained using KLF11. By down regulating oxidative stress genes, KLF11 directly correlates with either an excess of glucose or the alteration of glucose metabolism. The excess, leftover glucose or alteration in glucose metabolism, could lead to higher levels of glucose in the blood stream. If hyperglycemia is caused by KLF11, KLF11 could lead to a patient developing type 2 diabetes and subsequently pancreatic cancer. This link suggests that pancreatic cancer, that is caused by an altered KLF11 gene, could likely lead to type 2 diabetes. (Quincy Mehta)

= Glucose- Lowering Therapies increase risk of Pancreatic Cancer =

The evidence that pancreatic cancer causes diabetes is solid. New research suggests that long time diabetics (type 1 and 2) could be predisposed to developing pancreatic cancer caused by their prescribed medicine. Diabetes is probably not the cause of pancreatic cancer but anti-diabetic drugs that are given to routinely treat diabetes are increasing the incidence of pancreatic cancer. In a study conducted between 2004 to 2008, researchers focused on studying glucose-lowering drugs and the potential risk for pancreatic cancer. 13. These researchers studied an experimental sample of 973 patients with 863 controls. 13. These researchers found patients that use Metformin, an oral antidiabetic drug used to treat type 2 diabetes, show a 2.6 fold decrease in the incidence of pancreatic cancer. Metformin treats diabetes by supressing the liver's glucose production. In addition to its use in diabetes, Metformin is used in obese patients with normal pancreatic function. Diabetic patients who used Metformin had the lowest incidence risk of pancreatic cancer compared to patients that used insulin, which had a 1.8 fold increase in risk for pancreatic cancer. 13.

Mechanistically why Metformin likely decreases the incidence of pancreatic cancer is Metformin has direct antineoplastic effects--Metformin stops new and abnormal cell growth. Metformin activates an AMP activated protein kinase which alters the AMP to ATP ratio toward favoring AMP. Additionally, AMP activated protein kinase inhibits the mTOR pathway, which in turn, down regulates cell proliferation. AMP activated protein kinase also is involved with cell polarity and cell division. Metformin has direct effects within the signal transduction cascade (post receptor) that disrupts the PI3K/Akt/mTOR signaling pathway that regulates cell division. This stops the cancer hallmark of increased cell proliferation. 14.

In addition to the Metformin study, a similar study was conducted to see if glucose-lowering therapies increased the risk of developing general tumors in patients with type 2 diabetes. [|15]. These researchers had a sample size of 62,809 patients. This study had identical results to the previous Metformin study; insulin caused the highest risk for pancreatic cancer, while Metformin had the lowest risk. Above is an image depicting the rate of tumor free survival in diabetic patients. The figure analyzes patients who are currently taking glucose-lowering drugs and how long they avoid having tumors in the pancreas (Note: this experiment also studied tumors in the breasts, colorectal, and prostate, these were not included on this page. In addition, sulfonylurea is not insulin directly, but works by increasing insulin release from beta cells in the pancreas). 16.

In two different studies, synthesized insulin has proven to be a risk factor for pancreatic cancer. As of right now, there is no concrete evidence as to why taking insulin increases a patient's incidence of pancreatic cancer. A possible explanation could be due to decreased autophagy, a physiological effect of insulin. 17. When taking insulin, degradation and recycling of damaged organelles is decreased, and upon finishing a meal, autophagy is completely inhibited. 17. This could lead to the survival of improper functioning or mutated organelles and could allow for the replication of mutated organelles in new cells. These mutations could lead to cancer.

Aside from insulin's effects on autophagy, another possibility that explains the link between insulin and an increased risk for pancreatic cancer is insulin can stimulate IGF-1 receptors (insulin-like growth factor 1). The binding of IGF-1 receptors causes the release of insulin-like growth factor. Insulin-like growth factor can stimulate the formation of tumors. 18. Unfortunately, this study only tested if insulin will bind to IGF-1 receptors, when insulin receptors are not present, this could lead to flawed implications. Insulin's binding affinity to insulin receptors is 100 times higher than its affinity for IGF-1 receptors. However insulin analogues, often used in diabetes treatment, have a 8 times higher affinity to IGF-1 receptors than insulin receptors. Increased IGF-1 receptor binding can accelerate cancer progression. 18.

= Looking to the Future =


 * Non-Invasive Detection-** Recently, a non-invasive new method for pancreatic cancer detection has evolved. It uses the development of a multi-detector CT scanner that allows for a faster scan time and thinner tissue slices. The decreased scan time and the additional phases during the scan allow for better lesion contrast. Additionally, by exposing patients to less x-ray radiation, the patient's risk for developing radiation induced cancer decreases. While this method of detection has not been adopted in pancreatic cancer patients, it is being used for smokers who are predisposed to lung cancer. It has the potential to become a staple pancreatic cancer detection. 19.


