Departments of ¹ Pathology, ² Oncology, and ³ Radiation Oncology and Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center and ⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵ Torrey Pines Institute of Molecular Studies, San Diego, California; ⁶ Burnham Institute for Medical Research, La Jolla, California; and ⁷ Department of Pathology, Children’s Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas

Abstract

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (”XAntag”; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC₅₀ in the range of 2 to 5 µmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream “effector” caspases (caspase-3 and caspase-7) versus the upstream “initiator” caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957–66]

Footnotes

Grant support: R01CA113669, R21DK072532, AACR-PanCAN Career Development Award, the Sol Goldman Pancreatic Cancer Research Center and the Lustgarten Foundation for Pancreatic Cancer Research (A. Maitra). U19 CA113318 and the California Tobacco-Related Disease Program (J.C. Reed).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C.A. Karikari and I. Roy contributed equally to this work. Current address for I. Roy: Institute for Lasers, Photonics, and Biophotonics, University of Buffalo, Buffalo, NY.

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The pancreas is a pear-shaped gland, about six inches in length, located deep within the abdomen, between the stomach and the spine. It is referred to in three parts: the widest part is called the head, the middle section is the body, and the thin end is called the tail. The pancreas is responsible for making hormones, including insulin, which help regulate blood sugar levels, and enzymes, which are used by the bowel for the digestion of food. These enzymes are transported through ducts within the pancreas, emptied into the common bile duct, which carries the enzymes into the bowel.

What is Pancreatic Cancer?

Pancreatic cancer happens when cells in the pancreas begin to grow out of control. These cancer cells then have the ability to spread to nearby lymph nodes and organs (such as the liver and lungs). When cancer spreads, it is called metastatic. About seventy percent of pancreatic cancers occur in the head of the pancreas, and most of these begin in the ducts that carry the enzymes.

Am I at Risk For Pancreatic Cancer?

The incidence of pancreatic cancer is highest between 60 and 80 years of age, and is only rarely seen in people under 40. It is seen about equally in men and women, although the rates in women have risen in recent years, which may be due to higher rates of smoking in women. Cigarette smokers are two to three times more likely to develop pancreatic cancer. It is slightly more common in blacks and members of the Jewish community. It is seen more commonly in people who have diabetes, but this link is not yet well understood. Certain occupational exposures are thought to put a person at higher risk. These include chemists, coal, gas, and metal industry workers, and industries where pesticides are used more frequently. A person’s risk triples if their mother, father, or siblings have had the disease. A family history of breast or colon cancer also increases risk. This increased risk is due to inherited mutations in cancer causing genes (changes that allow cancer to develop). The actual cause of this disease is not known, but is thought to be a result of a combination of inherited genetic changes and changes caused by environmental exposures.

How Can I Prevent Pancreatic Cancer?

Unfortunately, no one really knows what causes the disease, so it is difficult to prevent. One important point is that the risk for smokers who quit does decrease; so giving up cigarettes is helpful. Be aware of your family’s health history. This can make you and your healthcare providers aware of any increased risk.

What Screening Tests are Available?

There are no screening tests currently available for pancreatic cancer. Researchers have been able to discover the genetic changes present in cancer of the pancreas. These genes are detectable in stool, bowel and enzyme fluid, bile, and blood. Researchers are looking at this as a way to screen people for pancreatic cancer in the future.

What are the Signs of Pancreatic Cancer?

Unfortunately, the signs of early stage pancreatic cancer are vague, and often attributed to other problems by both patients and physicians. More specific symptoms tend to develop after the tumor has grown to invade other organs or blocked the bile ducts. Symptoms include weight loss, loss of appetite, jaundice (a condition that causes yellowing of the eyes and skin and darkening of urine), pain in the upper abdomen or back, weakness, or nausea and vomiting. These symptoms can vary depending on where the tumor is located in the pancreas (head, body or tail). Newly developed diabetes is the presenting sign in ten to twenty percent of patients. This is caused by the cancerous pancreas’ inability to produce insulin.

