Julia B. Greer

Inflammation and pancreatic cancer: an evidence-based review.

There is a growing awareness that inflammation plays a contributory role in numerous pathologies, including pancreatic carcinogenesis. Inflammatory states are characterized by the creation of reactive oxygen species and the induction of cell cycling for tissue growth and repair. The initiation, promotion and expansion of tumors may be influenced by numerous components that function in the inflammatory response. Recognized risk factors for pancreatic cancer include cigarette smoking, chronic/hereditary pancreatitis, obesity and type II diabetes. Each risk factor is linked by the fact that the inflammatory state significantly drives its pathology. This article will outline how inflammatory mechanisms are etiologically linked to pancreatic adenocarcinoma.

Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

Background The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis. Methods and Findings The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59–15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16–7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09–24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83–41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I2 = 80.95%. Conclusion The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

Serum Immunoglobulin G Fraction 4 Levels in Pancreatic Cancer : Elevations Not Associated With Autoimmune Pancreatitis

CONTEXT Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. OBJECTIVE To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. DESIGN We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated. RESULTS Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology. CONCLUSIONS As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.

Microbial Induction of Immunity, Inflammation, and Cancer

The human microbiota presents a highly active metabolic that influences the state of health of our gastrointestinal tracts as well as our susceptibility to disease. Although much of our initial microbiota is adopted from our mothers, its final composition and diversity is determined by environmental factors. Westernization has significantly altered our microbial function. Extensive experimental and clinical evidence indicates that the westernized diet, rich in animal products and low in complex carbohydrates, plus the overuse of antibiotics and underuse of breastfeeding, leads to a heightened inflammatory potential of the microbiota. Chronic inflammation leads to the expression of certain diseases in genetically predisposed individuals. Antibiotics and a “clean” environment, termed the “hygiene hypothesis,” has been linked to the rise in allergy and inflammatory bowel disease, due to impaired beneficial bacterial exposure and education of the gut immune system, which comprises the largest immune organ within the body. The elevated risk of colon cancer is associated with the suppression of microbial fermentation and butyrate production, as butyrate provides fuel for the mucosa and is anti-inflammatory and anti-proliferative. This article will summarize the work to date highlighting the complicated and dynamic relationship between the gut microbiota and immunity, inflammation and carcinogenesis.

Role of BRCA1 and BRCA2 mutations in pancreatic cancer

Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by “allelic” or “phenotypic” heterogeneity, in that they demonstrate differing cancer expressivity between and within pedigrees that segregate their mutations. If the same mutation is present in all our cells, why do some families with a given mutation display predominantly breast cancer? Why do other lineages show a preponderance of ovarian cancer? And why would some families have members who develop mostly or exclusively pancreatic cancer—a cancer that occurs more commonly in men and that lacks consistent evidence for a hormonal basis to its aetiology—which is clearly the case for breast and ovarian cancer? The answer is that other modifying genetic and environmental factors must interact to preferentially incite carcinogenesis in one organ over another. We are just beginning to elucidate what these factors are.

Androgenic progestins in oral contraceptives and the risk of epithelial ovarian cancer.

OBJECTIVE: Oral contraceptives (OCs) have been consistently linked to reduced risk of ovarian cancer. Oral contraceptive formulations display varying degrees of androgenicity. Data linking androgens to ovarian cancer suggest that OC androgenicity may impact efficacy in preventing ovarian cancer. The authors investigated whether OC efficacy might differ according to androgenicity by using data from a large, population-based, case-control study (the Steroid Hormones and Reproductions [SHARE] Study). METHODS: Detailed data on OC formulation was obtained by an in-person interview for 568 cases and 1,026 controls. Multivariable logistic regression was used to assess the association of OC androgenicity with ovarian cancer while controlling for the known potential confounders of age, parity, family history of ovarian cancer, and tubal ligation. RESULTS: Androgenic and nonandrogenic OCs conferred a similar and significant reduction in ovarian cancer risk (odds ratio 0.52, 95% confidence interval 0.35–0.76 and odds ratio 0.59, 95% confidence interval 0.45–0.78, respectively). No differences in duration of use, age at first use, and time since last use were found between androgenic and nonandrogenic formulations. CONCLUSION: In general, the androgenicity of an OC does not alter chemopreventive efficacy. LEVEL OF EVIDENCE: II-2

Low serum adiponectin levels are associated with systemic organ failure in acute pancreatitis.