 * A Biomarker of Early Pancreatic Cancer-**As of recent, only one distinguishable biomarker exsists: CA 19-9. Unfortunately, it is a stage-dependent tumor marker is not sensitive enough to detect stage 1 pancreatic cancer. CA 19-9 can be used to detect any tissue where glucose metabolism is altered. Evidence has suggested that pancreatic cancer induced diabetes has the potential to cause more than just local tumor infiltration. By locating additional affected tissues, CA 19-9 could give doctors an advantage on cancer detection. 19


 * Future KLF11 Testing-** The newly found relevance of KLF11 has spurred scientists to believe that a quick test can be created to identify if a patient is carrying a dangerous mutation. This will allow a doctor to know if further tests should be conducted to screen for pancreatic cancer and diabetes. However, such a test that identifies an patient's KLF11 genotype may only come from sequencing the whole genome. KLF11's diverse effects opens up pancreatic cancer research to a wide array of links. Hopefully, concrete evidence that could explain exactly KLF11's role in both pancreatic cancer and diabetes can be discovered.

= Conclusion/ Final Thoughts =

This research paper has presented the correlation, and possible causation, between pancreatic cancer and diabetes. During the course of our research for this paper, we hoped that a strong connection could be made between diabetes and pancreatic cancer and subsequently diabetes could be used as a method for the early detection of pancreatic cancer. Sadly, due to the drugs used by diabetic patients, we cannot definitively say that pancreatic cancer causes diabetes or diabetes causes pancreatic cancer-- the association remains correlational. Pancreatic cancer is difficult to detect because its symptoms are shared with a plethora of other diseases, to warrant the invasive tests that are normally used to detect pancreatic cancer on a normal patient is excessive. Often times when doctors or patients raise a concern that they do have pancreatic cancer it is too late. Fortunately, the field of Oncology is rapidly growing with new treatments, research, and breakthroughs every day; maybe even tomorrow the cure for cancer, let alone pancreatic cancer, will be found.

= References =

A.D.A.M. Medical Encyclopedia. "Type 2 Diabetes: Noninsulin-dependent Diabetes." //A.D.A.M. Medical Encyclopedia// (2012). Web. 29 May 2012. .

Adriancraviotov. "Whipple Procedure, Pancreatoduodenectomy." //YouTube//. YouTube, 18 Feb. 2010. Web. 27 May 2012. .

American Diabetes Association. "Diagnosis and Classification of Diabetes Mellitus." //Diabetes Care// 27.90001 (2004): 5-10. //American Diabetes Association//. 2004. Web. 27 May 2012. .

Basso, D. "Altered Glucose Metabolism and Proteolysis in Pancreatic Cancer Cell Conditioned Myoblasts: Searching for a Gene Expression Pattern with a Microarray Analysis of 5000 Skeletal Muscle Genes." //Gut// 53.8 (2004): 1159-166. //An International Journal of Gastroenterology and Hepatology//. GUT, 2003. Web. 27 May 2012. .

Betz, Charles. "MTOR Pathway 2009." 1 Sept. 2009. Web. 28 May 2012. .

Bergamini E, Cavallini G, Donati A, Gori Z (October 2007). "The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction". //Ann. N. Y. Acad. Sci.// 1114: 69–78.

"Can Insulin Cause Cancer?" //DiabetesHealth//. 1 Feb. 2006. Web. 28 May 2012. .

Chari, S. "Detecting Early Pancreatic Cancer: Problems and Prospects." //Seminars in Oncology// 34.4 (2007): 284-94. //US National Library of Medicine National Institutes of Health//. PMC, 12 May 2009. Web. 27 May 2012. .

Currie, C. J., C. D. Poole, and E. A. M. Gale. "The Influence of Glucose-lowering Therapies on Cancer Risk in Type 2 Diabetes." //Diabetologia// 52.9 (2009): 1766-777. Diabetologia, 18 June 2009. Web. 27 May 2012. .

Donghui, Lili, Sai-Ching J. Yeung, Manal M. Hassan, Marina Konopleva, and James L. Abbruzzese. "Anti-diabetic Therapies Affect Risk of Pancreatic Cancer." //Gastroenterology// 2.137 (2009): 482-88. //NIH//. 2009. Web. 27 May 2012. .

"Endoscopic Retrograde Cholangiopancreatogram (ERCP)." //WebMD//. WebMD, 2012. Web. 27 May 2012. .

Fernandez- Zapico, Martin E. "An MSin3A Interaction Domain Links the Transcriptional Activity of KLF11 with Its Role in Growth Regulation." //EMBO Journal// 22.18 (2003): 4748-758. //NCBI//. US National Library of Medicine. Web. 29 May 2012. .