How is Pancreatic Cancer Diagnosed and Staged?

When a physician suspects that a patient may have pancreatic cancer there are several tests that can be done to make a diagnosis. A high quality CT Scan (called a spiral or helical CT) can detect a tumor in the pancreas, enlarged lymph nodes (which may indicate tumor involvement), tumors in the liver, or obstructions of the bile duct. It is the test most commonly used to diagnose this cancer in the United States. Ultrasound can also be used and is the more commonly used test in other areas of the world. Ultrasound uses a device that emits sound waves, which bounce off the organs, producing echoes that are used to create an image of the organ. This can be done on the outside of the abdomen (called transabdominal ultrasound) or from inside the bowel (a catheter is passed through the mouth down to the bowel), this is called endoscopic ultrasound.

If a patient has jaundice, the doctor may want to do a test to find out where the bile duct is blocked and if this blockage is caused by a tumor or another condition. Tests that can determine this are endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). In ERCP, a tube is passed through the mouth down the throat to the bowel, where a small catheter is inserted into the bile and pancreatic ducts. Dye is injected and x-rays are taken. The x-rays will show where the blockage is and what it is caused by. In PTC, dye is injected through a needle that is inserted through the skin, into the liver. The dye moves into the bile ducts, again allowing the blockage and its cause to be seen with an x-ray. In some cases, a small sample of tissue (biopsy) may be removed during these procedures to be examined by a pathologist.

Some patients with pancreatic cancer may have an elevated level of carbohydrate antigen 19-9 (CA 19-9), but this is not present in all cases and may be caused by other things. In patients who have an elevated level, it is useful in confirming a diagnosis in conjunction with other tests and for monitoring the disease during treatment. The level can be periodically checked during treatment to see if the cancer is stable or worsening.

When the physicians talk about staging, they are referring to determining the size of the tumor and if it has spread or not. This information is then used to determine the best treatment. In the case of pancreatic cancer, the size of the tumor and if it involves important blood vessels determines if it can be surgically removed. Pancreatic cancer is staged on the TNM system (also called tumor - node - metastasis system). This describes the size of the tumor (T), if the lymph nodes are involved (N), and if it has spread to other areas of the body (M).

What are the Treatments For Pancreatic Cancer?

A small percentage of patients have localized tumors and are offered surgery to remove the cancerous area of the pancreas. This surgery, called a Whipple procedure, is an extensive and complicated one, and recovery can be difficult for the patient. For this reason, it is important to only perform the procedure on patients who are likely to benefit.

Unfortunately, medical treatment (chemotherapy and radiation) for pancreatic cancer does not result in many cures, but new therapies and combinations of therapies are allowing patients to live longer and have a better quality of life. In the majority of patients with locally advanced cancer (cancer that has not spread to other organs), treatment consists of chemotherapy (either fluorouracil (5-FU) or gemcitabine (Gemzar^®)), in conjunction with radiation therapy. Sadly, the average survival for these patients is still only six to twelve months.

Patients with disease that has spread to other organs are usually treated with either chemotherapy (fluorouracil or gemcitabine) alone or palliative care, which aims to improve quality of life by controlling pain and other symptoms. Palliative care can consist of pain medications, radiation therapy or nerve blocks to control pain, and biliary stents to relieve symptoms of a bile duct obstruction. Unfortunately, even with treatment these patients have an average survival of three to six months.

Due to the poor results with standard therapies, patients may choose to participate in clinical trials, which test newly developed medications. Patients can discuss available clinical trials with their physician.

Follow-up Testing

After completion of therapy, patients are followed closely with CT scans and tumor marker levels (CA 19-9) for any sign of recurrence.

References

Abraham, J. & Allegra, C.: Bethesda Handbook of Clinical Oncology (2001). Lippincott, Williams & Wilkins, New York, New York.