Objectives: Obesity markedly increases the risk of severe acute pancreatitis (SAP), possibly through the action of adipokines. We tested the hypothesis that serum adiponectin, the primary anti-inflammatory adipokine, is associated with functional polymorphisms in the adiponectin gene (ADIPOQ) and inversely associated with SAP. Methods: Severe AP was defined as the presence of remote organ failure. ADIPOQ polymorphisms rs2241766T>G and rs1501299G>T were evaluated by DNA sequencing. Serum samples were assayed using a Luminex assay (Luminex, Austin, Tex). Results: One hundred thirty-three patients with AP and 94 healthy controls were ascertained. Adiponectin levels were measured in 60 patients with early serum samples (27 patients with mild AP and 33 patients with SAP). Adiponectin levels from days 1 to 3 were inversely correlated with body mass index (BMI) (&rgr; = −0.49; P = 0.002) and were significantly lower for patients with SAP (median, 3.74 &mgr;g/mL) than those with mild AP (6.58 &mgr;g/mL; P = 0.02). Neither ADIPOQ polymorphism affected susceptibility to or severity of AP. A receiver operating characteristics curve using adiponectin levels as the severity predictor provided an area under the curve of 0.75. Conclusions: Serum adiponectin levels in patients with AP are inversely correlated with BMI and organ dysfunction. Further studies are needed to determine whether adiponectin is a marker of low BMI or if it provides significant protection from SAP.

Pancreatic cancer patients who smoke and drink are diagnosed at younger ages.

BACKGROUND & AIMS Cigarette smoking is an established risk factor for pancreatic cancer, but there is conflicting evidence regarding the effects of alcohol consumption. The effects of cigarettes and alcohol on age of sporadic pancreatic cancer diagnosis have not been examined; we evaluated the independent and synergistic effects of lifetime cigarette smoking and alcohol consumption on age at pancreatic cancer diagnosis in the United States. METHODS We analyzed data on cigarette smoking and alcohol consumption from the IMPAC Services, Inc Cancer Information Resource File (CIRF), collected from June 1, 1993, to December 31, 2003, for 29,239 reported, histologically confirmed cases of pancreatic adenocarcinoma. We also analyzed data on cigarette smoking and alcohol consumption for 820 histologically confirmed cases of pancreatic adenocarcinoma from the University of Michigan Pancreatic Cancer Registry (UMPCR), collected from January 2004 to October 2007. RESULTS Current cigarette smokers were diagnosed at significantly younger ages than never smokers, according to data from the CIRF and UMPCR (8.3 and 6.3 y, respectively); the UMPCR data indicated dose effects. Past and current alcohol consumption were associated with younger age at diagnosis in both databases. Current smokers who were current drinkers were diagnosed significantly earlier (CIRF, 10.2 y; UMPCR, 8.6 y) than abstainers. Past cigarette smoking was associated modestly with younger diagnosis age. CONCLUSIONS Cigarette smoking and alcohol consumption were associated with younger age at pancreatic cancer presentation and have a combined effect on diagnosis age. Past cigarette smoking is less influential. Smoking cessation programs could help prevent pancreatic cancer.

The Inflammatory Bowel Disease Specialty Medical Home: A New Model of Patient-centered Care.

Abstract:New models of health care have emerged over the past decade. Accountable care organizations and patient-centered medical homes are designed to improve the patient experience, enhance health care quality, and decrease cost. These models have been developed in the primary care domain and have yet to be tested in specialty care. Certain chronic diseases require principal care by a specialist or health care team. The specialty medical home would provide patient-centered care for specific populations of patients whose health care derives from a single chronic disease. This article defines the parameters for a specialty medical home and provides a specific payer–provider experience for the comprehensive care of an inflammatory bowel disease population.

Hereditary pancreatic cancer: a clinical perspective.

Pancreatic cancer is an extraordinarily deadly disease and is responsible for over 220,000 deaths worldwide each year. One of the greatest risk factors for developing pancreatic cancer is a positive family history. Hereditary pancreatitis patients have a greatly elevated pancreatic cancer risk and individuals with cystic fibrosis may rarely develop this cancer, but often at very young ages. Various genetically linked cancer syndromes have been associated with pancreatic cancer in mutation-positive family members. Finally, familial pancreatic cancer-defined as families with two or more first-degree relatives who have pancreatic cancer but do not have a known cancer syndrome-is a known entity whose disease-causing mutation remains unidentified. This article describes research to date on hereditary pancreatic cancer, addresses how best clinicians should recognise hereditary forms of pancreatic cancer and explains the emotional burden of discovering a potentially lethal mutation. Many controversies and unanswered questions in hereditary pancreatic cancer remain.