"Insulin." //Wikipedia//. Wikimedia Foundation, 26 May 2012. Web. 28 May 2012. .

//Lancet Oncology// 10.1 (2009): 88-95. US National Library of Medicine National Institutes of Health, Jan. 2009. Web. 27 May 2012. .

Lowenfels, Albert B., and Patrick Maisonneuve. "Epidemiology and Risk Factors for Pancreatic Cancer." //Best Practice & Research Clinical Gastroenterology// 20.2 (2006): 197-209. //Univeristy of California: San Francisco//. Best Practice & Research Clinical Gasteroenterology, 2006. Web. 27 May 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795483/>.

Mayo Clinic Staff. "Pancreatic Cancer." //Mayo Clinic//. Mayo Foundation for Medical Education and Research, 10 Apr. 2012. Web. 27 May 2012. <http://www.mayoclinic.com/health/pancreatic-cancer/ds00357/dsection=tests-and-diagnosis>.

<span style="font-family: Arial,Helvetica,sans-serif;">Mayo Clinic Staff. "Treatments and Drugs." Mayo Clinic. Mayo Foundation for Medical Education and Research, 10 Apr. 2012. Web. 30 May 2012. <http://www.mayoclinic.com/health/pancreatic-cancer/ds00357/dsection=treatments-and-drugs>.

Neve, B. "Role of Transcription Factor KLF11 and Its Diabetes-associated Gene Variants in Pancreatic Beta Cell Function." //Proceedings of the National Academy of Sciences// 102.13 (2005): 4807-812. //US National Library of Medicine National Institutes of Health//. PMC, 2005. Web. 27 May 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC554843/>.

Olive, K. P., M. A. Jacobetz, C. J. Davidson, A. Gopinathan, D. McIntyre, D. Honess, B. Madhu, M. A. Goldgraben, M. E. Caldwell, D. Allard, K. K. Frese, G. DeNicola, C. Feig, C. Combs, S. P. Winter, H. Ireland-Zecchini, S. Reichelt, W. J. Howat, A. Chang, M. Dhara, L. Wang, F. Ruckert, R. Grutzmann, C. Pilarsky, K. Izeradjene, S. R. Hingorani, P. Huang, S. E. Davies, W. Plunkett, M. Egorin, R. H. Hruban, N. Whitebread, K. McGovern, J. Adams, C. Iacobuzio-Donahue, J. Griffiths, and D. A. Tuveson. "Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer." //Science//324.5933 (2009): 1457-461. //NIH Public Access//. 21 May 2009. Web. 3 June 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998180/>.

ORLivedotcom. "Live Webcast: Endoscopic Ultrasound For Abdominal Cancers." //YouTube//. YouTube, 27 Feb. 2007. Web. 27 May 2012. <http://www.youtube.com/watch?v=3VzbGcBfVMA>. "Pancreatectomy." //Pancreatectomy//. 2012. Web. 27 May 2012. <http://www.surgeryencyclopedia.com/La-Pa/Pancreatectomy.html>.

Pannala, R., A. Basu, G. Petersen, and S. Chari. "New-onset Diabetes: A Potential Clue to the Early Diagnosis of Pancreatic Cancer." //The//

"Sulfonylurea." //Wikipedia//. Wikimedia Foundation, 16 May 2012. Web. 28 May 2012. <http://en.wikipedia.org/wiki/Sulfonylurea>.

<span style="font-family: Arial,Helvetica,sans-serif;">"Tests That Examine the Pancreas Are Used to Detect (find), Diagnose, and Stage Pancreatic Cancer." National Cancer Institue. Web. 30 May 2012. <http://www.cancer.gov/cancertopics/pdq/treatment/pancreatic/Patient/page1>.

<span style="font-family: Arial,Helvetica,sans-serif;">WebMD Staff. "Pancreatic Cancer Treatments by Stage." WebMD. Web. 30 May 2012. <http://www.webmd.com/cancer/pancreatic-cancer/pancreatic-cancer-treatments-stage?page=2>.

"Whipple Operation." //Center for Pancreatic and Biliary Diseases//. University of Southern California, Department of Surgery, 2002. Web. 27 May 2012. <http://www.surgery.usc.edu/divisions/tumor/pancreasdiseases/web%20pages/pancreas%20resection/whipple%20operation.html>.

Zendehdel, K. "Cancer Incidence in Patients With Type 1 Diabetes Mellitus: A Population-Based Cohort Study in Sweden." //CancerSpectrum Knowledge Environment// 95.23 (2003): 1797-800. //Journal of the National Cancer Institute//. 26 Sept. 2003. Web. 27 May 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795483/>