Lorenzen Cancer Foundation: www.pancreatica.org

National Cancer Institute: What You Need To Know About Cancer of the Pancreas (2002)

Yarbro, C. H., Frogge, M. H., Goodman, M., & Groenwald, S. L. (Eds.): Cancer Nursing: Principles and Practice (2001). Jones and Bartlett Publishers, Boston, Massachusetts.

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¹ Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia and ² Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California

Background: Obesity and physical activity, in part through their effects on insulin sensitivity, may be modifiable risk factors for pancreatic cancer.

Methods: The authors analyzed data from the American Cancer Society Cancer Prevention Study II Nutrition Cohort to examine the association between measures of adiposity, recreational physical activity, and pancreatic cancer risk. Information on current weight and weight at age 18, location of weight gain, and recreational physical activity were obtained at baseline in 1992 via a self-administered questionnaire for 145,627 men and women who were cancer-free at enrollment. During the 7 years of follow-up, 242 incident pancreatic cancer cases were identified among these participants. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) and to adjust for potential confounding factors including personal history of diabetes and smoking.

Results: We observed an increased risk of pancreatic cancer among obese [body mass index (BMI) 30] men and women compared with men and women of normal BMI [<25; RR, 2.08; 95% confidence interval (95% CI), 1.48-2.93, P_trend = 0.0001]. After adjustment for between BMI, risk of pancreatic cancer was independently increased among men and women who reported a tendency for central weight gain compared with men and women reporting a tendency for peripheral weight gain (RR, 1.45; 95% CI, 1.02-2.07). We observed no difference in pancreatic cancer incidence rates between men and women who were most active (>31.5 metabolic equivalent hours per week) at baseline compared with men and women who reported no recreational physical activity (RR, 1.20; 95% CI, 0.63-2.27).

Conclusion: This study, along with several recent studies, supports the hypothesis that obesity and central adiposity are associated with pancreatic cancer risk.

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This article has no abstract so we have provided the first paragraph of the full text.

Genetic anticipation is a phenomenon whereby hereditary disease onset occurs at an earlier age in successive generations. Understanding genetic anticipation in familial pancreatic cancer could provide insight into the genes responsible for this disease, improve linkage analysis and prediction of disease occurrence. Studies on anticipation in familial pancreatic cancer have been small and subject to bias; therefore, McFaul et al. used a large study population of at-risk individuals, and standard and novel analytical methods that reduce biases, to investigate whether anticipation occurs in this disease.

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Researchers found that patients who received gemcitabine after surgery stayed disease-free almost twice as long as those who didn’t. Specifically, it took more than 13 months for the cancer to start growing again in people who got gemcitabine, versus about 7 months in the non-chemo group.

Based on that result, the investigators estimated that around 3 times as many patients in the chemo group would be cancer-free after 3 years (24% vs. 8%) and 5 years (17% vs. 6 %).

Findings from the 6-year-long study were reported in a recent issue of JAMA, the Journal of the American Medical Association.

“This finding confirms the notion that pancreatic cancer is a systemic disease even at an early stage and further emphasizes the need for effective adjuvant chemotherapy,” the study authors write. Adjuvant therapy is designed to aid surgery or other treatment actions, but doctors still aren’t certain what the best strategy is for treating pancreatic cancer after surgery.

The team of researchers — led by researchers from the Charité School of Medicine in Berlin, Germany — monitored 368 patients between 1998 and 2004 who had undergone surgical removal of their pancreatic cancer. A little more than half of them received gemcitabine for 6 months after surgery.

Although no difference was seen in overall survival between the two groups during the limited time of the study , the researchers say longer follow-up might show that gemcitabine can, in fact, help patients live longer.

An editorial accompanying the study suggests that doctors may want to discuss gemcitabine and other post-surgical options with patients. Even though they might not help them live longer, such options can have other important benefits.

“…Improved disease-free survival can offer patients with a notoriously lethal disease an opportunity to enjoy longer periods of time relatively free of symptoms,” writes Al B. Benson, MD, of the Feinberg School of Medicine at Northwestern University.

More Promising Research in Progress

Pancreatic cancer is known to be aggressive and hard to treat, and only a small percentage of patients survive more than a year after diagnosis. But researchers are actively pursuing new treatments.

The German gemcitabine study comes on the heels of other promising news about using radiation plus chemotherapy after pancreatic cancer surgery. A study from the Mayo Clinic in Rochester, Minn., found that people who received this combined treatment after surgery lived an average of about 6 months longer than people who got only surgery. The study included more than 450 patients treated at the Mayo Clinic. It was presented in January at the Gastrointestinal Cancers Symposium in Orlando.

In another promising but early finding, researchers from the University of Michigan Medical Center report that they’ve identified human pancreatic stem cells — the likely culprits behind the disease’s aggressive growth and spread. The cancer stem cell finding could lead researchers down the path toward new drugs that fight pancreatic cancer at the root without interfering with normal human stem cell function, the researchers say.

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Departments of ¹ Surgery, ² Molecular and Integrative Physiology, and ³ Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; ⁴ Department of Pathology, Karmanos Cancer Center, Detroit, Michigan; and ⁵ Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, California

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44⁺CD24⁺ESA⁺ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44⁺CD24⁺ESA⁺ cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44⁺CD24⁺ESA⁺ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44⁺CD24⁺ESA⁺ pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increase. ed expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. [Cancer Res 2007;67(3):1030–7]

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Authors’ Affiliations: ¹ Division of Pancreatic Surgery and Molecular Pancreatic Research, Department of General Surgery, ² Institute of Immunology, and ³ Department of Pathology, University of Heidelberg, Heidelberg, Germany

Heme oxygenase-1 (HO-1) is believed to represent a key enzyme for the protection of cells against “stress.” Its overexpression in different types of human cancers supports the notion that HO-1 provides a growth advantage and contributes to cellular resistance against chemotherapy and radiotherapy. Given the poor survival rates of patients with pancreatic cancer due to its aggressive growth behavior and its exceptional resistance to all known forms of anticancer treatment, we have investigated the expression of HO-1 in human pancreatic cancer cells growth behavior and prognosis. Expression of HO-1 was analyzed in human pancreatic cancer samples in comparison with normal pancreas by quantitative PCR, Western blot, and confocal microscopy. The influence of radiotherapy and chemotherapy on HO-1 expression in pancreatic cancer cell lines was evaluated. Furthermore, HO-1 expression was specifically suppressed by small interfering RNA transfection and subsequently the alterations of growth behavior and resistance to anticancer treatment were tested. Human pancreatic cancer showed a 6-fold and 3.5-fold HO-1 up-regulation in comparison to normal pancreas based on mRNA and protein level, respectively (P < 0.05). Cancer tissues revealed marked HO-1 immunoreactivity in tumor cells and in tumor associated immunocytes. Treatment of the pancreatic cancer cell lines with gemcitabine or radiation strongly induced HO-1 expression. Targeted knockdown of HO-1 expression led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radiotherapy and chemotherapy. Therefore, specific inhibition of HO-1 expression may be a new option in pancreatic cancer therapy and may be used as sensitizer to chemotherapy and radiotherapy.

Key Words: pancreatic cancer • radiation • chemotherapy • anticancer therapy

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Authors’ Affiliations: ¹ Cancer Research Program, Garvan Institute of Medical Research and ² Division of Surgery, St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales, Australia;³ Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia; and ⁴ University of Queensland, Department of Surgery, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

Requests for reprints: Robert L. Sutherland, Cancer Research Program Garvan Institute of Medical Research 384 Victoria Street, Darlinghurst. New South Wales 2010, Australia. Phone: 61-2-9295-8322; Fax: 61-2-9295-8321; E-mail: r.sutherland@garvan.org.au

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Purpose: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer.

Experimental Design: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry.

Results: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RAR, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors.

Conclusions: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.

Key Words: molecular markers • pancreatic cancer • molecular profiling • retinoic acid • HOXB2 prognosis

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Methods A total of 720 patients with pancreatic cancer and 720 control patients from 14 Italian centers were enrolled in the study. All subjects were interviewed personally and in detail about their clinical history. The diagnosis of diabetes was based on criteria recommended by the American Diabetes Association.

Results One hundred sixty-four patients with pancreatic cancer (22.8 percent) and 60 controls (8.3 percent) had diabetes. In the majority of the patients with pancreatic cancer (56.1 percent), diabetes was diagnosed either concomitantly with the cancer (in 40.2 percent), or within two years before the diagnosis of cancer (in 15.9 percent). The association between the two conditions was significant (odds ratio, 3.04; 95 percent confidence interval, 2.21 to 4.17). However, when only patients with diabetes of three or more years’ duration were considered, the association was no longer significant (odds ratio, 1.43; 95 percent confidence interval, 0.98 to 2.07). All the patients with pancreatic cancer whose diabetes had been diagnosed before the cancer had non-insulin-dependent diabetes; all but one of the control patients with diabetes had the non-insulin-dependent form of the disease.

Conclusions Diabetes in patients with pancreatic cancer is frequently of recent onset and is presumably caused by the tumor. Diabetes is not a risk factor for pancreatic cancer.

Source Information

From the Institute of Medicine and Gastroenterology, University of Bologna, St. Orsola Hospital, Bologna, Italy. The members of the Italian Pancreatic Cancer Study Group include Patrizia Priori, M.D., Orazio Campione, M.D., Riccardo Casadei, M.D., Maria Brambati, M.D., Carlo Lesi, M.D., and Antonio Frena, M.D. (Bologna); Alberto Malesci, M.D., and Alessandro Zerbi, M.D. (Milan); Angelo Andriulli, M.D., and Patrizio Acquadro, M.D. (Turin); Alessandro D’Ambrosi, M.D., and Vittorio Alvisi, M.D. (Ferrara); Giuseppe Montalto, M.D., and Antonio Carroccio, M.D. (Palermo); Valerio De Conca, M.D., Alberto Mornese, M.D., and Carlo Mansi, M.D. (Genoa); Carlo Battistini, M.D. (Parma); Cosimo Sperti, M.D., and Claudio Pasquali, M.D. (Padua); Luigi Gaeta, M.D., and Mario Mazzeo, M.D. (Naples); and Martina Felder, M.D. (Bolzano).

Address reprint requests to Professor Gullo at the Istituto di Clinica Medica e Gastroenterologia, Ospedale S. Orsola, Via Massarenti, 9, 40138 Bologna, Italy.

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While there have been many studies documenting the link between poor oral hygiene and other medical problems, such as heart disease and stroke, this is the first study to find a solid link that gum disease could actually increase the risk of pancreatic cancer.

This particular study began in 1986 and documented over 50,000 men working in health professions.

Between 1986 and 2002, researchers verified 216 cases of pancreatic cancer, with 67 of those cases having periodontal disease. In summary, after adjusting for factors such as diabetes, smoking and others, the findings showed that the men with gum disease were 63% more likely to develop pancreatic cancer by rate of comparison than men that did not have gum disease.

Dr. Dominique Michaud, assistant professor of epidemiology at Harvard, states that one possible reason for the link between gum disease and pancreatic cancer could be that “Individuals with periodontal disease have elevated serum biomarkers of systemic inflammation, such as C-reactive protein, and these may somehow contribute to the promotion of cancer cells.” Dr. Michaud also offers another explanation that a person with periodontal disease has increased levels of carcinogens and oral bacteria in their mouth.

Gum Disease is an infection in the gums surrounding the teeth. Gum disease is also one of the main causes of tooth loss among adults. There are two major stages of gum disease: Gingivitis and Periodontitis.

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